[DISCRETION]

[Invention Title]

SULFAMATE DERIVATIVE COMPOUNDS FOR USE IN TREATING OR ALLEVIATING PAIN

[Technical Field]

The present invention relates to sulfamate derivative compounds and a composition for treating and/o alleviating pain containing the sulfamate derivative compounds or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, the present invention relates to a pharmaceutical composition for treating or alleviating pain containing a sulfamate derivative compound and/or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a method for treatment or alleviation of pain comprising administering a sulfamate derivative compound in a pharmaceutically effective amount to a subject in need of treatment or alleviation of pain.

[Background Art]

Pain is one of the most common reasons for a patient to seek medical care and in consequence, pain results in a tremendous number of lost work days per year .

Pain is an unpleasant feeling often caused by intense or damaging stimuli, such as stubbing a toe, burning a finger, putting alcohol on a cut, and bumping the funny bone. The International Association for the Study of Pain's widely used definition states: "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain motivates the individual to withdraw from damaging situations, to protect a damaged body part while it heals, and to avoid similar experiences in the future. Most pain resolves promptly once the painful stimulus is removed and the body has healed, but sometimes pain persists despite removal of the stimulus and apparent healing of the body; and sometimes pain arises in the absence of any detectable stimulus, damage or disease.

Pain is the most common reason for physician consultation. It is a major symptom in many medical conditions, and can significantly interfere with a person's quality of life and general functioning. Psychological factors such as social support, hypnotic suggestion, excitement, or distraction can significantly modulate pain's intensity or unpleasantness.

In 1994, responding to the need for a more useful system for describing chronic pain, the International Association for the Study of Pain (.IASP) classified pain according to specific characteristics: (1) region of the body involved (e.g., abdomen, lower limbs), (2) system whose dysfunction may be causing the pain (e.g., nervous, gastrointestinal), (3) duration and pattern of occurrence, (4) intensity and time since onset, and (5) etiology.

This system has been criticized by Clifford J. Woo If and others as inadequate for guiding research and treatment. According to Woolf, there are three classes of pain: nociceptive pain (see hereunder), inflammatory pain which is associated with tissue damage and the infiltration of immune cells, and pathological pain which is a disease state caused by damage to the nervous system or by its abnormal function (dysfunctional pain, irritable bowel syndrome, tension type headache, etc.).

In nociceptive pain, the stimulation of the sensory nerve endings called nociceptors causes the sensation of pain. Such pain often occurs after injury or surgery. The pain signals are transmitted by the nociceptors to the brain. Often the pain is localised, constant and has an aching or throbbing quality. Once the damage to the tissue heals the pain usually resolves. Treatment with opioids may resolve nociceptive pain. Psychogenic pain is a pain disorder that is associated with psychological factors. Some types of mental or emotional problems can cause pain. They can also increase or prolong pain. Stomach pain is one of the most common types of psychogenic pain. People with this pain disorder actually have real pain. The diagnosis is made when all physical causes of pain are ruled out .

Neuropathic pain is caused by abnormalities in the nerves, spinal cord or brain and is a chronic type of non-malignant pain with an estimated prevalence of over 1% of the population. Optimizing pain relief in these patients is crucial in helping a patient regain control of his or her life. The most common cause of neuropathic pain is injury or dysfunction of nerves. Injury or dysfunction of peripheral nerves or nerves descending from the spinal cord results in dis inhibit ion of nerve impulses at the spinal cord which in consequence results in pain. Neuropathic pain can also be central ly mediated, rather than peripheral, in conditions such as spinal cord injury and multiple sclerosis.

Neuropathic pain can therefore be divided into two further classes; peripheral neuropathic pain and central neuropathic pain depending on whether the peripheral or central nervous system is affected.

Inadequate treatment of pain is widespread throughout surgical wards, intensive care units, accident and emergency departments, in general practice, in the management of all forms of chronic pain and in end of life care. This neglect is extended to all ages, from neonates to the frail elderly. African and Hispanic Americans are more likely than others to suffer needlessly in the hands of a physician; and women's pain is more likely to be under treated than men's.

Therefore, it is needed to develop therapeutic measures for treating or al leviat ing pain.

[Disclosure]

[Technical Problem]

Inadequate treatment of pain is widespread throughout surgical wards, intensive care units, accident and emergency departments, in general practice, in the management of all forms of chronic pain and in end of life care. This neglect is extended to all ages, from neonates to the frail elderly. African and Hispanic Americans are more likely than others to suffer needlessly in the hands of a physician; and women's pain is more likely to be under treated than men's.

[Technical Solution]

The present invention relates to sulfamate derivative compounds and a composition for treating and/or alleviating pain containing the sulfamate derivative compounds or a pharmaceutically acceptable salt thereof as an active ingredient.

[Advantageous Effects]

it is an object of this invention to provide a novel sulfamate derivative compounds or a pharmaceutically acceptable salt thereof.

Another object of this invention to provide a pharmaceutical composition for treating or alleviating pain containing the sulfamate derivative compound and/or the pharmaceutically acceptable salt thereof as an active ingredient.

A further object of this invention to provide a method for treatment or alleviation of pain comprising administering a sulfamate derivative compound in a pharmaceutically effective amount to a subject in need of treatment or alleviation of pain.

[Best Mode]

The present inventor has done intensive studies to develop a novel anti-pain drug with excellent activity and low toxicity which may be an effective treatment for pain. As a result, the present inventors have discovered that the sulfamate derivative compounds represented by the below formula 1 or f provide highly enhanced anti-pain activity with significantly decreased side effects.

Accordingly, it is an object of this invention to provide a novel sulfamate derivative compounds or a pharmaceutically acceptable salt thereof.

Another object of this invention to provide a pharmaceutical composition for treating or alleviating pain containing the sulfamate derivative compound and/or the pharmaceutically acceptable salt thereof as an active ingredient.

A further _. object of this invention to provide a method for treatment or alleviation of pain comprising administering a sulfamate derivative compound in a pharmaceutically effective amount to a subject in need of treatment or alleviation of pain.

[Mode for Invention]

In one aspect of this invention, there is provided a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof^

wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen, C -C5 alkyl group, C ₂ -C5 alkenyl and Ce-Cio aryl group, i and R ₂ together with the carbon atom to which they attach form a C3-C ₁₂ cycloalkyl group, or R ¹ and R" are bond and they together with the oxygen atom to which they attach form a carbonyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, hydroxy1 , C ₁ -C5 alkoxy, C ₁ -C5 alkyl, C2-C5 alkenyl, Ce-Cio aryl, C1.-C5 alkoxycarbonyl , carboxyl , C ₂ -C5 acyl , C ₁ -C5 alkylthio, cyano, nitro, amine, C ₁ -C5 alkylamine and halogen! R ⁸ and R ⁹ are each independently hydrogen or C ₁ -C3 alkyl group! 11 and m are each independently an integer of 0-4.

According to a concrete embodiment, R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C3 alkyl and phenyl or R ¹ and R ² together with the carbon atom to which they attach form a C3-C6 cycloalkyl group.

According to a concrete embodiment, R ⁸ and R ⁹ are each independently hydrogen or methyl. In a preferred embodiment according to the invention, m and n are each independently an integer of 0-2.

In a more preferred embodiment according to the invention, m and n are each independently an integer of 0-1.

In another aspect of this invention, there is provided a compound represented by the following formula or a pharmaceutically acceptable salt thereof^

wherein R and R are each independently selected from the group consisting of hydrogen, C1-C5 alkyl , C2-C5 alkenyl and e ^~ w aryl , R ¹ and R ² together with the carbon atom to which they attach form a C3-C12 cycloalkyl group, or R ¹ and R ² are bond and they together with the oxygen atom to which they attach form a carbonyl group; A is a heterocyclic moiety optionally substituted by one or more substituents selected from the group consisting of hydrogen, hydroxyl, C 1 _. -C5 alkoxy, C1-C5 alkyl, C2-C5 alkenyl, Ce-Cio aryl. C1-C5 alkoxycarbonyl , carboxyl , C2-C5 acyl , C1-C5 alkyl thio, cyano, nitro, amine, C1-C5 alkyl amine and halogen ^' , R ⁸ and R ⁹ are each independently hydrogen or C Cs alkyl; and 1 and m are each independently an integer of 0-4.

According to a concrete embodiment, R ¹ and R ² are each independently selected from the group consisting of hydrogen, C1-C3 alkyl and phenyl or R ¹ and R ^" together with the carbon atom to which they attach form a C3-C6 cycloalkyl group.

In a preferred embodiment according to the invention, A is a heterocyclic moiety representing a C3-C10 heterocycl ic group.

According to a concrete embodiment, R ⁸ and R ⁹ are each independently hydrogen or methyl .

In a preferred embodiment according to the invention, n and m are each independently an integer of 0-2.

In a more preferred embodiment according to the invention, n and m are each independently an integer of 0-1.

Particular examples of the substituents represented by A in Chemical Formula include the following: wherein X is each independently selected from the group consisting of halogen, nitro, amine and C1-C5 alkyl ; 0 is an integer of 0-4; and Z is selected from S, 0 or NH.

In a preferred embodiment according to the invention, 0 is an integer of 0-2.

In a more preferred embodiment according to the invention, 0 is an integer of 0-1.

The term "alkyl" as used herein, refers to a linear or branched chain of a saturated hydrocarbon group, e.g., methyl, ethyl, propyl, butyl, isobutyl, tert-butyl and pentyl . "C1-C5 alkyl group" as used herein, refers to an alkyl group with a carbon number of 1-5.

The term "alkenyl" , as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond whe r e i n a 1 ky 1 i. s a s cle f i ned above .

The term "alkoxy" , as used herein, unless otherwise indicated, includes 0-al.kyl groups wherein alkyl is as defined above.

The term "a Iky 1 thio" , as used herein, unless otherwise indi'cated, includes S-aLkyl groups wherein alkyl is as defined above.

The term "alkoxycarbonyl" , as used herein, unless otherwise indicated, includes -C(0)0-alk.y1 groups wherein alkyl. is as defined above.

The term "acyl" , as used herein, unless otherwise indicated, includes -C(0)-alkyl groups wherein alkyl is as defined above.

The term "aryl" or "aryl group" as used herein, refers to a totally or partially unsaturated monocyclic or polycyclic carbon rings having aromaticity. The aryl group of the present invention is preferably monoary 1 or biaryl, such as phenyl or naphthyl . The aryl radical may be optional, ly substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl. phenyl, alkoxy. haloalkyl, nitro, cyano, dialkylamino, aminoalky , acyl and alkoxycarbon l , as defined herein.

The term "cycloalkyl" or "cycloalkyl group" as used herein, refers to a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms .

The term "heterocyclic" or "heterocyclic group" , as used herein, unless otherwise indicated, means aromatic and. non-aromatic heterocyclic groups (including saturated heterocyclic groups) containing one or more heteroatoms each selected from 0, S and N, wherein each ring of a heterocyclic group has from 4 to 10 atoms. Non-aromatic heterocyclic groups may include rings having only 4 atoms, but aromatic heterocyclic rings must have at least 5 atoms. Heterocyclic groups of this invention unless otherwise indicated may contain one ring or more than one ring, i.e. they may be monocyclic or polycyclic, for example bicyclic (which may comprise non-aromatic and/or aromatic rings).

According to more concrete embodiment, the compound is selected from the group consisting of:

( 1) ( 5-(2-chloropheny1 )-2 , 2-di methy 1 -1 , 3-di oxo 1 an-4- yl )methyl sul amate;

(2) (5-(2-chlorophenyl )-2-methyl-l,3-dioxolan-4-yl ) methyl sulfamate;

(3) (5-(2-chlorophenyl )-2,2-diethyl-l,3-dioxolan-4-yl )methyl sul famate ;

(4) (3-(2-chloropheny1 )-l ,4-dioxas i ro[4,4]nonan-2-yl )methyl sulfamate;

(5) (3-(2-chlorophenyl )-l,4-dioxaspiro[4,5]decan-2-yl )methyl sulfamate;

(6) (5-(2-chlorophenyl )-2-phenyl-l,3-dioxolan-4-yl )methyl sul famate;

(7) ( 5-(2-f 1 uoropheny1 )-2 , 2-dimethy1 -1 , 3-d i oxo 1 an-4-y1 )met hy1 sulfamate;

(8) (5-(2-f 1 uorophenyl)-2-methy1-1, 3-di oxo I an-4-yl) methyl sulfamate;

(9) (5-(2-f 1 uoropheny1 )-2 , 2-d i e thy1 -1 , 3-dioxo 1 an-4-y1 )methy1 sulfamate;

( 10) (3-(2-f 1 uoropheny1 )-1 , 4—cl i oxasp i ro [4 , 4]nonan-2-y1 )methy1 sulfamate;

(11) (3-(2-f 1uoropheny1 )-1 , 4-di oxaspi ro [4 , 5] clecan-2-y1 )methy1 sulfamate;

( 12) (5-(2-f 1 uo opheny1 )-2-pheny1 -1 , 3-d i oxo 1 an-4-y1 )methy 1 su 1 fam te ;

( 13) (5-(2-i odopheny1 )-2 , 2-di methy1-1 , 3-d ioxo 1 an-4-y1 )methy1 sulfamate;

(14) (5-(2-iodophenyl)-2-methyl-l,3-dioxolan-4-yl) methyl sulfamate;

(15) ( 5-(2- i odopheny1 )-2,2-diethyl-l,3-dioxolan-4-yl ) methyl sul fama e;

(16) (3-(2-i odopheny1 )-l,4-dioxaspiro[4,4]nonan-2-yl ) methyl sulfamate;

( 17) (3-(2-i odopheny1 )-1 , 4-d i oxasp i ro [4 , 5] decaii-2-y1 )methy 1 sul famate;

( 18 ) (5-(2- i odopheny1 )-2-pheny1-1 , 3-di oxo 1 an-4-y1 )methy1 sul famate ;

( 19) ( 5-(2 , 4-d i ch1 oropheny1 )-2 , 2-dimethy1 -1 , 3-di oxo 1 an-4-y1 )methy1 sulfamate;

(20) (5-(2 , 4-di ch1 oropheny1 )-2-methy1 -1 , 3 ^~ d i oxo 1 an-4-y1 )methy1 sul famate;

(21) (5-(2,4-dichlorophenyl)-2,2-diethyl-l,3-dioxolan-4-yl)methyl sul famate ; (22) (3-(2 , 4-cli ch1oropheny1 )-1 , 4-di oxaspi ro[4 , 4]nonan-2-y1 )methy1 sul famate;

(23) (3-C2 , 4-di ch1oropheny1 )-1 , 4-dioxaspi ro[4 , 5]decan-2-y1 )methy1 sul famate ;

(24) (5-(2 , 4-di ch1oropheny1 )-2-pheny1-1 , 3-dioxo1 an-4-y1 )methy1 sul famate ;

(25) (5-(2 , 6-cli ch1oropheny1 )-2 , 2-dimethy1-1 , 3-dioxo 1 an-4- yl )methylsul famate;

(26) (5-(2 , 6-di ch1 oropheny1 )-2-methy1-1 , 3-di oxo1 an-4-y1 )methy1 sulfamate;

(27) (5-(2 , 6-di ch1oropheny1 )-2 , 2-di ethy1-1 , 3-d ioxo1 an-4-y1 )methy1 sulfamate;

(28) (3-(2 , 6-dichloropheny1 )-l ,4-dioxas iro[4,4]nonan-2-yl )methyl sulfamate;

(29) (3-(2 , 6-cli ch1oropheny1 )-1 , 4-di oxaspi ro[4 , 5] decan-2-y1 )methy1 sulfamate;

(30) (5-(2 , 6-di ch1 oropheny1 )-2-pheny1-1 , 3-dioxo 1 an-4-y1 )methy1 sul famate ;

(31) (5-(2-aminopheny1 )—2 , 2-dimethy1-1 , 3 ^~ d ioxo1 an-4-y1 )methy1 sul famate ;

(32) (5-(2-aminopheny1 )-2-methy1-1 , 3-di oxo1 an-4-y1 )methy1 sulfamate;

(33) (5-(2-aminopheny1 )-2 , 2-di ethy1-1 , 3-di oxo1 an-4-y1 )methy1 sulfamate;

(34) (3-(2-aminopheny1 )-l ,4-dioxaspiro[4,4]nonan-2-yl )methyl sul famate ;

(35) (3-(2-aminopheny1 )-1 , 4-clioxaspi ro [4 , 5]decan-2-y1 )methy1 sul famate ;

(36) (5-(2-aminopheny1 )-2-pheny1-1 , 3-di oxo1 n-4-y1 )methy1 su1 famate ;

(37) (5-(2-ni tropheny1 )-2 , 2-dimethy1-1 , 3-di oxo1 an-4-y1 )methy1 sulfamate;

(38) (5-(2-ni trophenyl )-2-methy1-1, 3-dioxo lan-4-yl ) methyl sulfamate!

(39) (5-(2-ni tropheny1 )-2 , 2-di ethy1-1 , 3 ^~ di oxo 1 an-4-y1 )methy1 sulfamate;

(40) (3-(2-ni trophenyl )-l ,4-dioxas iro [4,4] onan-2-yl )methyl sulfamate;

(41) (3-(2-ni t ropheny1 )-1 , 4-di oxaspi ro[4 , 5] decan-2-y1 )methy1 sul famate ;

(42) (5-(2-ni trophenyl )-2-pheny1-1 ,3-dioxolan-4-yl )methyl sul famate ;

(43) (5-(2-ni trophenyl )-2-oxo-l,3-dioxolan-4-yl )methyl sul famate;

(44) (5-(2-methy1pheny1 )-2 , 2-dimethy1-1 , 3-di oxo 1an-4-y1 )methy1 sulfamate; ( 5) (5-(2-methy1pheny1 )-2-inethy1-1 , 3-di oxo 1 an-4-y1 )methy1 su1 famate ;

(46) (5-(2-methy1pheny1 )-2 , 2-di ethy1-1 , 3-d i oxo1 an-4-y1 )methy1 sul famate

(47) (3-(2-methy1pheny1 )-1 , 4-di oxaspi ro[4 , 4]nonan-2-y1 )methy1 sul famate

(48) (3-(2-methyl phenyl ) -1 ,4-dioxas i ro[4, 5] decan-2-yl )methyl sul famate ;

(49) (5-(2-methy1pheny1 )-2-pheny1 -1 , 3-di oxo1 an ^~ 4-y1 )methy1 sul famate ;

(50) (5-(2-methy1 aminopheny1 )-2 , 2-dimethy1-1 , 3-dioxo 1 an-4-y1 )me hy1 methyl su Ifamate;

(51) (5-pheny1-2 , 2-dimethy1-1 , 3-dioxo1 an-4-y1 )methy1 su 1 famate ;

(52) (5-pheny 1-2 , 2-di ethy1-1 , 3 ^~ di oxo1 an-4-y1 )methy1 su 1 famate;

(53) (3-pheny1-1 , 4-di oxaspi ro [4 , 4]nonan-2-y1 )methy1 su1 famate ;

(54) (3-pheny1-1 ,4-dioxaspi ro[4, 5] decan-2-yl )methyl sul famate;

(55) 2-(5-benzyl-2,2-dimethyl-l,3-dioxolan-4-yl)ethyl su Ifamate;

(56) 2-(5-benzy1-2 , 2-dι ethy1 -1 , 3-di oxo1 an-4-y1 )ethy1 sul famate ;

(57) 2-(3-benzy1-1 , 4-dioxaspi ro [4 , 4]nonan-2-y1 )ethy1 su 1 famate ;

(58) 2-(3-benzy1-1 , 4-di oxaspi ro[4 , 5] decane-2-y1 )ethy1 su1 famate ;

(59) (5-benzyl-2,2-dimethyl-l,3-dioxolan-4-yl)methyl sul famate;

(60) (5-benzyl-2,2-diethyl-l,3-dioxolan-4-yl)methyl sul famate;

(61) (3-benzyl-l,4-dioxaspiro[4,4]nonan-2-yl )methyl sul famate;

(62) (3-benzy1 -1 , 4-dioxaspi ro[4 , 5]decan-2-y1 )methy1 su1 famate ;

(63) 2-(5-phenyl-2,2-dimethyl-l,3-dioxolan-4-yl)ethyl sulfamate;

(64) 2-(5-phenyl-2,2-cliethyl-l,3-dioxolan-4-y[)ethyl sulfamate;

(65) 2-(3-phenyl-l,4-dioxaspiro[4,4]nonan-2-yl )ethyl sulfamate;

(66) 2-(3-phen 1-1, 4-di oxaspi ro[4, 5]decan-2-yl )ethyl sul famate ;

(67) 2-(5-(2-ch1orobenzy1 )-2 , 2-dimethy1-1 , 3-di oxo 1 an-4-y 1 )ethy1 sul famate ;

(68) 2-(5-(2-ch1orobenzy1 )-2 , 2-di ethy1-1 , 3-di oxo 1 n-4-y1 )ethy1 sulfamate;

(69) 2-(3-(2-chlorobenzy1 )-l,4-dioxaspiro[4,4]nonan-2-yl )ethyl sul famate ;

(70) 2-(3-(2-ch1 orobenzy1 )-1 , -di oxaspi ro[4 , 5] decan-2-y1 )ethy1 sul famate ;

(71) (5-(2-ch1orobenzy1 )-2 , 2-dimethy1-1 , 3-di oxo1an-4-y1 )methy1 sul famate ;

(72) (5-(2-chlo obenzy1 )-2 ,2-diethyl-l ,3-dioxolan-4-yl )methyl sul famate;

(73) (3-(2-ch1orobenzy1 )-1 , 4-dioxaspi ro [4 , 4]nonan-2-y1 )methy1 sulfamate- ^' (74) ( 3- ( 2-ch 1 or obenzy 1 ) - 1 , 4-d i oxasp i r o [ 4 , 5 ] decan-2-y 1 )nie t hy 1 sulfamate;

( 75 ) 2- ( 5- ( 2-ch 1 or opheny 1 ) -2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 an-4-y 1 ) e t hy 1 sul f amate ;

( 76 ) 2- ( 5- ( 2-ch 1 or opheny 1 ) -2 , 2-d i et hy 1 - 1 , 3-d i oxo 1 an-4-y 1 ) e t hy 1 sulfamate;

( 77 ) 2- ( 3- ( 2-ch 1 or opheny 1 ) -1 , 4-d i oxasp i r o [ 4 , 4] nonan-2-y 1 ) e t hy 1 sul f amate ;

(78) 2-(3-(2-chlorophenyl)-l,4-dioxaspiro[4,5]decan-2-yl)ethyl sul f amate ;

(79) (5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-l,3-dioxolan-4- yOmethyl sulfamate;

( 80 ) ( 5- ( 2-ch I or o t h i azo 1 -5-y 1 ) -2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 an-4- yl )methylsul f amate; 1

(81) ( 2 , 2-d i me t hy 1 -5- ( 4-me t hy 11 h i azo 1 -5-y 1 ) - 1 , 3-d i oxo 1 an-4- yl )methylsul famate;

( 82 ) ( 2 , 2-d i me t hy 1 - 5- ( 2-ch 1 o r o-4-me t hy 11 h i azo 1 - 5-y 1 ) - 1 , 3-d i oxo 1 an-4- yl )methyl sul famate ;

( 83 ) ( 2 , 2 -d i me t hy 1 -5- ( t h i ophen-3-y 1 ) - 1 , 3-d i oxo 1 an-4-y 1 ) me t hy 1 su I f am a t e ;

(84) . (2,2-dimethyl-5-(5-chlorothiophen-2-yl)-l,3-dioxolan-4- yl )methylsul famate ;

( 85 ) (5- ( 3-ch 1 or opy r i d i n-4-y 1 ) -2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 an-4- yOmethyl sul famate;

( 86 ) ( 5- ( 4-ch 1 or opy r i d i n-3-y 1 ) -2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 an-4- yl )methyl sul famate ;

( 87 ) ( 2 , 2-d i me t hy 1 -5- ( py r i m i d i n-5-y 1 ) - 1 , 3-d i oxo 1 an-4-y 1 ) me t h 1 su 1 f ama t e and

( 88 ) ( 2 , 2-d i me t hy 1 -5- ( 2-ch 1 or opyr i m i d i n-5-y 1 ) - 1 , 3-d i oxo 1 an-4- yOmethyl sul famate.

According to a concrete embodiment, the compound is in the form of a racemate, an enantiomer, a diastereomer , a mixture of enantiomers or a mixture of diastereomers .

As seen in the Examples, the present inventors have synthesized the compounds of various stereochemistries, and investigated their relief pain act ivity by mul ti lateral experiments.

The term "enantiomer" as used herein, refers to one of two stereoisomers that are mirror images of each other which are non- superposable due to existence of one or more chiral carbons. According to a concrete embodiment, the enantiomer of the present invention is one in which chiral carbons of C and C5 are diverse in stereo-configuration.

The term "diastereome " as used herein, refers to stereoisomers that are not enant ionie s , which occurs when two or more stereoisomers of a compound have different configurations at one or more (but not all) of the equivalent chiral centers thus are not mirror images of each other.

The term "racemate" as used herein, refers to one that has equal amounts of two enantiomers of different stereo-configuration, and lack in optical activity.

It would be obvious to the skilled artisan from the Examples below that the compounds of this invention are not limited to those with specific stereochemistry.

According to a concrete embodiment, the pharmaceutically acceptable salt is produced by reacting the compound with an inorganic acid, an organic acid, an amino acid, sulfonic acid, an alkali metal or ammonium ion.

The pharmaceutically acceptable salts of the present invention are those which cam be manufactured by using a method known in the art, for example, but not limited to, salts with inorganic acids such as hydrochloric acid, broinic acid, sulfuric acid, sodium hydrogen sulfate, phosphate, nitrate and carbonate; and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, trif luoroacetic acid and acetylsal icyl ic acid (aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, and proline; salts with sulfonic acid such as methane sulfonate, ethane sulfonate, benzene sulfonate and toluene sulfonate; metal salts by- reaction with an alkali metal such as sodium and potassium; or salts with ammonium ion..

In another aspect of this invention, there is provided a method for management Pain comprising administering pharmaceutically effective amount of the compound of the present invention or the pharmaceutically acceptable salt thereof to a subject in need thereof.

The term "pharmaceutically effective amount" as used herein, refers to an amount enough to show and accomplish efficacies and activities for preventing, alleviating, treating a disease associated with pain.

The pharmaceutical composition of this invention includes a pharmaceutically acceptable carrier besides the active ingredient compound. The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention, which is commonly used in pharmaceutical formulations, but is not limited to, includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, rubber arable, potassium phosphate, arginate, gelatin, potassium silicate, microcrystal 1 ine cellulose, polyvinyl yrrolidone, cellulose, water, syrups, methylcel lulose, methylhydroxy benzoate, propylhyclroxy benzoate, talc, magnesium stearate, and mineral oils. The pharmaceutical composition according to the present invention may further include a lubricant, a humect ant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, and a preservative. Details of suitable pharmaceutically acceptable carriers and formulations can be found in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition according to the present invention may be administered orally or parenteral ly, and concretely, administered parenteral ly . For parenteral administration, it may be administered intravenously, subcutaneous ly , intramuscularly, intrape itoneal ly , transdermal ly or intra-art icular ly . More concretely, it is administered intramuscularly or intraper i toneal ly.

The compound - or the pharmaceutically acceptable salt thereof according to the pain is one or more selected from the group consisting of nociceptive pain, psychogenic pain, inflammatory pain, and pathological pain. More concretely, the pain is one or more selected from the group consisting of neuropathic pain, cancer pain, postoperative pain, trigeminal neuralgia pain, idiopathic pain, diabetic neuropathic pain, and migraine.

A suitable dosage amount of the pharmaceutical composition of the present invention may vary depending on pharmaceutical formulation methods, administration methods, the patient's age, body weight, sex, pathogenic state, diet, administration time, administration route, an excretion rate and sensitivity for a used pharmaceutical composition. Preferably, pharmaceutical composition of the present invention may be administered with a daily dosage of 0.001-10000 mg/kg (body weight).

According to the conventional techniques known to those skilled in the art, the pharmaceutical composition according to the present invention may be formulated with pharmaceutically acceptable carrier and/or vehicle as described above, finally providing several forms including a unit dose form and a multi-dose form. Non-limiting examples of the formulations include, but are not limited to, a solution, a suspension or an emulsion in oil or aqueous medium, an elixir, a powder, a granule, a tablet and a capsule, and may further comprise a dispersion agent or a stabilizer. The sulfamate derivative compound of the present invention may be prepared by the following reaction scheme.

[Reaction scheme 1] Synthesis of alcohol compound

Formula 2 Formula 3

An alcohol compound of formula 3 is synthesized by a reduction reaction using a reducing agent, including but not limited to, L i A 1 ¾ ( L i t h i urn a 1 urn i num hyd ride), NaBH ₄ ( Sod i urn bo r ohydr i de ) ,

Zn(B¾ ) ₂ (Zincborohydr icle) , NaH(Sodium hydride), H(Potassium hydride), A lH3(Alumi num ^■ hydride) , and NaOMe(Sodiummethoxyde) in a basic condition from the Carboxylic acid compound of formula 2.

[Reaction scheme 2] Synthesis of protected alcohol compound in

PG = Protecting group

Formula 3 Formula 4

OH of an alcohol compound of formula 3 is protected by a protecting group, including but not limited to, TMS(Tr imethyl silyl), TESCTriethyl silyl), TIPSCTriisopropyl silyl), TBDMSCtert-butyldimethyl silyl), TBDPS(tert-buty Id i henyl silyl), Piv(Pivaloyl ) , MOM(Methoxymethyl ) , Acetyl, Benzoyl, and Tityl(Triphenylmethyl) in a basic condition for using in a next reaction.

ound

Formula 4 Formula 5

The asymmetric dihydroxylat ion catalyst may be one or more selected from the group consisting of a chiral ligand (e.g., (DHQD) ₂ PHAL, (DHQ) ₂ PHAL, etc.), an osmium catalyst (e.g., 0s0 ₄ , K ₂ 0s0 ₂ (0H)4,etc. ) , K ₂ C0 ₃ , K3Fe(CN)e, N-methylmorphol ine oxide (NMO) , methane sulfone amide (CH3SO2NH2), and the like. For example, the asymmetric dihydroxylat ion catalyst may include, but is not limited to, AD-mix- a (K ₂ 0s0 ₂ (0H)4(cat ) , 2CO3, R ₃ Fe(CN) ₆ , (DHQ) ₂ PHAL(cat)) and methane sulfone amide (CH ₃ S0 ₂ NH ₂ ), or OSO4 and N-methylmorphol ine oxide [Reaction scheme 4] Synthesis of dioxolan-alcohoi compound

Formula 5 Formula 6

A diol compound of formula 5 is reacted with a ketone compound (such as acetone, 3-pentanone, cyclopentanone, or cyclohexanone) , an alkoxy compouncKsuch as dimethoxypropan, diethoxyethane, or methoxy propene), or an aldehyde compound (such as benzaldyde, cyclopentanecarboxalclehyde, or cyclohexaecarboxaldehyde) in an acidic condition, for example, a solution dissolved with an acid such as p-TsOH(p-toluenesul fonic acid), H2SO4 ( Su 1 fur ic acid), HNO3 (Nitric acid), followed by removing a protecting group to afford the Dioxolan-alcohoi compound of formula 6. But while we have described several examples of the ketone compound, the alkoxy compound, the aldehyde compound and the acid for the above reaction, it is not limited thereto and may be appropriately selected depending on the intended purpose.

[Reaction scheme 5] Synthesis of ester compound

Formula 2 Formula 7

An ester compound of formula 7 having R selected from the group consisting of linear or branched Ci-Cio alkyl, or cyclic C3-C10 alkyl, ally! and benzyl is synthesized by an ester i f icat ion reaction in an acidic condition from the carboxylic acid compound of formula 2.

[Reaction scheme 6] Synthesis of ester-diol compound

Formula 7 Formula 8

The asymmetric diliydroxylat ion catalyst may be one or more selected from the group consisting of a chiral ligand (e.g., (DHQD^PHAL, (DHQ) ₂ PHAL, etc.), an osmium catalyst (e.g., 0s0 ₄ , K ₂ 0s0 ₂ (0H) ₄ ,etc. ) , K ₂ C0 ₃ , K.3Fe(CN) ₆ , N-methylmorphol ine oxide (NMO) , methane sulfone amide (CH3SO2NH9), and the like. For example, the asymmetric diliydroxylat ion catalyst may include, but is not limited to, AD-mix-a (K ₂ 0s0 ₂ (0rl) ₄ (cat ) , 2CO3, K ₃ Fe(CN) ₆ , (DHQ) ₂ PHAL(cat)) and methane sulfone amide (CH ₃ S0 ₂ NH ₂ ) ,· or 0s0 ₄ and N-methylmorphol ine oxide (NMO).

[Reaction scheme7] Synthesis of dioxolan-ester compound

Formula 8 Formula 9

A cliol compound of formula 8 is reacted with a ketone compound (such as acetone, 3-pentanone, cyclopentanone , or cyclohexanone) , an alkoxy compouncKsLich as dimethoxypropan, diethoxy ethane , 3-methoxypente-2-ene, 1 ^~ methoxycyclopent-l-ene, 1-methoxycyclohex-l-ene or methoxy propene), or an aldehyde compound(such as benzaldyde, cyclopentanecarboxaldehyde , or cyclohexaecarboxaldehyde) in an acidic condition, for example, a solution dissolved with an acid such as p-TsOH(p-toluenesul f oni c acid), H2S0 ₄ ( Sulfuric acid), HN0 ₃ (Nitric acid) to afford the Dioxo lan-alcohol compound of formula 9. But while we have described several examples of the ketone compound, the alkoxy compound, the aldehyde compound and the acid for the above reaction, it is not limited thereto and may be appropriately selected dependin on the intended purpose.

lcohol compound

Formula 9 Formula 6

A dioxo lan-alcohol compound of formula 6 is synthesized by a reduction reaction using a reducing agent, including but not limited to, LiAlH ₄ (Lithium aluminum hydride), NaBH ₄ ( Sodium borohydr ide) ,

Zn(BH ₄ )2(Zincborohydride) , NaH( Sodium hydride), KH(Potassium hydride), AlH3(Aluminum hydride), and NaOMe(Sodiummethoxyde) in a basic condition from the dioxolan-ester compound of formula 9.

[Reaction scheme 9] Synthesis of Sulfamate compound

Chemical formula 6

Dioxolan-alcohol compound Sulfamate-compound

A dioxolan-alcohol compound of formula 6 is reacted with su If am ide or sulfamoyl chloride in a basic condition using a base, including but not limited to, pyridine, piperidine, and piperazine to produce the sulfamate compound of formula 1 or . [Reaction scheme 10] Synthesis of dioxolan-alcohol compound

Diol-ester compound Dioxolan-ester compound

A dioxolan-alcohol compound used in the synthesis of a sulfamate compound is synthesized by dihydroxylation, condensation and a deprotection reaction.

EXAMPLES

Pre aration example 1 ^' · (E)-3-(2-chlorophenyl )prop-2-en-l-ol

To a 100ml round-bottomed flask, 2-Chloroc.innamic acid (5g, 7.3mmol) and THF (20ml) were added and the reaction mixture was cooled to 0 ^° C. Tr iethylamine (4.2ml, 30.1mmol) and Ethyl chloroformate (2.88ml, 30.1mmol) were added. The reaction mixture was precipitated as a white solid during stirring. After 2hr, the reaction mixture was filtered with THF (white solid + yellow solution).

The yellow solution was added dropwise to Sodium borohyclride (2.68g, 142.3mmol) in H ₂ 0 at 0 ^° C and stirred for 2hrs, quenched with IN HCl solution. The reaction mixture was extracted by EtOAc and washed with ¾0. The combined organic extracts were dried over anhydrous magnesium sulfate (MgS0 ₄ ), filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (2.96g, 60-70%) .

¾ NMR (400MHz, CDCI.3) 61.67(s, 1H), 4.39(t, J=4.0, 2H) , 6.37(dt J=5.6, 16.0, 1H), 7.03(d, J=16.0, 1H) , 7.18 ^~ 7.38(m, 4H), Preparation example 2 ^' · (E)-l-chloro-2-(3-(methoxymethoxy)prop-l-enyl )benzene

To a 250ml round-bottomed flask, (E)-3-(2-chlorophenyl )prop-2-en-l-ol (2.96g, 17.5mmol, Preparation example 1) and Dichloromethane (17.5ml) were added and the reaction mixture was cooled to 0 ^° C. Di isopropyl ethyl amine (6.1ml, 35.1mmol) was added and stirred at 0 ^° C . Methyl chloromethyl ether (2.77ml, 35.1mmol) was added dropwise and stirred for overnight. The reaction mixture was quenched with IN NaOH solution, extracted by dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSOJ, filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (3.43g, 85~95%) .

¾ NMR (400MHz, CDC1 ₃ ) 53.44(s, 3H), 4.30(dcl, J=8.0, 1.6, 1H) , 4.73(s, 2H) , 6.30QH, dt, J=6.0, 16), 7.04(d, J=16.0, 1H), 7.20~7.57(m, 4H)

Preparation example 3: (lR,2R)-l-(2-chlorophenyl )-3-(methoxymethoxy)propane- 1,2-diol

A 250ml round-bottomed flask, equipped with a magnetic stirrer, was filled with 80 ml of tert-butyl alcohol, 80ml of water, and ₃ Fe(CN) ₆ (15.93g, 48.3mmol), K ₂ C0 ₃ (6.7g, 48.3mmol), (DHQD) ₂ -PHAL (0.12g, 0.16mmol), K ₂ 0s0 ₂ (0H) , (ll.Smg, 0.03mmol), and Methanesul fonamide (1.53g, 16.1mmol). Stirring at 0 ^° C . (E)-l-chloro-2-(3-(methoxymethoxy)prop-l-enyl )benzene (3.43g, 16.1mmol, Preparation example 2) was added at once, and the mixture was stirred vigorously at 0 ^° C overnight. While the mixture was stirred at 0 ^° C , solid sodium sulfite (Na2S0.3, 24.4g, 193.5mmol) was added and the mixture was allowed to warm to room temperature. Ethyl acetate was added to the reaction mixture, and after the separation of the layers, the aqueous phase was further extracted with the organic solvent. The combined organic layers were washed with 2 N K0H. The combined organic extracts were dried over anhydrous magnesium sulfate (MgS0 ₄ ) , filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (3.31g, 75-90%).

¾ NMR (400MHz, CDC1 ₃ ) δ 3.09(d, J=5.6, 1H), 3.27(d, J=4.4, 1H), 3.41(s, 3H), 3.69 ^~ 3.77(m, 2H), 3.96~3.99(m, 1H), 4.69(s, 2H), 5.19(t, J=4.4, 1H), 7.23~7.61(m, 1H)

Preparat ion example 4: (lS,2S)-l-(2-chlorophenyl )-3-(methoxymethoxy)propane- 1,2-diol

The substantially same method as described in Preparation Example 3 was conducted, except that (DHQ) ₂ -PHAL was used instead of (DHQD) ₂ -PHAL, to obtain the title compound. 3.1g (75~90 ).

¾ NMR (400MHz, CDC1 ₃ ) 53.09(d, J=5.6, 1H), 3.27(d, J=4.4, 1H), 3.41(s, 3H), 3.69 ^~ 3.77(m, 2H), 3.96~3.99(m, 1H), 4.69(s, 2H), 5.19(t, J=4.4, 1H), 7.23~7.61(m, 4H)

Preparation example 5· ^' l-(2-chlorophenyl )-3-(methoxymethoxy)propane-l,2-diol

(E)-l-chloro-2-(3-(methoxymethoxy)prop-l-enyl )benzene(9. lg, Preparation Example 2) was dissolved in 45mL of a mixture of acetone/t-BuOH/H ₂ 0(5:l:l V/V). At room temperature, N-methylmorphol ine-N-oxide (7.51g) and 0s0 ₄ (0.54g) were added thereto and stirred for 2-3 hours. When the reaction was completed, the obtained product was washed with water and methylenechlor icle (MC). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (7.42g, 70-90%).

¾ NMR (400MHz, CDC1 ₃ ) δ 3.09(d, J=5.6, 1H), 3.27(d, J=4.4, 1H), 3.41(s, 3H), 3.69~3.77(m, 2H), 3.96~3.99(m, 1H), 4.69(s, 2H) , 5.19(t, .1=4.4, 1H), 7.23-7.61(m, 4H) ( (4R, 5R)-5-(2-ch1oropheny1 )-2 , 2-dimethy1-1 , 3

To ( 1R , 2R)-1-(2-chloropheny1 )-3-(methoxymethoxy)propane-l , 2-diol (3.31g, 13.4mmol, Preparation example 3), Di chloromethane was added and cooled to 0 ^° C. 2,2-Dimethoxypropane (3.3ml, 26.8mmol) and p-toluenesul fonic acid (2g, 10.7mmol) was added and stirred at room temperature for 5hrs. The reaction mixture was quenched with H20, extracted with DCM, and washed with H20. The organic layer was dried over anhydrous magnesium sulfate (MgS0 ₄ ) , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (1.05g, 30-40%).

^] Ή MR (400MHz, CDC1 ₃ ) 51.57(s, 3H) , 1.63(s, 3H) , 1.95~1.98(m, 1H), 3.88~3.89(m, 1H) , 3.90~3.96(m. 2H) , 5.41(d, J=8.4, 1H) , 7.25 ^~ 7.66(m, 4H)

Preparation example 7- ((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- dioxo 1 an-4- 1 )methano1

The substantially same method as described in Preparation Example 6 was conducted, except that (lS,2S)-l-(2-chlorophenyl)-3-

(methoxymethoxy)propane-l,2-diol(Prepara ion example 4) was used instead of ( 1R, 2R)-1-(2-ch1oropheny1 )-3-(methoxyniethoxy)propane-1 , 2-di o1 (Preparat i on example 3), to obtain the title compound (l.lg, 30-40%).

¾ NMR (400MHz, CDC1 ₃ ) 51.57(s, 3H), 1.64(s, 3H) , 1.98(m, 1H), 3.76~3.83(m, 1H), 3.88~3.90(m, 2H), 5.41(d, J=8.4, 1H), 7.25~7.66(m, 4H)

Preparat ion exam 1e 8 : (5-(2-ch1oropheny1 )-2 , 2-dimethy1-1 , 3 ^~ dioxo1 an-4- yl )methanol

The substantially same method as described in Preparation Example 6 was conducted, except that l-(2-chlorophenyl )-3-(methoxymethoxy)propane-l,2- diol (Preparat ion example 5) was used instead of (lR,2R)-l-(2-chlorophenyl )- 3-(methoxymethoxy)propane-l,2-diol (Preparation example 3), to obtain the title compound (2.1g, 30-40%).

¾ NMR (400MHz, CDC1 ₃ ) 61.57(s, 3H), 1.63(s, 3H) , 1.95~1.98(m, 1H). 3.88~3.89(m, 1H), 3.90~3.96(m, 2H) , 5.41(d, J=8.4, 1H), 7.25-7.66(111, 4H)

Preparation example 9: (E)-3-(2-f luorophenyl )-acryl ic acid

Pi peri dine (247mg, 2.90mmol) was added to a striied solution of ma Ionic acid (3.1g, 29. OOmmo 1 ) and 2-f 1 uoroa 1 dehyde (3g , 24.17mmo 1 ) i n pyr i d i ne at room temperature under N ₂ condition. The solution was cooled to room temperature, then quenched with HC1 solution. The residue was treated with EA and ¾0. The organic layer was separated and the aqueous layer was extracted further with EA. The combined extracts were washed with brine. The organic layer was dried over Na2S(¾ , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (3.66g, 70-90%).

¾ NMR (400MHz, CDC13) δ 6.60(d, J=16.0, 1H), 7.24~7.50(m, 3H), 7.66(d, J=16.0, 1H), 7.84(t, J=8.0, 1H)

Preparation example 10· ^' (E)-3-(2-f luorophenyl )-prop-2-en-l-ol

The substantially same method as described in Preparation Example 1 was conducted, except that (E)-3-(2-f luorophenyl )-acryl ic acid (Preparation example 9) was used instead of 2-Chlorocinnamic acid, to obtain the title compound (1.6g, 30-40%).

lH NMR (400MHz, CDC1 ₃ ) 51.67 (s, 1H), 4.39 (t, J=4.0, 2H), 6.34-6.41 (m, 1H), 7.00-7.38 (m, 4H)

Preparation example 11: (E)-l-Fluoro-2-(3-(methoxymethoxy)prop-l- enyl )benzene

The substantially same method as described in Preparation Example 2 was conducted, except that (E)-3-(2-f luorophenyl)-prop-2-en-l-ol (Preparation example 10) was used instead of (E)-3-(2-chlorophenyl )-prop-2-en-l- ol (Preparat ion example 1), to obtain the title compound (2.23g, 85-95%).

Ή NMR (400MHz, CDC1 ₃ ) 53.44(s, 3H) , 4.30 (del, J=1.6, 8.0, 1H), 4.73(s, 2H), 6.27~6.37(m, 1H), 7.02~7.57(m, 4H)

Preparation example 12: (lR,2R)-l-(2-f luorophenyl )-3 ^~

(methoxymethoxy)propane-1 ,2-diol

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-l-Fluoro-2-(3-(methoxymethoxy)prop-l- enyObenzene (Preparation example 11) was used instead of (E)-l-chloro-2- (3-(me hoxymethoxy) prop-l-enyl )benzene(Preparat ion example 2), to obtain, the title compound (2.13g, 75-90%).

¾ NMR (400MHz, CDC1 ₃ ) δ 3.09(cl, J=5.6, 1H), 3.27(d, J=4.4, 1H), 3.41(s, 3H), 3.69~3.77(m, 2H), 3.96~3.99(m, 1H), 4.69(s, 2H) , 5.19(t, J=4.4, 1H), 7.23-7.61(m, 4H)

( (4R, 5R)-5-(2-f 1uoropheny1 )-2 , 2-dimethy1-1 , 3-

The substantially same method as described in Preparation Example 6 was conducted, except that (1R, 2R)-l-(2-f luoropheny1 )-3-

(methoxymethoxy)propane-l,2-diol(Preparation example 12) was used instead of (1R, 2R)-l-(2-chlorophenyl)-3-(methoxyniethoxy)propane-l,2- diol (Preparation example 3), to obtain the title compound (1.73g, 30-40%).

¾ NMR (400MHz, CDC1 ₃ ) 61.57(s, 3H), 1.63(s, 3H), 1.95-1.98(m, 1H), 3.88~3.89(m, 1H), 3.90~3.96(m, 2H) , 5.41(d, J=8.4, 1H), 7.25~7.66(m, 4H)

Preparation example 14: ( IS , 2S)-l-(2-f 1uoropheny1 )-3-

(methoxymethoxy)propane-l , 2-cliol

The substantially same method as described in Preparation Example 4 was conducted, except that (E)-l-Fluoro-2-(3-(methoxymethoxy)prop-l- enyl )benzene(Preparat ion example 11) was used instead of (E)-l-chloro-2-(3- (methoxymethoxy)prop-l-enyl )benzene(Preparat ion example 2), to obtain the title compound (2.13g, 75-90%).

¾ NMR (400MHz, CDC1 ₃ ) δ 3.09(d, J=5.6, 1H), 3.27(d, J=4.4, 1H), 3.41(s, 3H), 3.69~3.77(m, 2H), 3.96~3.99(m, 1H) , 4.69(s, 2H), 5.19(t, J=4.4. 1H), 7.23~7.61(m, 4H)

Preparation example 15: ((4S,5S)-5-(2-f Luoropheny1)-2, 2-dimethy1-1,3- dioxo1 an-4-y1 )methano1

The substantially same method as described in Preparation Example 6 was conducted, except that (IS, 2S)-l-(2-f 1 uoropheny1 )-3-

(methoxymethoxy)propane-l,2-diol (Preparation example 14) was used instead of ( 1R, 2R)-l-(2-chlorophenyl )-3-(methoxymethoxy)propane-l , 2- diol (Preparation example 3), to obtain the title compound (1.73g, 30~40%) .

¾ NMR (400MHz, CDC1 ₃ ) 61.57(s, 3H) , 1.63(s, 3H), i:95-1.98(m, 1H) , 3.88~3.89(m, 1H), 3.90~3.96(m, 2H) , 5.41(d, J=8.4, 1H) , 7.25~7.66(m, 4H)

Preparation example 16 ^' · 2-Iodobenzenealdehyde

In a flask, 2-iodobenzyl alcohol (4g, 17.09mmol) was dissolved in dichloromethane (MC, 85ml), and then, manganese oxide (Mn(¼, 14.86g, 170.92mmol) was added thereto. The obtained reaction product was stirred under reflux. When the reaction was completed, the obtained reaction product was cooled to room temperature, and then, filtered and concentrated using celite, to obtain the itle compound (8.6g, yield 75-90%).

¾ NMR (400MHz, CDC1 ₃ ) δ 7.30-7.99(m, 4H) , 10.10(s, 1H)

Preparation example 17: (E)-3-(2-iodophenyl )-acryl ic acid

The substantially same method as described in Preparation Example 9 was conducted, except that 2-Iodobenzenealdehyde (Preparation example 16) was used instead of 2-Fluoroaldehyde, to obtain the title compound (2.06g, 70-90%) ^:

¾ NMR (400MHz, CDC1 ₃ ) δ 6.60(d, J=16.0, 1H), 7.24~7.50(m, 3H) , 7.66(d, J=16.0, 1H), 7.84(t, J=8.0, 1H)

Preparation example 18· ^' (E)-3-(2-iodophenyl )-prop-2-en-l-ol _.

The substantially same method as described in Preparation Example 1 was conducted, except that (E)-3-(2-iodophenyl ) ^~ acryl ic acid (Preparation example 17) was used instead of 2-Chlorocinnamic acid, to obtain the title compound (l.OSg, 30-40%) .

¾ NMR (400MHz, CDC1 ₃ ) 51.67 (s, 1H), 4.39 (t, J=4.0, 2H), 6.34-6.41 (m, 1H), 7.00-7.38 (m, 4H)

Preparation example 19: (E)-l-Iodo-2-(3-(methoxymethoxy)prop-l-enyl )benzene

The substantially same method as described in Preparation Example 2 was conducted, except that (E)-3-(2-iodophenyl )-prop-2-en-l-ol (Preparat ion example 18) was used instead of (E)-3-(2-chlorophenyl )-prop-2-en-l- ol (Preparat ion example 1), to obtain the title compound (1.37g, 85-95%).

Ή NMR (400MHz, CDC1 ₃ ) 63.44(s, 3H), 4.30(dcl, J=8.0, 1.6, 1H), 4.73(s. 2H), 6.27~6.34(m, 1H) , 7.02~7.57(m, 4H)

Preparation example 20: (1R, 2R)-l-(2-iodophenyl )-3-(methoxymethoxy)propane- 1,2-diol

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-l-Iodo-2-(3-(methoxyniethoxy)prop-l- enyl )benzene(Preparat ion example 19) was used instead of (E)-l-chloro-2-(3- (methoxymethoxy)prop-l-enyl )benzene(Preparat ion example 2), to obtain the title compound (1.32g, 75-90%).

4 NMR (400MHz, CDC13 ) δ 3.09(d, J=5.6, 1H), 3.27(d, J=4.4, 1H), 3.41(s, 3H), 3.69-3.77(m, 2H), 3.96~3.99(m, 1H) , 4.69(s, 2H), 5.19(t, .1=4.4, 1H) ,

Preparation example 21: ((4R, 5R)-5-(2-iodophenyl)-2,2-dimethy]-l,3- dioxo1 an-4-y1 )methano1

The substantially same method as described in Preparation Example 6 was conducted, except that (1R, 2R)-l-(2-iodophenyl )-3-(methoxymethoxy)propane- l,2-cliol(Preparation example 20) was used instead of (lR,2R)-l-(2- chlorophenyl)-3-(methoxymethoxy)propane-l,2-diol(Preparation example 3), to obtain the title compound (1.33g, 30~40%) .

¾ NMR (400MHz, CDC1 ₃ ) 51.57(s, 3H), 1.63(s, 3H), 1.95-1.98(m, 1H), 3.88~3.89(m, 1H), 3.90~3.96(m, 2H) , 5.41(d, J=8.4, 1H) , 7.25~7.66(m, 4H)

Preparation example 22: (lS,2S)-l-(2-iodophenyl )-3-(methoxymethoxy)propane- 1,2-diol

The substantially same method as described in Preparation Example 4. was conducted, except that (E)-l-Iodo-2-(3-(methoxymethoxy)prop-l- enyl )benzene(Preparat ion example 19) was used instead of (E)-l-chloro-2-(3- (methoxymethoxy)prop-l-enyl )benzene(Preparat ion example 2), to obtain the title compound (1.32g, 75-90%).

¾ NMR (400MHz, CDC1 ₃ ) δ 3.09(d, J=5.6, 1H) , 3.27(d, J=4.4, 1H), 3.41(s, 3H), 3.69-3.77(m, 2H), 3.96~3.99(m, 1H), 4.69(s, 2H), 5.19(t, J=4.4, 1H), 7.23-7.61(m, 4H)

Preparat i on examp1 e 23 : ( (4S , 5S)-5-(2 ^~ ioclopheny1 )—2 , 2—dimethy1 -1 , 3 ^~ dioxo1 an- 4-yl )methanol

The substantially same method as described in Preparation Example 6 was conducted, except that ( IS, 2S)-l-(2-i oclopheny1 )-3-(methoxymethoxy)propane- l,2-cliol(Preparation example 22) was used instead of (lR,2R)-l-(2- chlorophenyl )-3-(methoxymethoxy)propane-l ,2-diol (Preparat ion example 3) , to obtain the title compound (1.33g, 30~40 ) .

¾ NMR (400MHz, CDC1 ₃ ) 51.57(s, 3H), 1.63(s, 3H), 1.95~1.98(m, 1H), 3.88~3.89(m, 1H), 3.90~3.96(m, 2H), 5.4lCd, J=8.4, 1H) , 7.25~7.66(m, 4H)

Preparation example 24: (E)-Methyl-3-(2-chlorophenyl )acrylate

To a 250ml round-bottomed flask, 2-Chlorocinnamic acid (25g, 136.9mmol) and MeOH (56ml) were added. POCI3 (1.27ml, 13.6mmol) was added dropwise. The reaction mixture was stirred under reflux for 3~4h. The reaction mixture was cooled to room temperature, quenched with IN NaOH solution. The mixture was extracted by EtOAc and washed with H ₂ 0. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgS0 ), filtered and concentrated under vacuum (26.98g, 85-97%)

¾ NMR (400MHz, CDC 13 ) 63.84 (s, 3H), 6.45 (cl, 7=16.0, 1H), 7.28-7.65 (m, 4H), 8.12 (d, 7=16.0, 1H)

Preparation example 25: (2R,3S)-methyl-3-(2-chlorophenyl ) di hydroxypropanoate

A 1000ml round-bottomed flask, equipped with a magnetic stirrer, was filled with 362 ml of tert-butyl alcohol, 362ml of water, R ₃ Fe(CN),5 (135.53g, 411.63mmol), K ₂ C0 ₃ (56.89g, 411.63mmol ) , (DHQ) ₂ PHAL (1.06g, 1.37mmol), R ₂ 0s0 ₂ (0H)4, (0. lg, 0.27mmol), and Methanesul f onamkle (13.05g, 137.21mmol) and stirred at 0 ^° C . (E)-Methyl-3-(2-chlorophenyl )acryl ate (26.98g, Preparation example 24) was added at once, and the mixture was stirred vigorously at 0 ^° C overnight. While the mixture was stirred at 0 ^° C , solid sodium sulfite (Na ₂ S0 ₃ , 24.4g, 193.5mmol), EtOAc and water was added and the mixture was allowed to warm to room temperature and stirred. After the separation of the layer, the aqueous layer was added to EtoAc, and the aqueous layer was separated. The combined organic layers were washed with 0.3M H2S0 ₄ Na ₂ S04 solution (¾S0 ₄ 76ml, H ₂ 0 2L, Na ₂ S0 ₄ 360g) twice. After separation of the organic layer, the organic layer was washed with H20. After separating of the layer, the organic layer were dried over anhydrous MgS0 , filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (24.42g, 70-90%)

¾ NMR (400MHz, CDC1 ₃ ) δ 7.62-7.26 (4H, m), 5.5K1H, del, J=7.2, 2.4), 4.50C1H, del, 7=5.6, 2.4), 3.86C3H, s), 3.13UH, d, .7=6.0), 2.79QH, d, 7=7.2)

Preparat ion example 26: (4R,5S)-methyl-5-(2-chlorophenyl )-2,2-dimehtyl-1.3- d i oxo 1 ane-4-ca boxy 1 at e

Dichloromethane(DMC) was added to (2R,3S)-methyl-3 ^~ (2-chlorophenyl )-2 ,3- dihydroxypropanoate(24.4g, Preparation example 25) and cooled to 0 ^° C . 2,2- Dimethoxypropane (26ml, 211.77mmol) and p-toluenesul fonic acid (2g, 10.58mmol) was added and stirred at room temperature. The reaction mixture was quenched with ¾0, extracted with DCM, washed with H2O, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (23.6g, 70~95%) .

¾ NMR (400MHz, CDC 13 ) 51.63(s, 3H), 1.65(s, 3H), 3.78(s, 3H), 4,30(d, 7=7.6, 1H), 5.62(d, 7=7.6, 1H), 7.28~7.64(m, 4H)

Preparation example 27: ((4S,5S)-5-(2-chlorophenyl)-2,2-dimehtyl-1.3- dioxolane-4-yl )methanol

A solution of To a solution LAH(LiAlH 3.31g, 87.25mmol) in THF was added clropwise to a solution of (4R,5S)-niethyl 5-(2-chlorophenyl )-2 , 2-dimethyl- l,3-dioxolane-4-carboxylate (23.6g, Preparation 26) in THF at 0 ^° C, and the mixture stirred at room temp. The reaction mixture was quenched with ¾0 at 0 ^° C , cellite filtered with EtOAc, washed with EtOAc, dried over anhydrous magnesium sul fate(MgS0 ) , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (21.13g 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) 61.57(s, 3H), 1.64(s, 3H), 1.98(m, 1H), 3.76~3.83(m, 1H), 3.88~3.90(m, 2H), 5.41(d, 7=8.4, 1H), 7.25~7.66(m, 4H)

Preparation example 28: (E)-Methyl-3-(2,4-dichlorophenyl )acrylate

The substantially same method as described in Preparation Example 24 was conducted, except that 2,4-clichlorocinnamic acid was used instead of 2- chlorocinnamic acid, to obtain the title compound(9.7g, 70~90%)

Ti NMR (400MHz, CDC13) : 63.84(s, 3H), 6.44(d, .7=16, 1H), 7.28~7.33(m, 1H), 7.41(d, J=2.0, 1H), 7.55(d, J= 8.4, 1H), 8.04(cl, J=16, 1H).

Preparation example 29 ^' · (2R,3S)-methyl-3-(2,4-dichlorophenyl)-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 25 was conducted, except that (E)-Methyl-3-(2,4-dichlorophenyl )acrylate (Preparation example 28) was used instead of (E)-Methyl-3-(2- chlorophenyl )acrylate (Preparation example 24), to obtain the title compound (3.8g, 60-80%)

¾ NMR (400MHz, CDC 1 ₃ ) : 53.11(s, 1H), 3.88(s, 3H), 4.42(d, J=2.4. H ), 5.43(cl, .7=2.0, 1H), 7.28~7.33(m, 1H), 7.41(d, J=2.0, 1H), 7.55(d, /= 8.4, 1H).

Preparat ion example 30: (4R,5S)-methyl-5-(2,4-dichlorophenyl )-2,2 ^~ dimehtyl- 1.3-d i oxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 26 was conducted, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl )-2,3 ^~ dihydroxypropanoate (Preparation example 29) was used instead of (2S,3R)- methyl-3-(2-chlorophenyl)-2,3-dihyclroxypropanoate (Preparation example 25), to obtain the title compound(3.5g, 60-80%)

¾ NMR (400MHz, CDCI3) : 51.59(s, 3H). 1.63(d, .7=8.8, 3H) , 3.78(s. 3H), 4.25(d, J=7.6, 1H), 5.56(d, J=8.0, 1H) , 7.28~7.33(m, 1H) , 7.41(d, J=2.0, 1H), 7.56(d, .7= 8.4, 1H).

Preparation example 31: ((4S,5S)-5-(2,4-clichlorophenyl)-2,2-climehtyl-1.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted, except that (4R,5S)-methyl-5-(2,4-dichlorophenyl)-2,2-dimehtyl- 1.3-dioxolane-4-carboxylate(Preparat ion example 30) was used instead of (4S , 5R)-methy1-5-(2-ch1oropheny1 )-2 , 2-di mehtyI-1.3-di oxo 1 ane-4-carboxylate (Preparation example 26), to obtain the title compound(3.2g, 70~95%)

¾ NMR (400MHz, CDC 13) : 51.56(s, 3H), 1.62(d, 7=4.8, 6H), 1.97(dd, .7=7.6, .7=7.2, 1H), 3.75~3.80(m, 1H), 3.82~3.86(m, 1H), 3.89~3.94(m. 1H), 5.36(d. J=8.4, 1H), 7.28~7.33(m, 1H) , 7.41(d, 7=2.0, 1H) , 7.56(d, 7= 8.4, 1H).

Preparation example 32· ^' (E)-Ethyl-3-(2,6-dichlorophenyl )acrylate

To a stirred solution of 2,6-dichlorobenzaldehyde (5.0g, 28.56mmol) in THF was added triethyl phosphono acetate (6.4g, 28.56mmo 1 ) at 0 ^° C. The reaction mixture was added f-Bu0 (3.2g, 28.56mmol) at room temperature. The mixture was stirred for lOh then the resulting mixture was quenched with IN HC1 , diluted with ether, washed with water, dried over MgS0 , filtered, and concentrated under reduced pressure. The crude product was purified by S1O2 gel column chromatography (4.3g 40-60% )

¾ NMR (400MHz, CDCI ₃ ) δ 1.36(t, J=3.6, 3H) , 4.31(q, J=3.7, 2H) , 6.61(d, 7=16, 1H), 7.21(t, 7=4.2, 1H), 7.38(d, 7=5.2, 1H), 7.81(cl, 7= 16, 1H).

Preparat ion examp1e 33: (2R, 3S)-ethy1-3-(2 , 6-di ch10ropheny1 )-2 , 3- dihyclroxypr0panoate

The substantially same method as described in Preparation Example 25 was conducted, except that (E)-ethyl-3-(2,6-dichlorophenyl )acrylate (Preparation example 32) was used instead of (E)-Methyl-3-(2- chlorophenyl )acrylate (Preparation example 24), to obtain the title- compound (3.9g, 60-80%)

¾ NMR (400MHz, CDC1 ₃ ) : δ 1.21(t, 7=7.2, 3H) , 3.22(s; 1H) , 3.69(s, 1H), 4.20~4.28(m, 1H), 4.70(d, 7=5.2, 1H), 5.62(d, 7=5.6, 1H), 7.19~7.36(m, 3H).

Preparation example 34: (4R,5S)-ethyl-5-(2,4-dichlorophenyl)-2,2-dimehtyl- 1.3—dioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 26 was conducted, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-2,3- dihydroxypropanoate (Preparation example 29) was used instead of (2R,3S) ^~ methy1-3-(2-chlorophenyl )-2 ,3-dihydroxypropanoate (Preparation example 25), to obtain the title compound(4. lg, 60-90%)

¾ NMR (400MHz, CDC1 ₃ ) · ^" δ 1.26(t, 7=7.2, 3H) , 1.58(s, 3H) , 1.70(s, 3H) , 3.77(s, 3H), 4.24(q, 7=7.2, 1H), 4.95(q, 7=4.4, 1H), 5.95(q, 7=3.0, 1H), 7.20~7.39(m, 3H). Preparation example 35: ((4S,5S)-5-(2,6-dichlorophenyl)-2,2-climehtyl-1.3- dioxo1 ane-4-y1 )methano 1

The substantially same method as described in Preparation Example 27 was conducted, except that (4R,5S)-ethyl-5-(2,6-dichlorophenyl)-2,2-dimehtyl- 1.3-dioxolane-4-carboxylate(Preparation example 33) was used instead of (4R, 5S)-methyl-5-(2-chloropheny1 )-2, 2-dimehty1-1.3-dioxo lane-4-carboxylate (Preparation example 26), to obtain the title compound(3.5g, 70-95%)

¾ NMR (400MHz, CDC1 ): 51.55(s, 3H) , 1.68(s, 3H), 3.66(q, J=5.5, 1H), 3.85(q, 7=5.1, 1H), 4.56~4.61(m, H), 5.78(d, 7=9.2, 1H), 7.19~7.37(m, 3H).

(2S ,3R)-methy1-3-(2 ,4-di ch1oropheny1 )-2 , 3-

The substan ially same method as described in Preparation Example 3 was conducted, except _ that (E)-Methyl-3-(2,4- dichloropheny1 )acrylate(Preparat ion example 28) was used instead of (E)-l- chloro-2-(3-(methoxymethoxy)prop-l-enyl )benzene(Preparat ion example 2) , to obtain the title compound (2.4g, 75-90%).

¾ NMR (400MHz, CDC13) : 53.11(s, 1H), 3.88(s, 3H), 4.42(d, 7=2.4, 1H), 5.43(d, 7=2.0, 1H), 7.28~7.33(m, 1H), 7.41(d, 7=2.0, 1H) ,.7.55(cl, 7= 8.4, 1H) .

Preparation example 37: (4S, 5R)-methyl-5-(2,4-dichlorophenyl)-2,2-dimehtyl- 1.3-dioxo1ane-4-carboxy1ate

The substantially same method as described in Preparation Example 26 was conducted, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl )-2,3- dihydroxypropanoate (Preparation example 36) was used instead of (2R,3S) ^~ methyl-3-(2-chloropheny1 )-2,3-dihydroxypropanoate (Preparation example 25), to obtain the title compound(3.2g, 60~80%)

¾ NMR (400MHz, CDC1 ₃ ): 51.59(s, 3H), 1.63(d, 7=8.8, 3H) , 3.78(s. 3H), 4.25(d, J=7.6, 1H), 5.56(d, 7=8.0, 1H) , 7.28~7.33(m, 1H) , 7.41(d, J=2.0, 1H), 7.56(cl, 7= 8.4, 1H) .

Preparation example 38: ((4R,5R)-5-(2,4-dichlorophenyl)-2,2-climehtyl-1.3- di oxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-methyl-5-(2,4-dichlorophenyl)-2,2-dimehtyl- 1.3-dioxolane-4-carboxylate(Preparation example 37) was used instead of (4S, 5R)-methyl-5-(2-ch Ioropheny1 )-2,2-dimehtyl-1.3-dioxolane-4-ca boxylate (Preparat ion example 26), to obtain the title compound(3.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 61.56(s, 3H) , 1.62(d, .7=4.8, 6H), 1.97(dcl, 7=7.6, 7=7.2, 1H), 3.75~3.80(m, 1H) , 3.82~3.86(m, 1H), 3.89~3.94(m, 1H) , 5.36(d, 7=8.4, 1H), 7.28~7.33(m, 1H), 7.41(d, 7=2.0, 1H), 7.56(d, 7= 8.4, 1H).

Preparation example 39: (2S,3R)-ethyl-3-(2,6-dichlorophenyl )-2,3- clihydroxypropanoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-ethyl-3-(2,6-dichlorophenyl )acrylate(Preparat ion example 32) was used instead of (E)-l-chloro-2-(3-(methoxymethoxy)prop-l- enyl )benzene(Preparat ion example 2), to obtain the title compound (2.8g, 75-90%) .

¾ NMR (400MHz, CDC1 ₃ ): 63.11(s, 1H), 3.88(s, 3H), 4.42(d, 7=2.4, 1H), 5.43(d, .7=2.0, 1H), 7.28~7.33(m, 1H) , 7.41(d, J=2.0, 1H), 7.55(d, 7= 8.4, 1H).¾ NMR (400MHz, CDC1 ₃ ): 5=1.21(t, J=7.2, 3H), 3.22(s, 1H), 3.69(s, 1H), 4.20~4.28(m, 1H), 4.70(d, 7=5.2, 1H), 5.62(d, 7=5.6, 1H). 7.19-7.36(m, 3H).

Preparation example 40: (4S,5R)-ethyl-5-(2,4-dichlorophenyl )-2,2-dimehtyl- 1.3-dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 26 was conducted, except that (2S,3R)-ethyl-3-(2 , 6-clichloropheny1)-2 ,3- dihydroxypropanoate (Preparation example 39) was used instead of (2R,3S)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate (Preparation example 25), to obtain the title compound(4. lg, 60~90%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.26 (t, 7=7.2, 3H), 1.58(s, 3H), 1.70(s. 3H), 3.77(s, 3H), 4.24(q, 7=7.2, 1H) , 4.95(q, 7=4.4, 1H), 5.95(q, 7=3.0, 1H), 7.20~7.39(m, 3H).

Preparation example 41: ((4R,5R)-5-(2,6-dichlorophenyl)-2,2-dimehtyl-1.3- dioxo 1 ane-4-y1 )methano 1

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-ethyl-5-(2,6-dichlorophenyl )-2,2-dimehtyl- 1.3-dioxolane-4-carboxylate(Preparat ion example 40) was used instead of (4R , 5S)-methy1 -5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-di oxo1 ane-4-carboxylate (Preparation example 26), to obtain the title compound(5.2g, 70-95%)

'Ή NMR (400MHz, CDC1 ₃ ) 61.55(s, 3H), 1.68(s, 3H), 3.66(q, 7=5.5, 1H), 3.85(q, 7=5.1, 1H), 4.56~4.61(m, 1H), 5.78(d, 7=9.2, 1H), 7.19-7.37(m, 3H).

Preparation example 42: (E)-3-(2-nitrophenyl)-acrylic acid

The substantially same method as described in Preparation Example 9 was conducted, except that 2-ni trobenzenealdehyde was used instead of 2- Fluoroaldehyde , to obtain the title compound (2.06g, 70~90%)

¾ NMR (400MHz, DMSO) δ 6.52(d, J=15.6, 1H) , 7.65(t, J=8.1, 1H) , 7.75(t, J=7.4, lH), 7.83(d, J=15.8, 1H) , 7.92(dd, J=7.6, 1.1, 1H), 8.05(dd, J=8.1, 1.2, 1H)

Preparation example 43· ^' (E)-Methyl-3-(2-nitrophenyl)acrylate

The substantially same method as described in Preparation Example 24 was conducted, except that (E)-3-(2-nitrophenyl )-acryl ic acid (Preparation example 42) was used instead of 2-chlorocinnamic acid, to obtain the title compound( 15.8g, 70-90%)

¾ NMR (400MHz, CDC1 ₃ ) δ 3.80 (s, 3H), 6.34 (d, J=15.9 Hz, 1H), 7.49-7.68 (m, 4H), 8.01 (d, J=7.9Hz, 1H), 8.08 (d, J=15.9, 1H).

Preparation example . 44: (2S,3R)-methyl-3-(2-nitrophenyl)-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-Methyl-3-(2-ni rophenyl )acrylate(Prepara ion example 43) was used instead of (E)-l-chloro-2-(3-(methoxymethoxy)prop-l- enyl )benzene (Preparation example 2), to obtain the title compound (12.5g, 75-90%) .

¾ NMR (400MHz, CDC1 ₃ ): 5=4.31(s, 3H) , 5.44(m, 4H), 5.89(s, 1H), 7.53~7.90(m, 4H) .

Preparation example 45: (4S, 5R)-methyl-5-(2-nitrophenyl )-2,2-dimehtyl-1.3- di oxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 26 was conducted, except that (2S,3R)-methyl-3-(2-nitrophenyl)-2,3- dihydroxypropanoate (Preparation example 44) was used instead of (2R,3S) ^~ methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate (Preparat ion example 25) , to obtain the title compounding, 60-80%)

T NMR (400MHz, CDC1 ₃ ) - 61.38(s, 3H), 1.40(s, 3H) , 3.75(s, 3H), 4.49(d, 7=7.4, 1H), 5.25(d, 7.4, 1H), 7.48~7.77(m, 3H, 8.08(m, 1H)

Preparat ion examp 1e 46 · ^' ( (4R, 5R)-5-(2-ni tropheny1 )-2 , 2-dimehty1-1.3- clioxolane-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conclucted, except that (4S , 5R)-methy1 -5-(2-ni tropheny1 )-2 , 2-dimehty 1-1.3- dioxolane-4-carboxylate (Preparation example 45) was used instead of (4S, 5R)-methy1-5-(2-chloropheny1 )-2,2-dimehty1-1.3-dioxolane-4-carboxylate (Preparat ion example 26), to obtain the title compound( 13. lg, 70 ^~ 95%)

¾ NMR (400MHz, CDCbV- 51.38(s, 3H) , 1.40(s, 3H) , 3.89(d, J=4.1, 2H), 4.26(dt, J=7.0, 4.1, 1H) , 5.26(d, J=7.0, lH), 7.55~7.86(m, 3H), 8.08(m, 1H).

Preparation example 47: ((4R,5R)-5-(2-aminophenyl)-2,2-dimehtyl-1.3- cli oxo 1 ane-4-y1 )methano 1

To a stirred solution of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimehtyl-1.3- dioxolane-4-yl )methanol (Preparation example 46, 14g) in EtOAc was added Pd(0H) ₂ (20wt%, 2.8g) under hydrogen gas(bal loon) . The mixture was stirred for 6h then the resulting mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by Si(½ gel column chromatography to give title compound (7.5g 65~85 )

¾ NMR (400MHz, CDC1 ₃ ): 51.39 (s, 3H), 1.40 (s, 3H), 3.88 (d, J=4.27, 2H), 3.99 (dt, J=7.02, J=4.30, 1H), 4.74 (d, J=7.02, 1H), 6.65-6.72 (m, 2H) , 6.98 (m, 1H), 7.25 (m, 1H) .

Preparation example 48: (2R,3S)-methyl-3-(2-ni tropheny1 )-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 25 was conducted, except that (E)-methyl-3-(2-ni trrophenyl )acrylate(Preparat ion example 43) was used instead of (E)-Methy 1—3—( 2— ch loropheny1 )acrylate(Preparat ion example 24), to obtain the title compound(21.7g, 60~80%)

¾ NMR (400MHz, CDC1 ₃ ): 54.31(s, 3H), 5.44(m, 4H) , 5.89(s, 1H), 7.53-7.90(m, 4H)

Preparation example 49: (4R,5S)-methyl-5-(2-nitrophenyl )-2, 2-dimehty1-1.3- di oxo lane-4-carboxylate

The substantially same method as described in Preparation Example 26 was conducted, except that (2R,3S)-methyl-3-(2-nitrophenyl)-2,3- dihydroxypropanoate (Preparation example 48) was used instead of (2S,3R) ^~ methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate (Preparation example 25), to obtain the title compound(2lg, 60~90%)

¾ NMR (400MHz, CDC1 ₃ ): 51.38(s, 3H), 1.40(s, 3H), 3.75(s, 3H) , 4.49(d, 7=7.4, 1H), 5.25(d, J=7.4, 1H) , 7.48~7.77(m, 3H, 8.08(m, 1H)

Preparation example 50: ((4S,5S)-5-(2-nitrophenyl)-2,2-dimehtyl-1.3- dioxo1ane-4-y1 )methano1 The substantially same method as described in Preparation

Example 27 was conducted, except that (4R,5S)-methyl-5-(2-nitrophenyl)-2,2- dimehtyl-1.3-dioxolane-4-carboxylate (Preparation example 48) was used instead of (4R, 5S)-methy1 -5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-di oxo1 ane-4- carboxylate (Preparation example 26), to obtain the title compound(14g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 61.38(s, 3H), 1.40(s, 3H), 3.89(d, J=4.1, 2H) , 4.26(dt, /=7.0, 4.1, 1H), 5.26(d, 7=7.0, 1H) , 7.55-7.86(m, 3H), 8.08(m, 1H).

Preparation example 51: ((4S,5S)-5-(2-aminophenyl)-2,2-dimehtyl-1.3- dioxo 1 ane-4-y1 )methano1

The substantially same method as described in Preparation Example 47 was conducted, except that (4S,5S)-methyl-5-(2-nitrophenyl )-2,2-dimehtyl-l .3- dioxolane-4-carboxylate (Preparation example 50) was used instead of (4R, 5R)-5-(2-ni tropheny1 )-2 , 2-dimehty1 -1.3-clioxo1 ane-4-y1 )methano1

(Preparation example 46), to obtain the title compound (llg, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 5 51.38(s, 3H) , 1.40(s, 3H), 3.89(d, 7=4.1, 2H), 4.26(dt, 7=7.0, 4.1, 1H) , 5.26(d, 7=7.0, 1H) , 7.55~7.86(m, 3H) , 8.08(m, 1H) . Preparation example 52: (E)-3- -tolyacryl ic acid

The substantially same method as described in Preparation Example 9 was conducted, except that 2-methylbenzenealclehyde was used instead of 2- Fluoroaldehyde, to obtain the title compound (1.5g, 70-90%)

¾ NMR (400MHz, CDC1 ₃ ) · ^' 52.48(s, 3H), 6.16(d, 7=15.1, 1H) , 7.00-7.10(m, 1H), 7.21-7.26(m, 3H), 8.04(d, J= 15.1, 1H), 11.0(s, 1H).

Preparation example 53: (E)-Methyl-3-o-tolyacrylate

The substantially same method as described in Preparation Example 24 was conducted, except that (E)-3-o ^~ tolyacryl ic acid (Preparation example 52)was used instead of 2-chlorocinnamic acid, to obtain the title compound (1.5g, 70-90%)

lH NMR (400MHz, CDC1 ₃ ) - 62.48(s, 3H), 3.77(s, 3H), 6.14(d, .7=15.1, 1H), 7.00-7.10(m, ΊΗ) , 7.21~7.26(m, 3H), 8.07(d, J= 15.1, 1H).

Preparation example 54: (2S,3R)-methyl-3-(2-methylphenyl )-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-Methyl-3-o-tolyacrylate(Preparat ion example 53) was used instead of (E)-l-chloro-2-(3-(methoxymethoxy)prop-l-enyl. )benzene (Preparation example 2), to obtain the title compound (1.3g, 75~90%) .

¾ NMR (400MHz, CDC1 ₃ >- 52.34(s, 3H), 2.80(s, 1H), 3.65(s, 1H), 3.68(s, 3H), 4.52(cl, J=7.0, 1H) , 5.22(d, .7=7.0, 1H), 7.19~7.39(m, 4H). Preparation example 55: (4S, 5R)-methyl-5-(2-methylphenyl)-2,2-dimehtyl-1.3- dioxo lane-4-carboxylate

The substantially same method as described in Preparation Example 26 was conducted, except that (2S,3R)-methyl-3-(2-methylphenyl)-2,3- clihydroxypropanoate (Preparation example 54) was used instead of (2R,3S)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate (Preparation example 25) , to obtain the title compound(1.7g, 60~80 )

¾ NMR (400MHz, CDC1 ₃ ): 5.1.27(s, 6H) , 2.34(s, 3H), 3.68(s, 3H) , 5.11(d, .7=7.0, 1H), 5.81(d, J=7.0, 1H), 7.19~7.26(m, 3H), 7.37~7.39(m, 1H).

Preparation example 56: ((4R,5R)-5-(2-methylphenyl)-2,2-dimehtyl-1.3- dioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-methyl-5-(2-methyl henyl )-2,2-dimehtyl-1.3- di oxolane-4-carboxylate (Preparation example 55) was used instead, of (4R,5S)-methyl-5-(2-chlorophenyl )-2, 2-dimehtyl-1.3-dioxolane-4-carboxylate (Preparation example 26), to obtain the title compound(1.3g, 70 ^~ 95%)

¾ NMR (400MHz, CDC13) : 61.27(s. 6H), 2.34(s, 3H), 3.52 ^~ 3.60(m, 2H) , 3.65(s, 1H), 4.36(dd, J=7.0, J=7.0, 1H), 5.17(d, 7=7.0, 1H), 7.19 ^~ 7.26(m, 3H), 7.37~7.39(m, 1H).

Preparation example 57: (2R, 3S)-methy1-3-(2-methy1pheny1 )-2 , 3- clihyclroxypropanoate The substantially same method as described in Preparation Example 25 was conducted, except that (E)-methyl-3-o-tolyacrylate(Preparat ion example 53) was used instead of (E)-Methyl-3-(2-chlorophenyl )acry ate(Preparat ion example 24), to obtain the title compound(1.7g, 60~80%)

¾ NMR (400MHz, CDC1 ₃ ): 62.34(s, 3H) , 2.80(s, 1H) , 3.65(s, 1H), 3.68(s, 3H), 4.52(d, 7=7.0, 1H), 5.22(d, J=7.0, 1H), 7.19~7.39(m, 4H).

Preparation example 58: (4R,5S)-methyl-5-(2-methylphenyl )—2 , 2-d imehty1-1.3- di oxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 26 was conducted, except that (2R,3S)-methyl-3-(2-methylphenyl)-2,3- dihydroxypropanoate (Preparation example 57) was used instead of (2R,3S)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate (Preparat ion example 25) , to obtain the title compound(1.9g, 60~90%)

¾ NMR (400MHz, CDC1 ₃ ): 51.27(s, 6H), 2.34(s. 3H), 3.68(s, 3H), 5.11(d, J=7.0, 1H), 5.81(d, 7=7.0, 1H) , 7.19 ^~ 7.26(m, 3H), 7.37~7.39(m, 1H).

Preparation example 59 ^' · ((4S, 5S)-5-(2-methylphenyl )-2,2-dimehty 1-1.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted , except that (4R, 5S)-methy1-5-(2-methy1 heny 1 )-2 , 2-dimenty1-1.3- dioxolane-4-carboxylate (Preparation example 58) was used instead of (4R, 5S)-methyl-5-(2-chlorophenyl )-2 , 2-dimehty1-1 ,3-dioxolane-4-carboxylate (Preparation example 26), to obtain the title compound(1.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 51.27(s, 6H) , 2.34(s, 3H), 3.52~3.60(m, 2H), 3.65(s, 1H), 4,36(dd, 7=7.0, .7=7.0, 1H), 5.17(d, J=7.0, 1H), 7.19~7.26(m, 3H), 7.37~7.39(m, 1H) . Preparation example 60 ^' · ((4S,5R)-methyl-5-(2-chlorophenyl)-2-mehtyl-1.3- d ioxo 1 ane-4-carboxylate

Dichloromethane (MC) was added to (2S,3R)-methyl-3-(2-chlorophenyl )-2,3- dihydroxypropanoate(Preparat ion example 433) at room temperature. 1,1- Diethoxyethane (8ml) and p-toluenesulfonic acid (0.27g) was added and stirred at room temperature. The reaction mixture was quenched with ¾(), extracted with MC, washed with ¾0, dried over anhydrous magnesium sulfate (MgS0 ) , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (3.6g, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, J=6.4, 3H) , 3.78(s, 3H), 4.30(d. J=7.6, 1H), 5.07(m, 1H), 5.62(cl, J=7.6, 1H), 7.28~7.64(m, 4H)

Preparation example 61: ( (4R, 5R)-5-(2-chlorophenyl )-2-mehtyl-l .3-dioxoUine- 4-yl )methanol

The substantially same method as described, in Preparation Example 27 was conducted, except that (4S, 5R)-methyl-5-(2-chlorophenyl )-2-inehty1-1.3- clioxolane-4-carboxylate (Preparation example 60) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl )-2, 2-dimehty1-1.3-dioxolane-4-carboxylate (Preparation example 26), to obtain the title compound(3. lg, 70~95%)

^] H NMR (400MHz, CDC13) ^: δ 1.37(d, 7=6.0, 3H), 3.62~3.70(m, 2H) , 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06 (in, 1H) , 5.17(d, 7=7.0, 1H) , 7.19~7.26(m, 3H) , 7.37~7.39(m, 1H) .

Preparat ion example 62· ^' ((4R,5S)-methyl-5-(2-chlorophenyl)-2-mehtyl-1.3- d i oxo lane-4-carboxyl te

The substantially same method as described in Preparation Example 60 was conducted, except that (2R,3S)-methyl-3-(2-chlorophenyl )-2.3- dihydroxypropanote(Preparat ion example 25) was used instead of (2S,3R) ^~ methyl-3-(2-chlorophenyl)-2.3-clihydroxypropa ^' note(Preparation example 54) , to obtain the title compound(2. lg, 70~95 ).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H) , 3.78(s, 3H), 4.30(d, J=7.6, 1H), 5.07(m, 1H), 5.62(d, 7=7.6, 1H), 7.28~7.64(m, 4H)

Preparation example 63: ((4S,5S)-5-(2-chlorophenyl)-2-mehtyl-1.3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted, except that (4R,5S)-methyl-5-(2-chlorophenyl )-2-mehtyl-l .3- dioxolane-4-carboxylate(Preparat ion example 62) was used instead of (4R, 5S)-methy1-5-(2-ch1oropheny1 )-2 , 2-d imenty1-1.3-cli oxo 1 ane-4- carboxylate(Preparation example 26), to obtain the title compound(3. lg, 70-95%)

4-1 NMR (400MHz, CDC1 ₃ ): δ 1.37(d, 7=6.0, 3H) , 3.62-3.70(m, 2H), 4.36(dd, /=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(cl, 7=7.0, 1H), 7.19~7.26(m, 3H), 7.37-7.39(m, 1H).

Preparation example 64: (4S, 5R)-methyl-5-(2-chlorophenyl)-2,2-cliehtyl-1.3- dioxo1 ane-4-carboxylate

3-pentanone was added to (2S,3R)-methyl-3-(2-chlorophenyl )-2,3- dihydroxypropanoateCPreparat ion example 433) at room temperature. Sulfuric acid (H2SO4) was added and stirred at room temperature. The reaction mixture was quenched with ¾0, extracted with EA, washed with ¾0, dried over anhydrous sodium sulfate (Na2S0 ) , filtered and concent ated. The crude compound was purified by a silica gel column to produce the title compound ( 1.6g , 60-85%) .

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H), 1.59(m, 4H) , 3.67(s, 3H), 5.11(d, 7=7.6, 1H), 5.81(d, 7=7.6, 1H) , 7.22~7.60(m, 4H)

Preparation example 65: ( (4R,5R)-5-(2-chlorophenyl )-2,2-cliehty1-1.3- di oxo 1 ane-4-y1 )methano 1

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diehtyl-1.3- clioxolane-4-carboxylate(Preparat ion example 64) was used instead of (4R , 5S)-methy1 -5-(2-ch 1oropheny1 )-2 , 2-dimehty1 -1.3-d i oxo 1 ane-4-ca boxylate (Preparation example 26), to obtain the title compound(2. Og, 70-95%)

^J H NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H) , 1.59(m, 4H), 3.66(d, J=8.0, 2H), 5.09 (d, 7=7.6, 1H), 5.88(d, 7=7.6, 1H) , 7.26~7.62(m, 4H) .

Preparation example 66: (4R, 5S)-methyl-5-(2-chlorophenyl)-2,2-diehtyl-1.3- di oxo lane-4-carboxylate .

The substantially same method as described in · Preparat ion Exam le 64 was conducted, except that (2R,3S)-methyl-3-(2-chlorophenyl )-2.3- dihydroxyp opanot e(Preparat ion example 25) was used instead of (2S.3R)- methyl-3-(2-chlorophenyl )-2.3-dihydroxypropanote(Preparat ion example 54) , to obtain the title compound( 1.4g , 70~95%) . ¾ NM (400MHz, CDC13) δ 0.96(m, 6H) , 1.59(m, 4H) , 3.67(s, 3H), 5. ll(cl , J=7.6, 1H), 5.81(d, J=7.6, 1H), 7.22~7.60(m, 4H)

Preparation example 67: ((4S,5S)-5-(2-chlorophenyl)-2,2-cliehtyl-1.3- clioxo1ane-4-y ^' l )methano1

The substantially same method as described in Preparation Example 65 was conducted, except that (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-diehtyl-1.3- dioxolane-4-carboxylate (Preparation example 66) was used instead of (4R , 5S)-methy1 -5-(2-ch1oropheiiy1 )-2., 2-di ehty1 -1.3-dioxo1 ane-4- carboxy1 ate(Preparat i on examp 1 e 64) , to obta in the title compound(2.2g , 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) : δ 0.96(m, 6H) , 1.59(m, 4H), 3.66(d, J=8.0, 2H), 5.09 (cl, J=7.6, 1H), 5.88(d, J=7.6, 1H), 7.26 ^~ 7.62(m, 4H) .

Preparation example 68: (2S, 3R)-methyl-3-(2-chlorophenyl )-l,4- di oxaspi ro[4 , 4]nonane-2-carboxy1 ate

The substantially same method as described in Preparation Example 64 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.2g, 70~95%).

¾ NMR (400MHz, DMS0) δ 1.69-1.71(m, 4H), 1.82-1.86(111, 1H), 1.91-2.00(m, 3H), 3.68(s, 3H), 4.40(d, 7=7.2 , 1H), 5.39(d, .7=7.2, 1H), 7.39-7.61(m, 4H)

Preparation example 69: ( (2R,3R)-3-(2-chloropheny 1 )-l ,4- dioxaspi r0[4 , 4-]nonane-2-yI )methano1

The substantially same method as described in Preparation Example 65 was conducted, except that (2S, 3R)-methyl-3-(2-chlorophenyl )-l,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 68) was used instead of . (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diehtyl-1.3-dioxolane- 4- carboxylate(Preparat ion example 64), to obtain the title compound (1.7g, 70-95%)

¾ NM (400MHz , DMS0) : δ 1.60~1.72(m , 4H) , 1.83~1.94(m , 1H) , 3.52-3.65(m , 2H), 3.82 ^~ 3.86(m, 1H), 4.90(t, J=5.2, 1H), 5.12(d, 7=7.6, 1H) , 7.34~7.58(m, 4H)

Preparation example 70 ^' · (2R, 3S)-methy1-3-(2-chlo opheny1 )-l ,4- di oxaspi ro[4 , 4]nonane-2-carboxyl ate

The substantially same method as described in Preparation Example 68 was conducted, except that (2R,3S)-methy1-3-(2-chlorophenyI )-2 ,3- dihyclroxypropanoate(Preparat ion example 25) was used instead of (2S,3R)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound(1.5g, 70-95%).

¾ NMR (400MHz, DMS0) δ 1.69-1.71(m, 4H), 1.82-1.86(in, 1H), 1.91 ^~ 2.00(m, 3H), 3.68(s, 3H), 4.40(d, 7=7.2, 1H), 5.39(d, 7=7.2, 1H) , 7.39~7.61(m, 4H)

Preparation example 71: ((2R,3R)-3-(2-chlorophenyl)-l,4- dioxaspi ro[4 ,4]nonane-2-y1 )methano1

The substantially same method as described in Preparation Example 69 was conducted, except that (2R, 3S)-inethyl-3-(2-chlorophenyl )-l ,4- dioxaspiro[4, ^' 4]nonane-2-carboxylate (Preparation example 70) was used instead of (2S, 3R)-methyl-3-(2-chlorophenyl )-l,4-dioxaspiro[4,4]nonane-2- carboxylate(Preparat ion example 68), to obtain the title compound(1.8g, 70~95%)

¾ NMR (400MHz, DMS0): δ 1.60-1.72(m, 4H), 1.83-1.94(m, 1H) , 3.52~3.65(m, 2H), 3.82~3.86(m, 1H) , 4.90(t, 7=5.2, 1H) , 5.12(d, 7=7.6, 1H) , 7.34~7.58(m,

4H)

Preparation example 72: (2S, 3R)-methyl-3-(2-chlorophenyl )-l ,4- di oxaspi ro [4 , 5] decane-2-carboxy1 ate

The substantially same method as described in Preparation Example 64 was conducted, except that cyclohexanone was used instead of 3-pentanone, to obtain the title compound (1.2g, 70~95%).

Hi NMR (400MHz, DMS0) δ 1.61-1.69(m, 10H) . 3.79(s, 3H), 4.33(d, 7=8.0, 1H), 5.85(d, 7=8.0, 1H) , 7.35~7.63(m, 4H)

Preparation example 73: ((2R,3R)-3-(2-chlorophenyl )-l,4- dioxas iro[4,5]decane-2-yl )methanol

The substantially same method as described in Preparation Example 65 was conducted, except that (2S, 3R)-methyl-3-(2-chlorophenyl)-l,4- clioxaspiro[4,5]decane-2-carboxylate (Preparation example 72) was used instead of (4S, 5R)-methyl -5-(2-chlorophenyl )-2,2-diehtyi-l .3-dioxolane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.8g, 70-95%) Tl NMR (400MHz, DMSO) : δ 1.63-1.75(m, 10H) , 3.52-3.81(in, 2H), 3.95(t, 7=8.0, 1H), 5.43(cl, 7=7.6, 1H), 7.48~7.87(m, 4H)

Preparation _. example 74: (2R, 3S)-methyl-3-(2-chlorophenyl)-l,4- dioxaspiro[4 ,5]decane-2-carboxylate

The substantially same method as described in Preparation Example 72 was conducted, except that (2R, 3S)-methy1-3-(2-chloropheny1 )-2,3- dihydroxypropanoate(Preparat ion example 25) was used instead of (2S,3R) ^~ methyl-3-(2-chlorophenyl )-2,3-dihyclroxypropanoate(Preparat ion example 433) , to obtain the itle compound (2.1 g, 70-95%).

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H). 3.79(s, 3H) , 4.33(d, 7=8.0, 1H), 5.85(cl, 7=8.0, 1H), 7.35~7.63(m, 4H)

Preparation example 75: ((2S,oS)-3-(2-chlorophenyl)-l,4- dioxaspi ro[4 , 5]decane-2-y1 )methano1

The substantially same method as described in Preparation Example 65 was conducted, except that (2R, 3S)-methy1-3-(2-chloropheny1 )-l ,4- clioxaspiro[4,.5]decane-2-carboxylate (Preparation example 74) was used instead, of (4S,5R)-inethyl-5-(2-chlorophenyl)-2,2-diehtyl-1.3-dioxolane -4- carboxylate(Preparat ion example 64), to obtain the title compound(1.6g, 70-95%)

lH NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H) , 3.52~3.81(m, 2H), 3.95(t, 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.48~7.87(m, 4H)

Preparation example 76 ^' - (4S, 5R)-methyl-5-(2-chlorophenyl)-2-phenyl-l,3- dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 64 was conducted, except that benzaldehyde was used instead of 3-pentanone, to obtain the title compound (l.lg, 50~70%) .

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H) , 3.79(s, 3H) , 4.33(d, -J=8.0, 1H), 5.85(d, .7=8.0, 1H) , 7.35~7.63(m, 4H)

Preparation example 77: ((4R,5R)-5-(2-chlorophenyl)-2-phenyl-l,3-clioxolane- 4-yl )methanol

The substantially same method as described in Preparation Example 65 was conducted, except that (2S, 3R)-methyl-3-(2-chlorophenyl )-2-pheny1-1,3- dioxolane-4-carboxylate (Preparation example 76) was used instead of (4S , 5R)-methy1-5-(2-ch1oropheny1 )-2 , 2-di ehty1-1.3-dioxo1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound(0.7g, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H) , 3.52 ^~ 3.81(m, 2H) , 3.95(t J=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.48 ^~ 7.87(m, 4H)

Preparation example 78 ^' · (4R, 5S)-methyl-5-(2-chlorophenyl)-2-phenyl-l,3- dioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 66 was conducted, except that benzaldehyde was used, instead of 3-pentanone, to obtain the title compound (1.9g, 50~70%) .

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H), 3.79(s, 3H) , 4.33(d, J=8.0, 1H), 5.85(d, .7=8.0, 1H), 7.35~7.63(m, 4H)

Preparation example 79: ((4S,5S)-5-(2-chlorophenyl)-2-phenyl-l,3-clioxolane- 4-yl )methanol

The substantially same method as described in Preparation Example 65 was conducted, except that (2R, 3S)-methyl-3-(2-chlorophenyl)-2-phenyl-l,3- dioxolane-4-carboxylate (Preparation example 78) was used instead of (4S , 5R)-methy1-5-(2-ch1oropheny1 )-2 , 2-di ehty1-1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.3g, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H), 3.52 ^~ 3.81(m. 2H), 3.95(t, J=8.0, 1H), 5.43(d, J=7.6, 1H), 7.48~7.87(m, 4H)

Preparation example 80: (E)-Methyl-3-(2-f luoropheny1 )acrylate

The substantially same method as described in Preparation Example 24 was conducted, except that (E)-3(2-f luoropheny1 )-acryl ic acid (Preparation example 9)was used instead of 2-chlorocinnamic acid, to obtain the title compound. (6.98g, 70-90%)

¾ NMR (400MHz, CDC1 ₃ ) 53.84 (s, 3H), 6.45 (cl, J=16.0, 1H), 7.24-7.62 (m, 4H), 8.12 (d, 7=16.0, 1H) (2S , 3R)-methy1 -3-(2-f 1 uoropheny1 )-2 , 3-

The substantially same method as described in Preparation Preparation Example 3 was conducted, except that (E)-Methyl-3-(2- f luorophenyl)acrylate(Preparation example 80) was used instead of (E)-l- chloro-2-(3-(methoxymethoxy)prop-l-enyl ) benzene(Preparat ion example 2), to obtain, the title compound (7.5g, 75~90 ).

¾ NMR (400MHz, CDC1 ₃ ): 6=4.31(s, 3H), 5.44(m, 4H) , 5.89(s, 1H), 7.32~7.70(m, 4H).

Preparation example 82: (2R,3S)-methyl-3-(2-f 1 uoropheny1 )-2,3- clihyclroxypropanoate

The substantially same method as described in Preparation Example 25 was conducted, except that (E)-methyl-3-(2-f 1 uoropheny1 )acrylate(Preparat ion example 80) was used instead of (E)-Methyl-3-(2- chlorophenyl )acrylate(Preparat ion example 24), to obtain the title compound (7.2g, 60 ^~ 80%) ^■

¾ NMR (400MHz , CDC1 ₃ ) : δ =4.31 ( s , 3H) , 5.44(m , 4H) , 5.89( s , ^' 1H) , 7.32-7.70(m, 4H).

Preparation example 83: ((4S,5R)-methyl-5-(2-f luorophenyl )-2-mehtyl-1.3- di oxolane-4-carboxylate

The substantially same method as described in Preparation Example 60 was conducted, except that (2S,3R)-methyl-3-(2-f luorophenyl )-2, 3- clihydroxypropanoate(Preparat ion example 81) was used instead of ((2S,3R)- methyl-3-(2-chlorophenyl )-2,3-clihydroxypropanoate(Preparat ion example 433) , to obtain the title compound(3. lg, 70~95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H) , 3.78(s, 3H) , 4.30(d, .7=7.6, 1H), 5.07(m, 1H), 5.62(d, J=7.6, H), 7.29 ^~ 7.67(m, 4H)

Preparat ion examp1e 84 ^' ■ ( (4R, 5R)-5-(2-f 1uoropheny1 )-2-mehty1-1.3-dioxo1 ane- 4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-methyl-5-(2-f luorophenyl )-2-mehtyl-1.3- dioxolane-4-carboxylate (Preparation example 83) was used instead of (4R, 5S)-methyl-5-(2-chlorophenyl )-2 ,2-dimehty1-1.3-dioxolane-4-carboxylate (Preparation example 26), to obtain the title compound(3.3g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.37(d, .7=6.0, 3H). 3.62~3.70(m, 2H), 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H), 7.19~7.39(m, 4H).

Preparation example 85 ^' · ((4R,5S)-methyl-5-(2-f luorophenyl )-2-mehtyl-l.3- dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 60 was conducted, except that (2R,3S)-methyl-3-(2-f luorophenyl )-2.3- clihyclroxypropanote(Preparat ion example 82) was used instead of (2S,3R)- methyl-3-(2-chlorophenyl )-2.3-dihydroxypropanote(Preparat ion example 433) , to obtain the title compound (2.9g, 70~95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H), 3.78(s, 3H), 4.30(d, 7=7.6, 1H), 5.07(m, 1H), 5.62(d, 7=7.6, 1H), 7.29 ^~ 7.69(m, 4H)

Preparat ion examp1e 86 : ( (4S , 5S)-5-(2-f 1uoropheny1 )-2-mehty1-1.3-dioxo 1 ane- 4-yl ) methanol

The substantially same method as described in Preparation Example 27 was conducted, except that (4R,5S)-methyl-5-(2-f luorophenyl )-2-mehtyl-1.3 ^~ dioxolane-4-carboxylate (Preparation example 85) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl )-2 ,2-dimehty 1-1.3-dioxol ane-4-car boxy late (Preparation example 26), to obtain the title compound ( 3.8g, 70-95%)

ll\ NMR (400MHz, CDC1 ₃ ): δ 1.37(d, J=6.0, 3H) , 3.62~3.70(m, 2H) , 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H), 7.19-7.4.2(m, 4H).

Preparation example 87: (4S, 5R)-methyl-5-(2-f luorophenyl ) -2 , 2-d i eht y 1 - 1.3- di oxo 1 ane-4-car boxy 1 at e

The substantially same method as described in Preparation Example 64 was conducted, except that (2S,3R)-methyl-3-(2-f luorophenyl )-2, 3- dihydroxypropanoate(Preparat ion example 81) was used instead of (2S.3R)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound (2.1g, 60-85%).

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H), 1.59(m, 4H) , 3.67(s, 3H), 5.11(d, 7=7.6, 1H), 5.81(d, 7=7.6, 1H), 7.20~7.61(m, 4H)

Preparation example 88: ((4 ,5R)-5-(2-f luorophenyl )-2,2-diehtyl-l.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-methyl-5-(2-f luorophenyl )-2 ,2-diehtyl-l .3- dioxolane-4-carboxylate (Preparation example 87) was used instead of (4R, 5S)-methy1 -5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-dioxo1 ane-4-carboxylate (Preparation example 26), to obtain the title compound (2.2g, 70 ^~ 95%) lti NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H) , 1.59(m, 4H), 3.66(d, J=8.0, 2H) , 5.09 (d, 7=7.6, 1H), 5.88(d, 7=7.6, 1H) , 7.23 ^~ 7.60(m, 4H).

Preparation example 89: (4R, 5S)-methyl-5-(2-f luorophenyl )-2,2-diehtyl-l.3- clioxolane-4-carboxylate

The substantially same method as described in Preparation Example 87 was conducted, except that (2R,3S)-methyl-3-(2-f luorophenyl )-2, 3- dihydroxypropanoate(Preparat ion example 82) was used instead of (2S,3R)- methyl-3-(2-f luorophenyl )-2.3-dihyclroxypropanote (Preparation example 81) , to obtain the title compound (2.3g, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H) , 1.59(m, 4H), 3.67(s, 3H), 5.11(d, 7=7.6, 1H), 5.81(d, 7=7.6, 1H), 7.20 ^~ 7.61(m, 4H)

Preparation example 90: ( (4S,5S)-5-(2-f luorophenyl )-2 , 2-di ehty1 -1.3- dioxo 1 ane-4-y1 )methano1

The substantially same method as described in Preparation Example 88 was conducted, except that (4R,5S)-methyl-5-(2-f luorophenyl )-2 , 2-di ehtyl-1.3- dioxolane-4-carboxylate (Preparation example 89) was used instead of ( S , 5R)-methy1 -5-(2-f 1 uoropheny1 )-2 , 2-d i ehty1-1.3-dioxo1 ane-4- carboxylate(Preparat ion example 87), to obtain the title compound(2.2g, 70-95%)

¾ NMR (400MHz, CDC13) : δ 0.96(m, 6H) , 1.59(m, 4H), 3.66(d, J=8.0, 2H), 5.09 (d, 7=7.6, 1H), 5.88(d, 7=7.6, 1H) , 7.23~7.62(m, 4H)

Preparation example 91: (2S, 3 )-methyl-3-(2-f luorophenyl )-l ,4- cli oxaspi ro[4 , 4]nonane-2-carboxy1 ate

The substantially same method as described in Preparation Example 87 was conducted, except that cyclopentanone was used instead of 3-pentanoie, to obtain the title compound (2.1g, 70~95%).

¾ NMR (400MHz, DMSO) δ 1.69-1.71(m, 4H) , 1.82-1.86(m, 1H), 1.91-2.00(m, 3H), 3.68(s, 3H), 4.40(cl, 7=7.2, 1H), 5.39(d, 7=7.2, 1H), 7.33 ^~ 7.62(m, 4H)

Preparation example 92: ((2R,3R)-3-(2-f luorophenyl )-l, 4- di oxaspi ro[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation Example 65 was conducted, except that (2S, 3R)-methyl-3-(2-f luorophenyl)-!, 4- dioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 91) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl )-2,2-diehtyl-1.3-dioxolane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.9g, 70-

¾ NMR (400MHz, DMSO): δ 1.60-1.72(m, 4H), 1.83-1.94(m, 1H), 3.52~3.65(m, 2H), 3.82-3.86(m, 1H), 4.90(t, 7=5.2, 1H) , 5.12(d, 7=7.6, 1H), 7.32~7.57(m, 4H)

Preparation example 93: (2R, 3S)-methyl-3-(2-f luorophenyl )-l ,4- dioxaspi ro[4 , 4]nonane-2-carboxy1 ate

The substantially same method as described in Preparation Example 91 was conducted, except that (2R,3S)-methyl-3-(2-f luorophenvl )-2, 3- dihydroxypropanoateCPrepa at ion example 82) was used instead of (2S.3R)- methyl-3-(2-f luorophenvl )-2.3-dihydroxypropanote (Preparation example 81), to obtain the title compound (1.5g, 70~95%).

¾ NMR (400MHz, DMSO) δ 1.69-1.71(m, 4H), 1.82~1.86(m, 1H) , 1.91 ^~ 2.00(m, 3H), 3.68(s, 3H), 4.40(d, J=7.2, 1H) , 5.39(d, 7=7.2, 1H), 7.39~7.61(m, 4H)

Preparation example 94: ((2R,3R)-3-(2-f 1 uoropheny1)-1, 4- clioxaspi ro[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation Example 88 was conducted, except that (2R,3S)-methyl-3-(2-f luorophenyl )-l,4- dioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 93) was used instead of (4S , 5R)-methy1-5-(2-f 1 uoropheny1 )-2 , 2-di ehty1-1.3-d i oxo 1 ane-4- carboxylate(Preparat ion example 87), to obtain the title compound (1.2g, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.60-1.72(m, 4H) , 1.83-1.94(m, 1H) , 3.52~3.65(m, 2H), 3.82~3.86(m, 1H), 4.90(t, J=5.2, 1H), 5.12(d, 7=7.6, 1H), 7.38~7.63(m, 4H)

Preparation example 95: (2S, 3R)-methyI-3-(2-f luorophenvl )-l ,4- dioxaspi ro [4 , 5Jdecane-2-carboxy1 ate

The substantially same method as described in Preparation Example 91 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(1.7g, 70~95%) .

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H), 3.79(s, 3H), 4.33(d, J=8.0, 1H), 5.85(d, J=8.0, 1H), 7.37~7.63(m, 4H)

Preparation example 96: ((2 ,3R)-3-(2-f luorophenyl)-1,4- clioxaspi ro [4 , 5] decane-2-y1 )methano1

The substantially same method as described in Preparation Example 73 was conducted, except that (2S, 3R)-methyl-3-(2-f luorophenyl )-l,4- clioxaspiro[4,5]decane-2-carboxylate(Preparat ion example 95) was used instead of (2S, 3R)- methyl-3-(2-chlorophenyl )-l , 4-dioxaspiro[4 , 5]decane-2- carboxylate (Preparation example 72), to obtain the title compound (1.4g, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H), 3.52~3.81(m, 2H), 3.95(t, J=8.0, 1H), 5.43(d, J=7.6, 1H), 7.42~7.89(rn, 4H)

Preparation example 97- ^' (2R, 3S)-methyl -3-(2-f luorophenyl )-l, 4- dioxaspiro[4,5]decane-2-carboxylate

The substantially same method as described in Preparation Example 95 was conducted, except that (2R,3S)-methyl-3-(2-f luorophenyl )-2, 3- clihydroxypropanoate(Preparat ion example 82) was used instead of (2S,3R)- methyl -3-(2-f luorophenyl )-2.3-dihydroxypropanote(Preparat ion example 81) , to obtain the title compound (1.8 g, 70~95%).

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H), 3.79(s, 3H), 4.33(d, J=8.0, 1H), 5.85(d, .7=8.0, 1H), 7.32~7.64(m, 4H) Preparation example 98: ((2S,3S)-3-(2-f 1uoropheny1 )-l,4- dioxaspi ro [4 , 5]decane-2-y1 )methano1

The substantially same method as described in Preparation Example 96 was conducted, except that (2R, 3S)-methyl-3-(2-f luorophenyl )-l,4- dioxaspiro[4,5]decane-2-carboxylate(Preparat ion example 97)was used instead of (2S , 3R)-methy1-3-(2-f 1uoropheny1 )-1 , 4-dioxaspi ro [4 , 5] decane-2- carboxylate(Preparat ion example 95), to obtain the title compound( 1.5g, 70-95%)

lH NMR (400MHz , DMS0) : δ 1.63-1.75(m , 10H) , 3.52-3.81(m , 2H) , 3.95( t , 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.33~7.67(m. 4H)

Preparation example 99: (4S, 5R)-methyl-5-(2-f luorophenyl )-2-pheuyl-l, 3- dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 87 was conducted, except that benzaldehyde was used instead of 3-pentanone, to obtain the title compound (1.6g, 50-70%).

¾ NMR (400MHz, DMS0) δ 1.61-1.69(m, 10H) , 3.79(s, 3H), 4.83(d, 7=8.0, 1H), 5.85(d, 7=8.0, 1H), 7.33~7,64(m, 4H)

Preparation example 100: ( (4R, 5R)-5-(2-f luorophenyl )-2-pheny1-1 , 3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 65 was conducted, except that (2S, 3R)-methyl-3-(2-f 1uoropheny1 )-2-phenyl-l ,3- dioxolane-4-carboxylate (Preparation example 99) was used instead of (4S , 5 )-methy1-5-(2-ch1oropheny1 )-2 , 2-di ehty1 -1.3-dioxo1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.3g, 70-95%)

H NMR (400MHz, DMSO) : δ 1.63-1.75(m, 10H) , 3.52~3.81(m, 2H) , 3.95(t, J=8.0, 1H), 5.43(cl, J=7.6, 1H) , 7.43~7.85(m, 4H)

Preparation example 101· ^' (4R, 5S)-methyl-5-(2-f luorophenyl )-2-pheny1-1, 3- dioxolane-4-carboxylate

The substantially same method as described in Preparation example 89 was conducted, except that benzaldehyde was used instead of 3-pentanone, to obtain the title compound ( 1.7g , 50~70%) .

lH NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H) , 3.79(s, 3H), 4.33(d, 7=8.0, 1H), 5.85(cl, .7=8.0, 1H), 7.33~7.64(m, 4H)

Preparation example 102: ((4S,5S)-5-(2-f luorophenyl )-2-phen 1-1, 3-dioxo lane- 4-yl )methanol

The substantially same method as described in Preparation example 65 was conducted, except that (2R, 3S)-methyl-3-(2-f luorophenyl )-2-phenyl-l ,3- di oxo lane-4-carboxylate (Preparation example 101) was used instead of (4S , 5R)-methy 1-5-(2-ch1 oropheny1 )-2 , 2-d i ehty1 -1.3-d i oxo 1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound (l.lg, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H) , 3.52~3.81(m, 2H) , 3.95(t, .7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.43~7.85(m, 4H)

Preparation example 103: (E)-Methyl-3-(2-iodophenyl )acrylate

The substantially same method as described in Preparation example 24 was conducted, except that (E)-3(2-iodophenyl )-acrylic acid (Preparation example 17)was used instead of 2-chlorocinnamic acid, to obtain the title compound. (3.2g, 70-90%)

^] H NMR (400MHz, CDC1 ₃ ) 53.84 (s, 3H) , 6.45 (d, 7=16.0, 1H) , 7.01-7.35 (m, 4H), 8.09 (cl, 7=16.0 _. , 1H)

Preparation. example 104: (2S,3R)-methyl-3-(2-iodophenyl )-2,3 dihydroxypropanoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-Methyl-3-(2-iodophenyl )acry late(Prepara ion example 103) was used instead of (E)-l-chloro-2-(3-(methoxymethoxy)prop-l- enyl )benzene(Preparat ion example 2), to obtain the title compound (3.2g, 75-90%) .

¾ NMR (400MHz, CDC1 ₃ )- ^' 6=4.31(s, 3H), 5.44(m, 4H), 5.89(s, 1H) , 7.30-7.71(m, 4H).

Preparation example 105: (2R,3S)-methyl-3-(2-iodophenyl ) d i hydroxypropanoate

The substantially same method as described in Preparation example 25 was conducted, except that (E)-methyl-3-(2-iodophenyl )acrylate(Preparat ion example 103) was used instead of (E)-Me thy 1-3-(2- chlorophenyl )acrylate(Preparat ion example 24), to obtain the title compound (3.1g, 60-80%).

¾ NMR (400MHz, CDC1 ₃ ): 5=4.31(s, 3H), 5.44(m, 4H) , 5.89(s, 1H), 7.31~7.72(m, 4H) .

Preparation example 106: ((4S,5R)-methyl-5-(2-iodophenyl)-2-mehtyl-1.3- d i oxo 1 ane-4-carboxylate

The substantially same method as described in Preparation example 60 was conducted, except · that (2S,3R)-methyl-3-(2-iodophenyl )-2,3- dihydroxypropanoate(Preparat ion example 104) was used instead of (2S,3R)- methyl-3-(2-chlo opheny 1 )-2 ,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound (2.7g, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, ./=6.4, 3H) , 3.78(s, 3H) , 4.30(cl, .7=7.6, 1H), 5.07(m, 1H), 5.62(d, J=7.6, 1H), 7.29-7.70 (m, 4H)

Prepara ion example 107: ((4R,5R)-5-(2-iodophenyl )-2-mehtyl-1.3-dioxolane-4- l )methanol

The substantially same method as described in Preparation example 27 was conducted, except that (4S,5R)-methyl-5-(2-iodophenyl)-2-mehtyl-1.3- dioxolane-4-carboxylate(Preparat ion example 106) was used instead of (4R , 5S)-methy1-5-(2-ch1oropheny1 )—2 , 2—dimehty1 -1.3-di oxo I ane-4- carboxylate(Preparat ion example 26), to obtain the title compound (2.3g, 70-95%)

¾ NMR (400MHz, CDC13) : δ 1.37(d, J=6.0, 3H) , 3.62-3.70(m, 2H) , 4.36(dd, J=7.0, .7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H), 7.17~7.41(m, 4H).

Preparation example 108: ((4R,5S)-methyl-5-(2-iodophenyl)-2-mehtyl-1.3- di oxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 60 was conducted, except that (2R,3S)-methyl-3-(2-iodophenyl)-2.3- clihydroxypropanote(Preparat ion example 104) was used instead of (2S,3R)- methyl-3-(2-chlorophenyl )-2.3-dihydroxypropanote(Preparat ion example 433) , to obtain the itle compound (2.4g, 70~95%) .

'Ή NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H), 3.78(s, 3H), 4.30(d, 7=7.6, 1H), 5.07(iii, 1H), 5.62(d, 7=7.6, 1H) , 7.29-7.70 (m, 4H)

Preparat ion examp1 e 109 · ^' ( (4S , 5S)-5-(2-iodopheny1 )-2-mehty1-1.3-di oxo1 ane ^~ 4- yl )methanol

The substantially same method as described in Preparation example 107 was conducted, except that (4R, 5S)-methyl-5-(2-i odopheny1 )-2-mehty1-1.3- dioxol ane-4-carboxyl te(Preparat ion example 108) was used instead of (4S , 5R)-methy1-5-(2- i odopheny1 )-2-mehty1-1.3-dioxo 1 ane-4- carboxylate(Preparat ion example 106), to obtain the title compound (1.9g, 70-95%)

¾ NMR (400MHz, CDC13) : δ 1.37(d, 7=6.0, 3H), 3.62-3.70(m, 2H), 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H), 7.17~7.41(m, 4H) Preparation example 110: (4S, 5R)-methyl-5-(2-iodophenyl )-2, 2-diehty1-1.3- dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation example 64 was conducted, except that (2R,3S)-methyl-3-(2-iodophenyl)-2,3- dihydroxypropanoate(Preparat ion example 104) was used instead of (2S,3R)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound (2.6g, 60-85%).

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H), 1.59(m, 4H), 3.67(s, 3H), 5.11(d, J=7.6, 1H), 5.81(d, J=7.6, 1H) , 7.23~7.65(m, 4H)

Preparation example 111: ((4R,5R)-5-(2-iodophenyl)-2,2-diehtyl-1.3- dioxo 1ane-4-y1 )methano1

The substantially same method as described in Preparation example 107 was conducted, except that (4S,5R)-methyl-5-(2-iodophenyl)-2,2-diehtyl-1.3- cli oxo lane-4-carboxylate (Preparation example 110) was used instead of (4S , 5R)-methy1-5-(2- iodopheny1 )-2-mehty1-1.3-dioxo1 ane-4- carboxylateCPreparat ion example' 106), to obtain the title compound(2. lg, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) · δ 1.37(d, .7=6.0, 3H), 3.62~3.70(m, 2H) , 4.36(dcl, .7=7.0, .7=7.0, 1H), 5.06(m, 1H), 5.17(d, .7=7.0, 1H), 7.17~7.41(m, 4H)

Preparation example 112: (4R, 5S)-methyl-5-(2-iodophenyl)-2,2-diehtyl-1.3- dioxo 1 ane-4-carboxy1ate

The substantially same method as described in Preparation example 110 was conducted, except that (2R,3S)-methyl-3-(2-iodophenyl )-2 ,3- dihydroxypropanoate (Preparation example 105) was used instead of (2S,3R)- methyl-3-(2-iodophenyl )-2,3-dihydroxypropanoate (Preparation example 104), to obtain the title compound (2.3g, 60~85%) .

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H), 1.59(m, 4H), 3.67(s, 3H) , 5.11(d, J=7.6, 1H), 5.81(d, J=7.6, 1H), 7.20~7.61(m, 4H)

Preparation example 113: ((4S,5S)-5-(2-iodophenyl)-2,2-diehtyl-l. di oxo 1 ne-4-y1 )methano1

The substantially same method as described in Preparation example 107 was conducted, except that (4R,5S)-methyl-5-(2-iodophenyl)-2,2-diehtyl-1.3- dioxolane-4-carboxylate (Preparation example 112) was used instead of (4S , 5R)-methy1 -5-(2- i odopheny1 )-2-mehty1 -1.3-d i oxo 1 ane-4- carboxylate(Preparat ion example 106), to obtain the title compound(1.8g, 70-95%)

Ή NMR (400MHz, CDC1 ₃ ): δ 1.37(d, J=6.0, 3H), 3.62-3.70(m, 2H) . 4.36(dd, J=7;0, 7=7.0, 1H), 5.06(m, 1H), 5.17(d, J=7.0, 1H) , 7.17~7.41(m, 4H)

Preparation example 114 ^' · (2S, 3R)-methyl-3-(2-iodophenyl)-l,4- dioxasp i ro [4 , 4] nonane-2-carboxylate

The substantially same method as described in Preparation example 110 was conducted, except that eye1opentanone was used instead of 3-pentanone, to obtain the title compound (2.7g, 70~95%).

¾ NMR (400MHz, DMSO) δ 1.69-1.71(m, 4H), 1.82-1.86(m, 1H) , 1.91~2.00(m, 3H), 3.68(s, 3H), 4.40(d, 7=7.2, 1H), 5.39(cl, 7=7.2, 1H), 7.19-7.44(m, 4H)

Preparation example 115· ^' ( (2R, 2R)-3-(2-iodopheny1 )-1 , 4- dioxaspi ro[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 107 was conducted, except that (2S,3R)-methyl-3-(2-iodophenyl )-l,4- dioxaspiro[4,4]nonane-2-carboxylate(Preparation example 114) was used instead of (4S,5R)-methyl-5-(2-iodophenyl )-2-mehtyl-1.3-dioxolane-4- carboxylate(Preparat ion example 106), to obtain the title compound (2.1g, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.60-1.72(m, 4H), 1.83-1.94(m, 1H), 3.52~3.65(m, 2H), 3.82-3.86(m, 1H) , 4.90(t, 7=5.2, 1H), 5.12(cl, 7=7.6, 1H), 7.20~7.45(m,

Preparation example 116: (2R, 3S)-methy1-3-(2-iodopheny1 )-l ,4- dioxas i ro[4 , 4]nonane-2-ca boxy1 a e

The substantially same method as described in Preparation example 112 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.9g, 70-95%).

¾ NMR (400MHz, DMSO) δ 1.69-1.71(m, 4H), 1.82~1.86(m, 1H), 1.91-2.00(m, 3H), 3.68(s, 3H), 4.40(d, 7=7.2, 1H), 5.39(cl, 7=7.2, 1H), 7.19-7.44(m, 4H) Preparation example 117: ((2S,2S)-3-(2-ioclophenyl )-l,4- dioxaspi ro[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 107 was conducted, except that (2R,3S)-methyl-3-(2-iodophenyl)-l,4- clioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 116) was used instead of (4S,5R)-methyl-5-(2-iodophenyl )-2-mehtyl-1.3-dioxolane-4- carboxylate(Preparat ion example 106), to obtain the title compoundCl .5g, 70-95%)

. ¾ NMR (400MHz, DMS0): δ 1.60-1.72(m, 4H) , 1.83-1.94(m, 1H) , 3.52~3.65(m, 2H), 3.82-3.86(m, 1H) , 4.90(t, J=5.2, 1H) , 5.12(d, .7=7.6, TH), 7.20~7.45(m, 4H)

Preparation example 118: (2S, 3R)-methyl-3-(2-iodophenyl)-l,4- dioxas iro[4 ,5]decane-2-carboxylate

The substantially same method as described in Preparation example 114 was conducted, except that cyclohexanone was used instead of eye 1ope tanone, to obtain the title compound (1.9g, 70-95%).

¾ NMR (400MHz, DMS0) δ 1.61-1.69(m, 10H) , 3.79(s, 3H), 4.33(cl, J=8.0, 1H), 5.85(d, J=8.0, 1H) , 7.17-7. 3(m, 4H)

Preparation example 119: ((2R,3R)-3-(2-iodophenyl)-l,4- dioxaspi ro[4 , 5Jdecane-2-y1 )methano1

The substantially same method as described in Preparation example 107 was conducted, except that (2S,3R)-methyl-3-(2-iodophenyl )-l,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 118) was used instead of (4S, 5R)-methyl-5-(2-iodophenyl )-2-mehtyl-l .3 ^~ dioxolane-4- carboxylate(Preparat ion example 106), to obtain the title compound(1.3g, 70-95%)

^] H NMR (400MHz, DMS0): δ 1.63-1.75(ra, 10H), 3.52~3.81(m, 2H) , 3.95(t, J=8.0, 1H), 5.43(d, J=7.6, 1H), 7.19~7.49(m, 4H)

Preparation example 120: (2R, 3S)-methyl-3-(2-iodophenyl )-l ,4- di oxaspi ro [4 , 5] decane-2-carboxy1 ate

The substantially same method as described in Preparation example 116 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (2.3g, 70-95%).

¾ NMR (400MHz, DMS0) 51.61-1.69(m, 10H), 3.79(s, 3H), 4.33(d, J=8.0, 1H), 5.85(d, J=8.0, 1H), 7.17~7.43(m, 4H)

Preparation example 121: ((2S,3S)-3-(2-iodophenyl)-l,4- di oxaspi ro [ , 5] decane-2-y1 )methano 1

The substantially same method as described in Preparation example 107 was conducted, except that (2R,3S)-methyl-3-(2-iodophenyl) ^~ l,4- dioxaspiro[4,5]decane-2-carboxylate(Preparat ion example 120) was used instead of (4S , 5R)-methy1-5-(2-i odopheny1 )-2-mehty1-1.3-dioxo1 ane-4- carboxylate(Preparat ion example 106), to obtain the title compound(1.7g, 70-95%)

¾ NMR (400MHz, DMS0) : δ 1.63-1.75(m, 10H), 3.52-3.81(m, 2H), 3.95(t, J=8.0, 1H), 5.43(d, J=7.6, 1H) , 7.19~7.49(m, 4H)

Preparation example 122: (4S, 5R)-methyl-5-(2-iodophenyl)-2-phenyl-l,3- clioxo1ane-4-carboxy1ate

The substantially same method as described in Preparation example 118 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the title compound(1.9g, 50-70%).

¾ NMR (400MHz, DMS0) 63.67(s, 3H) , 5.11(d, J=8.0, 1H) , 5.81(d, 7=8.0, 1H), 6.18(s, 1H), 6.96~7.57(m, 9H)

Preparat ion examp1e 123 : ( (4R, 5R)-5-(2-iodopheny1 )-2-pheny1-1 ,3-di oxo1 ane-4- yl )methanol

The substan ially same method as described in Preparation example 107 was conducted, except that (4S, 5R)-methy1-5-(2-i odophenyI )-2-pheny1-1 ,3- dioxolane-4-carboxylate (Preparation example 122) was used instead of (4S , 5R)-methy1-5-(2-iodopheny1 )-2-mehty1-1.3-dioxo1ane-4- carboxylate(Preparat ion example 106), to obtain the title compound(1.4g, 70-95%)

Tl NMR (400MHz, DMS0) : δ 3.66(cl, J=7.6, 2H), 4.36(m, 1H), 5.17(d, .7=8.0, 1H), 6.18(s, 1H), 6.94-7.59(m, 9H) Preparation example 124: (4R _; 5S)-methyl-5-(2-ioclophenyl)-2-phenyl-l,3- di oxo1ane-4-carboxy1 ate

The substantially same method as described in Preparation example 120 was conducted, except benzaldehyde that was used instead of cyclohexanone, to obtain the title compound (2.1g, 50~70 ) .

^J H NMR (400MHz, DMSO) 53.67(s, 3H), 5.11(d, J=8.0, 1H) , 5.81(d, J=8.0, 1H), 6.18(s, 1H), 6.96-7.57(m, 9H)

Preparation example 125: ((4S,5S)-5-(2-iodophenyl)-2-phenyl-l,3-dioxolane-4- yl )methanol

The substantially same method as described in Preparation example 107 was conducted, except that (4R, 5S)-methyl-5-(2-iodophenyl)-2-phenyl-l,3- dioxolane-4-carboxylate(Preparat ion example 124) was used instead of C4S , 5R)-methy1—5—(2-iodopheny1 )-2-mehty 1-1.3-dioxo 1 ane-4- carboxylate(Preparation example 106), to obtain the title compound(1.3g, 70-95%)

¾ NMR (400MHz, DMSO): δ 3.66(d, J=7.6, 2H) , 4.36(m, 1H), 5.17(d, J=8.0, 1H), 6.18(s, 1H), 6.94~7.59(m, 9H)

Preparat ion example 126 ^' · ((4S,5R)-methyl-5-(2,4-dichlorophenyl )-2-mehtyl- 1.3-dioxo 1ane-4-carboxylate

The substan ially same method as described in Preparation example 60 was conducted, except that (2S,3R)-methyl-3-(2,4-di chlorophenyl )-2,3- dihydroxypropanoate(Preparat ion example 36) was used instead of (2S,3R) ^~ methyl-3-(2-chlorophenyl )-2,3-di.hydroxypropanoate(Preparat ion example 433) , to obtain the title compound(0.9g, 70~95 ).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, J=6.4, 3H), 3.78(s, 3H) , 4.30(d, J=7.6, 1H), 5.07(m, 1H), 5.62(cl, 7=7.6, 1H) , 7.07~7.21(m, 3H)

Preparation example 127 ^' · ((4R,5R)-5-(2,4-dichlorophenyl)-2-mehtyl di oxo1 ane-4-y1 )methano 1

The substantially same method as described in Preparation example 27 was conducted , exce t that ( (4S , 5R)-methy1 -5-(2 , 4-d.i ch1 oropheny1 )-2-niehty 1 -1.3- dioxolane-4-carboxylate(Preparat ion example 126) was used instead of (4R , 5S)-methy1 -5-(2-ch 1 oropheny1 )-2 , 2-d imehty1 -1.3-di oxo 1 ane-4-carboxy late (Preparation example 26), to obtain ^' the title compound(0.7g, 70~95 )

¾ NMR (400MHz, CDC 13) : 6 1.37(d, 7=6.0, 3H) , 3.62-3.70(m, 2H), 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06(m, 1H) , 5.17(d, 7=7.0, Hi), 7.08~7.39(m, 3H) .

Preparat i on exam 1 e 128 : ( (4R , 5S)-methy1 -5-(2 , 4-d i chl oropheny 1 )-2-inehty1 - 1.3-di oxo 1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 126 was conducted, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl )-2,3- dihydroxypropanoate (Preparation example 29) was used instead of (2S,3R)- methy1-3-(2 , 4-dichloropheny1 )-2 ,3-dihydroxypropanoate (Preparat ion example 36), to obtain the title compound (1.9g, 70~95%) .

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H), 3.78(s, 3H), 4,30(d, 7=7.6, 1H), 5.07(m, 1H), 5.62(d, 7=7.6, 1H), 7.07~7.21(m, 3H).

Preparation example 129: ((4S,5S)-5-(2,4-dichlorophenyl)-2-mehtyl dioxolane-4-yl )methanol

The substantially same method as described in Preparation example 27 was conducted, except that (4R,5S)-methyl-5-(2,4-dichlorophenyl)-2-mehtyl-1.3- dioxolane-4-carboxylate(Preparat ion example 128) was used instead of (4R , 5S)-methy1-5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-di oxo1 ane-4-carboxylate (Preparation example 26), to obtain the title compound(1.5g, 70-95%)

¾ NMR (400MHz, CDC13) : δ 1.37(d, 7=6.0, 3H), 3.62 ^~ 3.70(m, 2H) , 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(cl, 7=7.0, 1H) , 7.08~7.39(m, 3H) .

Preparation example 130: (4S, 5R)-methy1-5-(2, 4-dichloropheny1 )-2,2-diehtyl- 1.3-dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation example 64 was, conducted, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl )-2,3- dihyclroxypropanoate(Preparat ion example 36) was used instead of (2S,3R)- methyI-3-(2-chloropheny1 )-2,3-d.ihydroxypropanoate(Preparat ion example 433) , to obtain the title compound (2.2g, 60-85%).

¾ NMR (400MHz, CDC13) δ 0.96(m, 6H) , 1.59(m, 4H) , 3.67(s, 3H), 5.11(d, 7=7.6, 1H), 5.81(d, 7=7.6, 1H) , 7.12-7.37(m, 3H) Preparat ion examp1e 131: ( (4R, 5R)-5-(2 , -dich1oropheny1 )-2 , 2-diehty1-1.3- dioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 27 was conducted, except that (4S,5R)-methyl-5-(2,4-dichlorophenyl )-2,2-diehtyl- 1.3-dioxolane-4-carboxylate(Preparation example 130)was used instead of (4R , 5S)-methy1-5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-di oxo1ane-4-carboxyl te (Preparation example 26), to obtain the title compound(1.4g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.37(d, J=6.0, 3H), 3.62~3.70(m, 2H), 4.36(dd, J=7.0, J=7.0. 1H), 5.06(m, 1H) , 5.17(d, 7=7.0, 1H) , 7.08~7.39(m, 3H) .

Preparation example 132: (4R, 5S)-methyl-5-(2,4--chlorophenyl )-2 ,2-cliehtyl- 1.3-dioxo1ane-4-carboxylate

The substantially same method as described in Preparation example 130 was conducted, except that (2R,3R)-methyl-3-(2,4-dichlorophenyl)-2,3- dihyclroxypropanoate (Preparation example 29) was used instead of (2S.3R)- methyl-3-(2,4-di chlo opheny1 )-2,3-dihydroxypropanoate (Preparat ion example 36), to obtain the title compound (2.1g, 70-95%).

Ή NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H) , 1.59(m, 4H), 3.67(s, 3H), 5.11(d, 7=7.6, 1H), 5.81(cl, 7=7.6, 1H) , 7.12~7.37(m, 3H)

Preparation example 133: ((4S,5S)-5-(2,4-chlorophenyl)-2,2-diehtyl-1.3- dioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 131 was conducted, except that (4R,5S)-methyl-5-(2,4-dichlorophenyl)-2,2-diehtyl- 1.3-dioxolane-4-carboxylate(Preparation example 132) was used instead of ( (4S , 5 )-methy1 -5-(2 , -di ch1 oropheny1 )-2 , 2-d i ehty1 -1.3-d i oxo 1 ane-4- carboxylate (Preparation example 130), to obtain the title compound (1.2g, 70-95%) .

¾ NMR (400MHz, CDC1 ₃ ) · ^" δ 1.37(d, J=6.0, 3H) , 3.62~3.70(m, 2H) , 4.36(dd, 7=7.0, .7=7.0, 1H), 5.06(m, 1H), 5.17(d, J=7.0, 1H), 7.08~7.39(m, 3H).

Preparation example 134: (2S, 3R)-methyl-3-(2,4-chlorophenyl)-l,4- clioxaspi ro1.4 , 4]nonane-2-carboxylate

The substantially same method as described in Preparation example 131 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.5g, 70~95%) .

¾ NMR (400MHz, DMS0) δ 1.69-1.71(m, 4H), 1.82~1.86(m, 1H) , 1.91-2.00(m, 3H), 3.68(s, 3H), 4.40(d, J=7.2, 1H) , 5.39(d, .7=7.2, 1H), 7.03~7.36(m, 3H)

Preparation example 135: ((2R,3R)-3-(2,4-chlorophenyl)-l,4- di oxaspi ro[4 , 4]nonane-2-y1 )methano 1

The SLibs t cin t ial ly same method as described in Preparation example 65 was conducted, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-l,4- clioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 134) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl )-2,2-diehtyl-1.3-dioxolane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.8g, 70-95%)

¾ NMR (400MHz, DMS0): δ 1.60-1.72(m, 4H), 1.83-1.94(m, 1H), 3.52~3.65(m, 2H), 3.82-3.86(m, 1H) , 4.90(t, J=5.2, 1H), 5.12(d. J=7.6, 1H), 7.02~7.37(m, 3H)

Preparation example 136: (2R, 3S)-methyl-3-(2,4-chlorophenyl )-l,4- dioxaspi ro[4 ,4]nonane-2-carboxy1 ate

The substantially same method as described in Preparation example 132 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.2g, 70-95%).

¾ NMR (400MHz, DMS0) δ 1.69-1.71(m, 4H), 1.82~1.86(m, 1H), 1.91-2.00(m, 3H), 3.68(s, 3H), 4.40(d, 7=7.2, 1H) , 5.39(d, 7=7.2, 1H), 7.03-7.36(m, 3H)

Preparation example 137: ((2S,3S)-3-(2,4-chlorophenyl )-l,4- dioxaspi ro[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 135 was conducted, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl)-l,4- clioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 136) was used instead of (2S, 3R)-methyl-3-(2,4-clichlorophenyl)-l,4- clioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 134), to obtain the title compound(1.2g, 70~95%)

^L H NMR (400MHz, DMS0): δ 1.60-1.72(m, 4H), 1.83-1.94(m, 1H), 3.52~3.65(m, 2H), 3.82-3.86(m, 1H) , 4.90(t, 7=5.2, 1H) , 5.12(d, 7=7.6, 1H), 7.02-7.37(m, 3H)

Preparation example 138: (2S, 3R)-methyl-3-(2,4-chlorophenyl )-l,4- dioxaspi ro[ , 5] decane-2-carboxylate

The substantially same method as described in Preparation example 134 was conducted, except that cyclohexanone was used instead of eye 1opentanone, to obtain the title compound(1.8g, 70-95%) .

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H) , 3.79(s, 3H) , 4.33(d, .7=8.0, 1H), 5.85(d, 7=8.0, 1H), 7.07-7.41(m, 3H)

Preparation example 139: ((2R,3R)-3-(2,4-chlorophenyl)-l,4- dioxaspi ro [4 , 5]decane-2-y1 )methano1

The substantially same method as described in Preparation example 73 was conducted, except that (2S,3R)-methyl-3-(2,4-clichlorophenyl)-l,4- dioxaspiro[4,5]decane-2-carboxylate(Preparat ion example 138) was used insteacl of (2S , 3R)-methy1-3-(2-ch1 oropheny1 )-1 , 4-dioxaspi ro[4 , 5] decane-2- carboxylate(Preparat ion example 72), to obtain the title compound(1.3g, 70-95%)

¾ NMR (400MHz, DMSO): 51.63-1.75(m, 10H), 3.52-3.81(m, 2H) , 3.95(t, J=8.0, 1H), 5.43(d, J=7.6, 1H) , 7.04~7.40(m, 3H)

Preparation example 140: (2R, 3S)-methyl-3-(2,4-chlorophenyl )-l,4- clioxaspi ro[4-, 5]decane-2-carboxy1 ate

The substantially same method as described in Preparation example 136 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(1.6g, 70~95%).

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H), 3.79(s, 3H) , 4.33(d, J=8.0, 1H), 5.85(d, .J=8.0, 1H), 7.07~7.41(m, 3H)

Preparation example 141: ((2S,3S)-3-(2,4-chlorophenyI )-l,4- dioxaspiro[4,5]decane ^~ 2-yl )methanol

The substcint ial ly same method as described in Preparation example 139 was conducted, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl )-l,4- dioxaspiro[4,5]decane-2-carboxylate(Preparation example 140)was used instead of (2S, 3R)-methyl-3-(2,4-dichlorophenyl)-l,4- clioxaspiro[4,5]decane-2-carboxylate(Preparat ion example 138), to obtain the title compound (1.2g, 70~95 )

¾ NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H), 3.52~3.81(m, 2H) , 3.95(t , J=8.0, 1H), 5.43(d, .7=7.6, 1H), 7.04~7.40(m, 3H)

Preparation example 142: (4S, 5R)-methyl-5-(2,4-chlorophenyl)-2-phenyl-l,3- di oxo 1 ane-4-carboxylate

The substantially same method as described in Preparation example 138 was conducted, except that benzaldehvde was used instead of cyclohexanone, to obt in the title compound (1.9g, 50~70%).

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H), 3.79(s, 3H), 4.33(d, 7=8.0, 1H), 5.85(d, .7=8.0, 1H) , 7.03~7.41(m, 3H)

Preparation example 143: ((4R,5R)-5-(2,4-chlorophenyl)-2-phenyl-l,3- clioxo 1ane-4-y1 )methano1

The substantially same method as described in Preparation example 65 was conducted, except that (4S,5R)-niethyl-5-(2,4-chlorophenyl )-2-pheny1-1, 3- dioxolane-4-carboxylate(Preparation example 142) was used instead of (4S , 5R)-meth l-5-(2-chloropheny1 )-2 , 2-diehty1-1.3-dioxolane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.5g, 70-95%)

H NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H), 3.52~3.81(m, 2H) , 3.95(t 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.04~7.42(m, 3H)

Preparation example 144 ^' · (4R, 5S)-methy1-5-(2, 4-chlorophenyl)-2-pheny1-1,3- dioxo1 ane-4-carboxy1ate

The substantially same method as described in Preparation example 140 was conducted, except that benzaldehvde was used instead of cyclohexanone, to obtain the title compound (1.6g, 50-70%).

lH NMR (400MHz, DMSO) 61.61-1.69(m, 10H) , 3.79(s, 3H) , 4..33(d, 7=8.0, 1H), 5.85(d, 7=8.0, 1H), 7.03~7.41(m, 3H) Preparation example 145: ((4S,5S)-5-(2,4-chlorophenyl)-2-phenyl-l,3- di oxo 1 ane-4-y1 )methanol

The substantially same method as described in Preparation example 143 was conducted, except that (4R, 5S)-methyl-5-(2,4-chlorophenyl )-2-pheny1-1 ,3- dioxolane-4-carboxylate (Preparation example 144) was used instead of (2S, 3R)-methy1—3—(2 , 4-ch1 oropheny1 )-2-pheny1 -1 , 3-di oxo 1 ane-4- carboxylate(Preparat ion example 142), to obtain the title compound(1.2g, 70-95%)

LH NMR (400MHz, DMSO) : δ 1.63-1.75(m, 10H), 3.52~3.81(m, 2H), 3.95(t, 7=8.0, 1H), 5.43(d, .7=7.6, 1H), 7.04~7.42(m, 3H)

Preparat i on exam l e 146 : ( (4S , 5R)-ethy 1 -5-(2 , 6-cli chl oropheny1 )-2-methy1 -1.3- d i oxo 1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 60 was conducted, except that (2S,3R)-ethyl-3-(2, 6-cli chl orophenyl )-2,3- dihydroxypropanoate(Preparat ion example 39) was used instead of (2S.3R)- methy1 -3-(2-chl orophenyl )-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound ( 1.7g , 70-95%).

^L H NMR (400MHz, CDC1 ₃ ) δ 1.36(d, J=6.4, 3H), 3.78(s, 3H), 4.15(m, 2H), 4.30(cl, J=7.6, 1H), 5.07(m, 1H), 5.62(d, J=7.6, 1H) , 7.17~7.36(m, 3H)

Preparation example 147: ((4R,5R)-5-(2,6-di chl orophenyl )-2-methy1-1.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation example 27 was conducted, except that ((4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2-mehtyl-1.3- dioxolane-4-carboxylate(Preparat ion example 146) was used instead of (4R , 5S)-methy1 -5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-dioxo 1 ane-4-carboxylate (Preparation example 26), to obtain the title compound(1.2g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.37(cl, J=6.0, 3H), 3.62~3.70(m, 2H), 4.36(dd, J=7.0, 7=7.0, 1H), 5.06(m, 1H) , 5.17(d, 7=7.0, 1H), 7.18~7.39(m, 3H). ■

Preparation example 148: ((4R,5S)-ethyl-5-(2,6-dichlorophenyl )-2-methy1-1.3- clioxo 1ane-4-carboxylate

The substantially same method as described in Preparation example 146 was conducted, except that (2R,3S)-ethyl-3-(2 ,6-ichlorophenyl )-2,3- dihydroxypropanoate (Preparation example 33) was used instead of (2S.3R)- methyl-3-(2 , 4-clichloropheny1 )-2,3-dihydroxypropanoate (Preparat ion example 39), to obtain the title compound(1.8g, 70-95%).

lH NMR (400MHz, CDC13) δ 1.36(d, 7=6.4, 3H), 3.78(s, 3H), 4.15(m, 2H). 4.30(d, 7=7.6, 1H), 5.07(m, 1H), 5.62(d, 7=7.6, 1H), 7.17~7.36(m, 3H).

Preparation example 149· ^' ((4S,5S)-5-(2,6-dichlorophenyl)-2-methyl-1.3- clioxo1ane-4-y1 )methano1

The substantially same method as described in Preparation example 147 was conducted, except that ((4R,5S)-ethyl-5-(2,6-dichlorophenyl )-2 ^~ methyl-1.3- dioxolane-4-carboxylate (Preparation example 148) was used instead of ( (4S, 5R)-ethyl-5-(2 , 6-di chlorophenyl )-2-mehtyl-l .3-dioxolane-4- carboxylate(Preparat ion example 146), to obtain the title compound (1.3g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.37(d, J=6.0, 3H) , 3.62~3.70(m, 2H) , 4.36(dd, J=7.0, .7=7.0, 1H), 5.06(m, 1H) , 5.17(d, J=7.0, 1H) , 7.18~7.39(m, 3H).

Preparation example 150 ^' · (4S, 5R)-ethyl-5-(2,6-clichlorophenyl)-2,2-diehtyl- 1.3-di oxo1 ane-4-carboxyl ate

The substantially same method as described in Preparation example 130 was conducted, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl )-2,3- dihydroxypropanoate(Preparat ion example 39) was used instead of (2S.3R)- methyl -3-(2 , 6-di chlorophenyl )-2 ,3-dihydroxypropanoate(Preparat ion example 36), to obtain the title compound (1.8g, 60~85%).

lH NMR (400MHz, CDC13) δ 0.96(m, 6H), 1.30(t, 7=8.0, 3H), 1.59(m. 4H), 4.12(m, 2H), 5.11(cl, 7=7.6, 1H) , 5.81(d, 7=7.6, 1H), 7.08~7.26(m, 3H)

Preparation example 151: ((4R,5R)-5-(2,6-dichlorophenyl)-2,2-diehtyl-1.3- dioxo1 ne-4-y1 )methano1

The substantially same method as described in Preparation example 147 was conducted, except that (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-diehtyl- 1.3-dioxolane-4-carboxylate(Preparat ion example 150)was used instead of ( ( S , 5R)-ethy1-5-(2 , 6 ^~ di ch1oropheny1 )-2-mehty1-1.3-di oxo1 ane-4-carboxylate (Preparation example 146), to obtain the title compound (1.2g, 70-95%)

^L H NMR (400MHz, CDC13) : δ 1.37(d, .7=6.0, 3H), 3.62~3.70(m, 2H) , 4.36(dcl, 7=7.0, 7=7.0, 1H), 5.06(m, 1H) , 5.17(d, 7=7.0, 1H) , 7.07-7.29(m, 3H). Preparation example 152: (4R, 5S)-ethyl-5-(2,6-chlorophenyl)-2,2-diehtyl- 1.3-dioxo1 ane-4-carboxy1ate

The substantially same method as described in Preparation example 150 was conducted, except that (2R,3S)-ethyl-3-(2,6-ichlorophenyl)-2,3- clihydroxypropanoate (Preparation example 33) was used instead of (2S,3R)- eth ^' yl-3-(2, 6-dichlorophenyl )-2,3-dihydroxypropanoate (Prepar t ion exam le 39), to obtain the title compound(2.5g, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H) , 1.30(t, J=8.0, 3H), 1.59(m, 4H), 4.12(m, 2H), 5.11(d, .7=7.6, 1H) , 5.81(cl, .7=7.6, 1H), 7.08~7.26(m, 3H)

Preparation example 153: ((4S,5S)-5-(2,6-chlorophenyl)-2,2-diehtyl-1.3- dioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 151 was conducted, except that (4R, 5S)-ethyl-5-(2, 6-dichlorophenyl )-2,2-diehtyl- 1.3-dioxolane-4-carboxylate (Preparation example 152) was used instead of (4S , 5R)-ethy1 -5-(2 , 6-di ch1oropheny1 )-2 , 2-di ehty1-1.3-di oxo1 ane-4- carboxylate(Preparat ion example 150), to obtain the title compound(2. lg, 70-95%)

H NMR (400MHz, CDC1 ₃ ) ^' - δ 1.37(d, 7=6.0, 3H), 3.62-3.70(m, 2H), 4.36(dd, 7=7.0, /=7.0, 1H), 5.06(m, 1H), 5.17(d, J=7.0, 1H), 7.07~7.29(m, 3H) .

Preparation example 154: (2S, 3R)-ethyl-3-(2,6-chlorophenyl )-l,4- dioxaspiro[4,4]nonane-2-carboxylate

The substantially same method as described in Preparation example 150 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.1g, 70~95%) .

¾ NMR (400MHz, DMS0) δ 1.30(t, J=7.8hz, 3H) , 1.69-1.71(m, 4H), 1.73~1.86(m, 4H), 4.07-4.14(m, 2H), 5.11(cl, J=7.2, 1H), 5.81(d, 7=7.2, 1H), 7.07-7.31(m, 3H)

Preparation example 155 ( (2R, 3R)-3-(2 , 6-ch1oropheny1 )-1 ,4- dioxas i ro[4 , 4]nonane-2-y1 )methano 1

The substantially same method as described in Preparation example 151 was conducted, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl )-l ,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 154) was used instead of (4S,5 )-ethyl-5-(2,6-dichlorophenyl)-2,2-cliehtyl-1.3-clioxolane- 4-carboxylate (Preparation example 150), to obtain the title compound (1.7g, 70-95%)

lH NMR (400MHz, DMS0) : δ 1.60-1.72(m, 4H), 1.83~1.94(m, 4H), 3.52~3.65(m, 2H), 4.90(t, J=5.2, 1H), 5.12(d, 7=7.6, 1H) , 7.08~7.32(m, 3H)

Preparation example 156· ^' (2R, 3S)-ethyl-3-(2,6-chlorophenyl)-l,4- dioxaspi ro[4 , 4]nonane-2-carboxy1 ate

The substantially same method as described in Preparation example 152 was conducted, except that eyelopentanone was used instead of 3-pentanone, to obtain the title compound (2.5g, 70 ^~ 95%) .

¾ NMR (400MHz, DMSO) δ 1.30(t, J=7.8hz, 3H), 1.69-1.7Km, 4H), 1.73~1.86(m, 4H), 4.07-4.14(m, 2H), 5.11(d, 7=7.2, 1H), 5.81(d, 7=7.2, 1H), 7.07~7.31(m, 3H)

Preparation example 157: ((2S,3S)-3-(2,6-chlorophenyl)-l,4- dioxaspi ro[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 155 was conducted, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl )-l,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 156)was used instead of (2S , 3R)-ethy1-3-(2 , 6 ^~ di ch1oropheny1 )-1 , 4-di oxaspi ro [4 , 4J nonane- 2-carboxylate(Preparat ion example 154), to obtain the title compound (2.0g, 70-95%)

lH NMR (400MHz, DMSO): δ 1.60-1.72(m, 4H), 1.83-1.94(m, 4H), 3.52-3.65(m, 2H), 4.90(t, 7=5.2, 1H) , 5.12(d, 7=7.6, 1H) . 7.08-7.32(m, 3H)

Preparation example 158: (2S, 3R)-ethyl-3-(2,6-chlorophenyl)-l,4- clioxaspi ro[4 , 5J decane-2-carboxy1 ate

The substantially same method as described in Preparation example 154 was conducted, except that cyclohexanone was used instead of eye lopentanone . to obtain the title compound (2.2g, 70-95%).

¾ NMR (400MHz, DMSO) δ 1.30(t, 7=7.6, 3H), 1.61~1.69(m, 10H) , 4.08-4.18(d, ^' 2Η), 4.33(cl, 7=8.0, 1H) , 5.85(d, 7=8.0, 1H), 7.07~7.31(m, 3H) Preparation example 159: ((2R,3R)-3-(2,6-chlorophenyl)-l,4- dioxaspiro[4,5]decane-2-yl )methanol

The substantially same method as described in Preparation example 155 was conducted, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-l _> 4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 158) was used instead of (2S, 3R)-ethyl-3-(2,6-dichlorophenyl)-l,4-dioxaspiro[4,4]nonane- 2-carboxylate (Preparation example 154), to obtain the title compound(1.7g, 70-95%)

¾ NMR (400MHz, DMS0) : δ 1.63-1.75(m, 10H), 3.52~3.81(m, 2H), 3.95(t. 7=8.0, 1H), 5.43(d, J=7.6, 1H) , 7.05~7.30(m, 3H)

Preparation example 160: (2R, 3S)-ethyl-3-(2,6-chlorophenyl )-l,4- di oxaspi ro [4 , 5]decane-2-carboxyl ate

The substantially same method as described in Preparation example 156 was conducted, except that cyclohexanone was used instead of eye 1opentanone, to obtain the title compound (1.9g, 70-95%).

¾ NMR (400MHz, DMS0) δ 1.30(t, J=7.6, 3H), 1.61-1.69(m, 10H), 4.08-4.18(d, 2H), 4.33(d, .7=8.0, 1H), 5.85(cl, ,7=8.0, 1H) , 7.07~7.31(m, 3H)

Preparation example 161: ((2S,3S) ^_ 3-(2,6-chlorophenyl )-l,4- dioxaspi ro[4 , 5]decane-2-y1 )methano1

The substantially same method as described in Preparation example 159 was conducted, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl )-l ,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 160)was used instead of (2S, 3R)-ethyl-3-(2,6-dichlorophenyl)-l,4-dioxaspiro[4,5]decane- 2-carboxylate (Preparation example 158), to obtain the title compound (1.5g, 70-95%)

¾ NMR (400MHz, DMS0) : δ 1.63-1.75(m, 10H), 3.52~3.81(m, 2H), 3.95(t. 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.05~7.30(m, 3H)

Preparation example 162: (4S, 5R)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-l,3- cli oxo1 ane-4-carboxy late

The substantially same method as described in Preparation example 158 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the title compound (2.0g, 50~70%) .

¾ NMR (400MHz , DMSO) δ 1.30( t , 7=7.6 , 3H) , 4- .08-4.18(d . 2H) , 5.13(d , 7=8.0, 1H), 5.85(d, 7=8.0, 1H), 6.18(s, 1H) , 7.03~7.22(m, 8H)

Preparation example 163: ((4R,5R)-5-(2,6-chlorophenyl)-2-phenyl-l,3- dioxo 1 ane.-4-y1 )methano1

The substantially same method as described in Preparation example 159 was conducted, except that (4S, 5R)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-l,3- dioxolane-4-carboxylate (Preparation example 162) was used instead of (2S, RS)-ethyl-3-(2,6-dichlorophenyl )-l,4-clioxaspiro[4,5]decane-2-carboxylate (Preparation example 158), to obtain the title compound (1.6g, 70-95%) l NMR (400MHz, DMSO) : δ 3.50-3.79(m, 2H) , 5.13(d, J=8.0, 1H), 5.85(d, 7=8.0, 1H), 6.18(s, 1H), 7.03~7.22(m, 8H)

Preparation example 164 ^' · (4R, 5S)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-l,3- dioxo lane-4-carboxylate

The substantially same method as described in Preparation example 160 was conducted, except that benzaklehyde was used instead of cyclohexanone , to obtain the title compound (1.8g, 50-70%).

¾ NMR (400MHz, DMSO) δ 1.30(t, 7=7.6, 3H), 4.08-4.18(d. 2H), 5.13(d, 7=8.0, 1H), 5.85(d, 7=8.0, 1H), 6.18(s, 1H), 7.03 ^~ 7.22(m, 8H)

Preparation example 165: ( (4S.5S)-5-(2, 6-chloropheny1 )-2-pheny1-1,3- clioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 163 was conducted, except that (4R, 5S)-ethy1-5-(2, 6-chloropheny1 )-2-pheny1-1, 3- di oxolane-4-carboxylate (Preparation example 164) was used instead of (2S, 3R)-ethy1 -3-(2 , 6-chloropheny1 )-2-pheny1-1 , 3-di oxo1 ane-4- carboxylate(Preparat ion example 162), to obtain the title compound(1.4g. 70-95%)

¾ NMR (400MHz, DMSO): δ 3.50-3.79(m, 2H) , 5.13(d, 7=8.0, 1H), 5.85(d, 7=8.0, 1H), 6.18(s, 1H), 7.03~7.22(m, 8H)

Preparation example 166: ((4S,5R)-methyl-5-(2-nitrophenyl)-2-mehtyl-1.3- dioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 60 was conducted, except that (2S,3R)-methyl-3-(2-nitrophenyl)-2,3- dihydroxypropanoate (Preparation example 44) was used instead of (2S.3R)- methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound (2.3g, 70~95%).

lH NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H), 3.78(s, 3H), 4.30(d, .7=7.6, 1H), 5.07(m, 1H), 5.62(d, 7=7.6, 1H), 7.45-8.12 (m. 4H)

Preparation example 167: ((4R,5R)-5-(2-ni trophenyl)-2-mehtyl-1.3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 27 was conducted, except that (4S, 5R)-methyl -5-(2-nitropheny1 )-2-mehty1-1.3- dioxolane-4-carboxylate (Preparation example 166) was used instead of (4R , 5S)-methy1 -5-(2-ch1 oropheny1 )-2 , 2-dimehty1 -1.3-di oxo 1 ane-4-carboxylate (Preparation example 26), to obtain the title compound(1.9g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.37(d, 7=6.0, 3H), 3.62-3.70(m, 2H), 4.36(dd, .7=7.0, .7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H) , 7.47-8. ll(m, 4H) .

Preparation example 168: ((4R,5S)-methyl-5-(2-ni tropheny1 )-2-mehty1-1.3- cli oxo 1 ane-4-carboxy late

The substantially sarnie method as described in Preparation example 160 was conducted, except that (2R,3S)-methyl-3-(2-nitrophenyl)-2,3- dihydroxypropanoate(Preparation example 48)was used instead of (2S.3R)- methyl-3-(2-ni tropheny1 )-2,3-dihydroxypropanoate(Preparat ion exam le 44) , to obtain the title compound(2. Og, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) 6 1.36(d, J=6.4, 3H), 3.78(s, 3H), 4.30(d, 7-7.6, 1H), 5.07(m, 1H), 5.62(d, 7=7.6, 1H), 7.45-8.12 (m, 4H)

Preparation example 169 ^' · ((4S,5S)-5-(2-nitrophenyl)-2-mehtyl-1.3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 167 was conducted, except that (4R,5S)-methyl-5-(2-nitrophenyl)-2-mehtyl-1.3- dioxol ane-4-carboxylate (Preparation example 168)was used instead of (4S , 5R)-methy1-5-(2-ni tropheny1 )-2-mehty1-1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 166), to obtain the title compound(1.6g, 70-95%)

¾ NMR (400MHz, CDC13) : δ 1.37(d, .7=6.0, 3H), 3.62~3.70(m, 2H) , 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H), 7.47-8. ll(m, 4H).

Preparation example 170: (4S, 5R)-methyl-5-(2-ni tropheny1 )-2 , 2-cliehty1-1.3- dioxolane-4-carboxylate

The substantially same method as described in Preparation example 150 was conducted, except that (2S,3R)-methyl-3-(2-ni tropheny1 )-2,3- dihydroxypropanoate (Preparation example 44) was used instead of (2S,3R)- ethyl-3-(2,6-dichlorophenyl)-2,3-clihydroxypropanoate (Preparat ion example 39), to obtain the title compound (2.4g, 60-85%).

¾ NMR (400MHz, CDC13) δ 0.96(m, 6H), 1.59(m, 4H), 3.67(s, 3H), 5.11(d, 7=7.6, 1H), 5.81(d, 7=7.6, 1H) , 7.43-8.10(m, 4H) Preparation example 171: ((4R,5R)-5-(2-nitrophenyl)-2,2-diehtyl-1.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation example 167 was conducted, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-diehtyl-1.3- dioxolane-4-carboxylate (Preparation example 170) was used instead of (4S , 5R)-methy1 -5-(2-ni t ropheny1 )-2-mehty1 -1.3-di oxo1 ane-4-carboxylate (Preparation example 166), to obtain the title compound (1.9g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H), 1.59(m, 4H), 3.62~3.70(m, 2H), 4.36(dd, J=7.0, J=7.0, 1H) , 5.17(d, 7=7.0, 1H), 7.37~8.09(m, 4H)

Preparation example 172: (4R, 5S)-methyl-5-(2-nitrophenyl)-2,2-diehtyl-1.3- clioxo 1 ane-4-ca boxylate

The substantially same method as described in Preparation example 170 was conducted, except that (2R,3S)-methyl-3-(2-ni trophenyl )-2,3- dihydroxypropanoate(Preparat ion example 48)was used instead of (2S,3R)- methyl -3-(2-ni trophenyl )-2,3-dihydroxypropanoate(Preparat ion example 44) , to obtain the title compound (2.5g, 60-85%).

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H), 1.59(m, 4H), 3.67(s, 3H), 5.11(cl, 7=7.6, 1H), 5.81(cl, 7=7.6, 1H), 7.43-8.10(m, 4H)

Preparation example 173: ((4S,5S)-5-(2-nitrophenyl)-2,2-diehtyl-1.3- di oxo1 ane-4-y1 )methano 1

The substantially same method as described in Preparation example 171 was conducted, except that (4R,5S)-methyl-5-(2-nitrophenyl)-2, 2-diehtyl-l.3- dioxolane-4-carboxylate (Preparation example 172) was used instead of (4S , 5R)-methy1 -5-(2-ni t ropheny1 )-2 , 2-diehtyl-l .3-d i oxo1 ane-4- carboxylate(Preparat ion example 170), to obtain the title compound(2. Og, 70-95%)

^L H NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H) , 1.59(m, 4H) , 3.62~3.70(m, 2H), 4.36(dd, 7=7.0, 7=7.0, 1H) , 5.17(d, 7=7.0, 1H), 7.37~8.09(m, 4H)

Preparation example 174· ^' (2S, 3R)-methyl-3-(2-nitrophenyl)-l,4- dioxaspi ro[4 , 4]nonane-2-carboxy1 ate

The substantially same method as described in Preparation example 170 was conducted, except that eye 1opentanone was used instead of 3-pentanone, to obtain the title compound (2.5g, 70-95%) .

¾ NMR (400MHz, DMS0) δ 1.69-1.71(m, 4H) , 1.82-1.86(m, 4H), 3.68(s, 3H), 4.40(d, 7=7.2, 1H), 5.39(d, 7=7.2, 1H), 7.44~8.06(m, 4H)

Preparation example 175: ((2R,3R)-3-(2-nitrophenyl)-l,4- dioxaspi ro [4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 171 was conducted, except that (2S, 3R)-methyl-3-(2-nitrophenyl)-l,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 174) was used instead of (4S,5R)-methyl-5-(2-nitrophenyl )-2, 2-diehtyl-l.3-dioxolane-4- carboxylate(Preparat ion example 170), to obtain the title compound (2.1g, 70-95%)

¾ NMR (400MHz, DMS0): δ 1.60-1.72(m, 4H), 1.83-1.94-(m, 4H), 3.52~3.65(m, 2H), 4.90(t, 7=5.2, 1H), 5.12(d, /=7.6, 1H), 7.46~8.09(m, 4H)

Preparation example 176: (2R, 3S)-methyl-3-(2-ni trophenyl )-l ,4- dioxaspi ro[4 , 4]nonane-2-carboxylate

The substantially same method as described in Preparation example 172 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.9g, 70~95%) .

¾ NMR (400MHz, DMSO) δ 1.69-1.71(m, 4H), 1.82-1.86(m, 4H), 3.68(s, 3H), 4.40(d, J=7.2, 1H), 5.39(d, 7=7.2, 1H) , 7.44~8.06(m, 4H)

Preparation example 177: ((2S,3S)-3-(2-ni trophenyl )-l,4- clioxasp i ro[4 , 4]nonane ^_ 2-y1 )methano1

The substantially same method as described in Preparation example 175 was conducted, except that (2R, 3S)-methyl-3-(2-ni trophenyl. )-l ,4- dioxaspiro[4,4]nonane-2-carboxyla e (Preparation example 176) was used instead of (2S, 3R)-methyl-3-(2-nitrophenyl)-l,4-dioxaspiro[4,4]nonane-2- carboxylate(Preparat ion example 174), to obtain the title compound (2.0g, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.60-1.72(m, 4H), 1.83-1.94(m, 4H), 3.52~3.65(m, 2H), 4.90(t, -7=5.2, 1H), 5.12(d, 7=7.6, 1H), 7.46~8.09(m, 4H)

Preparation example 178: (2S, 3R)-methyl-3-(2-ni trophenyl)-1,4- dioxaspiro[4,5]decane-2-carboxylate

The substantially same method as described in Preparation example 174 was conducted, except that cyclohexanone was used instead of eye 1opent anone , to obtain the title compound (1.7g, 70-95%).

¾ NM (400MHz, DMS0) δ 1.61-1.69(m, 10H) , 3.79(s, 3H) , 4.33(d, .7=8.0, 1H), 5.85(d, 7=8.0, 1H), 7.45-8.12(m, 4H)

Preparation example 179: ( (2R,3R)-3-(2^ni trophenyl -l ,4- di oxasp i ro [4 , 5J decane-2-y1 )methano 1

The substantially same method as described in Preparation example 175 was conducted, except that (2S, 3R)-methyl-3-(2 ^~ ni trophenyl )-l, 4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 178) was used instead of (2S, 3R)-methyl-3-(2-ni trophenyl )-l,4-dioxaspiro[4,4]nonane-2- carboxylate (Preparation example 174), to obtain the title compound (1.4g, 70-95%) lH NMR (400MHz, DMS0) : δ 1.63-1.75(m, 10H), 3.52-3.81 (m, 2H) , 3.95(t, 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.46-8.09(m, 4H)

Preparation example 180: (2R, 3S)-methyl-3-(2-nitrophenyl)-l,4- dioxas i ro[4 , 5jdecane-2-carboxylate

The substantially same method as described in Preparation example 176 was conducted, except that cyclohexanone was used instead of eye lopent anone, to obtain the title compound (2.2g, 70~95%).

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H) , 3.79(s, 3H) , 4.33(d, J=8.0, 1H), 5.85(d, .7=8.0, 1H), 7.45-8.12(m, 4H)

Preparation example 181: ((2S,3S)-3-(2-nitrophenyl)-l,4- dioxaspi ro[4 , 5]decane-2-y1 )methano 1

The substantially same method as described in Preparation example .179 was conducted, except that (2R, 3S)-niethyl-3-(2-ni trophenyl )-l,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 180) was used instead of (2S, 3R)-methyl-3-(2-nitrophenyl)-l,4-dioxaspiro[4,5]decane-2- carboxylate(Preparat ion example 178), to obtain the title compound( 1.5g, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.63-1.75(m, 10H), 3.52~3.81(m, 2H), 3.95(t, J=8.0, 1H),. 5.43(d, 7=7.6, 1H), 7.19~7.49(m, 4H)

Preparation example 182: (4S, 5R)-methyl-5-(2-ni trophenyl )-2-phenyl-l, 3- dioxo 1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 178 was conducted, except that benzaklehyde was used instead of cyclohexaiione, to obtain the title compound (1.9g, 50-70%).

¾ NMR (400MHz, DMSO) 63.67(s, 3H), 5.11(d, 7=8.0, 1H), 5.81(d, 7=8.0, 1H), 6.18(s, 1H), 6.96-8.12(m, 9H)

Preparation example 183: ((4R,5R)-5-(2-nitrophenyl)-2-phenyl-l,3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 179 was conducted, except that (4S, 5R)-methyl-5-(2-ni trophenyl )-2-pheny 1-1 ,3- dioxolane-4-carboxylate(Preparat ion example 182)was used instead of (2S, 3R)-methy1 -3-(2-ni t ropheny1 )-1 , 4-di oxaspi ro [ , 4] nonane-2- carboxylate(Preparat ion example 174), to obtain the title compound(1.5g, 70-95%)

¾ NMR (400MHz, DMS0) : δ 3.66(d. J=7.6, 2H), 4.36(m, 1H) . 5.17(d, .7=8.0, 1H), 6.1S(s, 1H), 7.06-8.14(m, 9H)

Preparation example 184: (4R, 5S)-methy1-5-(2-ni trophenyl)-2-phenyl -1,3- di oxolane-4-carboxylate

The substantially same method as described in Preparation example 180 was conducted, except benzaldehyde that was used instead of cyclohexanone, to obtain the title compound (1.8g, 50-70%).

¾ NMR (400MHz, DMS0) 63.67(s, 3H), 5.11(d, 7=8.0, 1H), 5.81(d, J=8.0, 1H), 6.18(s, 1H), 6.96-8.12(m, 9H)

Preparat i on exam 1e 185 : ( (4S , 5S)-5-(2-ni t ropheny1 )-2-pheny1 -1 , 3-d i oxo 1 ane- 4-yl )methanol

The substantially same method as described in Preparation example 18.3 was conducted, except that (4R, 5S)-methyl -5-(2-ni trophenyl )-2-phenyl-l ,3- dioxolane-4-carboxylate(Preparat ion example 184)was used instead of (2S, 3R)-methy 1-3-( 2-ni t ropheny1 )-2-pheny1 -1 , 3 ^~ di oxo1 ane-4- carboxyl ate(Preparat ion example 182), to obtain the title compound ( 1.3g , 70-95%)

¾ NMR (400MHz, DMS0) : δ 3.66(d, J=7.6, 2H). 4.36(m, 1H) , 5.17(d, J=8.0, 1H), 6.18(s, 1H), 7.06-8.14(m, 9H)

Preparat ion example 186■ ^" (4S, 5R)-methyl-5-(2-methylphenyl )—2—methyl—1.3- di oxol ane-4-carboxy1 ate

The substantially same method as described in Preparation example 60 was conducted. except that (2S,3R)-methyl-3-(2-methylphenyl)-2,3- dihydroxypropanoate(Preparat ion example 54) was used instead of (2S,8R)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the t i t le. compound(2. lg, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H), 2.35(s, 3H), 3.68(s, 3H) , 5.07(m, 1H), 5.11(d, 7=7.6, 1H), 5.82(d, 7=7.6, 1H) , 7.19-7.39 (m, 4H)

Preparation example 187 ^' · ((4R,5R)-5-(2-methylphenyl)-2-methyl-l,3clioxolane- 4-yl )methanol

The substan ially same method as described in Preparation example 185 was conducted, except that (4S,5R)-methyl-5-(2-methylphenyl)-2-mehtyl-1.3- dioxolane-4-carboxylate(Preparat ion example 186) was used instead of (2R, 3S)-methy1-3-(2-ni tropheny1 )-2-pheny1 -1 , 3-dioxo1 ane-4- carboxylate(Preparat ion example 184), to obtain the title compound (1.7g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.37(d, J=6.0, 3H), 3.62~3.70(m, 2H) , 4.36(clcl, J=7.0, J=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H) , 7.17~7.41(m, 4H).

Preparation example 188: (4R,5S)-methyl-5-(2-methylphenyl )-2-methy1-1.3- dioxolane-4-carbox late

The substantially same method as described in Preparation example 186 was conducted, except that (2R, 3S)-methyl-3-(2-methylphenyl )-2 ,3- clihyclroxypropanoate(Preparat ion example 57) was used instead of (2S,3R)- methy1-3-(2-methylphenyl )-2,3-dihydroxypropanoate(Preparat ion example 54) , to obtain the title compound (1.8g, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(cl, 7=6.4, 3H), 2.35(s, 3H), 3.68(s, 3H), 5.07(m, 1H), 5.11(d, 7=7.6, 1H), 5.82(d, 7=7.6, 1H), 7.19-7.39 (m, 4H)

Preparat i on examp1 e 189 : ( (4S, 5S)-5-(2-methy1 heny1 )-2-methy1-1.3-dioxo 1 ane- 4-yl )methanol

The substantially same method as described in Preparation example 187 was conducted, except that (4R,5S)-methyl-5-(2-methylphenyl )-2-mehty1-1.3- clioxolane-4-carboxylate (Preparation example 188)was used instead of (4S , 5R)-methy1 -5-(2-methy1 heny1 )-2-mehty1 -1.3-dioxo1 ane ^~ 4- carboxylate(Preparation example 186), to obtain the title compound(1.6g, 70-95%)

^L H NMR (400MHz, CDC1 ₃ ): δ 1.37(d, 7=6.0, 3H) , 3.62-3.70(m, 2H), 4.36(dd, 7=7.0, J=7.0, 1H), 5.06(m, 1H) , 5.17(d, 7=7.0, 1H) , 7.17 7.41(m, 4H).

Preparation example 190: (4S, 5R)-methyl-5-(2-methylphenyl)-2,2-diethyl-1.3- di oxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 170 was conducted, except that (2S,3R)-methyl-3-(2-methylphenyl )-2,3- clihydroxypropanoate(Preparat ion example 54) was used instead of (2S,3R) ^~ methyl-3-(2-ni trophenyl )-2,3-dihydroxypropanoate (Preparation example 44) , to obtain the title compound (2.1g, 60-85%).

Hi NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H), 1.59(m, 4H), 2.33(s, 1H) , 3.67(s, 3H), 5.11(d, 7=7.6, 1H), 5.81(d, 7=7.6, 1H), 7.00-7.17(m, 4H)

Preparation example 191: ((4R,5R)-5-(2-methylphenyl)-2,2-diethyl-1.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation example 187 was conducted, except that (4S,5R)-methyl-5-(2-methylphenyl)-2,2-diehtyl-l,3- dioxolane-4-carboxylate(Preparat ion example 190) was used instead of (4S,5R)-methyl-5-(2-methylphenyl )-2-mehtyl-1.3-dioxolane-4- carboxylate(Preparat ion example 186), to obtain the title compound (1.7g, 70-95%) lH NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H) , 1.59(m, 4H) , 2.37(s, 3H) , 3.62 ^~ 3.70(m, 2H) , 4.36(dd, 7=7.0, 7=7.0, 1H), 5.17(cl, 7=7.0, 1H), 7.15-7.39(m, 4H)

Preparation example 192: (4R, 5S)-methyl-5-(2-methy.phen l )-2,2-diethyl-1.3- dioxo1ane-4-carboxy1 ate

The substantially same method as described in Preparation example 190 was conducted, except that (2R,3S) ^~ methyl-3-(2-methylphenyl )-2,8- dihydroxypropanoate(Preparat ion example 57) was used instead of (2S,3R)- methy1 -3-(2-methyl henyl )-2,3-dihydroxypropanoate(Preparat ion example 54) , to obtain the title compound (2.2g, 60-85%).

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H), 1.59(m, 4H) , 2.33(s, 1H), 3.67(s, 3H), 5. lKcl, 7=7.6, 1H), 5.81(d, J=7.6, 1H), 7.00-7.17(m, 4H)

Preparat ion examp1e 193 : ( (4S , 5S)-5-(2-methy1pheny1 )-2 , 2-di ethy -1.3- clioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 191 was conducted, except that (4R,5S)-methyl-5-(2-methylphenyl)-2,2-diehtyl-1.3- dioxolane-4-carboxylate(Preparat ion example 192) was used instead of (4S, 5R)-methy1-5-(2-methy1phenyl )-2 , 2-diehty1-1.3-dioxo 1 ane-4- carboxylate(Preparat ion example 190), to obtain the title compound (1.8g, 70-95%) ¾ NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H), 1.59(m, 4H) , 2.37(s, 3H), 3.62~3.70(m, 2H), 4.36(dd, 7=7.0, 7=7.0, 1H), 5.17(d, 7=7.0, 1H) , 7.15-7.39(m, 4H)

Preparation example 194 ^' · (2S, 3R)-methyl-3-(2-methylphenyl.)-l ,4- dioxas i ro[4 , 4]nonane-2-carboxy1 ate

The substantially same method as described in Preparation example 190 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.1g, 70-95%).

¾ NMR (400MHz, DMS0) δ 1.49-1.57(m, 4H). 1.72~1.81(m, 4H) , 2.35(s, 3H), 3.68(s, 3H). 5.14(d, .7=7.2, 1H), 5.89(d, J=7.2. 1H), 7.02~7.25(m, 4H)

Preparation example 195: ((2R,3R)-3-(2-methylphenyl)-l,4- dioxaspiro[4,4]nonane-2-yl )methanol

The substantially same method as described in Preparation example 191 was conducted, except that (2S, 3R)-methyl-3-(2-methyl henyl )-l ,4- dioxaspiro[4,4]nonane-2-carboxylate(Preparation example 194) was used instead of (4S , 5R)-metby 1 -5-(2-methy1pheny1 )-2 , 2-di ehty1 -1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 190), to obtain the title compound(1.6g, 70~95%)

¾ NMR (400MHz, DMS0): δ 1.49-1.57(m, 4H) , 1.72-1.81(m, 4H) , 2.35(s. 3H), 3.52~3.65(m, 2H) , 4.90(t, 7=5.2, 1H), 5.12(cl, J=7.6, 1H), 7.02~7.25(m, 4H)

Preparation example 196: (2R, 3S)-methyl-3-(2-meth 1 phenyl )-l ,4- di oxasp i ro [4 , 4]nonane-2-carboxylate

The substantially same method as described in Preparation example 192 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.5g, 70-95%). ¾ NMR (400MHz, D SO) δ 1.49-1.57(m, 4H), 1.72-1.81(m, 411), 2.35(s, 3.68(s, 3H), 5.14(cl, 7=7.2, 1H), 5.89(cl, J=7.2, 1H), 7.02~7.25(m, 4H)

Preparation example 197: ((2S,3S)-3-(2-methylphenyl)-l,4- dioxaspiro[4,4]nonane-2-yl )methanol

The substantial ly _. same method as described in Preparation example 195 was conducted, except that (2R, 3S)-methyl -3-(2-methylphenyl )-l,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 196) was used instead of (2S, 3R)-methyl-3-(2-methylphenyl)-l,4-dioxaspiro[4,4]nonane-2- carboxyl ate(Preparat ion example 194), to obtain the title compound(2. Og, 70-95%)

¾ NMR (400MHz, DMSO): δ 1.49-1.57(m, 4H) , 1.72~1.81(m, 4H), 2.35(s, 3H), 3.52~3.65(m, 2H), 4.90(t, .7=5.2, 1H) , 5.12(d, J=7.6, 1H), 7.02~7.25(m, 4H)

Preparation example 198: (2S, 3R)-methyl-3-(2-methyl henyl )-l ,4- cli oxaspi ro[4 , 5]decane-2-carboxylate

The substantially same method as described in Preparation example 194 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (1.8g, 70-95%).

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H) , 2.34(s, 3H) , 3.79(s, 3H) , 4.33(d, J=8.0, 1H), 5.85(d, 7=8.0, 1H) , 7.01~7.30(m, 4H)

Preparation example 199: ((2 ,3 )-3-(2-methylphenyl)-l,4- dioxaspi ro[4 , 5J decane-2-y1 )methano1

The substantially same method as described in Preparation example 195 was conducted, except that (2S, 3R)-methyl-3-(2-methyl henyl )-l ,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 198) was used instead of (2S, 3R)-methyl-3-(2-methylphenyl)-l,4-dioxaspiro[4,4]nonane-2- carboxylate (Preparation example 194), to obtain the title compound (1.5g, 70-95%)

¾ NMR (400MHz, DMS0): δ 1.63-1.75(m, 10H), 2.33(s, 3H), 3.52~3.81(m, 2H), 3.95(t, J=8.0, 1H), 5.43(cl, J=7.6, 1H) , 7.02~7.28(m, 4H)

Preparation example 200: (2R, 3S)-methyl-3-(2-methylphenyl )-l ,4- dioxaspiro[4, 5]decane-2-carboxylate

The substantially same method as described in Preparation example 196 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(2.2g, 70-95%).

¾ NMR (400MHz, DMS0) δ 1.61-1.69(m, 10H) , 2.34(s, 3H), 3.79(s, 3H), 4.33(cl, 7=8.0, Hi), 5.85(d, 7=8.0, 1H), 7.01~7.30(m, 4H)

Preparation example 201: ((2S,3S)-3-(2-methylphenyl)-l,4- dioxaspi ro[4 , 5]decane-2-y1 )methano1

The substantially same method as described in Preparation example 199 was conducted, except that (2R, 3S)-methyl-3-(2-methylphenyl )-l ,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 200) was used instead of (2S, 3R)-methyl-3-(2-methylphenyl )-l ,4-dioxaspiro[4, 5]decane-2- carboxylate (Preparation example 198), to obtain the title compound (1.5g, 70-95%)

T NMR (400MHz, DMS0): δ 1.63-1.75(m, 10H) . 2.33(s. 3H), 3.52-3.81(m, 2H) , 3.95(t, 7=8.0, 1H), 5.43(d, J=7.6, 1H) , 7.02-7.28(m, 4H)

Preparation example 202: (4S, 5R)-methyl-5-(2-methylphenyl )-2-pheny1-1,3- dioxo1 ane-4-c-arboxylate

The substantially same method as described in Preparation example 198 was conducted, except that benzaldehyde was used instead of cyclohexanone. to obtain the title compound (2.2g, 50-70%).

¾ NMR (400MHz, DMS0) 62.33(s, 3H) , 3.67(s, 3H) , 5.11(d, J=8.0, 1H), 5.81(d, 7=8.0, 1H), 6.18(s, 1H), 6.96~7.32(m, 9H)

Preparation example 203: ((4R,5R)-5-(2-methylphenyl)-2-phenyl-l,3-dioxolane- 4-yl )me hanol

The substantially same method as described in Preparation example 199 was conducted, except that (4S, 5R)-methyl-5-(2-methy1 heny1 )-2-pheny1-1, 3- di oxo lane-4-carboxylate (Preparation example 202)was used instead of (2S, 3R)-methy1 -3-(2-methy1pheny1 )-1 , 4-di oxaspi ro[4, 5]decane-2- carboxylate(Preparat ion example 198), to obtain the title compound(1.6g. 70-95%)

^L H NMR (400MHz, D S0) : 62.32(s, 3H) , 3.66(d, J=7.6, 2H) , 4.36(m, 1H), 5.17(d, 7-8.0, 1H), 6.18(s, 1H), 6.99~7.33(m, 9H) Preparation example 204: (4R, 5S)-methyl-5-(2-methylphenyl)-2-phenyl-l,3- dioxo1ane-4-carboxylate

The substantially same method as described in Preparation example 200 was conducted, except benzaldehyde that was used instead of cyclohexanone , to obtain the title compound (1.9g, 50~70 ) .

¾ NMR (400MHz, DMSO) 52.33(s, 3H) , 3.67(s, 3H) , 5.11(d, J=8.0, 1H), 5.81(d, J=8.0, 1H), 6.18(s, 1H), 6.96 ^~ 7.32(m, 9H)

Prepa at ion examp1e 205 ^' · ( (4S , 5S)-5-(2-methy1pheny1 )-2-pheny1-1 , 3-dioxo1ane- 4-yl )methanol

The substantially same method as described in Preparation example 203 was conducted, except that (4R, 5S)-methyl-5-(2-methylphenyl)-2-phenyl-l,3- dioxolane-4-carboxylate (Preparation example 204) was used instead of (4-S, 5 )-methy1-5-(2-methy1pheny1 )-2-pheny1-1 , 3-di oxo1 ane-4-carboxylate

(Preparation example 202), to obtain the title compound (1.3g, 70~95%)

¾ NMR (400MHz, DMSO) ^' - 52.32(s, 3H), 3.66(d, J=7.6, 2H), 4.36(m, 1H), 5.17(d, J=8.0, 1H), 6.18(s, 1H), 6.99~7.33(m, 9H)

Preparation example 206 ^' · ((4R,5R)-5-(2-aminophenyl)-2-mehtyl-1.3-dioxolane- 4-yl ) ethanol

The substantially same method as described in Preparation example 47 was conduc ed, except that ( (4R, 5R)-5-(2-ni t opheny1 )-2-mehtyl-l .3 ^~ dioxolane-4- yOmethanoKPreparation example 167) was used instead of ((4R,5R)-5-(2- ni tropheny1 )-2,2-dimehtyl-1.3-dioxolane-4-yl )methanol (Preparat ion example 46), to obtain the title compound (1.5g, 65-85%)

¾ NMR (400MHz, CDC1 ₃ ): δ 1.37(d, 7=6.0, 3H), 3.62~3.70(m, 2H) , 4.36(dd, 7=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H) , 7.57~8.08(m, 4H) .

Preparation example 207: ((4S,5S)-5-(2-aminophenyl)-2-mehtyl-1.3-dioxolane- 4-y1 )methanol.

The substantially same method as described in Preparation example 47 was conducted, except that ((4S,5S)-5-(2-ni trophenyl )-2-mehtyl-1.3-dioxolane-4- yl )methanol (Preparat ion example 169) was used instead of ((4R,5R)-5-(2- ni tropheny1 )-2 , 2-dimehty1-1.3-dioxo1 ane-4-y1 )methano1 (P eparat i on exam 1 e 46), to obtain the title compound(1. lg, 65~85%)

¾ NMR (400MHz, CDC1 ₃ ): 6 1.37(d, 7=6.0, 3H), 3.62~3.70(m, 2H)

7=7.0, 7=7.0, 1H), 5.06(ni, 1H) , 5.17(d, 7=7.0. 1H) , 7.57~8.08(m,

Preparation example 208 ^' · ((4R,5R)-5-(2-aminohenyl)-2,2-diehtyl-1.3- dioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 47 was conducted, except that ((4R,5R)-5-(2-nitrophenyl)-2,2-cliehtyl-1.3- dioxolane-4-yl )methanol (Preparat ion example 171) was used instead of ( ( R, 5R)-5-(2-ni trophen 1 )-2 , 2-dimehty1-1.3-di oxo1 ane-4- yDmethanol (Preparat ion example 46), to obtain the title compound (1

65-85%)

¾ NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H), 1.59(m, 4H) , 3.62-3.70(in, 4.36(dd, 7=7.0, 7=7.0, 1H) , 5.17(d, J=7.0, 1H), 7.55~8.09(m, 4H)

Preparation example 209: ((4S,5S)-5-(2-aminophenyl)-2,2-diehtyl-1.3- dioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 47 was conducted, except that ((4S.5S)-5-(2-nitrophenyl)-2,2-diehtyl-1.3- dioxolane-4-yl )methanol (Preparat ion example 173) was used instead of ( (4R , 5R)-5-(2-ni tropheny1 )-2 , 2-dimehty 1 -1.3-di oxo 1 ane-4-y1 )methano 1

(Preparation example 46), to obtain the title compound(1.4g, 65-85%)

¾ NMR (400MHz, CDC1 ₃ ): δ 0.96(m, 6H) , 1.59(m, 4H), 3.62-3.70(m , 2H), 4.36(dd, J=7.0, 7=7.0, 1H), 5.17(cl, 7=7.0, 1H) , 7.55~8.09(m, 4H)

Preparation example 210 ^' · ( (2R,3R)-3-(2-aminophenyl )-l ,4- dioxaspi ro[ , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 47 was conducted, except that ((4R,5R)-5-(2-ni ropheny1 )-l,4- dioxaspiro[4,4]nonane-2-yl )methanol (Preparat ion example 175) was used instead of C(4R,5R)-5-(2-nitrophenyl)-2,2-dimehtyl-1.3-dioxolane-4- yOmethanol (Preparat ion example 46), to obtain the title compound (1.7g, 65-85%)

¾ NMR (400MHz, DMS0): δ 1.62-1.73(m, 4H), 1.82-1.95(m, 4H), 3.52~3.65(m, 2H), 4.90(t, 7=5.2, 1H), 5.12(d, 7=7.6, 1H), 7.56~8. ll(m, 4H) Preparation example 211: ((2S,3S)-3-(2-aminophenyI)-l,4- dioxaspi ro[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 47 was conducted, except that ((4S,5S)-5-(2-nitrophenyl)-l,4- clioxaspiro[4,4]nonane-2-yl )methanol (Preparation example 177) was used instead of ( (4 , 5R)-5-(2-ni tropheny1 )-2 , 2-dimehty1-1.3-di oxo1 ane-4- yl )methanol (Preparation example 46), to obtain the title compound(1.6g, 65-85%)

lH NMR (400MHz, DMS0): δ 1.62-1.73(m, 4H) , 1.82~1.95(m, 4H) , 3.52~3.65(m, 2H), 4.90(t, 7=5.2, 1H), 5.12(d, 7=7.6, 1H), 7.56-8. ll(ni, 4H)

Preparation example 212: ( (2R,3R)-3 _. -(2-aminophenyl )-l ,4- clioxaspiro[4,5]decane-2-yl )methanol

The substantially same method as described in Preparation example 47 was conducted, except that ((4R,5R)-5-(2-ni trophenyl )-l, 4- dioxaspiro[4,5]decane-2-yl)methanol (Preparation example 179) was used instead of ( (4R,5R) ^~ 5-(2-ni trophenyl )-2, 2-dimehtyl-l.3-di oxo l ane-4- yOmethanol (Preparation example 46), to obtain the title compound( 1. lg, 65-85%)

¾ NMR (400MHz, DMS0): δ 1.61-1.75(m, 10H), 3.52~3.81(m, 2H), 3.95(t, 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.49-8.12(m, 4H)

Preparation example 213· ^' ( (2S , 3S)-3-(2-ami nopheny1 )-1 , 4- clioxaspi ro [4 ,5] decane-2-y1 )methano1

The substantially same method as described in Preparation example 47 was conducted, except that ((4S,5S)-5-(2-nitrophenyl)-l,4- dioxaspiro[4, 5]decane ^~ 2-yl )methanol (Preparat ion example 181) was used instead of ( (4R,5R)-5-(2-ni trophenyl )-2,2-climehtyl-1.3-dioxolane-4- yOmethanol (Preparation example 46), to obtain the title compound(l.Og, 65-85%)

¾ NMR (400MHz, DMSO): δ 1.61-1.75(m, 10H) , 3.52~3.81(m, 2H), 3.95(t, 7=8.0, 1H), 5.43(d, .7=7.6, 1H), 7.49-8.12(m, 4H)

Preparat ion example 214: ((4R,5R)-5-(2-aminophenyl )-2-phenyl-l,3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 47 was conducted, except that ((4R,5R)-5-(2-nitrophenyl)-2-phenyl-l,3-dioxolaue-4- yl )methanol (Preparat ion example 183) was used instead of ((4R,5R)-5-(2- ni t ropheny1 )-2 , 2-dimehty1-1.3-di oxol ane-4-y1 )methanol (Preparat i on examp 1 e 46), to obtain the title compound (1.2g, 65-85%)

¾ NMR (400MHz, DMSO): δ 3.66(d, J=7.6, 2H) , 4,36(m, 1H), 5.17(d, .7=8.0, 1H), 6.18(s, 1H), 7.06-8.14(m, 9H)

Preparation example 215: ((4S,5S)-5-(2-aminophenyl )-2-phenyl-l,3-clioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 47 was conducted, except that ((4S,5S)-5-(2-nitrophenyl)-2-phenyl-l,3-dioxolane-4- yOmethanol (Preparation example 185) was used instead of ( (4R, 5R)-5-(2- ni trophenyl 2-dimehtyl-l .3-dioxolane-4-yl )methanol (Preparation example 46), to obtain the title compound(0.9g, 65~85%)

¾ NMR (400MHz, DMSO) : δ 3.66(d, J=7.6, 2H), 4.36(m, 1H) , 5.17(cl, .7=8.0, 1H), 6.18(s, 1H), 7.06-8.14(m, 9H)

Preparation example 216: (E)-Methyl cinnamate

To a round-bottomed flask, frazs-cinnamic acid (7g, 47.25mmol) and MeOH (70mL) were added. POC I 3 (0.43mL, 4.73mmol) was added dropwise. The reaction mixture was stirred under reflux for 3h. The reaction mixture was cooled to room temperature, quenched with IN NaOH solution. The mixture was extracted by EtOAc and washed with ¾0. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgS0 ₄ ), filtered and concentrated under vacuum (7.1g, 80-95%) ¾ NMR (400MHz, CDC13) : 63.81(s. 3H), 6.42(d, J=15.9, 1H). 7.37-7.39(111, 3H), 7.50~7.53(m, 2H) , 7.67(d, J=15.9, 1H)

Preparation example 217: (2S, 3R)-methyl-3-phenyl-2,3-clihydroxypropanoate

The substantially same method as described in Preparation example 36 was conducted, except that (E)-Methyl cinnamate (Preparation example 216) was used instead of (E)-methyl-3-(2,4-dichlorophenyl )acrylate (Preparation example 28), to obtain the title compound(6.2g, 70~95%)

H NMR (400MHz, CDC1 ₃ ) ^' - δ 2.70(bs, 1H), 3.08(bs, 1H), 3.82(s, 3H), 4.38(d, J=2.9, 1H), 5.03(d, J=2.9, 1H) , 7.30~ 7.42(m, 5H)

Preparation example 218: (4S, 5R)-methy1-2, 2—dimethyl-5-pheny1-1,3- dioxo1ane-4-carboxylate

The substantially same method as described in Preparation example 45 was conducted, except that (2S, 3R)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation example 217) was used instead of (2S, 3R)-methy1-3-(2- ni trophenyl )-2,3-dihydroxypropanoate (Preparation example 44), to obtain the title compound (5.6g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ) · ^" 61.56(s, 3H), 1.61(s, 3H), 3.79(s, 3H), 4.36(d, .1=7.8, 1H), 5.17(d, J=7.8, 1H). 7.31~7.40(m, 5H)

Preparation example 219 ^' · ((4R, 5R)-5-pheny1-2, 2-dimethyl-1, 3-dioxo1ane-4- yOmethanol

The substantially same method as described in Preparation example 46 was conducted, except that (4S, 5R)-methyl-2,2-dimethyl-5-phenyl-l,3-dioxolane-

4-carboxylate(Preparat ion example 218) was used instead of (4S, 5R)-niethyl-

5-(2-ni trophenyl )-l ,3-dioxolane-4--carboxylate (Preparation example 45), to obtain the title compound(4.4g, 70~95 )

Ή NMR (400MHz, CDC1 ₃ ): 61.41(s, 3H) , 1.46(s, 3H), 2.79(bs, 1H) , 3.48~3.52(m, 1H) . 3.68~3.76(m, 2H) , 4.76(cl, J=8.8, 1H), 7.18~7.28(m, 5H)

Preparation example 220: (2R, 3S)-methyl-3-phenyl-2,3-dihydroxypropanoate

The substantially same method as described in Preparation example 30 was conducted, except that (E)-Methyl cinnamate (Preparation example 216) was used instead of (E)-methyl-3-(2,4-dichlorophenyl )acrylate(Preparat ion example 28), to obtain the title compound(8.6g, 70-95%)

¾ NM (400MHz, CDC1 ₃ ): δ 2.70(bs, 1H) , 3.08(bs, 1H) , 3.82(s, 3H), 4.38(d, J=2.9, 1H), 5.03(d, J=2.9, 1H) , 7.30- 7.42(m, 5H)

Preparation example 221: (4R, 5S)-methyl-2,2-dimethyl-5-phenyl-l,3- cli oxo 1 ane-4-carboxylate

The substantially same method as described in Preparation example 45 was conducted, except , that (2S, 3R)-methy1-3-pheny1-2,3- dihyclroxypropanoate(Preparat ion example 217) was used instead of (2S, 3R) ^~ methyl -3-(2-ni rophenyl ) ^~ 2,3-dihydroxypropanoate (Preparation example 44), to obtain the title compound(5.6g, 70-95%)

^] H NMR (400MHz, CDC1 ₃ V- 51.56(s, 3H), 1.61(s, 3H), 3.79(s, 3H), 4.36(cl, J=7.8, IH), 5.17(d, J=7.8, 1H), 7.31~7.40(m, 5H)

Preparation example 222: ((4S, 5S)-5-phenyl-2,2-dimethyl-l,3-dioxolane-4- yl )methanol

The substantially same method as described in Preparation example 46 was conducted, except that (4R, 5S)-methyl-2,2-dimethyl-5-phenyl-1.3-dioxolane- 4-carboxylate(Preparat ion example 221) was used instead of (4S, 5R)-methyl- 5-(2-ni trophenyl )-l , 3-d i oxo lane-4-carboxy1 ate(Preparat ion example 45) , to obtain the title compound(6.5g, 70~95%) Ή NMR (400MHz, CDC13) : 51.41(s, 3H), 1.46(s, 3H) , 2.79(bs, 1H), 3.48-3.52(m, 1H) , 3.68~3.76(m, 2H) , 4.76(d, J=8.8, 1H), 7.18-7.28(m, 5H)

Preparation example 223: (4S, 5R)-methyl-2,2-cliethyl-5-phenyl-l,3-dioxolane- 4-carboxylate

The substantially same method as described in Preparation example 190 was conducted, except that (2S, 3R)-methyl-3-phenyl-2,3- dihydroxypropanoate(Preparat ion example 217) was used instead of (2S, 3R) ^~ methyl-3-(2-methylphenyl)-2,3-dihyclroxypropanoate (Preparation example 54), to obtain the title compound(1.9g, 70-95%)

¾ NMR (400MHz, CDCI3) : 5=1.01(t, J=7.4, 1H), 1.06(t, .1=7.6, 3H), 1.78~1.90(m, 4H), 3.78(s, 3H) , 5.12(d, J=8.4, 1H) , 7.32~7.45(m, 5H)

Preparation example 224: ((4R. 5R)-5-pheny1-2, 2-di ethyl -1, 3-dioxolane-4- yDmethanol

The substantially same method as described in Preparation example 219 was conducted, except that (4S, 5R)-methyl-2,2-diethyl-5-phenyl-l,3-dioxolane- 4-carboxylate (Preparation example 223) was used instead of (4S, 5R)- methy1-2 , 2-dimethy1-5-pheny1-1 , 3-dioxo1 ane-4-carboxy1 ate(Preparat ion example 218), to obtain the title compound(1.3g, 70-95%)

¾ NMR (400MHz, CDC13) : 5=1.00(t, J=7.6, 1H), 1.06(t, J=7.4, 1H), 1.74~1.90(m, 4H), 3.64(ddd, J=3.4, 8.4, 12.1, 1H), 3.84~3.91(m, 2H), 4.89(d, J=8.8, 1H), 7.30~7.43(m, 5H)

Preparation example 225· ^' (4R, 5S)-methyl-2,2-diethyl-5-phenyl-l,3-dioxolane- 4-carboxylate

The substantially same method as described in Preparation example 223 was conducted, except that (2R, 3S)-methy1-3-pheny 1-2, 3- dihydroxypropanoate(Preparat ion example 220)was used instead of (2S, 3R)- methy1-3-pheny1-2 ,3-dihydroxypropanoate(Preparat ion example 217), to obtain the title compound(5.6g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) : 5=1.01(t, J=7.4, 1H), 1.06(t, J=7.6, 3H), 1.78-1.90(m, 4H) , 3.78(s, 3H), 5.12(d, J=8.4, 1H), 7.32~7.45(m, 5H)

Preparation example 226: ((4S, 5S)-5-phenyl-2,2-dimethyl.-l,3-dioxolane-4- yl )methanol

The substantially same method as described in Preparation example 224 was conducted, except that (4R, 5S)-methyl-2,2-dimethyl-5-phenyl-l,3-dioxolane- 4-carboxylate (Preparation example 225) was used instead of (4S, 5R)- methy 1-2 , 2-dimethy1-5-pheny 1-1 , 3-di oxo 1 ane-4-carboxy 1 ate(Preparat i on example 218), to obtain the title compound(6.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) · ^' 6=1.00(t, J=7.6, 1H), 1.06(t, .1=7.4, 1H), 1.74-1.90(m, 4H) , 3.64(ddd, J=3.4, 8.4, 12.1, 1H), 3.84~3.91(m, 2H) , 4.89(d, J=8.8, 1H), 7.30-7.43(m, 5H)

Preparation example 227: (2S, 3R)-methyl-3-phenyl-l,4-dioxapiro[4,4]nonane- 2-carboxylate

The substantially same method as described in Preparation example 223 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (0.9g, 50~75%)

¾ NMR (400MHz, CDCI3) : δ =1.71-1.80(m, 4H), 1.87-1.94(m, 1H), 2.00~2.08(m, 3H) , 3.79(s, 3H), 4.35(d, J=7.2, 1H) , 5.08(d, J=7.2, 1H), 7.32~7.45(m, -5H)

Preparation example 228: ((2R, 3R)-3-phenyl-l,4-dioxapiro[4,4]nonan-2- yOmethanol

The substantially same method as described in Preparation example 224 was conducted, except that (2S, 3R)-methyl-3-phenyl-l,4-dioxapiro[4,4]nonane-2- carboxylate (Preparation example 227) was used instead of (4S, 5R)-methyl ^~ 2,2-diethyl-5-phenyl-l,3-dioxolane ^~ 4-carboxylate (Preparation example 223) , to obtain the ti le compound (0.7g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) ^' - δ =1.69-1.82(m, 4H) , 1.85~2.03(m, 4H), 3.66(ddd, J=3.7, 8.1, 12.1, 1H), 3.83~3.90(m, 2H), 4.84(d, J=8.4, 1H), 7.26~7.41(m, 5H)

Preparation example 229: (2R, 3S)-methyl-3-phenyl-l,4-dioxapiro[4,4jnonane- 2-carboxylate

The substantially same method as described in Preparation example 225 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (0.8g, 50-75%)

¾ NMR (400MHz, CDC13) : δ =1.71-1.80(m, 4H), 1.87-1.94(m, 1H), 2.00~2.08(m, 3H), 3.79(s, 3H), 4.35(d, J=7.2, 1H) , 5.08(d, J=7.2, 1H), 7.32-7.45(m, 5H) Preparation example 230: ((2S, 3S)-3-phenyl-l,4-dioxapiro[4,4]nonan-2- yl )methanol

The substantially same method as described in Preparation example 228 was conducted, except that (2R, 3S)-methyl-3-phenyl-l,4-dioxa iro[4,4]nonane-2- carboxylate (Preparation example 229) was used instead (2S, 3Rmethyl-3- phenyl-l,4-dioxapiro[4,4]nonane-2-carboxylate (Preparation example 227), to obtain the title compound(0.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.69-1.82(m, 4H) , 1.85-2.03(m, 4H), 3.66(ddd, J=3.7, 8.1, 12.1, 1H), 3.83~3.90(m, 2H), 4.84(d, J=8.4, 1H), 7.26~7.41(m,

5H)

Preparation example 231 ^' - (2S,3R)-methyl 3-phenyl-l,4-dioxapiro[4,5]decane-2- carboxyl te

The substantially same method as described in Preparation example 227 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (1.4g, 50~75%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.41-1.49(m, 2H), 1.58-1.76(m, 4H) , 1.79~1.90(m, 4H), 3.78(s, 3H), 4.36(cl, J=7.6, 1H), 5.16(d, J=7.2, 1H), 7.31~7.44(m, 5H)

Preparation example 232: ((2R, 3R)-3-phenyl-l,4-dioxapiro[4.5]decan-2- yl )methanol

The substantially same method as described in Preparation example 224 was conducted, except that (2S, 3 )-methyl 3-phenyl-l,4-clioxapiro[4,5]clecane-2- carboxylate (Preparation example 231) was used instead of (4S, 5R)-methyl- 2 , 2-d i ethy1 -5-pheny1 -1 , 3-d i oxo 1 ane-4-carboxy1 at e(Preparat i on examp 1 e 223) , to obtain the title coinpounclO.Og, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.41-1.50(m, 2H) , 1.61-1.89(m, 8H), 3.60~3.66(m, 1H) , 3.85~3.90(m, 2H), 4.91(d, J=8.4, 1H), 7.30~7.42(m, 5H)

Preparation example 233: (2R, 3S)-methyl-3-phenyl-l,4-dioxapiro[4,5]decane- 2-carboxylate

The substantially same method as described in Preparation example 229 was conducted, except that cyclohexanone was used instead of cyclope anone, to obtain the itle compound (1.2g, 50~75%) ¾ NMR (400MHz, CDC1 ₃ ) · ^' δ =1.41-1.49(m, 2H) , 1.58-1.76(m, 4H), 1.79~1.90(m, 4H), 3.78(s, 3H) , 4.36(cl, J=7.6, 1H), 5.16(d, J=7.2, 1H), 7.31~7.44(m, 5H)

Preparation example 234: ((2S, 3S)-3-phenyl-l,4-clioxapiro[4,5]decane-2- yDmethanol

The substantially same method as described in Preparation example 232 was conducted, except that (2R, 3S)-methyl-3-phenyl-l,4-dioxapiro[4,5]decane-2- carboxylate(Preparat ion example 233) was used instead of (2S, 3R)-methyl-3- phenyl-l,4-dioxapiro[4,5]decane-2-carboxylate (Preparation example 231), to obtain the title compound (0.8g, 70-95%) lH NMR (400MHz, CDC1 ₃ > · δ =1.41-1.50(m, 2H), 1.61~1.89(m, 8H), 3.60~3.66(iii, 1H) , 3.85-3.90(m , 2H) , 4.91(d, J=8.4, 1H) . 7.30~7.42(m, 5H) Preparation example 235: (E)-5-phenyl ent-3-enoic acid

A solution of maIonic acid (17.06g, 163.96mmol) in DMSO (65mL) was treated with a solution of AcOH (O.lmL, 1.49mmol) and piperidine (0.15mL, 1.49mmol) in DMSO (4mL) . The reaction solution was warmed to 65 ^° C and hydrocinnamaldehyde (lOg, 74.53mmol) was added dropwise within 1.5hr. After the addition ended, the reaction mixture was stirred for further 2h at 65 ^° C . The solution was cooled to room temperature, taken up in ¾0 and extracted with Et20 ^' . The combined organic extracts were washed with 5% aqueous KHS0 ₄ and brine, dried over MgS0 ₄ , and evaporated to dryness. The crude compound was purified by a silica gel column to produce the title compound (10.4g, 75-90%)

¾ NMR (400MHz, CDC1 ₃ ): 5=3.19(d, J=6.9, 2H) , 3.46(d, J= 6.9, 2H) , 5.69~5.78(m, 1H), 5.83~5.91(m, 1H) , 7.01~7.56(m, 5H) , 11.79(s, 1H)

Preparation example 236: (E)-5-phenylpent

To stirred solution of LAH (LiA1H ₄ . 3.3g, 86.73mmol) in THF(66mL) was added dropwise a solution (E)-5-phenylpent-3-enoic acid (Preparation example 235, 11. Og, 57.82mmol) in THF(44tnL) at 0 ^° C then stirred at room temperature for lh. The reaction mixture was quenched with ¾0 at 0 ^° C , filtered through celite, washed with EtOAc, dried over anhydrous magnesium sulfate (MgS0 ) , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (7.2g, 70-90%)

¾ NMR (400MHz, CDC1 ₃ ) · 6=1.40 (bs, 1H) , 2.31(q, J=6.3, 2H) , 3.37(d, J=6.8, 2H), 3.66(t, J=6.4, 2H), 5.49(dt, J=4.9, 11.0, 1H), 5.73(dt, J=4.8, 10.9, 1H), 7.17-7.31 (m, 5H)

Preparat ion example 237: (E)-1er t-buty1dimethy1 (5-pheny1 ent-3- enyloxy)si 1

To a stirred solution of (E)-5-phenylpent-3-en-l-ol (Preparat ion example 236, 6.3g, 38.83mmo 1 ) in CH2C I 2 was added imidazole (3.4g, 50.48mmo 1 ) and TBDMS-C1 (7.6g, 50.48mmol) at 0 ^° C then stirred for lh at room temperature. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSOz filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (10.6g, 80-98%)

¾ NMR (400MHz, CDC 13) : 5=0.00(s, 6H) , 0.84(s, 9H) , 2.21(ddd, J=6.8, 13.6, 0.8, 2H), 3.29(d, J=6.8, 2H), 3.59(t, J=6.8, 2H), 5.41~5.49(m, 1H), 5.56~5.63(m, 1H) , 7.13~7.26(m, 5H)

Preparation example 238: (E)-5-phenylpent-3 ^~ enyl pivalate

To a stirred solution of (E)-5-phenylpent-3-en-l-ol (Preparat ion example 236, 3.8g, 23.42mmol) 111 CH ₂ C1 ₂ (40mL) was added pyridine (2.3mL, 28.1mmol) and pivaloyl chloride (3.5mL, 28.1mmol) at 0 ^° C under N . The mixture was stirred for 14h. The resulting mixture was diluted with CH2CI2, washed with, water, dried over MgS0 ₄ , filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (5.5g, 80-95%)

¾ NMR (400MHz, CDCI3) ^: 5=1.17(s, 9H), 2.36(q, J=6.7, 2H) , 3.34(d, .1=6.8, 2H), 4.09U, J=6.8, 2H), 5.45~5.51(m, 1H), 5.64~5.69(m, 1H), 7.16-7.21(m.

3H), 7.26~7.30(m, 2H)

Preparation example 239 ^' · (2S,3S)-5-(tert-butyldimethylsi lyloxy)-l- pheny1pentane-2 , 3-di 01

The substantially same method as described in Preparation example 217 was conducted, except that (E)-tert-butyldimethyl (5~phenylpent-3- enyloxy)si lane(Preparat ion example 237) was used instead of (E)-Methyl cinnamate (Preparation example 216), to obtain the title compound(8.7g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=0.00(s, 6H), 0.82(s, 9H), 1.57-1.62(m, 1H), 1.73~1.80(m, 1H), 2.51(cl, J=6.0, 1H), 2.77(dq, J=6.9, 14.9, 2H), 3.50(d, J=3.6, 1H), 3.59-3.62(m, 1H) , 3.66(dq, J=3.1, 5.4, 1H), 3.72~3.82(m, 2H), 7.12~7.25(ni, 5H)

Preparation example 240: (2-((4S,5S)-5-benzyl-2,2-dimethyl-l,3-dioxola.ne-4- yl )ethoxy)(tert-butyl)climethylsi lane

The substantially same method as described in Preparation example 218 was conducted, except that (2S,3S)-5-(tert-butyldimethylsi lyloxy)-l- pheny1 ent ane ^~ 2,3-diol (Preparation example 239) was used instead of (2R, 3S)-methyl-3-phenyl-2,3-dihydroxypropanoate(Preparation example 217), to obtain the title compound(9.5g, 70-95%)

lH NMR (400MHz, CDC1 ₃ ) ^' - 5=0.00(s, 6H), 0.85(s, 9H), 1.29(s, 3H) , 1.34(s, 3H), 1.52~1.58(m, 2H) , 2.87(dq, J=5.5, 14.2, 2H), 3.64~3.69(m, 2H), 3.80~3.88(m, 2H) , 7.18~7.27(m, 5H)

Preparation example 241: 2-((4S,5S)-5-benzyl-2,2-dimethyl-l,3-dioxolane-4- yl )ethanol

To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-cIimethyl-l,3-dioxolan- 4-yl )ethoxy)(tert-butyl )dimethylsi lane (Preparation example 240, 11.5g, 32.80mniol) in THF (115inL) was slowly added tetrabutyl ammonium fluoride (TBAF, 1.0M in THF, 48.8mL, 48.8mmol) at room temperature. The mixture was stirred for 5h. The resulting mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (7.3g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.38(s, 3H), 1.40(s, 3H), 1.50-1.63(m, 2H), 2.29(t, J=5.4, 1H), 2.82(dd, J=5.8, 13.8, 1H), 3.01(dd, J=6.4, 14.0, 1H), 3.72(q, J=5.5, 2H), 3.86(dt, J=3.2, 8.4, 1H), 3.92~3.97(m, 1H), 7.22~7.32(m, 5H)

Preparation example 242: (2R,3R)-5-(tert-butyldimethylsi lyloxy)-l- pheny1 entane-2 , 3-dio1

The substantially same method as described in Preparation example 220 was conducted, except that (E)-tert-butyldimethyl (5-phenyl ent-3- enyloxy)si lane(Preparat ion example 237) was used instead of (E)-Methyl cinnamate (Preparation example 216), to obtain the title compound( 10.6g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=0.00(s, 6H), 0.82(s, 9H) , 1.57~1.62(m, 1H), 1.73~1.80(m, 1H), 2.51(d, J=6.0, 1H) , 2.77(dq, J=6.9, 14.9, 2H), 3.50(d, J=3.6. 1H), 3.59~3.62(m, 1H) . 3.66(dq, J=3.1, 5.4, 1H) , 3.72~3.82(m, 2H), 7.12~7.25(m, 5H)

Preparation example 243: (2-((4R,5R)-5-benzyl-2,2-dimethyl-l,3-dioxolane-4- yl )ethoxy)(tert-butyl )dimethylsi lane

The substantially same method as described in Preparation example 221 was conducted, except that (2R,3R)-5-(tert-butyldimethylsi lyloxy)-l- pheny1pentane-2, 3-diol (Preparation example 242) was used instead of (2R, 3S)-methyl-3-phenyl-2,3-dihydroxypropanoate(Preparat ion example 217) , to obtain the title compound(11.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) 5=0.00(s, 6H), 0.85(s, 9H) , 1.29(s, 3H), 1.34(s, 3H), 1.52 ^~ 1..58(m, 2H), 2.87(clq, .1=5.5, 14.2, 2H) , 3.64~3.69(m, 2H), 3.80~3.88(m, 2H), 7.18~7.27(m, 5H) Preparation example 244: 2-((4R,5R)-5-benzy1-2, 2-dimethy1-1, 3-dioxo lane-4- yl )ethanol

The substantially same method as described in Preparation example 241 was conducted, except that (2-((4R,5R)-5-benzyl-2,2-dimethyl-l,3-dioxolan-4- yl )ethoxy)(tert-butyl Mimethylsi lane(Preparat ion example 243) was used instead of (2-((4S, 5S)-5-benzy1-2, 2-dimethy1-1, 3-dioxo lan-4- yl )ethoxy) ( tert-butyl Mimethylsi lane(Preparat ion example 240), to obtain the title compound(7.4g, 80-95%)

¾ NMR (400MHz, CDC13) · ^' 6=1.38(s, 3H), 1.40(s, 3H) , 1.50-1.63(m, 2H), 2.29(t, J=5.4, 1H), 2.82(dd, J=5.8, 13.8, 1H), 3.01(dcl, J=6.4, 14.0, 1H), 3.72(q, J=5.5, 2H) , 3.86(dt, J=3.2, 8.4, 1H), 3.92~3.97(m, 1H), 7.22~7.32(m.

5H)

Preparation example 245: (3S,4S)-3,4-dihydroxy-5-phenylpentyl pivalate

The substantially same method as described in Preparation example 239 was conducted, except that (E)-5-phenylpent-3-enyl pivalate (Preparation example 238) was used instead of (E)-ter t-butyldimethyl (5-phenylpent-3- enyloxy)si lane(Preparat ion example 237), to obtain the title compound(5.5g, 70-95%)

lH NMR (400MHz. CDC1 ₃ )- ^" 6=1.16(s, 9H) , 1.83-1.88(m, 2H) , 2.08(d, J=4.8, 1H), 2.67(d, .1=5.2, 1H), 2.80(dd, J=8.0, 13.6, 1H), 2.92(dd, J=5.2, 13.6, 1H), 3.50~3.55(m, 1H), 3.66~3.71(m, 1H), 4.09-4.19(m, 1H), 4.35 ^~ 4.41(m, 1H), 7.22~7.25(m, 3H), 7.29~7.33(m, 2H)

Preparation example 246· ^' (2-((4S,5S)-5-benzyl-2,2-diethyl-l,3-dioxolane-4- yDethyl pivalate

The substantially same method as described in Preparation example 22,3 was conducted, except that (3S,4S)-3,4-dihydroxy-5-phenylpentyl pivalate(Preparat ion example 245) was used instead of (2R, 3S)-methyl-3- phenyl -2, 3-dihydr.oxypropanoate(Preparat ion example 217), to obtain the title compound(0.9g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.15(s, 9H) , 1.76(q, J=7.6, 2H) , 1.84-1.90(m, 2H), 2.00~2.07(m, 2H), 3.85(dt, J=3.7, 8.5, 1H) , 4.14~4.27(m, 2H), 5.17(d, J=8.4, 1H), 7.22~7.28(m, 1H), 7.32~7.38(m, 2H), 7.64(dd, J=1.4, 7.8, 1H)

Preparat ion example 247: 2-((4S,5S)-5-benzyl-2,2-diethyl-l,3-dioxolane-4- yl )ethanol

To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-diethyl-l,3-dioxolan-4- yDethyl pivalate(Preparat ion example 246, l.Og, 2.87mmol) in MeOH(lOmL) was added NaOMe (0.47g, 8.61mmol) and then warm to 45 ^° C. The mixture was stirred for 14h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgS04, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (0.7g, 80~95%);

¾ NMR (400MHz, CDC1 ₃ ) ^" · 6=0.89(t, J=7.4, 6H) , 1.44~1.50(m, 1H), 1.54~1.66(m, 5H), 2.37(t, J=5.6, 1H), 2.80(dd, J=5.6, 14.0, 1H). 3.03(dd, J=6.4, 14.0, 1H), 3.72(q, J=5.5, 2H), 3.80~3.85(m, 1H), 3.89~3.94(m, 1H), 7.21 ^~ 7.24(m, 3H), 7.28-7.31(m, 2H).

Preparation example 248: (3R,4R)-3,4-dihydroxy-5-phenylpentyl pivalate The substantially same method as described in Preparation example 242 was conducted, except that (E)-5-phenylpent-3-enyl pivalate (Preparation example 238). was used instead of (E)-tert-butyldimethyl (5-phenyl ent-3- enyloxy)si lane (Preparation example 237), to obtain the title compound (4.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.16(s, 9H), 1.83-1.88(m, 2H), 2.08(d, J=4.8, 1H), 2.67(cl, J=5.2, 1H) , 2.80(dd, J=8.0. 13.6, 1H), 2.92(dd, J=5.2, 13.6, 1H), 3.50-3.55(m, 1H), 3.66~3.71(m, 1H), 4.09-4.19(m, 1H), 4.35~4.41(m, 1H) , 7.22~7.25(m, 3H) , 7.29-7.33(m, 2H)

Preparation example 249: (2-((4R, 5R)-5-benzyl-2,2-diethyl-l,3-dioxolane-4- y ethyl pivalate

The substantially same method as described in Preparation example 246 was conducted, except that (3R,4R)-3,4-dihydroxy-5-phenyl entyl pivalate(Preparation example 248) was used instead of (3S,4S)-3,4- dihydroxy-5-phenyl entyl pivalate (Preparation example 245), to obtain the title compound(l.lg, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.15(s, 9H) , 1.76(q, J=7.6, 2H), 1.84-1.90(m, 2H), 2.00~2.07(m, 2H), 3.85(dt, J=3.7, 8.5, 1H), 4,14~4.27(m, 2H), 5.17(d, J=8.4, 1H), 7.22~7.28(m, 1H), 7.32~7.38(m, 2H) , 7.64(dd, .1=1.4, 7.8, 1H)

Preparation example 250: 2-((4R, 5R)-5-benzyl-2,2-diethyl-l,3-dioxolcine-4- yl )ethanol

The substantially same method as described in Preparation example 247 was conducted, except that (2-( (4R,5R)-5-benzy1-2, 2-cli ethyl -1,3-di oxo lan-4- yDethyl pivalateCPreparat ion example 249) was used instead of (2-((4S,5S)- 5-benzyl-2 , 2-diethyl-l ,3-dioxolan-4-yl )ethyl pivalate(Preparat ion example 246), to obtain the title compound (0.9g, 80~95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=0.89(t, J=7.4, 6H), 1.44-1.50(m, 1H), 1.54 ^~ 1.66(m, 5H), 2.37(t, J=5.6, 1H), 2.80(dd, J=5.6, 14.0, 1H) , 3.08(dd, J=6.4, 14.0, 1H), 3.72(q, J=5.5, 2H) , 3.80~3.85(m, 1H) , 3.89~3.94(m, 1H), 7.21~7.24(m, 3H) , 7.28~7.31(m, 2H)

Preparation example 251: 2-((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.4]nonane-2- yDethyl pivalate

The substantially same method as described in Preparation example 246 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (1.2g, 60~85%)

¾ NMR (400MHz, CDCI3) : 6=1.18(s, 9H), 1.53~1.80(m, 10H) , 2.81(dd, .1=6.0, 13.6, 1H), 3.00(dd, J=6.4, 14.0, 1H), 3.75~3.80(m, 1H), 3.84~3.89(m, 1H), 4.05-4.16(m, 2H) , 7.20~7.24(m, 3H) , 7.27~7.31(m, 2H)

Preparation example 252: 2-((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.4]nonane-2- yl jethanol

The substantially same method as described in Preparation example 247 was conducted, except that 2-((2S,3S)-3-benzyl-l,4-dioxaspiro[4.4]nonan-2- yDethyl pivalate (Preparation example 251) was used instead of (2- ( (4S , 5S)-5-benzy1-2 , 2-cli ethyl—1 , 3-di oxo1 an-4-y1 )ethy1 piva1 ate (Preparation example 246), to obtain the title compound (0.7g, 80~95%)

¾ NMR (400MHz, CDCI3) : δ =1.44-1.51(m, 1H), 1.56~1.60(m, 1H), 1.63~1.70(m, 4H), 1.72~1.81(m, 4H) , 2.26(t, J=5.4, 1H), 2.80(dd, J=6.0, 14.0, 1H), 3.03(dd, J=6.4, 14.0, 1H) , 3.71(q, J=5.5, 2H) , 3.81~3.92(m, 2H) , 7.22~7.24(m, 3H), 7.28-7.32(m, 2H) Preparation example 253: 2-((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.4]nonane-2- yDethyl pivalate

The substantially same method as described in Preparation example 249 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (1.7g, 60~85%)

¾ NMR (400MHz,- CDC1 ₃ ): 5=1.18(s, 9H), 1.53-1.80(m, 10H) , 2.81(dd, J=6.0, 13.6, 1H), 3.00(dd, J=6.4, 14.0, 1H) , 3.75~3.80(m, 1H) , 3.84~3.89(m. 1H) , 4.05-4.16(m, 2H), 7.20~7.24(m, 3H) , 7.27~7.31(m, 2H)

Preparation example 254: 2-((2R, 3R)-3-benzyl-l,4-clioxaspiro[4.4]nonane-2- yl )ethanol

The substantially same method as described in Preparation example 252 was conducted, except that 2-((2R,3R)-3-benzyl-l,4 ^~ dioxaspiro[4.4]nonan-2- yOethyl pivalate (Preparation example 253) was used instead of 2-((2S,3S) ^~ 3-benzyl-l,4-dioxaspiro[4.4]nonan-2-yl )ethyl pivalate (Preparation example 251), to obtain the title compound (0.8g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ) · ^' δ =1.44-1.51(m, 1H), 1.56-1.60(m, 1H) , 1.63~1.70(m, 4H), 1.72~1.81(m, 4H) , 2.26(t, J=5.4, 1H), 2.80(dd, J=6.0, 14.0, 1H), 3.03(dcl, J=6.4, 14.0, 1H), 3.71(q, J=5.5, 2H), 3.81~3.92(m, 2H) , 7.22~7.24(m, 3H) , 7.28~7.32(m, 2H)

Preparation example 255· ^' 2-((2S, 3S)-3 ^~ benzyl-l,4-dioxaspiro[4.5]decane-2- yOethyl pivalate

The substantially same method as described in Preparation example 251 was conducted, except that cyclohexanone was used instead of cyclopetanone , to obtain the title compound (1.4g, 60~85 )

¾ NMR (400MHz, CDC1 ₃ ): 6=1.18(s, 9H), 1.53~1.60(m, 10H), 1.61-1.66(m, 2H), 2.83(dd, J=5.6. 14.0, 1H) , 2.98(dcl, J=6.0, 14.0, 1H), 3.78(dt, J=3.5, 8.2, 1H), 3.86~3.91(m, 1H), 4.11-4.15(m , 2H), 7.20~7.31(m, 5H)

Preparation example 256: 2-((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.5]decane-2- yDethanol

The substantially same method as described in Preparation example 254 was conducted, except that 2-((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.5]decan-2- y Dethyl pivalate (Preparation example 255) was used instead of 2-((2R,3R)- 3-benzyl-l,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 253), to obtain the title compound (l.Og, 80-95%)

lH NMR (400MHz, CDC1 ₃ ): δ =1.34-1.43(m, 2H) , 1.48~l,61(m, 10H) , 2.42(t, J=5.6 , 1H), 2.81(dd, J=5.6, 14.0, 1H), 3.02(dcl , J=6.2, 13.8, 1H) , 3.72(q, J=5.5, 2H), 3.82 ^~ 3.87(m, 1H) , 3.91~3.96(m, 1H), 7.21~7.31(m. 5H)

Preparation example 257: 2-((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.5]c1ecane-2- yDethyl ivalate

The substantially same method as described in Preparation example 253 was conducted, except that cyclohexanone was used instead of cyclope anone, to obtain the title compound ( 1.6g , 60-85%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.18(s, 9H) , 1.53-1.60(m, 10H) , 1.61-1.66(m, 2H), 2.83(dd, J=5.6, 14.0, 1H), 2.98(dd, J=6.0, 14.0, 1H) , 3.78(dt, J=3.5, 8.2, 1H), 3.86~3.91(m, 1H), 4.11~4.15(m, 2H), 7.20~7.31(m, 5H)

Preparation example 258: 2-((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.5]decane-2- yDethanol

The substantially same method as described in Preparation example 256 was conducted, except that 2-((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.5]decan-2- yOethyl pivalate (Preparation example 257) was used instead of 2-((2S, 3S)-3-benzy1-1 , 4 ^{^} -di oxaspi ro [4.5] decan-2-y1 )ethy1 pi va1 ate (Prepara ion example 255), to obtain the title compound (l.lg, 80 ^~ 95%)

¾ NMR (400MHz, CDC13) : 6 =1.34-1.43(m, 2H), 1.48~1.61(m, 10H), 2.42(t, J=5.6, 1H), 2.81(dd, J=5.6, 14.0, 1H), 3.02(dd, J=6.2, 13.8, 1H), 3.72(q, J=5.5, 2H), 3.82~3.87(m, 1H) , 3.91~3.96(m, 1H), 7.21~7.31(m, 5H)

Preparation example 259: (E)-methyl-4-phenylbut-2-enoate

To a solution of phenyl acetaldehyde (5.0g, 41.61mmol) in toluene (500mL) was added methyl (tr iphenylphosphorany1 idene) acetate (13.9g, 41.61mmol). The reaction mixture was stirred at reflux for 3 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgS0 ₄ , filtered, and concentrated under reduced pressure. The crude product was added ether/hexane(=l ^' -l, v/v) at 0 ^° C then stirred for 30min. The filtrate was concentrated then purified by a silica gel column to produce the title compound (5.9g, 70-90%)

¾ NMR (400MHz, CDC13) : 5=3.47(d, J=6.8, 2H) , 3.67(s, 3H), 5.79(d. J=15.4, 1H), 7.06(dt, J=15.4, 6.8, 1H), 7.28-7.12(m, 5H) Preparation example 260· ^' (2R, 3S)-methyl 2,3-dihydroxy-4-phenylbutanoate

The substantially same method as described in Preparation example 245 was conducted, except that (E)-methyl-4-phenylbut-2-enoate(Preparat ion example 259) was used instead of (E)-5-phenylpent-3-enyl pivalate(Preparat ion example 238), to obtain the title compound(3.5g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=2.96(ddd, .1=7.3, 13.5, 17.1, 2H), 3.10(d, J=5.2, 1H), 3.80(s, 3H), 4.08(dd, J=1.4, 5.4, 1H) , 7.23~7.34(m, 5H)

Pre arat i on exam 1 e 261 : (4R , 5S)-methy1-5-benzy1-2 , 2-dimethyl-1 , 3-d i oxo1 ane 4-carboxylate

The substantially same method as described in Preparation example 240 was conducted, except that (2R, 3S)-methyl 2,3-dihydroxy-4- phenyl butanoateCPreparat ion example 260) was used instead of (2S,3S)-5- ( t ert-buty1 dimeth 1 s i 1y Ioxy)-1-phen 1pent ane-2 , 3-di o 1 (Preparat i on examp 1 e 239), to obtain the title compouncl(3. lg, 70-95%)

¾ NMR (400MHz, CDC 13) : 6=1.42(s, 3H) , 1.43(s, 3H) , 3.01(dd, J=6.8, 14.4, IH), 3.12(dd, J=4.4, 14.4, 1H) , 3.72(s, 3H) , 4.19(d, J=7.6, 1H), 4.40(ddd, J=4.4, 7.0, 7.8, 1H), 7.22~7.33(m, 5H)

Preparation example 262- ^' ((4S, 5S)-5-benzyl-2,2-climethyl-l,3-dioxolan-4- yDmethanol

The substantially same method as described in Preparation example 234 was conducted, except that (4-R, 5S)-methyl 5-benzy1-2, 2-dime thy I-1, 3-di oxo lane- 4-carboxylate(Preparat ion example 261) was used instead of (4S, 5R)-methyl- 3-phenyl-l,4-dioxapiro[4,5]decane-2-carboxylate (Preparation example 233) , to obtain the title compound(2.3g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.41(s, 6H), 1.79(q, J=4.3, 1H), 2.83(dd, J=6.2, 13.8, 1H), 3.07(dd, J=6.4, 14.0, 1H), 3.29(ddd, J=4.7, 7.5, 12.1, 1H), 3.54(ddd, J=2.8, 5.2, 12.0, 1H), 3.83(ddd, J=3.9. 3.9, 7.1, 1H), 4.15(q, J=7.1, 1H), 7.22~7.32(m, 5H)

Preparation example 263: (4R,5S)-methyl-5-benzyl-2,2-diethyl-l,3-dioxolane- 4-carboxylate

To a stirred solution of (2R, 3S)-methyl 2,3-dihydroxy-4- phenylbutanoate(Preparat ion example 260, 2.0g, 9.51mmol) in 3-pentanone (5mL, 47.55mmol) was added a catalytic amount of H ₂ SO ₄ (0.051mL, 0.951mmol) at room temperature. The mixture was stirred for 20h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgS0 ₄ , filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (1.2g, 50-75%)

4-1 NMR (400MHz, CDC13) : 5=0.85(t, J=6.0, 3H), 0.92(t, J=7.6, 3H) , 1.66(dq, J=7.6, 14.7, 4H), 3.01(dcl, J=6.6, 14.2, 1H) , 3.10(dd, J=4.4, 14.4, 1H), 3.71(s, 3H), 4.17(d, J=8.4, 1H), 4.32~4.37(m, 1H) , 7.23~7.32(m, 5H)

Preparation example 264· ^' ((4S, 5S)-5-benzy1-2, 2-di ethyl-1, 3-d i oxol an-4- yl )methanol

The substantially same method as described in Preparation example 262 was conducted, except that (4R,5S)-methyl-5-benzyl-2,2-dimethyl-l ,3-dioxolane-

4-carboxylate (Preparation example 263) was used instead of (4R,5S)-methyl

5-benzy 1-2 , 2-dimethy1-1 , 3—d i oxol ane-4-carboxy1 ate(Preparat i on exanipl e 261 ) , to obtain the title compound(0.8g, 70-95%) H NMR (400MHz, CDC1 ₃ ): 6=0.91(dt, J=1.9, 7.5, 6H) , 1.61-1.68( 111 , 4H),

1.77(t, J=6.2, 1H), 2.81(dd, J=6.4, 14.0, 1H), 3.09(dd, J=6.2, 13.8, 1H),

3.24 ^~ 3.30(m, 1H) , 3.49~3.54(m, 1H), 3.78~3.82(m, 1H) , 4.08-4.13(m, 1H), 7.21~7.32(m, 5H)

Preparation example 265: (2R, 3S)-methyl 3-benzyl-l,4-dioxaspiro[4.4]nonane- 2-carbox late

The substantially same method as described in Preparation example 263 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (1.3g, 60~85%)

¾ NMR (400MHz, CDC13) : δ =1.61-1.79(m, 5H), 1.85~1.92(m, 3H), 3.00~3.11(m, 2H), 3.70(s, 3H) , 4.17(d, J=7.2, 1H) , 4.32 (dt, J=4.9, 7.0, 1H), 7.21-7.33(m, 5H)

Preparation example 266· ^' ((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.4.|nonane-2- yl )methanol

The substantially same method as described in Preparation example 264 was conducted, except that (2R, 3S)-methyl 3-benzyl-l,4-dioxaspiro[4.4]nonane- 2-carboxylate (Preparation example 265) was used instead of (4R,5S)-methyl- 5-benzyl-2,2-dimethyl-l,3-dioxolane-4-carboxylate(Preparat ion example 263) , to obtain the title compound (0.8g, 70~95%)

¾ NMR (400MHz, CDC13) : δ =1.57-1.88(m, 8H) , 2.82(dd, J=6.6, 13.8, 1H) , 3.08(dcl, J=6.4, 14.0, 1H), 3.27~3.33(m, 1H), 3.47~3.52(m, 1H), 3.79-3.83(m, 1H), 4.07(c|, J=6.8, 1H), 7.21~7.32(m, 5H)

Preparation example 267: (2R,3S)-methyl-3-benzyl-l,4-dioxaspiro[4.5]decane- 2-carboxylate

The substantially same method as described in Preparation example 265 was conducted, except that cyclohexanone was used instead of cyclopetanone , to obtain the title compound (1.5g, 60~85%)

¾ NM (400MHz, CDC1 ₃ ): δ =1.54-1.74(m, 10H), 2.99-3.12(m, 2H) , 3.70(s, 3H), 4.18(d, J=7.6, 1H) , 4.36~4.41(m, 1H) , 7.21~7.32(m, 5H)

Preparation example 268: ((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.4]decan-2- yOmethanol

The substantially same method as described in Preparation example 266 was conducted, except that (2R, 3S)-methyl-3-benzyl-l,4-dioxaspiro[4.5jdecane- 2-carboxylate (Preparation example 267) was used instead of (2R, 3S)-methyl 3-benzyl-l,4-dioxaspiro[4.4]nonane-2-carboxylate (Preparation example 265), to obtain the title compound (0.8g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.53-1.65(m, 10H) , 2.82(dd, 3=6.2, 13.8, 1H) , 3.07(dd, J=6.4, 13.6, 1H), 3.24~3.30(m, 1H), 3.52~3.56(m, 1H), 3.80~3.84(m, 1H), 4.10~4.15(m, 1H), 7.21~7.31(m, 5H)

Preparation example 269: (2S, 3R)-methyl-2,3-dihydroxy-4-phenylbutanoate

The substantially same method as described in Preparation example 242 was conducted, except that (E)-methyl-4-phenylbut-2-enoate(Preparat ion example 259) was used instead of (E)-tert-butyldimethyl (5-phenylpent-3- enyloxy)si lane(Preparat ion example 237), to obtain the title compound(3.5g, 70-95%)

Ή NMR (400MHz, CDC1 ₃ ): δ =2.96(ddd, J=7.3, 13.5, 17.1, 2H), 3.10(d, J=5.2, 1H), 3.80(s, 3H), 4.08(dd, 3=1 A, 5.4, 1H), 7.23~7.34(m, 5H)

Preparation example 270: (4S, 5R)-methyl-5-benzyl-2,2-dimethyI-l,3- d i oxo1 ane-4-c rboxylate

The substantially same method as described in Preparation example 261 was conducted, except that (2S, 3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation example 269) was used instead of (2R, 3S)-methyl 2,3- dihydroxy-4-phenylbutanoate (Preparation example 260), to obtain the title compound(3.4g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.41(s. 6H) , 1.79(q, J=4.3, 1H), 2.83(dd, J=6.2, 13.8, 1H), 3.07(dd, J=6.4, 14.0, 1H), 3.29(dd.cl, J=4.7, 7.5, 12.1, 1H), 3.54(ddcl, J=2.8, 5.2, 12.0, 1H), 3.83(ddd, J=3.9, 3.9, 7.1, 1H), 4.15(q, J=7.1, 1H), 7.22~7.32(m, 5H)

Preparation example 271: ((4R, 5R)-5-benzyl-2,2-dimethyl-l,3-dioxolan-4- yOmethanol

The substantially same method as described in Preparation example 262 was conducted, except that (4S, 5R)-methyl-5 ^~ benz l-2 , 2-dimethy1-1 ,3-di oxo lane-

4-carboxylate (Preparation example 270) was used instead of (4R, 5S)-iiiethyi

5-benzyl-2,2-dimethyl-l,3-dioxolane-4-carboxylate(Prepara t ion example 261) , to obt in the title compound (2.7g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.41(s. 6H), 1.79(q, .1=4.3, 1H), 2.83(dd, J=6.2, 13.8, 1H), 3.07(dd, J=6.4, 14.0, 1H), 3.29(ddd, J=4.7, 7.5, 12.1. 1H), 3.54(ddd, J=2.8, 5.2, 12.0, 1H), 3.83(ddd, J=3.9, 3.9, 7.1, 1H), 4.15(q, J=7.1, 1H), 7.22~7.32(m, 5H) Preparation example 272 ^' · (4-S, 5R)-methyl-5-benzyl-2,2-diethyl-l,3-dioxolane- 4-carboxylate-

The substantially same method as described in Preparation example 263 was conducted, except that (2S, 3R)-methyl-2,3-dihydroxy ^~ 4-phenylbutanoate (Preparation example 269)was used instead of (2, 3-dihydroxys- phenyl but anoate (Preparation example 260), to obtain the title compound (1.5g. 50-75%)

¾ NM (400MHz, CDC1 ₃ ) ^' - 5=0.85(t, J=6.0, 3H) , 0.92(t, J=7.6, 3H), 1.66(dq, J=7.6, 14.7, 4H) , 3.01(dd, J=6.6, 14.2. 1H) , 3.10(dd, J=4.4, 14.4, 1H), 3.71(s, 3H), 4.17(d, J=8.4. 1H), 4.32~4.37(m, 1H), 7.23-7.32(m, 5H)

Preparation example 273: ((4R. 5R)-5-benzyl-2,2-diethyl-l,3-dioxolan-4- yDmethanol

The substantially same method as described in Preparation example 264 was conducted , except that (4S , 5R)-methy1-5-benzy1-2 , 2-dimethy 1-1 , 3-dioxo 1 ane- 4-carboxylate (Preparation example 272) was used instead of (4R,5S)-methyl- 5-benzyl-2,2-dimethyl-l,3-dioxolane-4-carboxylate (Preparation example 263), to obtain the title compound (1.2g, 70-95%)

^X H NMR (400MHz, CDC1 ₃ ): 6=0.91(dt, J=1.9, 7.5, 6H) , 1.61-1.68(m, 4H).

1.77(t, J=6.2, 1H), 2.81(dd, J=6.4, 14.0, 1H), 3.09(dd, J=6.2, 13.8, 1H),

3.24~3.30(m, 1H), 3.49~3.54(in, 1H), 3.78~3.82(m, 1H), 4.08-4.13(m, 1H), 7.21~7.32(m, 5H)

Preparation example 274: (2S, 3R)-met.hyl-3-benzyl-l,4-dioxaspiro[4.4jnonaiie- 2-carboxylate

The substantially same method as described in Preparation example 272 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (1.2g, 60~85%)

'Ή NMR (400MHz, CDC1 ₃ ): δ =1.61-1.79(m, 5H) , 1.85-1.92(m, 3H), 3.00~3.11(m, 2H), 3.70(s, 3H), 4.17(cl, J=7.2, IH), 4.32(dt, J=4.9, 7.0, 1H) , 7.21~7.33(m, 5H)

Preparation example 275: ((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.4]nonane-2- yl )methanol

The substantially same method as described, in Preparation example 266 was conducted, except that (2S, 3R)-methyl-3-benzyl-l,4-dioxaspiro[4.4]nonane- 2-carboxylate (Preparation example 274) was used instead of (2R, 3S)- methy1-3-benzyI-1 , 4-d ioxaspi ro[4.4]nonane-2-carboxy1ate (Preparat ion example 265), to obtain the t i t 1 e compound (l.lg, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) δ 8H), 2.82(dd, J=6.6, 13.8, 1H), 3.08(dd, J=6.4, 14.0, 1H), 3.27~3.33(m, 1H), 3.47-8.52(m, 1H), 3.79~3.83(m, 1H), 4.07(q, J=6.8, 1H), 7.21~7.32(m, 5H)

Preparation example 276 ^' · (2S, 3R)-methyl-3-benzyl-l,4-dioxaspiro[4.5]decane- 2-carboxylate

The substantially same method .as described 111 Preparation example 274 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (1.4g, 60-85%) ¾ NMR (400MHz, CDC1 ₃ ) : δ =1.54-1.74(m, 10H), 2.99-3.12(m, 2H), 3.70(s, 3H), 4.18(cl, J=7.6, 1H) , 4.36~4.41(m, 1H), 7.21 ^~ 7.32(m, 5H)

Preparation example 277: ((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.4]nonane-2- yDmethanol

The substcint ial ly same method as described in Preparation example 268 was conducted, except that (2S, 3R)-methyl-3-benzyl-l,4-dioxaspiro[4.5]decane- 2-carboxylate (Preparation example 276) was used instead of (2R, 3S)- methy1 -3-benzy1-1 , -di oxaspi ro[ .5] decane-2-carboxylate (Preparat i on example 267), to obtain the itle compound (1.4g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ 10H), 2.82(dd, J=6.2, 13.8, Hi), 3.07(dd, J=6.4, 13.6, 1H), 3.24~3.30(m, Hi), 3.52~3.56(m, Hi), 3.80-3.84(m, 1H), 4.10~4.15(m, Hi), 7.21~7.31(m, 5H)

Preparation example 278 ^' · (E)-4 ^' -phenylbut-3-enoic acid

To a stirred solution of 2-phenylace aldehyde (5.0g, 32.3mmol) and malonic acid (4.0g, 38.8mmol) in pyridine (25.0mL) was added a catalytic amount of piperidine (0.64mL, 6.46mmol) then heated to reflux. After 3h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was slowly added 2N HC1. The white precipitate was filtered off and dried under vacuum to produce the title compound (3.5g, 55-80%)

¾ NMR (400MHz, CDC1 ₃ ): 6=3.39(d, J=8.8, 2H) , 6.31(td, J=7.9, 14.8, 1H) , 6.94(d, J=16, Hi), 7.17~7.45(m, 3H) , 7.56~7.59(m, Hi)

Preparation example 279: (E)-4-phenylbut

To stirred solution of Zn(BH ₄ ) ₂ (40.0mL, 20.0inmol) in THF(40mL) was added dropwise a solution (E)-4-phenylbut-3-enoic acid (Preparation example 278, 2.0g, lO.Ommol) in THF(5mL) at 0 ^° C then heated to reflux for 0.5h. The reaction mixture was quenched with ¾0 at 0 ^° C, filtered through celite, washed with EtOAc, dried over anhydrous magnesium sul fate(MgS0 ₄ ) , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (l.Og, 50-75%)

¾ NMR (400MHz, CDC1 ₃ ): 5=2.55(cldd, J= 4.1, 11.9, 21.5, 2H) , 3.82(t, .1=5.8, 2H), 6.24(td, J=7.2, 15.7, 1H), 6.87(d, J=14.8, 1H), 7.12~7.25(m, 3H), 7.36(dd, J=1.2, 8.0, 1H), 7.52(dd, J=1.6, 9.2, 1H)

Preparation example 280: (E)-tert-butyldimethyl (4-phenylbut-3-enyloxy)si lane

The substantially same method as described in Preparation example 237 was conducted, except that (E)-4-phenylbut-3-en-l-ol (Preparation example 279) was used instead of (E)-5-phenylpent-3-en-l-ol (Preparat ion example 236), to obtain the title compound(1.7g, 80-98%)

¾ NMR (400MHz, CDC13) : 6=0.07(s, 3H), O.lOCs, 3H) , 0.92(d, J=6.4, 9H), 2.51(q, J=4.5, 2H) , 3.78(t, J=6.6, 2H), 6.26(tcl, J=7.2, 15.7, 1H), 6.84(cl, J=15.6, 1H), 7.13-7.24(m, 3H), 7.36(dd, J=5.6, 12.4, 1H), 7.53(dd, J=l .4 , 7.8, 1H)

Preparation example 281 ^' · (E)-4-phenylbut-3-enyl pivalate

The substantially same method as described in Preparation example 238 was conducted, except that (E)-4--phenylbut-3-en-l-ol (Preparation example 279) was used instead of (E)-5-phenylpent-3-en-l-ol (Preparation example 236), to obtain the title compound( 10.8g, 75~95%) ¾ NMR (400MHz, CDC13) : 6=1.22(s, 9H), 2.57(ddd, J=1.3, 6.7, 13.5, 2H), 4.22(t, J=6.6, 2H), 6.19(td, J=7.0, 16.0, 1H), 6.49(d, J=16.0, 1H) , 7.23~7.26(m, 1H), 7.31~7.41(m, 4H)

Preparation example 282: (1R, 2R)-4-(tert-butylclimethylsi lyloxy)-l- pheny1butane-1 , 2-di 01

The substantially same method as described in Preparation example 239 was conducted, except that (E)-tert-butyldimethyl (4-phenylbut-3- enyloxy)si lane(Preparat ion example 280) was used instead of (E)-tert- butyldimethyl (5-phenylpent-3-enyloxy)si lane (Preparation example 237), to obtain the title compound(0.8g, 70-95%)

Tl NMR (400MHz, CDC13) : 6=0.10(s, 3H) , O.lKs, 3H), 0.92(s. 9H), 1.69~1.70(m, 1H), 1.93-2.07(m, 1H), 3.51(cl, J=4.8, 1H), 3.86(cl, J=3.2, 1H) , 3.87(dcl, J=3.2, 9.2, 1H), 3.91~3.96(m, 1H), 4.01~4.06(m, 1H) , 5.05(t, J=4.6, 1H), 7.22~7.26(m, 1H) , 7.31~7.37(m, 2H), 7.59(dd, J=1.2, 7.6, 1H)

Preparation example 283: (3R, 4R)-3,4-dihydroxy-4-phenyl butyl pivalate

The substantially same method as described in Preparation example 282 was conducted, except that (E)-4-phenylbut-3-enyl pivalate (Preparation example 281) was used , instead of (E)-tert-butyldimethyl (4-phenylbut-3- enyloxy)si lane (Preparation example 280), to obtain the title compound(8.7g, 70-95%)

¾ NMR (400MHz, CDC13) : 5=1.18(s, 9H), 1.65~1.74(m, 2H), 2.83(d, .1=2.4, 1H), 2.96(d, J=3.2, 1H), 3.74~3.79(m, 1H) , 4.10-4.17(m, 1H) , 4.33(ddd, .1=4.0, 7.2, 12.6, 1H), 4.49(d, J=5.6, 1H), 7.31~7.41(m, 5H)

Preparation example 284: tert-butyl (2-( (4R, 5 )-5-pheny1-2, 2-dimethy1-1,3- dioxo 1 an-4-y1 )ethoxy)climethyl si l ne

The substantially same method as described in Preparation example 218 was conducted, except that (1R, 2R)-4-(tert-butyldimethylsi lyloxy)-l- phenylbutane-l,2-diol (Preparation example 282) was used instead of (2R, 3S)-methyl-3-phenyl-2,3-dihydroxypropanoate(Preparat ion example 217), to obtain the title compound(1.6g, 70~95 )

¾ NMR (400MHz, CDC1 ₃ ): 5=0.02(s, 3H), 0.07(s, 3H), 0.86(s, 9H), 1.50(s, 3H), 1.58(s, 3H), 1.82~1.99(m, 2H), 3.68~3.78(m, .2H) , 3.95(dt, J=3.3, 8.7, 1H), 5.16(d, J=8.4, 1H) , 7.21~7.27(m, 1H) , 7.31~7.38(m, 2H), 7.60(dd, J=1.6, 7.6, 1H)

Preparation example 285 ^' · 2-((4R, 5R)-5-phenyl-2,2-dime hyl-l,3-clioxolan-4- yDethanol

The substantially same method as described in Preparation example 244 was conducted, except that tert-butyl(2-((4R,5 )-5-phenyl-2,2-dimethyl-l,3- dioxolan-4-yl )ethoxy)dimethylsi lane (Preparation example 284) was used instead of (2-( (4R, 5R)-5-benzy1-2,2-dimethyl-1, 3-di oxo 1an-4- yl )ethoxy)(tert ^~ butyl )dimethylsi lane(Preparat ion example 243), to obtain the title compound (1.4g, 80~95%) .

¾ NMR (400MHz, CDC1 ₃ ) · 5=1.56(s, 3H), 1.62(s, 3H), 1.92~2.04(m, 2H), 2.26(q, J=3.7, 1H), 3.75~3.90(m, 2H), 3.94(td, J=3.9, 8.5, 1H), 5.23(d, J=15.6, 1H), 7.22~7.27(m, 1H), 7.33 ^~ 7.39(m, 2H), 7.62(dd, J=1.6, 7.6, 1H)

Preparation example 286: (IS, 2S)-4-(tert-butyldimethylsi lyloxy) ^~ l- pheny1butane-1 , 2-clio1

The substantially same method as described in Preparation example 242 was conducted, except that (E)-ter t-butyldimethyl (4-phenylbut-3- enyloxy)s i lane(Preparat ion example 280)was used instead of (E)-tert- butyldimethyl (5-phenylpent-3-enyloxy)si lane (Preparation example 237), to obtain the title compound(0.7g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=0.10(s, 3H) , O.lKs, 3H), 0.92(s, 9H) , 1.69~1.70(m, 1H), 1.93-2.07(m, 1H), 3.51(d, J=4.8, 1H), 3.86(d, J=3.2, 1H), 3.87(dcl, J=3.2, 9.2, 1H) , 3.91~3.96(m, 1H) , 4.01~4.06(m, 1H), 5.05(t, J=4.6, 1H), 7.22-7.26(m, 1H), 7.31~7.37(m, 2H) , 7.59(cld, J=1.2, 7.6, 1H)

Preparation example 287: (3S, 4S)-3 ,4-dihydroxy- -phenylbutyl pivalate

The substantially same method as described in Preparation example 286 was conducted, except that (E)-4-phenylbut-3-enyl pivalate (Preparation example 281) was used instead of (E)-tert-butyldimethyl (4-phenyl but-3- enyloxy)si lane(Preparat ion example 280), to obtain the title compound( 10. g, 70-95%)

lH NMR (400MHz, CDC1 ₃ ) ^' - 5=1.18(s, 9H), 1.65~1.74(m, 2H) , 2.83(d, .1=2.4, 1H), 2.96(d, J=3.2, 1H) , 3.74~3.79(m, 1H), 4.10~4.17(m, 1H) , 4.33(ddd, J=4.0, 7.2, 12.6, 1H), 4.49(d, J=5.6, 1H) , 7.31~7.41(m, 5H)

Preparation example 288: tert ^~ butyl (2-((4S, 5S)-5-pheny1-2, 2-dimethy1-1,3- dioxo1 an-4-y1 )ethoxy)climethy1 s i 1 ane

The substantially same method as described in Preparation example 284 was conducted, except that (IS, 2S)-4-(tert-butyldimethylsi lyloxy)-l- phenyl butane-1 , 2-di ol (Preparation example 286) was used instead of (1R, 2R)-4-(tert-butyldimethylsi lyloxy)-l-phenylbutane-1, 2-di ol (Preparat ion example 282), to obtain the title compound(0.7g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=0.02(s, 3H), 0.07(s, 3H), 0.86(s, 9H) , 1.50(s, 3H), 1.58(s, 3H), 1.82~1.99(m, 2H), 3.68~3.78(m, 2H), 3.95(dt, J=3.3, 8.7, 1H), 5.16(cl, J=8.4, 1H) , 7.21~7.27(m, 1H), 7.31-7.38(m, 2H) , 7.60(dd, J=1.6, 7.6, 1H)

Preparation example 289: 2-((4S, 5S)-5-phenyl-2,2-dimethyl-l,3-dioxolan-4- yOethanol

The SLibstant ial ly same method as described in Preparation example 285 was conducted, except that tert-butyl(2-((4S,-5S)-5-phenyl-2,2-dimethyl-l,3- dioxolan-4-yl )ethoxy)climethylsi lane (Preparation example 288) was used instead of that tert-butyl(2-((4R,5 )-5-phenyl-2,2-climethyl-l,3-clioxolan-4- yl )ethoxy)dimethylsi lane (Preparation example 284), to obtain the title compound(0.4g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.56(s, 3H). 1.62(s, 3H) , 1.92~2.04(m, 2H), 2.26(q, J=3.7, 1H) , 3.75~3.90(m, 2H), 3.94(td, .1=3.9, 8.5, 1H), 5.23(d, J=15.6, 1H), 7.22~7.27(m, 1H) , 7.33~7.39(m, 2H), 7.62(dd, J=1.6, 7.6, 1H)

Preparation example 290: 2-((4R, 5R)-2,2-diethyl-5-phenyl-l,3-dioxolan-4- yOethyl pivalate

The substantially same method as described in Preparation example 264 was conducted, except that (3R, 4R)-3,4-dihydroxy-4-phenylbutyl pivalate(Preparat ion example 283) was used instead of (4R,5S)-methyl-5- benzyl-2,2-dimethyl-l,3-dioxolane-4--carboxylate (Preparation example 263), to obtain the title compound(1.8g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) · 5=1.00(t, J=7.4, 3H) , 1.08(t, J=7.6, 3H) , 1.14(s, 9H), 1.76(q, J=7.5, 2H), 1.81-1.89(m, 2H), 1.91-1.98(m, 2H), 3.87(td, J=5.8, 8.8, 1H), 4.13~4.18(m, 1H), 4.22~4.28(m, 1H), 4.58(d, J=8.8, 1H), 7.31~7.43(m, 5H) Preparation example 291: 2-((4R, 5R)-2, 2-diethyl-5-pheny1-1, 3-dioxol an-4- yDethyl pivalate

The substantially same method as described in Preparation example 258 was conducted, except that 2-((4R, 5R)-2,2-diethyl-5-phenyl-l,3-dioxolan-4- yDethyl pivalate (Preparation example 290) was used instead of 2-((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.5]decan-2-yl)ethyl pivalate (Preparation example 257), to obtain the title compound (0.9g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.01(t . J=7.4, 3H) , 1.07(t, J=7.6, 3H) , 1.79(q, J=7.5, 2H), 1.83-1.90(m, 4H) , 2.38(q, J=3.7, 1H), 3.75~3.87(m, 2H) , 3.90-3.95(m, 1H), 4.63(d, .1=8.8, 1H), 7.32~7.43(m, 5H) ·

Preparation example 292 ^" . 2-((2R, 3R)-3-phenyl-l ,4-dioxaspi ro[4.4jnonan-2- yDethyl pivalate

The substantially same method as described in Preparation example 290 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (1.8g, 60-85%)

¾ NMR (400MHz, CDC13) : 6=1.14(s, 9H), 1.67-1.83(m, 4H), 1.88-2.07(m, 6H), 3.84(td, J=6.0, 8.4, 1H), 4.13(td, J=7.0, 11.1, 1H), 4.24(tcl, .1=6.4, 11.2, 1H), 4.55(d, J=8.4, 1H), 7.31~7.39(m, 5H)

Preparation example 293: 2-((2R, 3R)-3-phenyl-l,4-dioxaspiro[4.4]iionan-2- yOethanol

The substantially same method as described in Preparation example 291 was conducted, except that 2-((2R, 3R)-3-phenyl-l,4-dioxaspiro[4.4]nonan-2- yDethyl pivalate(Preparat ion example 292) was used instead of that 2- ( (4S, 5S)-2 , 2-di ethyl-5-pheny1 -1 , 3-dioxo1 an-4-y1 )ethy1 piva1ate(Preparat i on example 290), to obtain the title compound (0.9g. 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.71-1.81(m, 4H), 1.87-2.07(m, 6H), 2.27(q, .1=3.7, 1H), 3.79-3.85(m. 2H) , 3.89~3.92(m, 1H) , 4.59(d. J=8.4, 1H), 7.32-7.41(m, 5H)

Preparation example 294· ^' 2-((2R, 3R)-3-phenyl -l,4-di oxaspi ro[4.5] decan-2- yDethyl pivalate

The substantially same method as described in Preparation example 292 was conducted, except that cyclohexanone was used instead of cyclopetanone , to obtain the title compound(2. Og, 60-

H NMR (400MHz, CDC1 ₃ ): 6=1.14(s, 9H), 1.67~1.83(m, 4H) , 1.88~2.07(m, 6H), 3.84(td, J=6.0, 8.4, 1H) , 4.10~4.17(m, 1H) , 4.21~4.27(m, 1H) , 4.55(d, J=8.4, IH), 7.31~7.39(m, 5H)

Preparation example 295:2-((2R, 3R)-3-phenyl-l,4-dioxaspiro[4.5jdecan yDethanol

The substantially same method as described in Preparation example 293 was conducted, except that 2-((2R, 3R)-3-phenyl-l,4-dioxaspiro[4.5jdecan-2- yDethyl pivalate(Preparat ion example 294) was used instead of that 2-((2R, 3R)-3-phenyl-l,4-dioxaspiro[4.4]nonan-2-yl )ethyl pivalate (Preparation example 292), to obtain the title compound (1.2g, 80-95%)

Ή NMR (400MHz, CDC13) : δ =1.71-1.83(m, 4H) , 1.87~2.05(m, 6H), 2.27(q, J=3.7, 1H), 3.79~3.85(m, 2H) , 3.86~3.91(m. 1H) , 4.59(d, J=8.4, 1H) , 7.32-7.41(m, 5H)

Preparation example 296 ^' · 2-((4S, 5S)-2,2-diethyl-5-phenyl-l,3-dioxolan-4- yOethyl pivalate

The substantially same method as described in Preparation example 290 was conducted, except that (3S, 4S)-3,4-dihydroxy-4-phenylbutyl pivalate(Preparat ion example 287) was used instead of (3R, 4R)-3,4- dihydroxy-4-phenylbutyl pivalate(Preparat ion - example 283), to obtain the title compound(2.2g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) · 6=1.00(t, J=7.4, 3H), 1.08(t, J=7.6, 3H), 1.14(s, 9H), 1.76(q, J=7.5, 2H), 1.81-1.89(m, 2H), 1.91-1.98(m, 2H), 3.87(tcl, J=5.8, 8.8, 1H), 4.13 ^~ 4.18(m, 1H), 4.22~4.28(m, 1H) , 4.58(d, .1=8.8, 1H), 7.31~7.43(m, 5H)

Preparation example 297: 2-((4S, 5S)-2 ₍ 2-diet yl-5-phenyl-l,3-dioxolan-4- yDethyl pivalate

The substantially same method as described in Preparation example 295 was conducted, except 2-((4S, 5S)-2,2-diethyl-5-phenyl-l,3-dioxolan-4-yl )ethyl pivalate (Preparation example 296)was used instead of 2-((2R, 3R)-3-phenyl- l,4-dioxaspiro[4.5]decan-2-yl)ethyl pivalate (Preparation example 294), to obtain the title compound (0.7g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.01(t, J=7.4, 3H) , 1.07(t, J=7.6, 3H) , 1.79(q, .1=7.5, 2H), 1.83-1.90(m, 4H), 2.38(q, J=3.7, 1H), 3.75~3.87(m, 2H), 3.90-3.95(m, 1H), 4.63(d, J=8.8, 1H) , 7.32-7.43(m, 5H) Preparation example 298: 2-((2S, 3S)-3-phenyl-l,4-dioxaspiro[4.4]nonan-2- yDethyl pivalate

The substantially same method as described in Preparation example 296 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (2.4g, 60~85%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.14(s, 9H) , 1.67~1.83(m, 4H) , 1.88-2.07(m, 6H), 3.84(td, J=6.0, 8.4, 1H) , 4.13(td, J=7.0, 11.1, 1H), 4.24(td, 3=6 A, 11.2, 1H), 4.55(d, J=8.4, 1H) , 7.31~7.39(m, 5H)

Preparation example 299: 2-((2S, 3S)-3-phenyl-l,4-dioxaspiro[4.4]nonan-2- yl )ethanol

The substantially same method as described in Preparation exam le 297 was conducted, except that 2-((2S. 3S)-3-phenyl-l,4-dioxaspiro[4.4]nonan-2- yDethyl pivalate(Preparat ion example 298) was used instead of that 2-((4S, 5S)-2 , 2-diethyl-5-phenyl-l ,3-dioxolan-4-yl )ethyl pivalate(Preparat ion example 296), to obtain the title compound (07g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6 =1.71-1.81(m, 4H), 1.87~2.07(m, 6H), 2.27(q, J=3.7, 1H), 3.79~3.85(m, 2H), 3.89~3.92(m, 1H), 4.59(d, J=8.4, 1H). 7.32~7.41(m, 5H)

Preparation example 300: 2-((2S, 3S)-3-phenyl-l,4-dioxaspiro[4.5 _. |decan-2- yDethyl pivalate

The substantially same method as described in Preparation example 298 was conducted, except that eye 1ohexanone was used instead of cyclopetanone, to obtain the title compound(2.4g, 60-85%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.14(s, 9H), 1.67~1.83(m, 4H) , 1.88-2.07(m, 6H), 3.84(td, J=6.0, 8.4, 1H), 4.10~4.17(m, 1H), 4.21~4.27(m, 1H), 4.55(d, J=8.4, 1H), 7.31~7.39(m, 5H)

Preparation example 301 ^' · 2-((2S, 3S)-3-phenyl-l,4-dioxaspiro[4.5]decan-2- yl )ethanol

The substantially same method as described in Preparation example 299 was conducted, except that 2-((2S, 3S)-3-phenyl-l,4-dioxaspiro[4.5]decan-2- yDethyl pivalate(Preparat ion example 300) was used instead of that 2-((2S, 3S)-3-pheny1-1 ,4-clioxaspi ro[4.4]nonan-2-y1 )ethy1 piva1 ate(Preparat ion example 298), to obtain the title compound (1.2g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.71-1.83(m, 4H), 1.87~2.05(m, 6H), 2.27(q, J=3.7, 1H), 3.79~3.85(m, 2H), 3.86~3.91(m, 1H), 4.59(d, J=8.4, 1H), 7.32-7.41(m, 5H)

Preparation example 302: (E)-5-(2-chlorophenyl )pent ^~ 3-enoic

The substantially same method as described in Preparation example 235 was conducted, except that 3-(2-chlorophenyl )propanal was used instead of that hydrocinnamaldehyde (6.1g, 70-90%)

¾ NMR (400MHz, CDC13) : 6=3.15(dcl, J=0.8, 6.8, 2H) , 3.53(d, J=6.4, 2H), 5.61~5.69(m, 1H), 5.75~5.82(m, 1H) , 7.16~7.28(m, 3H) , 7.36~7.38(m, 1H)

Preparation example 303: (E)-5-(2-chlorophenyl )pent-3-en-l-ol

The substantially same method as described in Preparation example 236 was conducted, except that (E)-5-(2-chlorophenyl )pent-3-enoic acicKPreparat ion example 302) was used instead of that (E)-5-phenylpent ^~ 3-enoic acidCPreparat ion example 235), to obtain the title compound (4.6g, 70~90%)

^L H NMR (400MHz, CDC1 ₃ ) ^' - 5=2.33(dq, J=1.0, 6.5, 2H) , 3.50(dd, J=1.8, 5.0, 2H), 3.67(q, J=6.0, 2H), 5.45~5.53(m, 1H) , 5.70~5.77(m, 1H) , 7.15-7.37(m, 4H)

Preparation example 304: (E)-tert-butyl (5-(2-chlorophenyl ) en -3- eny1oxy)dimethy1s i 1 ane

The substan ially same method as described in Preparation example 237 was conducted, except that (E)-5-(2-chlorophenyl )pent ^~ 3-en-l-ol (Preparation example 303) was used instead of that (E)-5-phenylpent ^~ 3-en-l- ol (Preparation example 236), to obtain the title compound (4.9g, 75-95%)

¾ NMR (400MHz, CDC1 ₃ ) 6=0.60(s, 6H) , 0.90(s, 9H) , 2.28(dq, J=1.0, 6.7, 2H), 3.47(d, J=6.4, 2H), 3.65(t, J=6.8, 2H), 5.49~5.56(m, 1H), 5.62~5.70(m,

1H), 7.14 ^~ 7.36(m, 4H)

Preparation example 305: (E)-5-(2-chlorophenyl )pent ^~ 3-enyl pivalate

The substantially same method as described in Preparation example 238 was conducted, except that (E)-5-(2-chlorophenyl )pent-3-en-l-ol (Preparation example 303) was used instead of that (E)-5-phenylpent-3-en-l- ol (Preparation example 236), to obtain the title compound (7.2g, 75~95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.18(s, 9H), 2.36(q, J=6.7, 2H), 3.45(d, .1=6.4, 2H), 4.08(t, J=6.6, 2H), 5.43~5.50(m, 1H), 5.63~5.70(m, 1H) , 7.12~7.35(m, 4H) Preparation example 306 ^" · (2S, 3S)-5-(tert-butyldimethylsi lyloxy)-l-(2- ch1oropheny1 )pentane-2 ,3-diol

The substantially same method as described in Preparation example 239 was conducted, except that (E)-tert-butyl (5-(2-chlorophenyl )pent-3- enyloxy)dimethylsi lane (Preparation example 304) was used instead of that (E)-tert-butyldimethyl (5-phenylpent-3-enyloxy)si lane (Preparation example 237), to obtain the title compound (2.8g, 90%)

¾ NMR (400MHz, CDCI3) : 6=0.11(s, 6H), 0.92(s, 9H), 1.68-1.77(m, 1H),

1.87~1.96(m, 1H), 2.64(d, .1=6.0, 1H), 2.93(dd, J=8.2, 13.4, 1H) , 3.07(dd,

J=4.8, 13.6, 1H), 3.68(d, J=3.2, 1H), 3.76~3.96(m, 4H) , 7.17~7.25(m, 2H), 7.35~7.39(m, 2H)

Preparation example 307: (2-(4S, 5S)-5-(2chlorobenzyl)-2,2-dimethyl-l,3- dioxolan-4-yl )ethoxy)(tert-butyl )dimethylsi lane

The substantially same method as described in Preparation example 240 was conducted, except that (2S, 3S)-5-(tert-butyldimethylsi lyloxy)-l-(2- chlorophenyl)pentane-2,3-diol (Preparation example 306) was used instead of that (2S ,3S)-5-(tert-butyldimethyl si lyloxy)-l-phenylpentane-2 ,3-diol

(Preparation example 239), to obtain the title compound (3.6g, 75~90%) lH NMR (400MHz, CDC1 ₃ ) · 5=0.06(s, 6H), 0.91(s, 9H), 1.39(s, 3H), 1.40(s, 3H), 1.69(q, J=6.5, 2H), 3.05(dq, J=5.8, 15.1, 2H) , 3.70~3.80(m, 2H), 3.86 ^~ 3.93(m, 1H) , 3.97~4.02(m, 1H), 7.17~7.25(m, 2H), 7.36~7.38(m, 2H)

Preparation example 308: 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-l,3- dioxo1an-4-y1 )ethano1

The substantially same method as described in Preparation example 241 was conducted, except that (2-(4S, 5S)-5-(2chlorobenzyl)-2,2-dimethyl-l,3- dioxolan-4-yl )ethoxy) (tert-butyl )dimethylsi lane (Preparation example 307) was used instead of that (2-(4S,5S)-5-benzyl-2,2-dimethyl-l,3-dioxolan-4- yl )ethoxy) ( ert-butyl ) dimethylsi lane (Preparation example 240), to obtain the title compound (3.2g, 80-95%)

lH NMR (400MHz, CDC1 ₃ ): 5=1.38(s, 3H), 1.40(s, 3H), 1.50-1.63(m, 2H), 2.29(t, J=5.4, 1H), 2.82(dd, J=5.8, 13.8, 1H), 3.01(dd, J=6.4, 14.0, 1H) , 3.72(q, J=5.5, 2H), 3.86(clt, J=3.2, 8.4, 1H) , 3.92~3.97(m. 1H), 7.17~7.25(m, 2H), 7.36-7.38(m, 2H)

Preparation example 309: (2R, 3R)-5-(tert-butyldimethylsi lyloxy)-l-(2- ch1oropheny1 )pentane-2 , 3-dio 1

The substantially same method as described in Preparation example 242 was conducted, except that (E)-tert-butyl (5-(2-chl oropheny1 ) ent-3- enyloxy)dimethylsi lane (Preparation example 304) was used instead of that (E)-tert-buty1dimethy1 (5-pheny1pent-3-eny1oxy)s i 1 ane(Preparat ion examp1 e 237), to obtain the title compound (4.4g, 90%)

¾ NMR (400MHz, CDC1 ₃ ): 6=0.11(s, 6H). 0.92(s, 9H) , 1.68~1.77(m, 1H),

1..87-1.96(m, 1H) , 2.64(d, J=6.0, 1H) , 2..93(dd, J=8.2, 13.4, 1H), 3.07(dd,

J=4.8. 13.6, 1H), 3.68(d, J=3.2, 1H), 3.76~3.96(m, 4H) , 7.17-7.25(m , 2H), 7.35-7.39(m, 2H)

Preparation example 310: (2-(4R, 5 )-5-(2chlorobenzyl)-2,2-dimethyl-l,3- dioxo 1 n-4-y1 )ethoxy) ( tert-buty1 )dimethy1 s i 1 ane The substan ially same method as described in Preparation example 307 was conducted, except that (2R, 3R)-5-(tert-butyldimethylsi lyloxy)-l-(2- chlorophenyl )pentane-2,3-diol (Preparat ion example 309) was used instead of (2S, 3S)-5-( tert-buty1dimethy1 s i 1y1oxy)-1-(2-ch1oropheny1 ) entane-2 , 3-di o1 (Preparation example 306), to obtain the title compound (4.6g, 70-95%)

¾ NMR (400MHz, CDC13) : 6=0.06(s, 6H), 0.91(s, 9H) , 1.39(s, 3H) , 1.40(s, 3H), 1.69(q, J=6.5, 2H) , 3.05(dq, J=5.8, 15.1, 2H) , 3.70~3.80(m, 2H) , 3.86 ^~ 3.93(m, 1H), 3.97~4.02(m, 1H) , 7.17~7.25(m, 2H), 7.36~7.38(m, 2H)

Preparation example 311: 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-dimethyl-l,3- dioxolan-4-ylMethanol

The substantially same method as described in Preparation example 241 was conducted, except that (2-(4S, 5S)-5-(2chlorobenzyl )-2,2-dimethyl-l ,3- dioxolan-4-yl )ethoxy)(tert-butyl)dimethylsi lane (Preparation example 307) was used instead of that (2-(4S, 5S)-5-benzyl-2,2-dimethyl-l,3-dioxolan-4- yl )ethoxy)(tert ^~ butyl)dimethylsi lane (Preparation example 240), to obtain the title compound (3.0g, 80~95%)

¾ NMR (400MHz, CDC1 ₃ ) - 5=1.38(s, 3H) . 1.40(s, 3H) , 1.50~1.63(m. 2H) , 2.29(t, J=5.4, 1H), 2.82(dcl, J=5.8, 13.8, 1H), 3.01(dd, J=6.4, 14.0, IH), 3.72(q, .1=5.5, 2H), 3.86(dt, J=3.2, 8.4, 1H), 3.92~3.97(m, IH), 7.17~7.25(m, 2H), 7.36 ^~ 7.38(m, 2H)

Preparation example 312 ^' - (3S,4S)-3,4-dihydroxy-5-(2chlorophenyl )pentyl pivalate

The substantially same method as described in Preparation example 306 was conducted, except that (E)-5-(2-chlorophenyl )pent ^~ 3-enyl pivalate (Preparation, example 305) was used instead of (E)-tert-butyl (5-(2- chlorophenyl )pent-3-enyloxy)dimethylsi lane (Preparation example 304), to obtain the title compound(6. Og, 70-95%) ¾ NMR (400MHz, CDC1 ₃ ) · ^" 6=1.16(s, 9H), 1.85-1.91(m, 2H), 2.17(cl, J=6.0, 1H), 2.73(d, J=5.2, 1H), 2.91(dd, J=8.4, 13.6, 1H), 3.08(dd, J=5.6, 13.6, 1H), 3.52~3.55(m, 1H), 3.77~3.80(m, 1H) , 4. ll~4.19(m, 1H), 4.37~4.41(m, 1H) , 7.18~7.23(m, 2H), 7.31(dd, J=2.2, 7.0, 1H) , 7.36(dd, J=1.8, 7.4, 1H)

Preparation example 313: 2-((4S,5S)-5-(2-chorobenzyl)-2,2-diethyl-l,3- dioxo1 an-4-y1 )ethyl piva 1ate

The substantially same method as described in Preparation example 246 was conducted, except that (3S,4S)-3,4-dihydroxy-5-(2chlorophenyl)pentyl pivalate(Preparat ion example 312) was used instead of (3S,4S)-3,4- dihydroxy-5-phenyl ent l pivalate (Preparation example 245), to obtain the title compound(1.7g, 70-95%)

¾ NMR (400MHz, CDCI ₃ ) : 5=0.90(t, J=7.4, 6H) , 1.21(s, 9H), 1.58-1.66(m, 4H), 1.70-1.77(m, 2H), 3.06(d, J=5.6, 2H) , 3.81 ^~ 3.86(m, 1H), 3.94~3.99(m, 1H), 4.15~4.25(m, 2H) , 7.18-7.24(m, 2H), 7.36~7.38(m, 2H)

Preparation example 314 ^' - 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-l,3- dioxo1 an-4-y1 )ethano1

The substantially same method as described in Preparation example 247 was conducted, except that 2-((4S,5S)-5-(2-chorobenzyl)-2,2-diethyl-l,3- dioxo 1an-4-y1 )ethyl pivalate (Preparation example 313) was used instead of 2-( (4S , 5S)-5-benzy1-2, 2-cliethyl-l ,3-cli oxo1 an-4-y1 )ethy 1

pivalate(Preparation example 246), to obtain the title compound (0.9g, 80-95%) ;

¾ NMR (400MHz, CDC13) ^' · 5=0.91(dt, J=2.5, 7.5, 6H), 1.46~1.79(m, 6H), 2.42(t, J=5.6, lH), 3.01~3.12(m, 2H), 3.79(q, J=5.6. 2H) , 3.88~3.93(m, 1H), 3.98~4.06(ni, 1H), 7.18~7.25(m, 2H), 7.35~7.39(m, 2H) Preparation example 315: (3R,4R)-3,4-dihyclroxy-5-(2-chlorophenyl )pentyl pivalate

The substantially same method as described in Preparation example 309 was conducted, except that (E)-5-(2-chlorophenyl )pent-3-enyl pivalate (Preparation example 305) was used instead of (E)-tert-butyl (5-(2- chloropheny1 )pent-3-enyloxy)dimethylsi lane (Preparation example 304), to obtain the title compound (4.4g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=0.11(s, 6H), 0.92(s, 9H), 1.68~1.77(m, 1H),

1.87~1.96(m, 1H), 2.64(d, J=6.0, 1H), 2.93(dcl, J=8.2, 13.4, 1H), 3.07(dd,

J=4.8, 13.6, 1H), 3.68(d, J=3.2, 1H), 3.76~3.96(m, 4H) , 7.17~7.25(m, 2H), 7.35~7.39(m, 2H)

Preparation example 316: 2-((4R, 5R)-5-(2-chlorobenzyl)-2.2-diethyl-l,3- dioxo1an-4-y1 )ethyl pivalate ·

The substantially same method as described in Preparation example 313 was conducted, except that (3R, 4R)-3,4-dihydroxy-5-(2chlorophenyl )pentyl pivalate (Preparation example 315) was used instead of (3S, 4S) ^~ 3,4- dihydroxy-5-(2chlorophenyl )pentyl pivalate (Preparation example 312), to obtain the title compound(1.7g, 70-95%)

^L H NMR (400MHz, CDC1 ₃ ) · ^' 5=0.90(t, 3=7 A, 6H), 1.21(s, 9H), 1.58-1.66(m, 4H), 1.70~1.77(m, 2H), 3.06(d, J=5.6, 2H), 3.81~3.86(m, 1H) , 3.94~3.99(m, 1H), 4.15~4.25(m, 2H) , 7.18~7.24(m, 2H) , 7.36~7.38(m, 2H)

Preparation example 317: 2-((4R, 5R)-5-(2-chlorobenzyl)-2,2-dimethyl-1.3- di oxo1an-4-y1 )ethano 1

The substantially same method as described in Preparation example 314- was conducted, except that 2-((4R, 5R)-5-(2-chorobenzyl )-2,2-di ethyl-1,3- dioxolan-4-yl )ethyl pivalate (Preparation example 316) was used instead of 2-( ( S , 5S)-5-(2-chorobenzy1 )-2 , 2-di ethy1-1 , 3-di oxo1 an-4-y1 )ethy1 pivalate(Preparat ion example 313), to obtain the title compound (0.9g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=0.91(dt, J=2.5, 7.5, 6H), 1.4-6-1.79(m, 6H). 2.42(t, J=5.6, 1H), 3.01~3.,12(m, 2H), 3.79(q, .1=5.6, 2H), 3.88~3.93(m, 1H) , 3.98~4.06(m, 1H) , 7.18~7.25(m, 2H), 7.35~7.39(m, 2H)

Preparation example 318: 2-((2S, 3S)-3-(2-chlorobenzyl )-l ,4- dioxaspiro[4.4]nonan-2-yl )ethyl pivalate

The substantially same method as described in Preparation example 313 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (1.2g, 60~85%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.21(s, 9H), 1.64~1.74(m, 5H), 1.75-1.88(m, 5H), 3.03-3. lKm, 2H) , 3.81~3.86(m, 1H), 3.97(q, J=6.5, 1H), 4.12-4.22(m, 2H), 7.18~7.25(m, 2H) , 7.34~7.39(m, 2H)

Preparation example 319: 2-((2S, 3S)-3-(2-chlorobenzy1 )-1,4- dioxaspiro[4.4Jnonan-2-yl )ethanol

The substantially same method as described in Preparation example 317 was conducted, except that 2-((2S,3S)-3-(2-chlorobenzyl )-l,4- dioxaspiro[4.4]nonan-2-yl )ethyl pivalate (Preparation example 318) was used instead of 2-((4R, 5R)-5-(2-chorobenzyl )-2,2-diethyl-1, 3-dioxol an-4- yOethyl pivalate(Preparat ion example 316), to obtain the title compound (0.7g, 80~95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.62-1.74(m, 6H) , 1.75-1.88(m, 4H), 2.28(t, J=5.6, 1H), 3.03~3.12(m, 2H) , 3.78(q, J=5.6, 1H), 3.88~3.95(m, 1H), 3.97~4.06(m, 1H) , 7.18~7.26(m, 2H) , 7.34~7.39(m, 2H)

Preparation example 320: 2-((2R, 3R)-3-(2-chlorobenzyl)-l,4- dioxaspi ro [4.4Jnonan-2-y1 )ethy1 piva1 ate

The substantially same method as described in Preparation example 316 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (1.4g, 60-85%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.21(s, 9H), 1.64~1.74(m, 5H) , 1.75-1.88(m, 5H), 3.03~3.11(m, 2H), 3.81~3.86(m, 1H) , 3.97(q, J=6.5, 1H), 4.12~4.22(m, 2H), 7.1.8~7.25(m, 2H) , 7.34~7.39(m, 2H)

Preparation example 321: 2-((2R, 3R)-3-(2-chlorobenzyl )-l ,4- clioxaspi ro[4.4]nonan-2-y1 )ethano1

The substantially same method as described in Preparation example 319 was conducted, except that 2-((2R, 3R)-3-(2-chlorobenzyl)-l,4- dioxaspiro[4.4]nonan-2-yl )ethyl pivalate (Preparation example 320)was used instead of 2-( (2S ,3S)-3-(2-chlorobenzyl )-l ,4-dioxas i ro[4.4]nonan ^~ 2- yOethyl pivalate (Preparation example 318), to obtain the title compound. (0.8g, 80-95%) H NMR (400MHz, CDC1 ₃ ) ^" - δ =1.62-1.74(m, 6H), 1.75-1.88(m, 4H) , 2.28(t, J=5.6, 1H), 3.03-3.12(m, 2H) , 3.78(q, J=5.6, 1H) . 3.88~3.95(m, 1H), 3.97~4.06(m, 1H) , 7.18~7.26(m, 2H), 7.34~7.39(m, 2H)

Preparation example 322: 2-((2S, 3S)-3-(2-chlorobenzyl)-l,4- clioxaspiro[4.5]decan-2-yl)ethyl pivalate

The substantially same method as described in Preparation example 318 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (l.lg, 60-85%)

¾ NMR (400MHz, CDCI3) : 6=1.21(s, 9H) , 1.58~1.61(m, 8H) , 1.77(q, J=6.8, 2H), 3.07(cl, J=6.0, 2H), 3.81~3.88(m, 1H) , 3.96~4.01(m, 1H), 4.16~4.22(m, 2H), 7.17~7.25(m, 2H), 7.36~7.39(m, 2H)

Preparation example 323: 2-((2S, 3S)-3-(2-chlorobenzyl)-l,4- dioxaspi ro[4.5]decan-2-y1 )ethano1

The substantially same method as described in Preparation example 321 was conducted, except that 2-((2S, 3S)-3-(2-chlorobenzyl )-l ,4- clioxaspiro[4.5]decan-2-yl)ethyl pivalate (Preparation example 322) was used instead of 2-((2R, 3R)-3-(2-chlorobenzyl)-l,4-dioxaspiro[4.4]nonan-2- yDethyl pivalate (Preparation example 320), to obtain the title compound (0.7g, 80-95%) lH NMR (400MHz, CDC13) : δ =1.51-1.64(m, 8H), 1.65~1.74(m, 2H), 2.59~2.63(m, 1H), 3.06(d, J=6.0, 2H), 3.76~3.78(m, 2H), 3.89~3.94(m, 1H) , 3.99~4.04(m, 1H), 7.16~7.24(m, 2H), 7.35~7.38(m, 2H) Preparation example 324: 2-((2R, 3R)-3-(2-chlorobenzyl )-l ,4- dioxaspi ro[4.5]decan-2-yl )ethyl pivalate

The substantially same method as described in Preparation example 320 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (1.5g, 60~85%)

¾ NMR (400MHz, CDC1 ₃ ) · ^" 5=1.21(s, 9H), 1.58 ^~ 1.61(m, 8H), 1.77(q, .1=6.8, 2H), 3.07(cl, J=6.0, 2H), 3.81~3.88(m, 1H), 3.96~4.01(m, 1H) , 4.16~4.22(m, 2H), 7.17~7.25(m, 2H) , 7.36~7.39(m, 2H)

Preparation example 325: 2-((2R, 3R)-3-(2-chlorobenzyl )-l .4- dioxaspi ro[4.5]decan-2-y1 )ethano 1

The substantially same method as described in Preparation example 323 was conducted, except that 2-((2R, 3R)-3-(2-chlorobenzyl )-l ,4- dioxaspiro[4.5]decan-2-yl )ethyl pivalate (Preparation example 324) was used instead of 2-((2S, 3S)-3-(2-chlorobenzyl)-l,4-dioxaspiro[4.5]deccin-2- yDethyl pivalate (Preparation example 322), to obtain the title compound (0.9g, 80-95%)

^L H NMR (400MHz, CDC1 ₃ ) ^: δ =1.51-1.64(m, 8H) , 1.65~1.74(m, 2H), 2.59~2.63(m, 1H), 3.06(d, J=6.0, 2H), 3.76~3.78(m, 2H), 3.89 ^~ 3.94(m, 1H), 3.99~4.04(m, 1H) , 7.16~7.24(m, 2H), 7.35~7.38(m, 2H)

Preparation example 326: (E)-methyl-4-(2-chlorophenyl )but-2-enoate

The substantially same method as described in Preparation example 259 was conducted, except that 2-chlorophenyl acetaldehyde was used instead of phenyl acetaldehyde, to obtain the title compound (5.0g, 65~85%)

¾ NMR (400MHz, CDC13) : 6=3.47(d, J=6.8, 2H), 3.67(s, 3H) , 5.79(d, J=15.4, IH), -7.06(dt, J=15.4, 6.8, 1H) , 7.12 ^~ 7.28(m, 4H)

Preparation example 327: (2R, 3S)-methyl-4-(2chlorophenyl)-2,3- dihydroxybutanoate

The substantially same method as described in Preparation example 260 was conducted, except that (E)-methy1-4-(2-chlorophenyl )but-2- enoate(Preparat ion example 326) was used instead of (E)-methyl-4-phenylbut- 2-enoate(Preparat ion example 259), to obtain the title compound(3.0g, 70-95%)

1-1 NMR ( 00MHz , CDC13) : δ =3.08~3.17(m , 2H) , 3.84( s , 3H) , 4.12(dd , J=1.6 , 5.2, IH), 4.28~4.34(m, IH), 7.20~7.27(m, 2H), 7.33~7.36(m, IH), 7.39~7.41(m, IH)

Preparation example 328: (4R, 5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl- 1 , 3-dioxo1 ne-4-carboxy1 ate

The substantially same method as described in Preparation example 261 was conducted, except that (2R, 3S)-methyl-4-(2chlorophenyl ) 2,3- clihydroxybutanoate(Preparat ion example 327) was used instead of (2R, 3S) ^~ methyl 2 ,3-dihydroxy-4-phenylbutanoate(Preparat ion example 260), to obtain the title compound(0.6g, 70~95%)

¾ NMR (400MHz, CDC13) : 5=1.45(s, 3H), 1.49(s, 3H), 3.11(dd, J=7.6, 14.4, IH), 3.35(dcl, J=4.4, 14.4, IH), 3.74(s, 3H), 4.30(d, J=7.6, IH), 4.50(dt, J=4.0, 7.6, IH), 7.19~7.26(m, 2H), 7.36~7.40(m, 2H) Preparation example 329: ((4S, 5S)-5-(2-chlorobenzyl )-2,2-dimethyl-l,3- dioxo 1an-4-y1 )methano1

The substantially same method as described in Preparation example 262 was conducted, except that (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-l,3- dioxolane-4-carboxylate (Preparation example 328) was used instead of

(4R,5S)-methyl 5-benzy1-2 , 2-dimethyl -1 , 3-di oxo1 ane-4- carboxylate(Preparat ion example 261), to obtain the title compound(0.5g, 70-95%) ¾ NMR (400MHz, CDC1 ₃ ): 5=1.43(s, 6H), 1.83(q, J=4.3, 1H) , 3.06-3.17(m, 2H), 3.45(ddd, J=4.6, 7.4, 12.0, 1H), 3.68(ddd, J=3.2, 5.2, 12.0, 1H), 3.91(ddd, J=3.3, 4.7, 8.0, 1H), 4.22~4.27(m, 1H), 7.20~7.26(m, 2H), 7.35 ^~ 7.40(m, 2H)

Preparation example 330: (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-cliethyl-l,3- dioxo1ane-4-carboxylate

The substantially same method as described in Preparation example 263 was conducted, except that (2R, 3S)-methyl-4-(2chlorophenyl)-2,3- dihydroxybutanoate(Preparat ion example 327) was used instead of (2R, 3S) ^~ methyl 2,3-dihyclroxy-4-phenylbutanoate(Preparat ion example 260), to obtain the title compouncKO .8g, 50~75%)

Hi NMR (400MHz, CDC13) : 6=0.93(t, J=7.4, 6H) , 1.67~1.74(m, 4H), 3.10(dd, J=8.0, 14.4, 1H), 3.35(dd, J=4.0, 14.4, 1H) , 3.73(s, 3H), 4.27(d, J=8.4, lH), 4.42-4.47(m, 1H), 7.18~7.26(m, 2H) , 7.37~7.40(m, 2H)

Preparation example 331: ((4S, 5S)-5-(2-chlorobenzyl)-2,2-diethyl-l,3- dioxolan-4-yl )methanol

The substantially same method as described in Preparation example 329 was conducted, except that (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-l,3- dioxo lane-4-carboxylate (Preparation example 330) was used instead of (4R , 5S)-methy1-5-(2-ch1orobenzy1 )-2 , 2-dimethy1-1 , 3-di oxo1 ane-4- carboxylate(Preparation example 328), to obtain the title compound(0.6g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) ^' - 5=0.93(dt, J=2.1, 7.5, 6H), 1.62~1.70(m, 4H), 1.83(q, J=4.3, IE), 3.11(ddd, J=6.0, 14.2, 28.0, 2H), 3.44(ddd, J=4.8, 7.2, 12.0, 1H), 3.64~3.69(m, 1H), 3.88(ddd, J=3.3, 4.9, 8.3, 1H), 4.18~4.24(m, 1H), 7.19~7.26(m, 2H) , 7.36~7.39(m, 2H)

Preparation example 332 ^' · (2R, 3S)-methyl-3-(2-chlorobenzyl )-l,4- clioxaspi ro[4.4]nonane-2-ca boxylate

The substan ially same method as described in Preparation example 330 was conducted, except that cyclopetanone was used instead of 3-pantanoiie, to obtain the title compound (0.8g, 60~85%)

lH NMR (400MHz, CDC1 ₃ ): δ =1.65-1.80(m, 5H) , 1.89~2.00(m, 3H) , 3.13(dd, J=7.8, 14.2, 1H), 3.32(dd. J=4.6, 14.2, 1H), 3.72(s, 3H), 4.28(d. .1=7.2, 1H), 4.41~4.46(m, 1H), 7.19~7.26(m, 2H) , 7.35~7.40(m, 2H)

Preparation example 333: 3S)-3-(-2chlorobenzyl)-l,4- dioxaspi ro [4.4]nonan-2-y1 )methano1

The substantially same method as described in Preparation example 331 was conducted, except that (2R, 3S)-methyl-3-(2-chlorobenzyl )-l,4- dioxaspiro[4.4]nonane-2-carboxylate (Preparation example 332) was used instead of (4R, 5S)-methyl-5-(2-chlorobenzyl )-2 ,2-dimethy l-l ,3-dioxolane-4- carboxylate (Preparation example 330), to obtain the title compound (0.6g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ) · ^" δ =1.69-1.74(m, 3H), 1.77~1.85(m, 5H) , 3.11(ddd, J=6.3, 14.1, 31.3, 2H), 3.42~3.48(m, 1H) , 3.61-3.66(111, 1H), 3.87~3.91(m, 1H), 4.19(q, J=6.8, 1H), 7.19-7.26(m, 2H), 7.34~7.40(m, 2H)

Preparation example 334: (2R,3S)-methyl-3-(2-chlorobenzyl )-l ,4- dioxaspiro[4.5]decane-2-carboxylate

The substantially same method as described in Preparation example 332 was conducted, except that cyclohexanone was used instead of eye Iopetanone , to obtain the title compound (0.5g, 60-85%)

¾ NMR (400MHz, CDCI3) · δ =1.54-1.77(m, 10H) , 3.12(dd, J=7.6, 14.4, 1H), 3.32(dd, J=4.4, 14.4, 1H), 3.72(s, 3H) , 4.30(d, J=7.6, 1H), 4.46 ^~ 4.51(m, 1H), 7.18~7.26(m, 2H), 7.37~7.39(m, 2H)

Preparation example 335: ((2S, 3S)-3-(-2chlorobenzyl )-l ,4- dioxaspi ro[4.5]decan-2-y1 )methano1

The substantially same method as described in Preparation example 333 was conducted, except that (2R, 3S)-methyl-3-(2-chlorobenzyl)-l,4- dioxaspiro[4.5 _. |decane-2-carboxylate(Preparation example 334) was used instead of (2R, 3S)-methyl-3-(2-chlorobenzyl)-l,4-dioxaspiro[4.4]nonane-2- carboxylate(Preparat ion example 332), to obtain the title compound(0.5g, 70-95%) ^! H NMR (400MHz, CDC1 ₃ ) : δ =1.38-1.45(m, 2H), 1.58-1.63(m, 8H), 1.84(q, J=4.3, 1H), 3. lKcldcl, J=7.9, 15.9, 22.1, 2H), 3.43(ddd, J=4.6, 7.6, 12.1, 1H), 3.66~3.71(m, 1H) , 3.88~3.92(m, 1H) , 4.21~4.26(m, 1H) , 7.18~7.26(m, 2H) , 7.37~7.39(m, 2H)

Preparation example 336: (2S, 3R)-methyl-4-(2chlorophenyl )-2,3- dihydroxybutanoate

The substantially same method as described in Preparation example 269 was conducted, except that (E)-methyl-4-(2-chlorophenyl )but-2- enoate(Preparat ion example 326) was used instead of (E)-methyl-4-phenylbut- 2 ^~ enoate(Preparat ion example 259), to obtain the title compound(3.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6 =3.08-3.17(m, 2H), 3.84(s, 3H), 4.12(dd. J=1.6, 5.2, 1H), 4.28~4.34(m, 1H), 7.20-7.27(m, 2H), 7.33-7.36(m, 1H) , 7,39-7. 1(m, IH)

Preparation example 337: (4S, 5R)-methyl-5-(2-chlorobenzyl )-2 ,2-dime hy l- 1 , 3-dioxo1 ne-4-carboxylate

The substantially same method as described in Preparation example 328 was conducted, except that (2S, 3R)-methyl-4-(2chlorophenyl )-2,3 ^~ dihydroxybutanoate(Preparat ion example 336) was used instead of (2R, 3S)- methyl-4-(2chlorophenyl )-2,3-dihydroxybutanoate(Preparation example 327) , to obtain the title compound(3.4g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.41(s, 6H) , 1.79(q, J=4.3, IH), 2.83(dd, J=6.2, 13.8, IH), 3.07(dd, J=6.4, 14.0, IH), 3.29(ddd, J=4.7, 7.5, 12.1, IH), 3.54(ddd, J=2.8, 5.2, 12.0, IH), 3.83(ddd, J=3.9, 3.9, 7.1, IH), 4,15(q, J=7.1, IH), 7.22-7.32(m, 5H) Preparation example 338: ((4R, 5R)-5-(-2chlorobenzyl)-2,2-dimethyl-l,3- di oxo 1an-4-y1 )methano1

The substantially same method as described in Preparation example 335 was conducted, except that (4S,5R)-methyl-5-(2-chlrobenzyl)-2,2-climethyl-l,3- di oxo lane-4-carboxylate (Preparation example 337) was used instead of (2R, 3S)-methyl-3-(2-chlorobenzyl )-l ,4-dioxaspiro[4.5]decane-2- carboxylate(Preparat ion example 334), to obtain the title compound (2.7g, ^■ 70-95%) .

lH NMR (400MHz, CDC1 ₃ ): 6=1.41(s, 6H) , 1.79(q, J=4.3, 1H) , 2.83(dd, J=6.2, 13.8, 1H), 3.07(dd, J=6.4, 14.0, 1H), 3.29(ddcl, J=4.7, 7.5, 12.1, 1H), 3.54(ddd, J=2.8, 5.2, 12.0, 1H), 3.83(ddd, .1=3.9, 3.9, 7.1, 1H) , 4.15(q, J=7.1, 1H), 7.22~7.32(m, 5H)

Preparation example 339: (4S, 5R)-methyl-(5-2-chlprp)benzyl-2,2-cliethyl-l,3- clioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 330 was conducted, except that (2S, 3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation example 336) was used instead of that (2R, 3S)-methyl-4- (2chlorophenyl)-2,3-dihydroxybutanoate (.Preparation example 327), to obtain the title compound (0.6g, 50~75%)

¾ NMR (400MHz, CDC1 ₃ ): 6=0.93(t, J=7.4, 6H), 1.67~1.74(m, 4H) , 3.10(dcl, J=8.0, 14.4, 1H), 3.35(dd, J=4.0, 14.4, 1H), 3.73(s, 3H), 4.27(d, J=8.4, 1H), 4.42~4.47(m, 1H), 7.18-7.26(m, 2H) , 7.37~7.40(m, 2H)

Preparation example 340: ((4R, 5R)-5-(2-chlorobenzyl)-2,2-diethyl-l,3- dioxolan-4-yl )methanol

The substantially same method as described in Preparation example 338 was conducted, except that (4S, 5R)-methyl-(5-2-chlprp)benzyl-2,2-diethyl-l,3- di oxo lane-4-carboxylate (Preparation example 339) was used instead of (4S , 5R)-methy1-5-(2-ch1 robenzy1 )-2 , 2-dimethy1-1 , 3-di oxo1 ane-4-carboxyla e (Preparation example 337), to obtain the title compound (0.5g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=0.93(dt, J=2.1, 7.5, 6H) , 1.62~1.70(m, 4H), 1.83(q, J=4.3, 1H), 3.11(ddd, J=6.0, 14.2, 28.0, 2H), 3.44(ddd, J=4.8, 7.2, 12.0, 1H), 3.64~3.69(m, 1H), 3.88(ddd, J=3.3, 4.9, 8.3, H), 4.18-4.24(m, 1H), 7.19~7.26(m, 2H), 7.36~7.39(m, 2H)

Preparation example 341 ^' · (2S, 3R)-methyl-3-(2-chlorobenzyl )-l ,4- dioxas i o[4.4]nonane-2-carboxyl ate

The substantially same method as described in Preparation example 339 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (0.5g, 60-85%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.65~1.80(m, 5H), 1.89~2.00(m, 3H) , 3.13(dd, J=7.8, 14.2, 1H), 3.32(dd, J=4.6, 14.2, 1H), 3.72(s, 3H), 4.28(d, J=7.2, 1H), 4.41~4.46(m, 1H), 7.19~7.26(m, 2H), 7.35~7.40(m, 2H)

Preparation example 342: ((2R, 3R)-3-(2-chlorobenzyl )-l ,4- dioxaspi ro[4.4]nonan-2-yl )methanol

The substantially same method as described in Preparation example 340 was conducted, except that (2S, 3R)-methyl-3-(2-chlorobenzyl)-l,4- clioxaspiro[4.4]nonane-2-carboxylate (Preparation example 341) was used instead of that (4S, 5 )-methyl-(5-2-chlprp)benzyl-2,2-diethyl-l,3- dioxolane-4-carboxylate(Preparat ion example 339), to obtain the title compound(0.4g, 70~95%)

lH NMR (400MHz, CDC1 ₃ ): δ =1.69-1.74(m. 3H), 1.77~1.85(m, 5H) , 3.11(ddd, J=6.3, 14.1, 31.3, 2H), 3.42~3.48(m. 1H) , 3.61-3.66(111, 1H) , 3.87~3.91(m, 1H), 4.19(q, J=6.8, 1H) , 7.19~7.26(m, 2H), 7.34~7.40(m, 2H)

Preparation example 343· ^' (2S, 3R)-methyl-3-(2-chlorobenzyl )-l,4- dioxaspiro[4.5]decane-2-carboxyla e

The substantially same method as described in Preparation example.341 was conducted, except that eye 1 ohexanone was used instead of cyclope anone, to obtain the title compound (0.9g, 60-85%)

lH NMR (400MHz, CDCI ₃ ) : δ =1.54-1.77(m, 10H), 3.12(dd, J=7.6, 14.4, 1H), 3.32(dcl, J=4.4, 14.4, 1H), 3.72(s, 3H), 4.30(cl, J=7.6, 1H), 4.46~4.51(.m, 1H), 7.18~7.26(m, 2H), 7.37~7.39(m, 2H)

Preparation example 344: ((2R, 3R)-3-(2-chlorobenzyl)-l,4- dioxaspiro[4.5]decan-2-yl)methanol

The substantially same method as described in Preparation example 342 was conducted, except that (2S, 3R)-niethyl-3-(2-chlorobenzyl)-l,4- dioxaspiro[4.5]decane-2-carboxylate (Preparation example 343) was used instead of (2S, 3R)-niethyl-3-(2-chlorobenzyl)-l,4-dioxaspiro[4.4]nonane-2- carboxylate (Preparation example 341), to obtain the title compound (0.7g, 70-95%)

^L H NMR (400MHz, CDCI ₃ ) : δ =1.38-1.45(m, 2H), 1.58~1.63(m, 8H), 1.84(q, J=4.3, 1H), 3.11(ddd, J=7.9, 15.9, 22.1, 2H), 3.43(ddd, J=4.6, 7.6, 12.1, 1H), 3.66~3.71(m, 1H) , 3.88~3.92(m, 1H), 4.21~4.26(m, 1H), 7.18~7.26(m, 2H), 7.37~7.39(m, 2H)

Preparation example 345· ^' (E)-4-(2chlorophenyl )but-3-enoic acid

The substantially same method as described in Preparation example 278 was conducted, except that 2-(2-chloropheny1 )acetaldehyde was used instead of phenylacetaldehyde, to obtain the title compound (4.0g, 55-80%)

¾ NMR (400MHz, CDC1 ₃ ): 6=3.39(d, J=8.8, 2H) , 6.31(td, J=7.9, 14.8, 1H), 6.94(d, J=16. 1H), 7.17~7.45(m, 3H), 7.56~7.59(m, 1H)

Preparation example 346: (E)-4-(2-chlorophenyl )but

The substantially same method as described in Preparation example 279 was conducted, except that (E)-4-(2chlorophenyl)but-3-enoic acicKPreparat ion example 345) was used instead of (E)-4-phenylbut-3-enoic acid(Preparation example 278), to obtain the title compound (1.2g, 55-80%)

¾ NMR (400MHz, CDC13) ^: 6=2.55(ddd, J= 4.1, 11.9, 21.5, 2H) , 3.82(t, J=5.8, 2H), 6.24(td, J=7.2, 15.7, 1H) , 6.87(d, J=14.8, 1H), 7.12~7.25(ni, 3H), 7.36(dd, J=1.2, 8.0, 1H) , 7.52(dd, J=1.6, 9.2, 1H)

Preparat ion example 347: (E)-tert-butyldimethyl (4-(2-chloropheny1 )but-3- enyloxy)si lane

The substantially same method as described in. Preparation example 280 was conducted, except that (E)-4-(2-chlorophenyl )but-3-en-l-ol (Preparat ion example 346) was used instead of (E)-4-phenylbut-3-en-l-ol (Preparat ion example 279), to obtain the title compound( 1. lg, 80~98%)

¾ NMR (400MHz, CDC1 ₃ ): 5=0.07(s, 3H), 0.10(s, 3H), 0.92(d, J=6.4, 9H), 2.51(q, J=4.5, 2H) , 3.78(t, J=6.6, 2H) , 6.26(td, J=7.2, 15.7, 1H), 6.84(d, J=15.6, 1H), 7.13~7.24(m, 3H), 7.36(dd, J=5.6, 12.4, 1H) , 7.53(dd, J=1.4, 7.8, 1H)

Preparation example 348: (E)-4-(2-chlorophenyl )but-3-enyl pivalate

The substantially same method as described in Preparation example 281 was conducted, except that (E)-4-(2-chlorophenyl )but-3-en-l-ol (Preparation example 346) was used instead of (E)-4-phenylbut-3-en-l-ol (Preparation example 279), to obtain the title compound(3.5g, 75~95 )

¾ NMR (400MHz, CDC1 ₃ ): 5=1.21(s, 9H), 2.55 ^~ 2.64(m, 2H), 4.24(t, J=6.4, 2H), 6.18(td, J=7.9, 14.8, lH), 6.86(d, J=16.0, 1H), 7.22~7.26(m, 2H), 7.38(dcl, J=3..6, 10.8, 1H), 7.51(dd, J=1.6, 7.6, 1H)

Preparation example 349: (1R, 2R)-4-(tert-butyldimethylsi lyloxy)-l-(2- ch1oropheny1 )butane-1 , 2-diol

The substantially same method as described in Preparation example 282 was conducted, except that (E)-tert-butyldimethyl (4-2-chloropheny1 )but-3- enyloxy)si lane(Preparat ion example 347) was used instead of (E)-tert- butyldimethyl (5-phenylpent-3-enyloxy)si lane (Preparation example 237), to obtain the title compound (0.7g, 70 ^~ 95%)

¾ NMR (400MHz, CDC1 ₃ ) ^: 6=0.10(s, 3H) , O.lKs, 3H) , 0.92(s, 9H), 1.69~1.70(m, 1H), 1.93~2.07(m, 1H), 3.51(d, J=4.8, 1H), 3.86(d, .1=3.2, 1H), 3.87(dd, J=3.2, 9.2, 1H), 3.91~3.96(m, 1H) , 4.01~4.06(m, 1H) , 5.05(t, J=4.6, 1H), 7.22~7.26(m, 1H) , 7.31~7.37(m, 2H), 7.59(dd, J=1.2, 7.6, 1H)

Preparation example 350: (3R, 4R)-3,4-dihydroxy-4-(2-chlorophenyl)butyl pivalate

The substantially same method as described in Preparation example 349 was conducted, except that (E)-4-(2-chlorophenyl )but-3-enyl pivalate (Preparation example 348) was used instead of (E)-tert-butyldimethyl (4-2- chlorophenyl )but-3-enyloxy)si lane (Preparation example 347), to obtain the title compound(3.2g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.19(s, 9H), 1.76-1.84(m, 1H), 1.90-1.98(m,

1H), 2.70(d, J=4.4, 1H), 2.86(d, J=5.2, 1H), 3.84~3.90(m, 1H) , 4.14 ^~ 4.21(m, 1H), 4.35~4.41(m, 1H), 5.05(t, J=5.0, 1H), 7.23~7.39(m, 3H), 7.54(dd, J=1.6,

7.6, 1H)

Preparation example 351: tert-butyl (2-((4R, 5R)-5-(2-chlorophenyl )-2,2- dimethy1-1 , 3-di oxo1 an-4-y1 )ethoxy)dimethy1 si 1ane

The substanti lly same method as described in Preparation example 284 was conducted, except that (1R, 2R)-4-(tert-butyldiinethylsi lyloxy)-l-(2- chlorophenyl )butane-l,2-diol (Preparation example 349) was used instead of ( 1R, 2R)-4-( tert-buty1dimethy1 s i 1 1oxy)-1-pheny1 butane-1 , 2-dio 1 (Preparation example 282), to obtain the title compound (0.8g, 70~95 )

¾ NMR (400MHz, CDC1 ₃ ): 6=0.02(s, 3H) , 0.07(s, 3H), 0.86(s, 9H), 1.50(s, 3H), 1.58(s, 3H), 1.82~1.99(m, 2H), 3.68~3.78(m, 2H) , 3.95(dt, J=3.3, 8.7, 1H), 5.16(d, J=8.4. 1H) , 7.21~7.27(m, 1H) , 7.31~7.38(m, 2H) , 7.60(dd, J=1.6, 7.6, 1H)

Preparation example 352: 2-((4R, 5 )-5-(2-chlorophenyl)-2,2-climethyl-l,3- dioxo1 an-4-y1 )ethano1 The substantially same method as described in Preparation example 285 was conducted, except tert ^~ butyl (2-((4R, 5R)-5-(2-chlorophenyl )-2,2-dimethyl- l,3-dioxolan-4-yl )ethoxy)dimethylsi lane (Preparation example 351) was used instead of tert-butyl (2-( (4R , 5R)-5-pheny1-2 , 2-dimethy1-1 , 3-di oxo 1 an-4- yl )ethoxy)dimethylsi lane (Preparation example 284), to obtain the title compound(0.7g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.56(s, 3H), 1.62(s, 3H), 1.92~2.04(m, 2H), 2.26(q, J=3.7, 1H), 3.75-3.90(m, 2H), 3.94(td, J=3.9, 8.5, 1H), 5.23(d, J=15.6, 1H), 7.22~7.27(m, 1H), 7.33~7.39(m, 2H), 7.62(dd, J=1.6, 7.6, 1H)

Preparation example 353 ^' · (IS, 2S)-4-(tert-butyldimethylsi lyloxy)-l-(2- ch1oropheny1 )butane-1 , 2-dio1

The substantially same method as described in Preparation example 286 was conducted, except that (E)-tert-butylclimethyl (4-(2-chlorophenyl. )but ^~ 3- enyloxy)si lane (Preparation example 347)was · used instead of (E)-tert- butyldimethyl (4-phenylbut-3 ^~ enyloxy)si lane (Preparation example 280), to obtain the title compouncl(0.7g, 70-95%)

T-I NMR (400MHz, CDC1 ₃ ) 6=1.19(s, 9H), 1.76~1.84(m, 1H), 1.90-1.98(m, 1H), 2.70(d, J=4.4, 1H), 2.86(d, J=5.2, 1H), 3.84~3.90(m, 1H), 4.14~4.21(m,

1H), 4.35~4.41(m, 1H), 5.05(t, J=5.0, 1H), 7.23~7.39(m, 3H), 7.54(dd, J=1.6,

7.6, 1H)

Preparation example 354: (3S, 4S)-3,4-dihydroxy-4-(2-chlorophenyl )butyl pivalate

The substantially same method as described in Preparation example 353 was conducted, except that (E)-4-(2-chlorophenyl )but-3-enyl pivalate (Preparation example 348) was used instead of ( (E)-ter t-butyldimethyl (4-(2- chloropheny1 )but-3-enyloxy)si lane (Preparation example 347), to obtain the title compound(3. Og, 70-95%) ¾ NMR (400MHz, CDC1 ₃ ) - 6=1.19(s, 9H). 1.76-1.84(m, 1H) , 1.90-1.98(m,

1H), 2.70(d, J=4.4, 1H), 2.86(d, J=5.2, 1H), 3.84~3.90(m, 1H), 4.14~4.21(m,

1H), 4.35~4.41(m, 1H), 5.05(t, J=5.0, 1H), 7.23~7.39(m, 3H), 7.54(dd, J=1.6,

7.6, 1H)

Preparation example 355· ^' tert-butyl(2-((4S, 5S)-5-(2-chlorophenyl)-2,2- dimethyl-l,3-dioxolan-4-yl )ethoxy)dimethylsi lane

The substantially same method as described in Preparation example 351 was conducted, except that (IS, 2S)-4-(tert-butyldimethylsi lyloxy)-l-(2- chlorophenyl )butane-l,2-diol (Preparation example 353) was used instead of 1R, 2R)-4-( tert-buty1dimethy1 s i 1y1 oxy)-1-(2-ch1oropheny1 )butane-1 , 2-cli 01 (Preparation example 349), to obtain the title compound(0.7g, 70~95%)

¾ NMR (400MHz, CDC I 3 ) : 6=0.02(s, 3H), 0.07(s, 3H), 0.86(s, 9H) , 1.50(s, 3H), 1.58(s, 3H), 1.82~1.99(m, 2H) , 3.68~3.78(m, 2H) , 3.95(dt, J=3.3, 8.7, 1H), 5.16(d. J=8.4, 1H), 7.21~7.27(m, 1H) , 7.31~7.38(m, 2H) , 7.60(dd, J=1.6, 7.6, 1H)

Preparation example 356: 2-((4S, 5S)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- dioxolan-4-yl )ethanol

The substan ially same method as described in Preparation example 352 was conducted, except that tert-butyl (2-( (4S, 5S)-5-(2-chlorophenyl )-2,2- climethy1-1 , 3-dioxo 1 an-4-y1 )ethoxy)climethy1 si 1 ane(Preparat ion examp1 e 355) was used instead of that tert-butyl (2-((4R,5R)-5-(2-chlorophenyl )-2, 2- climethyl-l,3-dioxolan-4-yl )ethoxy)dimethyl si lane (Preparation example 351), to obtain the title compound (0.3g, 80~95%) .

Ί-ί NMR (400MHz, CDCI3) : 6=1.56(s, 3H), 1.62(s, 3H), 1.92~2.04(m, 2H) , 2.26(q. J=3.7, 1H) , 3.75~3.90(m, 2H) , 3.94(td, J=3.9, 8.5, 1H) , 5.23(d, J=15.6, 1H), 7.22~7.27(m, 1H), 7.33~7.39(m, 2H), 7.62(dd, J=1.6, 7.6, 1H) Preparation example 357: 2-((4R, 5R)-2,2-diethyl-5-(2-chlorophenyl)-l,3- clioxolan-4-yl)ethyl pivalate

The substantially same method as described in Preparation example 290 was conducted, except that (3R, 4R)-3,4-dihydroxy-4-(2-chlorophenyl )butyl pivalate (Preparation example 350) was used instead of (3R, 4R)-3,4- dihydroxy-4-phenylbutyl pi.valate(Preparat ion example 283), to obtain the title compouncKO.Sg, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.15(s, 9H) , 1.76(q, ,1=7.6, 2H), 1.84-1.90(m, 2H), 2.00~2.07(m, 2H), 3.85(dt, J=3.7, 8.5, 1H) , 4.14~4.27(m, 2H) , 5.17(d, J=8.4, 1H), 7.22~7.28(m, 1H), 7.32~7.38(m, 2H) , 7.64(dd, J=1.4, 7.8, 1H)

Preparation example 358: 2-((4R, 5R)-2,2-diethyl-5-(2-chlorophenyl)-l,3- dioxo1 n-4-y1 )ethyl pivalate

The substantially same method, as described in Preparation example 291 was conducted, except that 2-((4R, 5R)-2,2-diethyl-5-(2-chlorophenyl)-l,3- dioxolan-4-yl )ethyl pivalate (Preparation example 357) was used instead of 2-( (4R , 5R)-2 , 2-di eth 1-5-pheny1-1 ,3-dioxo 1an-4-y 1 )ethy1 pivalate(Preparat ion example 290), to obtain the title compound (0.6g, 80-95%)

T-I NMR (400MHz, CDC1 ₃ ): 5=1.02(t, J=7.4, 3H) , 1.08(t, J=7.4, 3H) , 1.80(q, .1=7.5, 2H), 1.86~1.91(m, 2H) , 1.96-2.00(m, 2H), 2.37(q, J=3.7, 1H), 3.76~3.95(m, 3H) , 5.23(d, J=8.4, 1H), 7.25~7.27(m, 1H) , 7.32~7.39(m, 2H) , 7.65(dd, J=1.8, 7.8, 1H)

Preparation example 359: 2-((2R, 3R)-3-(2-chlorophenyl)-l,4- dioxaspiro[4.4]nonan-2-yl )ethyl pivalate

The substantially same method as described in Preparation example 357 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound CO.Sg, 60~85%)

¾ NMR (400MHz, CDC1 ₃ )■ ^" 6=1.17(s, 9H), 1.58-2.02(m, 10H). 3.86(ddd, J=3.8, 8.2, 8.2, 1H), 4.11~4.28(m, 2H). 5.13(d, J=8.0, 1H), 7.20-7.39(m, 3H), 7.58(dd, J=1.6, 8.0, 1H)

Preparation example 360: 2-((2R, 3R)-3-(2-chIorophenyl)-l,4- dioxaspiro[4.4]nonan-2-y1 )ethano1

The substantially same method as described in Preparation example 358 was conducted, except that 2-((2R, 3R)-3-(2-chlorophenyl)-l ,4- clioxaspiro[4.4jnonan-2-yl )ethyl pivalate (Preparation example 359) was used instead of that 2-((4R, 5R)-2,2-diethyl-5-(2-chlorophenyl ^-clioxolan^- yDethyl pivalate (Preparation example 357), to obtain the title compound (0.5g, 80-95%)

^L H NMR. (400MHz, CDC1 ₃ ): δ =1.72-1.90(m, 4H), 1.93 ^~ 1.98(m, 6H), 2.28(q, J=3.7, 1H), 3.76~3.93(m, 3H) , 5.18(d, J=8.0, 1H), 7.24~7.29(m, 1H), 7.32 ^~ 7.38(m, 2H), 7.60(dd, J=1.8, 7.8, 1H)

Preparation example 361: 2-((2R, 3R)-3-(2-chlorophenyl)-l,4- di oxaspi ro[4.5] decan-2-y1 )etby 1 pivalate

The substantially same method as described in Preparation example 359 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (l.Og, 60~85%)

H NMR (400MHz, CDC1 ₃ ): 6=1.15(s, 9H), 1.70~1.94(m, 10H), 2.06~2.09(m, 2H), 3.86(dt, J=3.5, 8.5, 1H) , 4.16~4.26(m, 2H) , 5.18(d, J=8.4, 1H) , 7.22~7.28(m, 1H), 7.32~7.38(m, 2H) , 7.61(dd, J=1.4, 7.8, 1H)

Preparation - example 362: 2-((2 , 3R)-3-(2-chlorophenyl )-l ,4- dioxaspi ro[4.5]decan-2-y1 )ethano1

The substantially same method as described in Preparation example 360 was conducted, except that 2-((2R, 3R)-3-(2-chlorophenyl )-l ,4- dioxaspiro[4.5]decan-2-yl )ethyl pivalate (Preparation example 361) was used instead of that 2-((2R, 3R)-3-(2-chlorophenyl)-l,4-dioxaspiro[4.4]nonaii-2- yDethyl pivalate(Preparat ion example 359), to obtain the title compound (0.6g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6 =1.42-1.50(m, 2H), 1.63-1.77(m, 5H), 1.82~1.89(m, 5H), 2.41(q, J=3.9, 1H) , 3.78~3.96(m, 3H), 5.25(cl, J=8.4, IH) . 7.21~7.28(m, 1H), 7.32~7.38(m, 2H) , 7.63(dd, J=1.4, 7.8, 1H)

Preparation example . 363: 2-((4S, bS)-2,2-diethyl-5-(2-chlorophenyl)-l,3- dioxolan-4-y Oethyl pivalate

The substantially same method as described in Preparation example 357 was conducted, except that (3S, 4S)-3,4-dihydroxy-4-(2-chlorophenyl )butyl pivalate (Preparation example 354) was used instead of (3R, 4R)-3,4- dihydroxy-4-(2-chlorophenyl)butyl pivalate (Preparation example 850), to obtain the title compound (0.7g, 70-95%). ¾ NMR (400MHz, CDCI 3 ) : 5=1.15(s, 9H), 1.76(q, J=7.6, 2H) , 1.84~1.90(m, 2H), 2.00~2.07(m, 2H), 3.85(dt, J=3.7, 8.5, 1H), 4.14~4.27 (111 , 2H), 5.17(d, J=8.4, 1H), 7.22~7.28(m, 1H) , 7.32~7.38(m, 2H), 7.64(dd, J=1.4, 7.8, 1H)

Preparation example 364: 2-((4S, 5S)-2,2-diethyl-5-(2-chlorophenyl)-l,3- dioxo1 an-4-y1 )ethano1

The substantially same method as described in Preparation example 358 was conducted, except that 2-((4S, 5S)-2,2-diethyl-5-(2-chlorophenyl )-l,3- dioxolan-4-yl )ethyl pivalate(Preparat ion example 363) was used instead of 2-( (4R, 5R)-2 , 2-di ethy1-5-(2-ch1oropheny1 )-1 , 3-dioxo1 an-4-y1 )ethy1 pivalate (Preparation example 357), to obtain the title compound (0.5g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ) · ^' 5=1.02(t, J=7.4, 3H), 1.08(t, J=7.4, 3H), 1.80(q, J=7.5, 2H), 1.86~1.91(m, 2H) , 1.96-2.00(m, 2H) , 2.37(q, J=3.7. 1H) , 3.76~3.95(m, 3H), 5.23(d, J=8.4, 1H), 7.25~7.27(m, 1H), 7.32~7.39(m, 2H) , 7.65(dcl, J=1.8, 7.8, 1H)

Preparation example 365· ^' 2-((2S, 3S)-3-(2-chlorophenyl )-1.4- di oxaspi r 0[4.4]nonan-2-y1 )ethy1 piva1 ate

The substantially same method as described in Preparation example 363 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (0.6g, 60-85%)

¾ NMR (400MHz, CDCI ₃ ) : 6=1.17(s, 9H) , 1.58~2.02(m, 10H) , 3.86(ddd, J=3.8, 8.2, 8.2, 1H), 4.11~4.28(m, 2H), 5.13(d, J=8.0, 1H), 7.20~7.39(m, 3H) , 7.58(dd, J=1.6, 8.0, 1H)

Preparation example 366: 2-((2S, 3S)-3-(2-chloropheny1 )-l,4- di oxaspi ro[4.4]nonan-2-y1 )ethano1

The substantially same method as described in Preparation example 364 was conducted, except that 2-((2S, 3S)-3-(2-chlorophenyl )-l,4- dioxaspiro[4.4]nonan-2-yl )ethyl pivalate (Preparation example 365) was used instead of that 2-((4S, 5S)-2 ,2-diethyl-5-(2-chlorophenyl )-l .3-dioxo rid ^¬ yl )ethyl pivalate (Preparation example 363), to obtain the title compound (0.4g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.72-1.90(m, 4H) , 1.93-1.98(m, 6H) , 2.28(q, J=3.7, 1H), 3.76~3.93(m, 3H) , 5.18(d, J=8.0, 1H), 7.24~7.29(m, 1H), 7.32~7.38(m, 2H) , 7.60(dd, J=1.8, 7.8, 1H)

Preparation example 367: 2-((2S, 3S)-3-(2-chlorophenyl. )-l ,4- dioxaspiro[4.5]decan-2-yl )ethyl pivalate

The substantially same method as described in Preparation example 366 was conducted, except that cvclohexanone was used instead of cyclopetanone, to obtain the title compound (0.7g, 60~85 )

¾ NMR (400MHz, CDC1 ₃ ): 5=1.15(s, 9H), 1.70~1.94(m, 10H), 2.06~2.09(m, 2H), 3.86(dt, J=3.5, 8.5, 1H), 4.16~4.26(m, 2H), 5.18(d, J=8.4, 1H), 7.22-7.28(m, 1H), 7.32~7.38(m, 2H), 7.61(dcl, J=1.4, 7.8, 1H)

Preparation example 368: 2-((2R, 3R)-3-(2-chlorophenyl)-l,4- clioxaspiro[4.5jdecan-2-yl )ethanol

The substantially same method as described in Preparation example 366 was conducted, except that 2-((2S,3S)-3-(2-chlorophenyl)-l,4- dioxaspiro[4.5]decan-2-yl )ethyl pivalate (Preparation example 367) was used instead of that 2-((2S, 3S)-3-(2-chlorophenyl)-l,4-dioxaspiro[4.4]nonan-2- yOethyl pivalate (Preparation example 365), to obtain the title compound (0.4g, 80-95%).

¾ NMR (400MHz, CDC1 ₃ ) ^" · 5=1.42-1.50(m, 2H) , 1.63~1.77(m, 5H), 1.82~1.89(m, 5H) , 2.41(q, J=3.9, 1H), 3.78~3.96(m, 3H) , 5.25(d, J=8.4, 1H), 7.21~7.28(m, 1H) , 7.32~7.38(m, 2H), 7.63(dd, J=1.4, 7.8, 1H)

Preparation example 369: (E)-l-(3(benzyloxy)prop-lenyl )2-chlorobenzen

To a solution of ^' (E)-3-(2-chlorophenyl ) prop-2-en-l-ol (Preparat ion example 1, 5.3 g, 31.6 mmole) in THF was added NaH (60 % in mineral oil, 0.91g, 37.7 mmole) and Benzyl bromide (4.12 mL, 34.8 mmole), sequent ly at 0 ^° C. The reaction mixture was stirred at room temperature for 18 nr. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0 ^° C then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgS0 ₄ and evaporated under reduced pressure. The crude compound was purified by silica gel column to produce the title compound (4.94 g, 70-90%).

¾ NMR (400 MHz, CDC13 ) δ 7.57 (dd, J = 7.76, 2, 1H), 7.42-7.13 (m. 3H) , 7.05 (d, J = 16 Hz, 1H), 6.37-6.30 (m, 1H) , 4.62 (s, 2H) , 4.26 (dd, /= 6, 1.6, 2H).

Preparation example 370: (+ )-2-(benzyloxymethy1 )-3-(2-chlorophenyl )oxirane

To a solution of (E)-l-(3-(benzyloxy)prop-l-enyl )-2- chlorobenzene(Preparat ion example 369, 4.94 g, 22 mmole) in CH ₂ C1 ₂ (HO mL) was added 3-chloroperoxybenzoic acid (70-75 %, 8 g, 33 mmole) portionwise at 0 ^° C. The mixture was stirred for 18 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0 ^° C then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined orgcinic layer was washed with sat' NaHCOs, H ₂ O , then dried over MgS0 and evaporated under reduced pressure. The crude compound was purified by silica gel column to produce the title compound (4.3 g, 60~80 ).

¾ NMR (400 MHz, CDC1 ₃ ) δ 7.42-7.24 (m, 9H), 4.68 (cl, J = 14.8, 2H), 4.18 (d, ./= 2 Hz, 1H), 3.96 (del, J = 11.6, 2.8 Hz, 1H), 3.69-3.64 (111, 1H), 3.14 (qt, J = 2.4 Hz, 1H)

Preparation example 371: ( ± )-3-(benzyloxy)-l-(2-chlorophenyl )-2- hydroxypropyl & (± )-3-(benzyloxy)-l-(2-chlorophenyl )-l-hydroxypropan-2-yl acetate

To a so1 Lit i on of ( + )-2-(benzy1oxymethy 1 )-3-(2- chlorophenyDoxi rane(Preparat ion example 370, 4.3 g, 15.6 mniole) in Acetic acid (78 mL) was added Cerium Ammonium Nitrate (1.71 g, 3.1 mmole) at room temperature. The mixture was stirred for 18 hr at room temperature. The TLX showed complete consumption of SM. The reaction mixture was quenched with sat ^' NaHCOs to pH7 at 0 ^° C then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O , then dried over MgS0 ₄ and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (1) (1.2 g, 23 %) . (2)(1.8 g, 34 %) .

(1) ¾ NMR (400 MHz, CDC 13) δ 7.55-7.22 (m, 9H) , 5.41 (t, / = 5 Hz, 1H), 5. 33-5.29 (m, 1H) , 4.61-4.47 (m, 2H) , 3.70-3.63 (m, 2H, -OH), 2.09 (s, 3H) .

(2) ^l H NMR (400 MHz , CDC13) δ 7.46-7.24 (in, 9H) , 6.31 (d, J = 5.6 Hz, 1H), 4.55 (d, J = 9.6 Hz, 2H) , 4.24-4.22 (m, 1H), 3.67-3.55 (m, 2H), 2.52 (cl, J

= 5.2 Hz, -OH), 2.10 (s, 3H) .

Preparation example 372: ( + )-3-(benzyloxy)-l-(2-chlorophenyl )propane ^~ l,2- dioKAnti mixture)

To a solution of ( + )-3-(benzyloxy)-l-(2-chlorophenyl )-2-hydroxypropyl and ( ± )-3-(benzyloxy)-l-(2-chlorophenyl )-l-hydroxypropan-2-yl acetate (Preparation example 371, 3 g, 8.9 mmole) in MeOH (36 mL) and H ₂ 0 (4 mL) was added ₂ CO (3.69 g, 26.7 mmole) at 0 ^° C . The mixture was stirred for 1.5 hr at 0 ^° C. The TLC showed complete consumption of SM. The reaction mixture was quenched with H ₂ 0 at 0 ^° C then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H ₂ 0, then dried over MgS0 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (2.4 g, 80-95 %) .

¾ NMR (400 MHz , CDC 13) δ 7.50 (del, / = 7.6, 1.2 Hz, 1H), 7.35-7.19 (m, 8H), 5.28 (t, .7 =4.8 Hz, 1H), 4.46 (d, J = 6 Hz, 2H), 4.18-4.13 (m, 1H), 3.55-3.42 (m, 3H, -OH), 3.02 (d, J = 5.2 Hz, -OH).

Preparation example 373: ( + )-4-(benzyloxymethyl )-5-(2-chlorophenyl )-2,2- dimethyl-1 , 3-dioxolane

To a solution of ( + )-3-(benzyloxy)-l ^~ (2-chlorophenyl )propane-l ,2-diol (Preparation example 372, 2.4 g, 8.2 mmole) in CH ₂ CI ₂ (40 mL) was added p- toluenesul fonyl chloride (15.2 g, 0.08 mmole), and 2,2-dimethoxypropan (8.4mL, 9.84mmole) at 0 ^° C sequent ly. The mixture was stirred for 1.5 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with ¾0 then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with ¾0, then dried over MgS0 ₄ and evaporated under reduced pressure. The crude compound was purified by silica gel column to produce the title compound (2.2 g, 75~90 %) . TT NMR (400 MHz, CDC 13) δ 7.61 (del, J = 7.4, 1.6 Hz, 1H) , 7.35-7.16 (m, 8H), 5.63 (d, J = 6.8, 1H), 4.83-4.78 (m, 1H). 4.26 (d, J = 12 Hz, 2H), 3.14-3.06 (m, 2H) , 1.66 (s, 3H) , 1.53 (s, 3H). Preparation example 374: 5-(2-chlorophenyl )-2, 2—dimethyl -1,3-dioxolan-4- yl )methanol (SR & RS mixture)

To a solution of ( + )-4-(benzyloxymethyl )-5-(2-chlorophenyl )-2,2- dimethyl-1,3 -dioxolane (Preparation example 375, 2.2 g, 6.6 mniole) in EtOAc (33 mL) was added 10% Pd/C on carbon (0.11 g) at room temperature. The mixture was stirred for 1 hr at room temperature under ¾ (g). The TLC showed complete consump ion of SM. The reaction mixture was filtered through celite pad then evaporated under reduced pressure. The crude compound was purified by silica gel column to produce the title compound (1.5 g, 80-95 %).

¾ NMR (400 MHz, CDC1 ₃ ) δ 7.61 (dd, J = 7.4. 1.6, 1H) , 7.35-7.16 (m, 8H), 5.63 (d, J = 6.8 Hz, 1H), 4.83-4.78 (m, 1H), 4.26 (d, J = 12, 2H), 3.14- 3.06 (in, 2H), 1.66 (s, 3H), 1.53 (s, 3H).

Preparation example 375: (2R,3R)-2-(benzyloxymethyl )-3-(2- ch1oropheny1 )ox i rane

To a solution of (£)-l-(3-(benzyloxy)prop-l-enyl )-2- chlorobenzene(Preparat ion example 369, 4.16 g, 18.58 mmole) and l,2;4,5-di- (9- i sopropy1 idene- ?-Z?-erj^ :?r^2,3-hexodiulo-2,6-pyranose (5.76 g, 22.30 mmole) in ACN-DMM (3:1, v/v) (185 mL) was added buffer (0.2M R ₂ C0 ₃ -Ac0H in 4 X 10 ^" M aq. EDTA, buffer pH = 8.0) (185 mL) and B11 ₄ NHSO4 (0.26 g, 0.75 mmole). After the mixture was cooled to 0 ^° C, a solution of Oxone (15.76 g, 25.64 mmole) in 4 X 10 ^"4 M aq. EDTA (100 mL) and a solution of K2CO3 (13.6 g, 98.47 mmole) H?0 (100 mL) were added dropwise separately over a period of 3.5hr via a syringe pump at 0 ^° C . The reaction mixture was stirred for 14hr at 0 ^° C . The reaction mixture was quenched with ¾0 then extracted with. EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with ¾0 then dried over MgSO.-i and evaporated under reduced pressure The crude compound was purified by silica ge column to produce the title compound (2.9 g, 50~65 %). ^L H NMR (400 MHz, CDC13) 63.14 (qt, J = 2.4 Hz, 1H). 3.69-3.64 (m, 1H), 3.96 (del, J = 11.6, 2.8 Hz, 1H), 4.18 (d, J = 2 Hz, 1H), 4.68 (d, /= 14.8, 2H), 7.42-7.24 (m, 9H),

Preparation example 376: (IS, 2R)-3-(benzyloxy)-l-(2-chlorophenyl )-2- hydroxypropyl acetate

To a solution of (2R,3R)-2-(benzyloxymethyl )-3-(2-chlorophenyl)oxirane (Preparation example 375, 2.9 g, 10.55 mmole) in Acetic acid (55 mL) was added Cerium Ammonium Nitrate (1.15 g, 2.11 mmole) at room temperature. The mixture was stirred for 18 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with sat' NaHCO?, to pH7 at 0 ^° C then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with ¾0. then dried over MgS0 ₄ and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound(1.2 g, 30-50 %),

¾ NMR (400 MHz, CDC1 ₃ ) 62.10 (s, 3H) , 2.52 (d, J = 5.2 Hz, -OH), 3.67- 3.55 (m, 2H), 4.24-4.22 (m, 1H), 4.55 (cl, /= 9.6 Hz, 2H), 6.31 (d, /= 5.6 Hz, 1H), 7.46-7.24 (m, 9H) .

Preparation example 377: (IS, 2R)-3-(benzyloxy)-l-(2-chlorophenyl )propane- 1,2-diol

To a solution of (IS, 2R)-3-(benzyloxy)-l-(2-chlorophenyl )-2-hydroxypropyl acetate (Preparation example 376, 1.2 g, 3.58 mmole) in MeOH (16.2 mL) and H ₂ 0 (1.8 mL) was added K ₂ C0 ₃ (1.48 g, 10.74 mmole) at 0 ^° C . The mixture was stirred for 1.5 hr at 0 ^° C. The TLC showed complete consumption of SM. The reaction mixture was quenched with ¾0 at 0 ^° C then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with ¾0, then dried over MgS0 ₄ and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (1.0 g, 80~100 %).

¾ NMR (400 MHz, CDC13 ) 63.02 (d, /= 5.2 Hz, 1H), 3.55-3.42 (m, 3H, -OH), 4.18-4.13 (m, 1H), 4.46 (d, / = 6 Hz, 2H) , 5.28 (t, / =4.8 Hz, 1H), 7.35- 7.19 (m, 8H), 7.50 (dd, /= 7.6, 1.2 Hz, 1H).

Preparation example 378: (4R, 5S)-4-(benzyloxymethyl )-5-(2-chlorophenyl )- 1 , 3-dioxo1ane

The substantially same method as described in Preparation example 373 was conducted, except that (IS, 2R)-3-(benzyloxy)-l-(2-chlorophenyl )propane- 1,2-diol (Preparation example 377) was used instead of that (±)-3- (benzyloxy)-l-(2-chlorophenyl )propane-l,2-diol (Preparation example 372), to obtain the title compound(0.77 g, 80-100 %) .

¾ NMR (400 MHz, CDC1 ₃ ) 51.53 (s, 3H) , 1.66 (s, 3H), 3.14-3.06 (m, 2H), 4.26 (d, J = 12 Hz, 2H), 4.83-4.78 (m, 1H) , 5.63 (d, J = 6.8, 1H),.7.35- 7.16 (m, 8H), 7.61 (dd, J = 7.4, 1.6 Hz, 1H). Preparation example 379: ((4R, 5S)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- cli oxo1 an-4-y1 )methano1

The substantially same method as described in Preparation example 374 was conducted, except that ((4R, 5S)-4-(benzyloxymethy1 )-5-(2-chloropheny1 )- 2,2-dimethyl-l,3-dioxolane (Preparation example 378) was used instead of that ( ± )-4-(benzyloxymethyl )-5-(2-chlorophenyl )-2 , 2-dimethy1-1 , 3 di oxolane (Preparation example 373), to obtain the title compound (0.58 g, 80-100 %) .

T-I NMR (400- MHz, CDC1 ₃ ) 61.66 (s, 3H), 1.53 (s, 3H), 3.14-3.06 (m, 2H), 4.26 (d, J = 12, 2H), 4.83-4.78 (m, 1H), 5.63 (cl, J = 6.8 Hz, 1H), 7.35- 7.16 (m, 8H), 7.61 (del, J = 7.4, 1.6, 1H).

Preparation example 380: (E)-ethyl 3-(2,4-dichlorothiazol-5-yl )acrylate To a stirred solution of 2,4-dichlorothiazole-5-carbadehyde(5.0g, 27.5mmol) in THF (200mL) was added tr iethylphosphonoacetate(6.6mL, 32.9mmol) and Li thiumhydroxide (0.79mL, 32.9mmol), 4A molecular sieve 5g at room temperature under N2. The mixture was stirred for 3h. The resulting mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sul fate(MgS0 ₄ ) , filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (6.1g, 80-95%)

¾ NMR (400MHz, DMS0) : δ= 1.22(q, 7=12.5, 3H), 4.23(q, J=7.0, 2H), 6.54(d, 7= 16, 1H), 7.54(d, 7= 16, 1H).

Preparation example 381: (2S,3S)-ethyl 3-(2,4-dichlorothiazol-5-yl )-2,3- clihydroxypropanoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-ethyl 3-(2,4-dichlorothiazol-5-yl)acrylate (Preparation example 380) was used instead of (E)-l-chloro-2-(3- (methoxymethoxy)prop-l-enyl )benzene(Preparat ion example 2), to obtain the title compound (3.94g, 50-70%); ¾ NMR (400MHz, DMS0) · ^' δ= 1.22(q, 7=12.5, 3H), 4.18(q, 7=7.0, 2H) , 4.20(dd, 7= 2.4, 7= 7.6, 1H), 5.19(cld, 7= 2.6, 7= 5.8, 1H), 6.03(d, 7= 7.6, 1H) , 6.37(d, 7= 5.6, 1H).

Preparation example 382: (4S,5S)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2- dimethy1-1 , 3-d i oxo1 ane-4-carboxylate

The substantially same method as described in Preparation example 26 was conducted, except that (2S,3S)-ethyl 3-(2,4-dichlorothiazoi-5-yl )-2,3- dihydroxypropanoate (Preparation example 381) was used instead of (2S.3R)- methyl-3-(2-chlorophenyl )-2,3-dihydroxypfopanoate (Preparation example 25) , to obtain the title compound (0.13g, 65-80%) i NMR (400MHz, DMSO) · ^' δ= 1.20(t, 7=7.2, 3H), 1.42(s, 3H), 1.49(s, 3H), 4.18(m, 2H), 4.66(d, 7= 6.8, 1H) , 5.44(d, 7= 6.8, 1H).

Preparation example 383: ((4R,5S)-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl- 1 , 3-dioxo 1 an-4-y1 )methano1

The substantially same method as described in Preparation example 27 was conducted, except that (4S,5S)-ethyl 5-(2,4-dichlorothiazol-5-yl )-2,2- dimethyl-l,3-dioxolane-4-carboxylate(Preparation example 382) was used instead of (4S,5R)-inethyl-5-(2-chlorophenyl)-2,2-dimehtyl-1.3-dioxolan e-4- carboxylate (Preparation example 26), to obtain the title compound (0.05g, 50-70%)

4. NMR (400MHz, DMSO): δ= 1.42(d, 7=6.0, 6H), 3.59(m, 1H), 3.67(m, 1H) , 3.97(m, 1H), 5.04(t, 7= 5.4, 1H) , 5.10(d, 7= 8.4, 1H).

Preparation example 384: (2R, 3R)-ethyl 3-(2,4-dichlorothiazol-5-yl )-2,3- dihydroxypropanoa e

The substantially same method as described in Preparation Example 381 was conducted, except that (DHQVPHAL was used instead of (DHQD) ₂ -PHAL, to obtain the title compound(3.9g , 50~70%) .

¾ NMR (400MHz, DMSO): δ= 1.22(q, 7=12.5, 3H). 4.18(q, 7=7.0, 2H), 4.20(dd, 7= 2.4, 7= 7.6, 1H), 5.19(dd, 7= 2.6. 7= 5.8, 1H), 6.03(d, 7= 7.6, 1H), 6.37(d, 7= 5.6, 1H) .

Preparation example 385: (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2- dimethy1-1 , 3-dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 382 was conducted, except that (2R, 3R)-ethyl 3-(2,4-dichlorothiazol-5-yl)-2,3- dihydroxypropanoate(Preparat ion example 384) was used instead of (2S, 3S) ^~ ethyl 3-(2,4-dichlorothiazol-5-yl )-2,3-dihydroxypropanoate(Prepara ion example 381), to obtain the title compound(0.13g, 65-80%).

¾ NMR (400MHz, DMS0) : δ= 1.20(t, .7=7.2, 3H) , 1.42(s, 3H), ^' 1.49(s, 3H) , 4.18(m, 2H), 4.66(d, 7= 6.8, 1H) , 5.44(d, J= 6.8, 1H) .

Preparation example 386: ((4S, 5R)-5-(2,4-clichlorothiazol-5-yl )-2,2- dimethy1 -1 , 3-di oxo 1 an-4-y1 )methanol

The substantially same method as described in Preparation Example 388 was conducted, except that (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl )-2,2- dimethyl-1 ,3-dioxolane-4-carboxylate (Preparation example 385) was used instead of (4S, 5S)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2-climethyl-l,3- clioxolane-4-cai'boxylate(Preparat ion example 382), to obtain the title compound(0.05g, 50-70%).

¾ NMR (400MHz, DMS0): δ= 1.42(d, 7=6.0, 6H), 3.59(m, 1H), 3.67(m, 1H), 3.97(m, 1H), 5.04(t, /= 5.4, 1H) , 5.10(d, 7= 8.4, 1H).

Preparation example 387: (E)-ethyl 3-(2-chlorothiazol-5-yl )acrylate

The substantially same method as described in Preparation Example 380 was conducted, except that 2-chlorothi azole-5-carbadehyde was used instead of 2,4-dichlorothiazole-5-carbadehycle, to obtain the title compound (4.7g,

80-95%)

^X H NMR (400MHz, DMS0) : δ = 1.25(t, 7=7.0, 3H), 4.19(q, .7=7.2, 2H), 6.40(d, 7= 16, 1H), 7.81(d, 7= 16, 1H), S.lKs, 1H)

Preparation example 388: (2S,3S)-ethyl-3-(2-chlorothiazol-5-yl)-2,3- clihydroxypropanoate

The substantially same method as described in Preparation Example 381 was conducted, except that (E)-ethyl 3-(2-chlorothiazol-5- yl)acrylate(Preparat ion example 387) was used instead of (E)-ethyl 3-(2,4- dichlorothiazol-5-yl)acrylate(Preparation example 380), to obtain the title compound(4. lg, 50~70 ) .

. ^L H NMR (400MHz, DMS0) : δ= 1.20(t, 7=7.0, 3H), 4.12(q, 7=7.2, 2H), 5.18(d, 7= 1.6, Hi), 5.87(s, 1H), 6.12(s, 1H), 7.63(s, 1H).

Preparation example 389: (4S,5S)-ethyl-5-(2-chlorothiazol-5-yl)-2,2- dimethy1-1 , 3-dioxo1 ane-4-ca boxylate

The substantially same method as described in Preparation Example 382 was conducted, except that (2S, 3S)-ethyl 3-(2-chlorothiazol-5-yl)-2,3- dihydroxypropanoate(Preparat ion example 388) was used instead of (2S, 3S)- ethyl 3-(2,4-dichlorothiazol-5-yl )-2, 3-dihydroxypropanoate(Prepar t ion example 381), to obtain the title compound(1.0g, 65~80%).

^L H NMR (400MHz, DMS0): δ= 1.44(d, 7=16.8, 3H), 4.18(m, 2H) , 4.62(d, 7= 7.6, 1H), 5.50(d, 7= 7.2, 1H) , 7.74(s, 1H).

Preparation example 390: (4R, 5S)-5-(2-chlorothiazol-5-yl)2,2-dimethyl-l,3- di oxo 1 an-4-y1 )metha o 1

The substantially same method as described in Preparation Example 386 was conducted, except that (4S, 5S)-ethyl 5-(2-chlorothiazol-5-yl)-2,2- dimethyl-l,3-dioxolane-4-carboxylate(Preparation example 389) was used instead of (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-l,3- clioxo lane-4-carboxylate (Preparation example 385), to obtain the title compound(0.84g, 70-90%)..

H NMR (400MHz, DMSO): δ= 1.40(d, 7=2.0, 6H) , 3.59(q, 7=4.7, 2H), 3.94(m, 1H), 5.06(t, 7=6.6, 1H), 5.09(d, 7= 0.8, 1H), 7.69(s, 1H).

Preparation example 391: (2R, 3R)-ethyl 3-(2-chlorothiazol-5-yl)-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 384 was conducted, except that (E)-ethyl-3-(2-chlorothi azol-5- yl )acrylate(Preparat ion example 387) was used instead of (E)-ethyl 3-(2,4- dichlorothiazol-5-yl )acrylate(Preparat ion example 380), to obtain the title compound(3.9g, 50~70%) . lH NMR (400MHz, DMSO): δ= 1.20(t, 7=7.0, 3H) , 4.12(q, 7=7.2, 2H), 5.18(cl, 7= 1.6, 1H), 5.87(s, 1H) , 6.12(s, 1H), 7.63(s, 1H).

Preparation example 392: (4R, 5R)-ethyl-5-(2-chlorothiazol-5-yl)-2,2- dimethy1 -1 , 3-di oxo 1 a e-4-carboxylate

The substantially same method as described in Preparation Example 382 was conducted, except that (2R, 3R)-ethyl-3-(2-chlorothiazol-5-yl)-2,3- clihyclroxypropanoate(Preparat ion example 391) was used instead of (2S, 3S) ^~ ethyl 3-(2,4-dichlorothiazol-5-yl )-2,3-dihydroxypropanoate(Preparat ion example 381), to obtain the title compound(0.73g, 65~80%) .

¾ NMR (400MHz, DMSO): δ= 1.44(d, J=16.8, 3H) , 4.18(m, 2H) , 4.62(d, ./= 7.6, H ), 5.50(d, 7= 7.2, 1H), 7.74(s, 1H).

Preparation example 393: (4S, 5R)-5-(2-chlorothiazol-5-yl)2,2-dimethyl-l,3- di oxo 1 an-4-y 1 )methanol

The substantially same method as described in Preparation Example 386 was conducted, except that (4R, 5R)-ethyl-5-(2-chlorothiazol-5-yl)-2,2- climethyl-1 ,3-dioxolane-4-carboxylate(Prepara ion example 392) was used instead of (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl )-2 , 2-diniethyl-l , 3- dioxolane-4-carboxylate (Preparation example 385), to obtain the title compound(0.60g, 70-90%) ..

'Ή NMR (400MHz, DMSO): 6= 1.40(cl, 7=2.0, 6H), 3.59(q, 7=4.7, 2H) , 3.94(m, Hi), 5.06(t, 7=6.6, 1H), 5.09(d, 7= 0.8, 1H), 7.69(s, 1H).

Preparation example 394: (E)-ethyl-3-(4-methylthi azol-5-yl)aerylate

The substantially same method as described in Preparation Example 380 was conducted, except that 4-methyl thiazole-5-carbadehyde was used instead of 2,4-dichlorothiazole-5-carbadehyde, to obtain the title compound (15g, 80-95%)

¾ MR (400MHz, DMS0): δ= 1.25(t, 7=7.0, 311) , 1.45(s 3H), 4.19(q, J=7.0,

2H), 6.12(d, J= 16, 1H), 7.77(d, J= 16, 1H) , 9.09(s, 1H).

Preparation example 395: (2S,3S)-ethyl-3-(4-methyl thiazol-5-yl )-2,3- dihydroxypropanoate

The substan ially same method as described in Preparation Example 2 was conducted, except that (E)-ethyl-3-(4-methlythiazol-5- )acrylate(Preparat ion example 394) was used instead of (E)-ethyl-3-(2,4- clichlorothiazol-5-yl )acrylate(Preparat ion example 381), to obtain the title compound(4. Og, 50~70%) .

¾ NMR (400MHz, DMS0) : 6= l.ll(t, J=7.0, 3H), 1.43(s, 3H), 4.04(m, 2H) , 5.11(t, .7= 3.8, 1H), 5.70(d, 7=20.7, 1H) , 5.92(d, 7= 4.0, 1H), 6.81(s, 1H) , 8.86(s, 1H).

Preparation example 396: (4S,5S)-ethyl-5-(4-methylthiazol-5-yl)-2,2- di methy1-1 ,3-dioxo1ane-4-carboxy1ate

The substantially same method as described in Preparation Example 382 was conducted, except that (2S, 3S)-ethyl-3-(4-methylthiazol-5-yl)-2,3- clihyclroxypropanoate(Preparat ion example 395) was used instead of (2S, 3S) ^~ ethyl 3-(2 , 4-di ch1orothi azo1-5-y1 )-2 , 3-dihydroxypropanoate(Preparat ion example 381), to obtain the title compound(2.6g, 55~70%) .

¾ NMR (400MHz, DMS0): δ= 1.17(t, 7=3.6, 3H), 1.43CS, 3H), 1.49(s, 3H), 2.34(s, 3H), 4.17(q, 7=7.0 2H), 4.40(cl, 7= 14.0, IH), 5.53(cl, 7= 7.2, 1H), 9.01(s, 1H). Preparation example 397: (4R, 5S)-b-(4-methylthiazol-5-yl)2,2-dimethyl-l,3- dioxo1an-4-y1 )methano1

The substantially same method as described in Preparation Example 386 was conducted, except that (4S, 5S)-ethyl-5-(4-methyl thiazol-5-yl )-2 , 2- dimethyl-l,3-dioxolane-4-carboxylate(Preparation example 396) was used instead of (4R, 5 )-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-l,3- dioxolane-4-carboxylate (Preparation example 385), to obtain the title compound( 1.7g , 70~90%) ..

^L H NMR (400MHz, DMS0) : 5= 1.42(d, 7=7.6, 6H), 2.36(s. 3H) , 3.58(m; 2H), 3.80(d, 7=3.2, 1H), 5.02(t, 7=5.4, 1H) , 5.17(d, 7= 8.4, 1H), 8.98(s, 1H) .

Preparation example 398: (2R, 3R)-ethyl-3-(4-methyl thiazol-5- dihydroxypropanoate

The substantially same method as described in Preparation Example 384 was conducted, except that (E)-ethyl-3-(4-methyl thiazol-5- yl )acrylate(Prepara ion example 394) was used instead of (E)-ethyll3-(2,4- dichlorothiazol-5-yl )acrylate(Preparat ion example 380), to obtain the title compound(6. Og, 50~70%) .

¾ NMR (400MHz, DMS0): δ= l.lKt, 7=7.0, 3H) , 1.43(s, 3H), 4.04(m, 2H) , 5.11(t, 7= 3.8, 1H), 5.70(d, 7=20.7, 1H), 5.92(d, 7= 4.0, 1H), 6.81(s, 1H), 8.86(s, 1H).

Preparation example 399: (4R, 5R)-ethyl-5-(4-methylthiazol-5-yl)-2,2- dimethy1-1 , 3-dioxo1ane-4-c rboxylate

The substantially same method as described in Preparation Example 382 was conducted, except that (2R, 3R)-ethyl-3-(4-methylthiazol-5-yl)-2,3- dihydroxypropanoate(Preparat ion example 398) was used instead of (2S, 3S) ^~ ethyl 3-(2,4-dichlorothiazol-5-yl )-2, 3-d ihydroxypropanoate(Preparat ion example 381), to obtain the title compound(5. Og, 65~80%) .

¾ NMR (400MHz, DMSO) : δ= 1.17(t, J=3.6, 3H), 1.43CS, 3H) , 1.49(s, 3H), 2.34(s, 3H), 4.17(q, .7=7.0 2H), 4.40(d, J= 14.0, 1H), 5.53(d, .1= 7.2, 1H), 9.01(s, 1H).

Preparation example 400: (4S, 5R)-5-(4-methylthiazol-5-yl)2,2-dimethyl-l,3- dioxolan-4-vl )methanol

The substantially same method as described in Preparation Example 386 was conducted, except -that (4R, 5R)-ethyl-5-(4-methylthiazol-5-yl)-2,2- dimethyl-1 , 3-dioxolane-4-carboxy1 ate(Preparat i on example399) was used instead of (4R, 5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-l,3- di oxo lane-4-carboxylate (Preparation example 385), to obtain the title compound(4. lg, 70~90%) .

LH NMR (400MHz, DMSO): δ= 1.42(d, .7=7.6, 6H), 2.36(s, 3H) , 3.58(m, 2H),

3.80(d, 7=3.2, 1H), 5.02(t, J=5.4, 1H) , 5.l7(d, J= 8.4, 1H), 8.98(s, 1H).

Preparation example 401: (4R, 5S)-ethyl-5-(2-chloro-4-methylthiazol-5- y1 )-2 , 2-dimethy1-1 , 3-di oxo1ane-4-carboxylate

To a stirred solution of (4R, 5S)-5-(4-methylthiazol-5-yl)2,2-dimethyl- 1 ,3-dioxolan-4-yl )methanol (Preparat ion example 397, 3.1g, 14.3mmol) in THF (20mL) was added n-Buthyl 1 i thium (14.3mL, 35.7mmol) and CC1 ₄ (4.1mL, 42.8mmol) at -78 ^° C. The mixture was stirred for 0.5h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgS0 ₄ , filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (2.8g, 70-90%)

¾ MR (400MHz, DMS0): δ= 1.40(d, J=5.6, 6H), 2.28(s, 3H) , 3.58(m, 2H), 3.80(m, 1H), 5.06(m, 1H), 5.13(d, J= 8.4, 1H).

Preparation example 402: (4S, 5R)-ethyl-5-(2-chloro-4-methyl t.hiazol-5- y1 )-2 , 2-dimethy1 -1 , 3-dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation. Example 401 was conducted, except that (4S, 5R)-5-(4-methylthiazol-5-yl)2,2-dimethyl-l,3- d i oxo 1 an-4-yl )methanol (Preparat ion example 400) was used instead of (4R, 5S)-5-(4-methy11hi azo 1 -5-y 1 )2 , 2-d imethy1 -1 , 3-di oxo 1 an-4- yl )methanol (Preparat ion example 397), to obtain the title compouncK 1.5g , 70-90%) . l\\ NMR (400MHz, DMS0): 6= 1.40(d, 7=5.6, 6H), 2.28(s, 3H) , 3.58(m, 2H), 3.80(m, 1H), 5.06(m, 1H), 5.13(d, 7= 8.4, 1H) .

Preparation example 403: (E)-ethyl 3-(thiophen-3-yl )acrylate

To a stirred solution of tr iethylphosphnoacetate(5.36ml , 26.7mmol) in THF(40ml) was added to t-BuOK(3g,26.7mmol) dropwise at rt and stirred at this temperature for 30min. Then thiophene-3-carbaldehyde (3g, 26.7mmol) was added and stirred at 90 ^° C and stirred at this temperature for 30min. The product was quenched with 1M HC1 solution. The resulting mixture was extracted with ethyl acetate form water. The combined organic layer was dried (Na2S0 ₄ ) , filtered and concentrated. The residue was purified by silica gel column to produce the title compound (3.9g, 70-90%).

T-I NMR (400MHz, CDC1 ₃ ): 6=1.34(t, J=7.2, 3H) , 4.26(q, J=7.2, 2H) , 6.31(d, 7=15.6, 1H), 6.89 (d, 7=4, 1H), 7.69(s, 1H), 7.73(d, J=4, 1H) , 7.80(d, 7=15.6, 1H)

example 404: (2R.3S)-ethyl 2,3-dihydroxy-3-(thiophen-3-

The substantially same method as described in Preparation Example 384 was conducted, except that (E)-ethyl 3-(thiophen-3-yl)acrylate (Preparation example 403) was used instead of (E)-ethyll3-(2,4-dichlorothiazol-5- yl)acrylate(Preparation example 380), to obtain the title compound(6.0g, 60-80%).

¾ NMR (400MHz, CDC1 ₃ )- ^" 6=1.34(t, 7=7.2, 3H), 4.26(q, 7=7.2, 2H), 4.65(d, 7=5.5, 1H), 5.13(d, J=5.5, 1H), 6.93(dd, J=6.09, J=1.32, 1H), 7.47(dd, J=6.09, J=1.73, 1H), 7.88(dd, J=1.73, J=1.32, 1H)

Preparation example 405: (4R.5S)-ethyl 2,2-dimethyl-5-(thiophen-3 dioxo1 ane-4-carboxy1ate

The substantially same method as described in Preparation Example 382 was conducted, except that (2R,3S)-ethyl 2,3-dihydroxy-3-(thiophen-3- yl )propanoate(Preparat ion example 404) was used instead of (2S, 3S)-ethyl 3-(2,4-dichlorothiazol-5-yl )-2,3-dihydroxypropanoate(Preparat ion example 381), to obtain the title compound(3.0g, 65-80%).

¾ NMR (400MHz, CDC1 ₃ ): δ =1.18(t , J=7.1, 3H) , 1.41(S, 3H) , 1.43(S, 3H) , 4.16(q, J=7.1, 2H), 4.21(d, J=7.0,1H). 4.94(d, J=7.0, 1H) 6.95( dd, J=6.0, J=1.3, 1H), 7.48(dd, J=6.0, J=1.7, 1H) , 7.90(dd. J=1.7, J=1.3, 1H)

Preparation example 406: ((4S,5S)-2,2-dimethyl-5-(thiophen-3-yl)-l,3- dioxo 1 an-4-y1 )methano1

The substantially same method as described in Preparation Example 386 was conducted, except that (4R, 5R)-ethyl 2,2-dimethyl-5-(thiophen-3-yl)-l,3- dioxolane-4-carboxylate(Preparat ion example 405) was used instead of (4R, 5R)-ethyl-5-(2,4-dichlorothi zol-5-yl)-2,2-cliniethyl-l,3-dioxolane-4- carboxylate (Preparation example 385), to obtain the title compound(2.2g, 70-90%) .

^[ H NMR (400MHz, CDC1 ₃ ): 5=1.39 (S, 3H) . 1.42 (S, 3H) , 3.47-3.6 (m,2HJ 3.84~3.88(m.lH) 4.82 (d, J=7.0, 1H), 6.93 (dd, J=6.1, J=1.3, 1H), 7.47 (del, J=6.1, J=1.7, 1H,), 7.89 ( dd, J=1.7, J=1.3, 1H)

Preparation example 407 ^' · (E)-ethyl 3-(5-chlorothiophen-2-yl )acrylate

The substantially same method as described in Preparation Example 403 was conducted, except that 5-chlorothiophene-2-carbaldehyde was used instead of thiophene-3-carbaldehyde , to obtain the title compound (4.0g, 70-90%).

¾ NMR (400MHz, CDC1 ₃ ): 5=1.36(t, J=7.2, 3H) , 4.20(q, J=7.2, 2H), 6.13(d, 7=15.6, 1H), 6.89 (d, .7=4, 1H), 7.65(d, .7=15.6, 1H) , 7.83(d, .7=4.2, 1H)

Preparation example 408: (2R,3S)-ethyl 2,3-dihydroxy-3-(5-chlorothiopheir yDpropanoate

The substantially same method as described in Preparation Example 404 was conducted, except that (E)-ethyl 3-(5-chlorothiophen-2-yl )acrylate (Preparation example 407) was used instead of (E)-ethyl 3-(thiophen-3- yDacrylate (Preparation example 403), to obtain the title compound(2.8g, 60-80%) .

^J H NMR (400MHz, CDC1 ₃ ) 51.34(t, J=7.2 ,3H), 2.76(d, J=8.4,1H), 3.32(d, 5.6,1H), 4.33(q, .7=7.2 2H) , 4.4(dd, .7=2.4 .7=5.2 1H), 5.16(dd, 7=2 .7=8, 1H), 6.82(d, 7=4, 1H), 6.88(dd, 7=0.8 7=3.6, 1H)

Preparation example 409: (4R,5S)-ethyl 2,2-dimethyl-5-(5-chlorothiophen-2- yl )-l , 3-dioxolane-4-carboxylate

The substantially same method as described in Preparation Example 405 was conducted, except that (2R,3S)-ethyl 2,3-dihydroxy-3-(5-chlorothiophen-2- yl )propanoate(Preparat ion example 408) was used instead of (2R,3S)-ethyl 2,3-dihydroxy-3-(thiophen-3-yl)propanoate(Preparation example 404), to obtain the title compound(0.85g, 65-80%).

¾ NMR (400MHz, CDC1 ₃ ) ^: 6=1.31(t, 7=7.2 3H), 1.54(s, 3H), 1.58(s, 3H), 4.29-4.36 (m,2H), 4.42(d, 7=7.2 1H), 5.29(d, .7=7.2 1H) , 6.81(q, 7=4 IH), 6.88(d, 7=3.2 1H)

Preparat ion example 410 ^' · ((4S,5S)-2,2-climethyl-5-(5-chlorothiophen-2-yl )- 1 , 3-dioxo1 an-4-y1 )methano1

The substantially same method as described in Preparation Example 406 was conducted, except that (4R, 5R)-ethyl 2,2-dimethyl-5-(5-chlorothiophen-2- yl)-l,3-dioxolane-4-carboxylate(Preparation example 409) was used instead of (4R, 5R) -ethyl 2,2-dimethyl-5-(thiophen-3-yl)-l,3-dioxolane-4- carboxylate(Preparat ion example 405), to obtain the title compound (0.8g, 70-90%) .

¾ NMR (400MHz, CDC1 ₃ ): 5=1.39 (S, 3H), 1.42 (S, 3H), 3.54-3.79 (m, 2H,) 4.28-4.42(m, 1H), 5.17(d, J=7.2, 1H), 6.47 (d, J=6.1, 1H,), 6.51(d, J=6.1,1H)

Preparation example 411: 3-chloroi son i cot inaldehyde

To a 250 ml round-bottomed flask, LDA (11ml, 22.02mmol) was added to 3- chloropyr idinedg, S.SOmmol) in THF(20 ml) dropwise at -78 ^° C and stirred at same temperature for l~2hr. Then DMF(822,d' , 10.56mmol )was added and stirred at room temperature for lhr. EA (Ethyl acetate) and water were added to the reaction mixture, and after the separation of the layers, the aqueous phase was further extracted with the organic solvent. The combined organic extracts were dried over anhydrous Sodium sulfate (Na ₂ S0 ₄ ) , filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (0.33g, 30-65%)

¾ NMR (400MHz, CDC1 ₃ ) δ 7.73 (d, J = 8.0, 1H) 8.71 (d, J = 4.0, 1H) 8.81 (s, 1H) 10.52 (s, 1H)

Preparation example 412: (E)-ethyl 3-(3-chloropyr idin-4-yl )acrylate

3-chloroisonicot inaldehyde (Preparation example 411, 0.54g, 3.79mmol) was dissolved in benzene. At the room temperature, triethyl phosphoacetate (753 ,αί , 3.79mmol) and potassium tert-butoxide (468 mg, 4.17 mmol) were added and stirred. When the reaction was completed, the obtained product was washed with water and ethylacetate (EA) . Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (0.57g, 70~90%) .

¾ NMR (400MHz, CDC1 ₃ ) δ 1.40 (t, J = 12, 3H) 4.13 (q, J = 6.6, 2H) 6.61(d, J = 16.0, 1H) 7.46 (d, J = 16.0, 1H) 7.97 (cl J = 8.0, 1H) 8.51 (d, J = 4.0, 1H) 8.66 (s, 1H).

Preparation example 413· ^' Ethyl 3-(3-chloropyridin-4-yl)-2,3- dihydroxypropanoate

(E)-ethyl 3-(3-chloropyridin-4-yl)acrylate(Preparation example 412, 0.57g, 2.69mmol) was dissolved in the mixture of actone(11.4ml)/water(2.3ml)/t- BuOH(2.3ml). NM0(0.47g, 4.03mmol), Osmium tetroxide (13.6mg, O.OSmmol) were added thereto and stirred at 40 ^° C . When the reaction was completed, the obtained product was washed with water and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (0.44g, 60-80%) .

¾ NMR (400MHz, CDC1 ₃ ) δ 1.28 (t, J = 12.0, 3H) 4.15 (q, J = 6.6, 2H) 4.26 (d, J = 4.0, 1H) 5.24 (d, J = 4.0, 1H) 5.44 (br s, 1H) 5.98 (br s, 1H) 7.59(d, J = 8.0, 1H) 8.52 (cl, J = 4.0, 1H) 8.56 (s, 1H)

Preparation example 414 ^' · Ethyl 5-(3-chloropyridin-4-yl )-2,2-dimethyl-l,3- dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 405 was conducted, except that Ethyl 3-(3-chloropyr idin-4-yl )-2,3- dihydroxypropanoate(Preparation example 413) was used instead of (2R,3S)- ethyl 2,3-dihydroxy-3-(thiophen-3-yl)propanoate(Preparation example 404), to obtain the title compound(5.26g, 70~90%).

¾ MR (400MHz, CDC1 ₃ ) δ 1.28 (t, J = 12.0, 3H) 1.61 (s, 3H) 1.65 (s, 3H) 4.23 (q, J = 6.0 2H) 4,38 (d.J = 7.2 1H) 5.67 (d, J = 8.0 ,1H) 7.55 (d, J - 8.0 ,1H) 8.56 (d, J = 4.0 ,1H) 8.57 (s, 1H)

(5-(3-ch1oropyr idin-4-y1 )-2 , 2 ^~ dimethy1-1 , 3·

The substantially same method as described in Preparation Example 406 was conducted, except that Ethyl 5-(3-chloropyridin-4-yl)-2,2-climethyl-l,3- dioxolane-4-carboxylate(Preparat ion example 414) was used instead of (4R, 5R)-ethy1 2 , 2-dimethy1-5-(thiophen-3-y1 )-1 , 3-di oxo1 ane-4- carboxylate(Preparat ion example 405), to obtain the title compound(0.18g, 70-90%) .

Tl NMR (400MHz, CDC1 ₃ ) δ 1.56 (s, 3H) 1.59 (s, 3H) 3.79-3.67 (m, 1H) 3.85 (del, J = 8.0, 6.0, 1H) 4.06-3.90 (m, 1H) 4.14 (dd, J = 8.0, 6.0, 1H) 5.37 (d, J = 8.0 ,lH) 7.57(d, J = 6.0, 1H) 8.57 (d, J = 12, 2H)

Preparation example 416: 4-chloroisonicot inaldehyde

The substantially same method as described in Preparation Example 411 was conducted, except that Ethyl 4-chloropyr icline was used instead of 3- chloropyridine, to obtain the title compound(3. Og, 60-80%).

¾ NMR (400MHz, CDC1 ₃ ): 5=7.45(cl, 7=5.2, 1H) , 8.70(d, 7=5.2, 1H), 9.06(s, 1H), 10.52(s, 1H)

Preparation example 417: (E)-ethyl 3-(4-chloropyr idin-3-yl )acrylate

The substantially same method as described in Preparation Example 412 was conducted, except that Ethyl 4-chloroni cot inealdehyde(Preparat ion example 416) was used instead of 3-chloroisonicot inaldehyde(Preparat ion example 411), to obtain the title compound(4. Og, 70~90%) .

¾ NMR (400MHz, CDC1 ₃ ): 5=1.37(t, 7=7.0, 3H) , 4.33(q, 7=6.6, 2H), 6.57(cl, 7=16.4, 1H), 7.39 (d, 7=5.2, 1H), 7.98(d, 7=16.0, 1H), 8.49(d, 7=5.2, 1H), 8.82(s, 1H)

Preparation example 418: Ethyl 3-(4-chloropyr iclin-3-yl )-2,3 ^~ dihyclroxypropanoate

The substantially same method as described in Preparation Example 413 was conducted, except that (E)-ethyl 3-(4-chloropyr idin-3-yl )acrylate (Preparation example 417) was used instead of (E)-ethyl 3-(3-chloropyr idin- 4-yl )acrylate(Preparation example 412), to obtain the title compound(2.4g, 60-80%) .

¾ NMR (400MHz, CDCI ₃ ) 5=1.34(t, 7=7.2, 3H), 4.35(q, 7=7.0, 2H), 4.45(d, 7=2.4, 1H), 5.49 (d, 7=2.0, 1H) , 7.32(d, 7=5.2, 1H), 8.46(d, 7=4.4, 1H) , 8.79(s, 1H)

Preparation example 419: Ethyl 5-(4-chloropyridin-3-yl )-2,2-dimethyl-l,3- dioxo1 ne-4-carboxylate

The substantially same method as described in Preparation Example 414 was conducted, except that Ethyl 3-(4-chloropyridin-3-yl )-2,3- dihydroxypropanoate(Preparat ion example 418) was used instead of Ethyl 3- (3-chloropyr idin-4-yl )-2,3-clihydroxypropanoate(Preparat ion example 413), to obtain the title compound(1.3g, 70~90%) .

¾ NMR (400MHz, CDC1 ₃ ): 6=1.25(t, J=7.2 3H), 1.59(s,3H), 1.64(s, 3H) ; 4.22 (q, 7=8.27 2H) , 4.37(d, J=7.6,1H), 5.56(d, J=7.6, 1H) , 7.31(d, J=5.2,1H), 8.48(d, J=5.2, 1H), 8.78(s,lH)

Preparation example 420: (5-(4-chloropyridin-3-yl)-2,2-dimethyl-l,3- dioxo1 n-4-y1 )methano1

The substantially same method as described in Preparation Example 415 was conducted, except that Ethyl 5-(4-chloropyr idin-3-yl )-2,2-dimethy1-1,3- dioxolane-4-carboxylate(Preparat ion example 419) was used instead of Ethyl 5-(3-ch1oropyr i d in-4-y1 )-2 , 2-dimethy1-1 , 3-dioxo 1 ane-4- carboxylate(Preparat ion example 414), to obtain the title compound(0.8g, 70~90%).

¾ NMR (400MHz, CDC1 ₃ ): δ =1.56(s,3H) , 1.63(s,3H), 1.64(s, 3H), 3.73-3.77 (m, iH), 3.95~3.99(m, 2A) 5.39(cl, J=8.4, 1H) , 7.32(d, J=5.6,1H), 8.46(d, 7=5.2, 1H), 8.82(s,lH)

Preparation example 421 ^' - (E)-ethyl 3-(pyr imidin-5-yl )acrylate

5-bromopyr imidine (5 g, 31.4- mmol) in DMF (75 mi) was added ethyl acrylate (9.5 mft, 94.4 mmol) at room temperature. Di isopropyl amine (7.5 mi, 42.8 mmol), trimethyl phosphate (0.19 mi, 1.6 mmole), Pd(Pac) ₂ (0.18g, 0.78 mmol) were added. The reaction mixture was heated at 110 ^° C for 2hr. The reaction mixture was cooled to room temperature and quenched with H2O then extracted wi th EA(Ethyl acetate). The aqueous layer was extracted with EA and separated. The combined organic layer was washed with ¾0, then dried over anhydrous magnesium sulfate(MgS0 ₄ )and evaporated under reduced. The crude compound was purified by a silica gel column to produce the title compound (3.9g, 70~90%) .

'Ή NMR (400 MHz, CDC 13) δ 1.38 (t, J = 6.8, 3H) , 4.29-4.35 (m, 1H), 6.61 (d, /= 17.2, 1H), 7.63 (d, J = 16.4, 1H), 8.90 (s, 2H), 9.22 (s, 1H). Preparation example 422: Ethyl 3-(py imidin-5-yl )-2,3-dihydroxypropanoate

The substan ially same method as described in Preparation Example 418 was conducted, except that (E)-ethyl 3-(pyr imidin-5-yl )acrylate (Preparation example 421) was used instead of (E)-ethyl 3-(4-chloropy iclin-3- y 1 )acrylate(Preparat ion example 417), to obtain the title compound(1.6g, 40-60%) .

¾ NMR (400 MHz, CDC1 ₃ ) 6 1.07-1.39 (m, 3H), 4.16-4,34 (m, 2H), 4.39 (s, 1H), 4.69 (s, 1H), 5.04 (s, 1H), 5.10 (s, 1H), 8.98 (s, 2H), 9.01 (s, 1H) . Preparation example 4-23: Ethyl 2,2-dimethyl-5-(pyrimidin-5-yl)-l,3- d ioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 419 was conducted, except that Ethyl 3-(pyrimidin-5-yl)-2,3- dihyclroxypropanoateCPreparat ion example 422) was used instead of Ethyl 3- (4-chloropyr idin-3-yl )-2 ,3-clihydroxypropanoate(Preparat ion example 418) , to obtain the title compouncKO .97g, 4060%) .

¾ NMR (400 MHz, CDC1 ₃ ) δ 1.30 (t, J =.7.2, 3H) , 1.55 (s, 3H) , 1.61 (s, 3H), 4.25-4.32 (m, 1H), 4.35 (d, /= 8.0, 1H) , 5.18 (cl, /= 7.6, 1H), 8.82 (s, 2H), 9.20 (s, 1H).

Preparation example 424 ^' · (2,2-dimethyl-5-(pyrimidin-5-yl)-l,3-dioxolan-4- yl )methanol

The substantially same method as described in Preparation Example 420 was conducted, except that Ethyl 2,2-dimethyl-5-(pyrimidin-5-yl)-l,3-dioxolane- 4-carboxylate(Preparat ion example 423) was used instead of Ethyl 5-(4- ch1oropyr i clin-3-y1 )-2 , 2-dimethy1-1 , 3-dioxo1 ane-4-carboxy1 ate(Preparat ion example 419), to obtain the title compound(0.65g, 70-90%).

¾ NMR (400 MHz, CDC1 ₃ ) δ 1.53 (s, 3H) , 1.56 (s, 3H), 2.75 (s, -OH), 3.68- 3.73 (m, 1H), 3.69-3.64 (m, 1H), 3.89-3.93 (m, 2H) , 5.0 (d, /= 8.4, 1H), 8.79 (s, 2H), 9.18 (s, 1H).

Preparation example 425: (E)-ethyl 3-(2-chloropyr imidin-5-yl )acrylate

The substantially same method as described in Preparation Example 421 was conducted, except that 2-chloro-5-bromopyr imicline was used instead of 5- bromopyr imidine , to obtain the title compound(9.7g, 50~70%) . lH NMR (400 MHz, CDC1 ₃ ) δ 1.37 (t, ./ = 6.8, 3H) , 4.32 (qt , ./ = 7.2, 2H), 6.59 (cl, J= 16.4, 1H), 7.60 (d, /= 16.4, 1H), 8.77 (s, 2H). Preparation example 426- ^' Ethyl 3-(2-chloropyrimidin-5-yl)-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 422 was conducted, except that (E)-ethyl 3-(2-chloropyr imidin-5-yl )acrylate (Preparation example 425) was used instead of (E)-ethyl 3-(pyr imidin-5- yl )acrylate(Preparat ion example 421), to obtain the title compound(2. lg, 40-60%) . ¾ NMR (400 MHz , CDC1 ₃ ) δ 1.33-1.37 (m, 3H) , 2.97 (d, J = 7.2, 1H), 3.31 (d, J = 18.4, 1H), 4.34-4.55 (m, 3H), 5.10 (d, /= 7.2, 1H) , 8.72 (s, 2H).

Preparation example 427: Ethyl 2,2-dimethyl-5-(2-chloropyrimidin-5-yl )-l,3- cli oxolane-4-carboxylate

The substantially same method as described in Preparation Example 423 was conducted, except that Ethyl 3-(2-chloro.pyr imidin-5-yl )-2,3 ^~ dihydroxypropanoate(Preparat ion example 426) was used instead of Ethyl 3- (pyr imidin-5-yl )-2,3-dihydroxypropanoate(Preparat ion example 422), to obtain the title compound(0.98g, 40~60%) .

Ή NMR (400 MHz , CDC1 ₃ ) δ 1.32 (t, J = 7.2 3H), 1.55 (s, 3H) , 1.60 (s, 3H), 4.27-4.34 (m, 3H) , 5.19 (d, J = 7.6, 1H), 8.71 (s, 2H).

Preparation example 428: (2,2-dimethyl-5-(2-chloropyrimidin-5-yl)-l,3- dioxolan-4-yl )methanol

The substantially same method as described in Preparation Example 424 was conducted, except that Ethyl 2,2-dimethyl-5-(2-chloropyr iniidin-5-yl )-l,3- dioxolane-4-carboxylate(Preparat ion example 427) was used instead of Ethyl 2,2-dimethyl-5-(pyrimidin-5-yl )-l,3-dioxolane-4-carboxylate(Preparat ion example 423), to obtain the title compouncKO .71g, 70~90%) .

¾ NMR (400 MHz, CDC1 ₃ ) δ 1.54 (s, 3H), 1.56 (s, 3H), 2.21 (s, -0H) _; 3.71-3.76 (m, 1H), 3.69-3.64 (m, 1H) , 3.88-3.96 (m, 2H), 5.02 (d, J = 8.0, 1H), 8.68 (s, 2H).

Preparation example 429: (1R, 2S)-3-(benzyloxy)-l-(2-chlorophenyl )-l- hyclroxypropan-2-y1 acet ate

A regioisomer of acetate was separated and purified by conducting the silica gel column chromatography as described in Preparation example 376, to obtain the title compound (0.42g, yield 10-30%)

¾ NMR (400 MHz, CDC 1 ₃ ) 62.09 (s, 3H), 3.63-3.70 (m, 2H), 4.47-4.61 (m. 2H), 5.29-5.33(m, 1H), 5.41(t, /= 5.0 Hz, 1H), 7.22-7.55 (m, 9H) . Preparation example 430: (1R, 2S)-3-(benzyloxy)-l-(2-chlorophenyl )propane- 1,2-diol

The substantially same method as described in Preparation Example 377 was conducted, except that (1R, 2S)-3-(benzyloxy)-l-(2-chlorophenyl )-l- hydroxypropan-2-yl acetate (Preparation example 429) was used instead of (IS, 2R)-3-(benzyloxy)-l-(2-chlorophenyl )-2-hydroxypropyl acetate

(Preparation example 376), to obtain the title compound (0.31 g, 80-95 %) .

¾ NMR (400 MHz, CDC1 ₃ ) 63.02 (d, /= 5.2 Hz, 1H), 3.55-3.42 (m, 3H, -OH), 4.18-4.13 (m, 1H), 4.46 (d, / = 6 Hz, 2H), 5.28 (t, / =4.8 Hz, 1H) . 7.35- 7.19 (m, 8H), 7.50 (del, J= 7.6, 1.2 Hz, 1H). Preparation example 431: (4S, 5R)-4-(benzyloxymethyl )-5-(2-chloropheny1 )- 1 , 3-dioxo1 ane

The substan ially same method as described in Preparation example 373 was conducted, except that (1R, 2S)-3-(benzyloxy)-l-(2-chlorophenyl )propane ^~ 1,2-diol (Preparation example 430) was used instead of that ( + )-3- (benzyloxy)-l-(2-chlorophenyl)propane-l,2-diol (Preparation example 372), to obtain the title compound(0.84 g, 80-100 %) .

¾ NMR (400 MHz, CDC1 ₃ ) 61.53 (s, 3H) , 1.66 (s, 3H) , 3.14-3.06 (m, 2H) , 4.26 (d, J = 12 Hz, 2H), 4.83-4.78 (m, 1H) . 5.63 (d, J = 6.8, 1H), 7.35- 7.16 (m, 8H), 7.61 (dd, J = 7.4, 1.6 Hz, 1H) .

Preparation example 432: ((4S, 5R)-5-(2-chlorophenyl)-2,2-dimethyl-1.3- dioxo1an-4-y1 )methano1

The substantially same method as described in Preparation example 374 was conducted, except that ((4S, 5R)-4-(benzyloxymethyl )-5-(2-chlorophenyl )- 2,2-dimethyl-l,3-dioxolane (Preparation example 431) was used instead of that (+ )-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2-dimethyl-l,3 di oxo lane (Preparation example 373), to obtain the title compound (0.82 g, 80-100 %) .

¾ NMR (400 MHz, CDC1 ₃ ) 51.66 (s, 3H), 1.53 (s, 3H), 3.14-3.06 (m, 2H), 4.26 (d, J = 12, 2H), 4.83-4.78 (m, 1H) , 5.63 (d, J = 6.8 Hz, 1H), 7.35- 7.16 (m, 8H), 7.61 (del, J = 7.4, 1.6, 1H) .

Preparation example 433: (2S,3R)-methyl-3-(2-chlorophenyl )-2.3- dihydroxypropanoate

The substantially same method as described in Preparation example 3 was conducted, except that (E)-methyl-3-(2-chlorophenyl )acrylate(Preparat ion example 24) was used instead of that (E)-l-chloro-2-(3- (methoxymethoxy)prop-l-enyl )benzene(Preparat ion example 2), to obtain the t i 11 ecompound( 14.2g , 70~90 )

¾ NM (400MHz, CDC1 ₃ ) δ 2.79(d, j=7.2, 1H), 3.13(d, J=6.0, 1H), 3.86(s, 3H), 4.50(dd, J=5.6, 2.4, 1H) , 5.51(dd, J=7.2, 2.4, 1H), 7.62-7.26 (m, 41)

Table 1 ^' · Example of sulfamate compouncKA = Phenyl)

2-F 1 0 0 Me Me H H R R

2-F 1 0 0 Me Me H H S S

2-F 1 0 0 Me H H H R R

2-F 1 0 0 Me H H H S S

2-F 1 0 0 Et Et H H R R

2-F 1 0 0 Et Et H H S S

2-F 1 0 0 Cyclopentyl H H R R

2-F 1 0 0 Cyclo entyl H H S S

2-F 1 0 0 Cyclohexyl H H R R

2-F 1 0 0 Cyclohexyl H H S S

Methylbenzen

2-F 1 0 0 H H R R e

Methylbenzen

2-F - 1 0 0 H H S S e

2-1 1 0 0 Me Me H H R R

2-1 1 0 0 Me Me H H S S

2-1 1 0 0 Me H H H R R

2-1 1 0 0 Me H H H S S

2-1 ^■ 1 0 0 Et Et H H R R

2-1 1 0 0 Et Et H H S S

2-1 I 0 0 Cyclopentyl H H R R

2-1 1 0 0 Cyclopentyl H H S S

2-1 1 0 0 Cyclohexyl H H R R

2-1 1 0 0 Cyclohexyl H H S S

Methylbenzen

2-1 1 0 0 H H R R e Meth l benzen

2-1 1 0 0 H H S S e

2,4-Cl 2 0 0 Me Me H H R R

2,4-Cl 2 0 0 Me Me H H S S

2,4-Cl 2 0 0 Me H H H R R

2,4-Cl 2 0 0 Me H H H S S

2,4-Cl 2 0 0 Et Et H H R R

2,4-Cl 2 0 0 Et Et H H S S

2,4-Cl 2 0 0 Cyclopentyl H H R R

2,4-Cl 2 0 0 Cyclo entyl H H S S

2,4-Cl 2 0 0 Cyclohexyl H H R R

2,4-Cl 2 0 0 Cyclohexyl H H S S

Methylbenzen

2,4-Cl 2 0 0 H H R R e

Methylbenzen

2,4-Cl 2 0 0 H H S S e

2,6-Cl 2 0 0 Me Me H H R R

2,6-Cl 2 0 0 Me Me H H . S S

2,6-Cl 2 0 0 Me H H H R R

2,6-Cl 2 0 0 Me H H H s S

2,6-Cl 2 0 0 Et Et H H R R

2,6-Cl 2 0 0 Et Et H H S S

2,6-Cl 2 0 0 Cyclopentyl H H R R

2,6-Cl 2 0 0 Cyclopentyl H H S S

2,6-Cl 2 0 0 Cyclohexyl H H R R

2,6-Cl 2 0 0 Cyclohexyl H H S S Methyl benzen

2,6-Cl 2 0 0 H H R R e

Methylbenzen

2,6-Cl 2 0 0 H H S S e

2-NH2 1 0 0 Me Me H H R R

2-NH2 ^■ 1 0 0 Me Me H H S S* 2-NH2 1 0 0 Me Me H H R R* 2-NH2 1 0 0 Me Me H H S S

2-NH2 1 0 0 Me H H H R R

2-NH2 1 0 0 Me H H H S S

2-NH2 1 0 0 Et Et H H R R

2-NH2 1 0 0 Et Et H H S S

2-NH2 1 0 0 Cyclopent l H H R R

2-NH2 1 0 0 Cyclopentyl H H S S

2-NH2 1 0 0 Cyclohexyl H H R R

2- H2 1 0 0 Cyclohexyl H H S S

Methylbenzen

2-NH2 1 0 0 H H R R.

e

Methyl benzen

2-NH2 1 0 0 H H S S e

2-N02 1 0 0 Me Me H H R R

2-N02 1 0 0 Me Me H H S S

2-N02 1 0 0 Me H H H R R

2-N02 1 0 0 Me H H H S S

2-N02 1 0 0 Et Et H H R R

2-N02 1 0 0 Et Et H H S S 83 2-N02 1 0 0 Cyclopentyl H H R R

84 2-N02 1 0 0 Cyclopentyl H H S S

85 2-N02 1 0 0 Cyc1ohexy1 H H R R

86 2-N02 1 0 0 Cyclohexyl H H S S

Methylbenzen

87 2-N02 1 0 0 H H R R e

Methvlbenzen

88 2-N02 ^■ 1 0 0 H H S S e

Cyclocarbony

89 2-N02 1 0 0 H H R R

1

Cyclocarbony

90 2-N02 1 0 0 H H S S

1

91 2-Me 1 0 0 Me Me H H R R

92 2-Me ^■ 1 0 0 Me Me H H S S

93 2-Me 1 0 0 Me H H H R R

94 2-Me 1 0 0 Me H H H S S

95 2-Me 1 0 0 Et Et H H R R

96 2-Me 1 0 0 Et Et H H S S

97 2-Me 1 0 0 Cyclopentyl H H R R

98 2-Me 1 0 0 Cyclopentyl H H S S

99 2-Me 1 0 0 Cyc 1ohexy1 H H R R

100 2-Me 1 0 0 Cyc 1ohexy1 H H S S

Methylbenzen

101 2-Me 1 0 0 H H R R e

Methylbenzen

102 2-Me ^■ 1 0 0 H H S S e

103 2-MeNH 1 0 0 Me Me Me H R R 104 2-MeNH 1 0 0 Me Me Me H S s

105 H 1 0 0 Me Me H H R R

106 H 1 0 0 Me Me H H S S

107 H 1 0 0 Et Et H H R R

108 H 1 0 0 Et Et H H S S

109 H 1 0 0 Cyclopentyl H H R R

110 H 1 0 0 Cyclopentyl H H S S

111 H 1 0 0 Cyclohexyl H H R R

112 H 1 0 0 Cyclohexyl H H S S

113 H 1 1 1 Me Me H H R R

114 H 1 1 1 Me Me H H S S

115 H 1 1 1 Et Et H H R R

116 H 1 1 1 Et Et H H S S

117 H 1 1 1 Cyclopentyl H H R R

118 H 1 1 1 Cyclopentyl H H S S

119 H 1 1 1 Cycl hexyl H H R R

120 H 1 1 1 Cyclohexyl H H S S

121 H 1 1 0 Me Me H H R R

122 H 1 1 0 Me Me H H S S

123 H 1 1 0 Et Et H H R R

124 H 1 1 0 Et Et H H S S

125 H . 1 1 0 Cyclopentyl H H R R

126 H 1 1 0 Cyclopentyl H H S S

127 H 1 1 0 Cyclohexyl H H R R

128 H 1 1 0 Cyc 1 ohexy 1 H H S S 129 H 1 0 1 Me Me H H R R

130 H 1 0 1 Me Me H H S S

131 H 1 0 1 Et Et H H R R

132 H 1 0 1 Et Et H H S S

133 H 1 0 1 Cyclopentyl H H R R

134 H 1 0 1 Cyclopentyl H H S S

135 H 1 0 1 Cyclohexyl H H R R

136 H 1 0 1 Cyclo exyl H H S S

137 CI 1 1 1 Me Me H H R R

138 CI 1 1 1 Me Me H H S S

139 CI 1 1 1 Et Et H H R R

140 CI 1 1 1 Et Et H H S S

141 CI 1 1 1 Cyclopentyl H H R R

142 CI 1 1 1 Cyclopentyl H H S S

143 CI 1 1 1 Cyclohexyl H H R R

144 CI 1 1 1 Cyclohexyl H H S S

145 CI 1 1 0 Me Me H H R R

146 CI 1 1 0 Me Me H H S S

147 CI 1 1 0 Et Et H H R R

148 CI 1 1 0 Et Et H H S S

149 CI 1 1 0 Cyclopentyl H H R R

150 CI 1 1 0 Cyclopentyl H H S S

151 CI 1 1 0 Cyc 1ohexy1 H H R R

152 CI 1 1 0 Cyclohexyl H H S S

153 CI ^■ 1 0 1 Me Me H H R R 4-Me

2-

17

Thiazole Cl, 2 0 0 Me Me H H S R

0

4-Me

17

Th i ophene H 1 0 0 Me Me H H S S

1

17

Th i ophene 2-Cl 1 0 0 Me Me H H

2 s R

17

Pyridine 3-Cl 1 0 0 Me Me H H Rac . (syn) Rac . (syn) 3

17

Pyridine 4-Cl 1 0 0 Me Me H H Rac . (syn) Rac . ( syn ) 4

17 Pyr i mi din

H 1 0 0 Me Me H H Rac . (syn) Rac . ( syn ) 5 e

17 Pyr i m i d i n

2-Cl 1 0 0 Me Me H H Rac . (syn) Rac . (syn) 6 e

Example 1-1 : ((4 ,5 )-5-(2-chlorophenyl )-2,2-dimethyl-l,3-dioxolan-4- yOmethyl sulfamate

To a 100ml flask, Acetonitrile (2.26ml, 43.2mmol) was added and cooled to 0 ^° C . Chlorosul fonyl isocyanate (1.5ml, 17.3mmol), and formic acid (0.65ml, 17.3mmol) was added dropwise and stirred at room temperature for 6 hours. ( ( 4 , 5R ) -5- ( 2-ch 1 o r opheny 1 ) -2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 an-4-y 1 ) me t hano 1

(Preparation example 6, 1.05g, 4.3mmol) in N, N-d i me t hy 1. ace t amide (13.2ml, 142.7mmol) was slowly added at 0 ^° C and stirred at room temperature for 1 hours. The reaction mixture was quenched with ¾0, extracted with EtOAc, and washed with ¾0. The organic layer was dried over anhydrous magnesium sul f ate(MgS0 ) , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (l.OOg, 50~80%).

¾ NMR (400MHz, CDC 13 ) δ 1.57 (s, 3H), 1.63 (s, 3H) , 4.11-4.10 (m, 1H), 4.53-4.42 (m, 2H), 4.88 (s, 2H) , 5.37 (d, J = 8.4, 1H), 7.28-7.56 (m, 4H)

Example 1-2 : ((4R,5 )-5-(2-chlorophenyl)-2 _I 2-dimethyl-l,3-clioxolan-4- yOmethyl sulfamate To a 100 mL RB flask, ((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- di oxo 1 an-4-yl )methanol (Preparation example 6, 10.0 g, 41.2mmol), 50 ml of toluene, 7.92 g (82.4 mmol) of sulf mide and 13.0 g (165 mmol) of pyridine were added at RT. The mixture was refluxed for 1.5 hr (bath temperature 135 ^° C). The reaction mixture cooled to room temperature then solution was extracted with 27.5 ml (82.4 mmol) of 3N NaOH solution. The aqueous layer was washed with 50 mL of toluene. To the mixture 50 ml of methanol and 35 ml of water was added then acidified to pH 6.0 by slow adding acetic acid to give title compound. (9.9g 60~80%) .

According to the method described in Example 1, the following compounds of Examples 2 to 64, 67 to 88, 91 to 102, 105 to 176 were prepared:

[Table 3] Characterization of the examples of sulfamate compounds

dioxolan-4- 1H), 4.75(d,

sul famate 1H), 5.79(s, 1H),

can-2-yl )methyl 4.42(dt, J = 7.02, siil fama e 268 J = 3.27, IH),

5.17(d, J = 7.0, IH), 7.62~7.64(m, 2H), 7.77~7.90(m, 2H).

°δ 1.33~1.72(m, 10H), 2.0(s, 2H),

((2R, 3R)-3- 3.96-4.21(m, 2H),

Prepara

benz l-1,4- 4.42(dt, / = 7.02, t ion

128 clioxaspiro[4,5]de J = 3.27, IH), exam 1e

can-2-yl )methyl 5.17(d, J = 7.0,

277

sul famate IH), 7.62-7.64(m,

2H), 7.77-7.90(m, 2H).

^D 5 1.27(s, 6H), 1.40(s, 3H),

2-((4R, 5R)-5- 2.0(s, 2H), phenyl-2,2- Prepara 3.96-4.21(m, 2H), dimethyl-1 ,3- t ion 4.42(dt, J = 7.02,

129

dioxolan-4- example / = 3.27, IH), yDethyl 285 5.17(d, / = 7.0, sul famate IH), 7.62~7.64(m,

2H), 7.77~7.90(m, 2H)

^D 6 1.27(s, 6H), 1.40(s, 3H),

2-((4S, 5S)-5- 2.0(s, 2H), phenyl-2,2- Prepara 3.96-4.21(m, 2H), cUmethyl-1,3- t ion 4.42(dt, / = 7.02,

130

dioxolan-4- exam 1e ./ = 3.27, IH), yDethyl 289 5.17(d, J = 7.0, sul famate IH), 7.62~7.64(m,

2H), 7.77~7.90(m, 2H) .

2-((4R, 5R)-5- Prepara ^c 6 0.90(t, J = phenyl-2,2- t ion 8.0, 6H), 1.59(q,

131 diethyl-1,3- exam le ./ = 8.0, 4H), dioxolan-4- 291 2.0(s, 2H), yDethyl 3.96~4.21(m, 2H) ,

sul famate J = 3.27, IH),

e IH), 7.65(brs.

Example 65: Sodium ((((4R, 5R)-5-(2-aminopheny1 )-2,2-cUmethyl-l,3-dioxolan- -y1 )methy1 su1 fony1 )amide

To stirred solution of ((4R,5R)-5-(2-aminophenyl)-2,2-dimethyl-l,3- dioxolan-4-yl )methyl sul famate(Example 63, 5.5g) in distilled water (55ml) was added IN Na0H(23ml) then heated. After 30min, the resulting mixture cooled to room temperature and concentrated under reduced pressure. The crude product in EA(ethyl acetate, 16.5ml) was slowly added to Ether (200 l) at low temperature. The precipitate was filtered off, washed with Hexane, and dried under vacuum to obtain the title compound(4.7g, 65-85%)

¾ NMR(400MHz, DMS0) δ 1.42(s, 3H), 1.46(s, 3H), 3.79~3.81(m, 211), 3.99-4.00(m, 1H), 4.94(d, J=8.4, 1H), 6.59~7.16(m, 4H).

Example 66: Sodium ((((4S, 5S)-5-(2-aminophenyl)-2,2-dimethyl-l,3-dioxolan- 4-y1 )methy1 su1 fony1 )ami de

The substantially same method as described in Example 65 was conducted, except that (( 4R, 5R) -5- (2-ami nopheny 1 )-2,2-dimethyl-l,3-dioxolan-4- yOmethyl sulfamate (Example 64)was used instead of ((4R,5R)-5-(2- am i nopheny 1 ) -2, 2-d i me t hy 1-1, 3-d i oxo lan-4-yl) methyl sul famate (Example 63) , to obtain the title compound ( 4.23g, 65~85%) .

¾ NMR(400MHz, DMSO) δ 1.42(s, 3H) , 1.46(s, 3H) , 3.79~3.81(m, 2H) , 3.99-4. OOCin, 1H), 4.94(d, J=8.4, 1H) , 6.59-7; 16 (m, 4H).

((4R, 5R)-5-(2-nitrophenyl )-2-oxo-l,3-dioxolan-4-yl ) methyl

To a stirred solution of ((4R, 5R)-5-(2-nitrophenyl)-2,2-dimethyl-l,3- dioxolan-4-yl ) methyl sul f amate( Example 77, 5.2g, 16mmol) in EtOAc (50mL) was added 3N HC1 (24.6mL, SO.Ommol) at room temperature. The mixture was stirred for 5h. The resulting mixture was diluted with EtOAc, washed with sat. NaHCOs, dried over MgS0 ₄ , filtered, and concentrated under reduced pressure. The crude product stirred in THF (35mL) was added CDI (2.91g, 17.9mmol) at room temperature. The mixture was stirred for Ih. The resulting mixture was diluted with EtOAc, washed with water, dried over MgS0 ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by S1O2 gel column chromatography to produce the title compound ( 2.6g, 60-80%)

H N R( 400MHz, CDC 13 ) δ 2.0(s, 2H) , 4.08~4.33(m, 2H), 4.72(dt, J = 7 = 3.27, 1H), 5.47(d, J= 7.0, 1H) , 7.62-7.64(m, 2H) , 7.77~7.90(m, 2H)

Example 90 : ((4S, 5S)-5-(2-nitrophenyl)-2-oxo-l,3-dioxolan-4-yl)methyl sul famate

The substantially same method as described in Example 89 was conducted, except that ((4S, 5S)H5-(2-nitropheny1)-2, 2-dimethyl -4, 3 ^~ dioxolan-4- yOmethyl sul famate(Exam le 78) was used instead of ((4R, 5R)-5-(2- nitropheny1 )-2,2-dimethyl-l,3-dioxolan-4-yl )methyl sul famate(Exam le 77) , to obtain the title compound(0.9g, 50~80 )

¾ N R(400MHz, CDC1 ₃ ) 6 2.0(s, 2H) , 4.08-4.33(m, 2H) , 4.72(dt, 7= 7.02, / = 3.27, 1H), 5.47(d, 7= 7.0, 1H) , 7.62~7.64(m, 2H), 7.77~7.90(m, 2H),

Example 103 ^' · ((4R, 5R)-5-(2-methylaminophenyl)-2,2-dimethyl-l,3-clioxolan y1 )methy1 meth 1 su1 famate

To a stirred solution of ((4R, 5R)-5-(2-aminophenyl)-2,2-dimethyl-l,3- di oxo1 an-4-y1 )methyl sul famate(Example 63, 0.68g, 2.25mmol) and benzotr iazole (0.27g, 2.25mmol) in 'EtOH (lOmL) was slowly added formaldehyde (10wt in H ₂ 0, 0.62mL, 2.25mmol) and NaBH (0.085g, 2.25mmol) at 0 ^° C . The resulting mixture was diluted with EtOAc, washed with water, dried over MgS0 ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by S1O2 gel column chromatography to obtain the title compound(0.3g, 30~50%)

¾ NMR(400MHz, CDC13) 51.40(s, 6H), 2.62(s, 3H) , 2.96(s, 3H) , 4.25(dt, 7=7.0, 7=3.3, 1H), 4.75(d, 7=3.3, 2H) , 4.84(d, 7=7.0, 1H), 6.99~7.20(m, 4H)

Example 104 : ((4S, 5S)-5-(2-methylaminophenyl)-2,2-climethyl-l,3-clioxolan-4- yOniethyl methyl sul famate

The substantially same method as described in Example 103 was conducted, except that ((4S, 5S ) ^~ 5-(2-ami nopheny 1) -2, 2-d i me thy 1-1, 3-d ioxol an-4- yOmethyl sul famate (Exam le 64) was used instead of ((4R, 5R)-5-(2- am i nopheny 1 ) -2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 an-4-y 1 )me t hy 1 su 1 f am a t e ( Exam 1 e 63 ) , to obtain the title compound (0.5g, 50-80%)

¾ NMRUOO Hz, CDC1 ₃ ) 61.40(s, 6H), 2.62(s, 3H) , 2.96(s, 3H), 4.25(dt, J=7.0, J=3.3, 1H) , 4.75(d, 7=3.3, 2H), 4.84(d, 7=7.0, 1H), 6.99~7.20(m, 4H)

Example 177: sodium ((((4S,5S)-5-(2-chlorophenyl)-2,2-climethyl-l,3-dioxolan- 4-yl )methoxy)sLilfonyl )amide

To a stirred solution of ((4S,5S)-5-(2-chlorophenyl )-2,2-dimethyl-l,3- dioxolan-4-yl methyl sul famate (Example 2, 5.0g, 15.5mmol) in a mixture of MTBE and IPA (50mL, 3:1, v/v) was added 6 N NaOH aqueous solution (2.5mL, 14.2mmol) at room temperature then stirred for 1 hr at 0 ^° C . The resulting mixture was removed solvent. The concentrated residue was added a mixture of ¾0 and IPA (15mL, 1:2, v/v) at room temperature then stirred for 30 min. The mixture was added MTBE (75mL) then stirred for 1 hr at 0 ^° C. Solid product was filtered and air-dried to give a title compound. (4.76g, 70-90%) .

Water content _. : 1.54%, MP: 1 ^st 67.6-67.7 ^° C , 2 ^nd 126.9 ^° C

¾ NMPv (400 MHz, DMS0-d ₆ ) δ 1.43 (s, 3H), 1.50 (s, 3H) , 3.77 (dd, 7=7.2, 11.2, 1H), 3.87 (dd, 7=2.8, 11.2, 1H) , 3.99-4.03 (m, 1H) , 5.09 (cl, 7=8.4, 1H), 7.35-7.47 (m, 3H) , 7.61 (dd, 7=1.8, 7.4, 1H)

Experimental Example l: Evaluation of Ant ial lodynic Activity on Complete Freund' s Adjuvant (CFA)-induced Inflammatory Pain Model.

Male, Spr ague-Daw ley rats (200-220 g, Nara Bio, Korea) were habituated for 1 week before surgery and allowed free access to food and water throughout the experimentation. Room temperature and humidity were maintained at 24±2 ^° C and 50+10%, respectively. CFA-inducecl inflammatory pain was induced by the procedure of Nagakura et al . (2003) and Gregory P. et al . (2010) with minor modifications. CFA (sigma, USA) was injected in the left plantar with a 100 ill volume under gaseous anesthesia with isoflurane a 4 ^' -4 flow ratio of NO ₂ Sham controls were injected, with lOOul of saline and vehicle controls were identical to CFA infusion model, except for administration of vehicles.

Tactile sensitivity (Mechanical allodynia) was evaluated using von. Frey monofilaments before and after treatment, and animals were used withdrawal threshold value was less than 4g. One week after surgery, CFA- infused animals (n=4~6), sham-operated animals (n=12), and vehicle-operated animals (n=17) were tested for tactile sensitivity with von Frey monofilaments 3 trials in each animal. All Animals were placed in a stainless steel mashed chamber and habituated for 30 min in the test box. The tactile sensitivity for ipsi lateral hind paw was measured using the up- and-down method (Dixon, 1980) with seven von Frey monofilaments (0.4, 1, 2, 4, 6, 8, and 15 g) to 31 r i a 1 s . Tactile sensitivity test was followed by Dixon' s method (Dixon, 1980). The 50% paw withdrawal threshold for each paw was calculated using the following formula: [Xth] log = [vFr] log + ky where [vFr] is the force of the last von Frey used, k - 0.2249 which is the average interval (in log units) between the von Frey monofilaments, and y is a value that depends upon the pattern of withdrawal responses (Dixon, 1980). If an animal did not respond to the highest von Frey hair (15 g), then the paw was assigned a value of 18.4 g.

The antiallodynic effect of compound of Examples was evaluated at the dose of 10, 30 and 60 mg/kg (n=4~6), intraperitoneal ly administrated in a volume of 5 ul/g bw in a vehicle of 30% (v/v) PEG. The test was performed peak time of efficacy (0.5hr) after compound administration.

The relative values compared to the sham (% control) were calculated and shown in Table 4, which show an antiallodynic effect of the compound of Examples on. CFA- induced pain model in rats.

(Table 4) Antiallodynic effect of the compound of Examples on CFA- induced pain model

"60 (24.0%, 0.5h)

"60 (49.9%, 0.5h)

"60 (22.4%, 0.5h) 40 (23.3%, 0.5h)

^# 60 (20.7%, 0.5h) 18 (48.8%, 0.5h)

^# 18 (20.2%, 0.5h)

^# 40 (17.8%, 0.5h) 60 (22.5%, 0.5h)

"60 (33.3%, 0.5h)

"60 (16.5%, lh)

"40 (18.8%, 0.5h)

"40 (22.6%, 0.5h)

"60 (37.1%, 0.5h)

"40 (25.7%, 0.5h)

"60 (15.6%, 0.5h)

"18 (22.3%, 0.5h)

"40 (24.1%, 0.5h)

"18 (23.2%, 0.5h)

"40 (37.5%, 0.5h)

"40 (42.7%, 0.5h)

"40 (41.1%, 0.5h)

"40 (29.8%, 0.5h)

"40 (14.5%, 0.5h)

"40 (25.0%, 0.5h) 167 60 (38.6%, 0.5h)

168 ^# 60 (77.2%, 0.5h)

170 60 (24.2%, 0.5h)

171 ^# 60 (29.8%, 0.5h)

172 60 (35.9%, 0.5h)

173 ^# 60 (33.9%, 0.5h)

174 ^# 60 (24.7%, 0.5h)

175 60 (44.4%, 0.5h)

176 ⁿ 60 (40.0%, 0.5h)

177 15 (67.2%, 0.5h) the concentration administered and effect (%) compared to that of control treated with vehicle only

Experimental Example 2: Evaluation of Ant ial lodynic Activity on Chung Mode 1.

Male. Spr ague-Daw ley rats (200-220 g, Orient Bio, Korea) were habituated for 1 week before the experiment and allowed free access to food and water throughout the experimentation. Room temperature and humidity were maintained at 24±2 ^° C and 50+10%, respectively. Neuropathic surgery (SNL, Spinal nerve ligation) model was done as described in Kim and Chung (1992). Briefly, animal under gaseous anesthesia with isoflurane a 4:4 flow ratio of NO2. The left lumber spinal nerve L5 and L6 were isolated and tightly li gated with 4-0 silk thread. The wound was treated with a gentamicin antibiotics solution (4 mg/kg, 4 ul/g, bw) , and the wound muscle was closed with cat cut chrom 4/0 thread and skin was closed dafilon 4/0 tread. Sham controls were prepared in the same manner as the spinal nerves were exposed, but no ligated L5 and L6 nerves. But, vehicle controls were identical to SNL model, except for administration of vehicles.

Tactile sensitivity (Mechanical allodynia) was evaluated using von Frey monofilaments before and after treatment and animals were used withdrawal threshold value was less than 4g. One week after surgery, SNL- operated animals (n=4~6), sham-operated animals (n=4~10) and vehicle- operated animals (n=4~13) were tested for tactile sensitivity with von Frey monofilaments 3 trials in each animal. All Animals were placed in a stainless steel mashed chamber and habituated for 30 min in the test box. The tactile sensitivity for ipsilateral hind paw was measured using the up- and-down method (Dixon, 1980) with seven von Frey monofilaments (0.4, 1, 2, 4, 6, 8, and 15 g) to 3 trials. Tactile sensitivity test was followed by Dixon' s method (Dixon, 1980). The 50% paw withdrawal threshold for each paw was calculated using the following formula- ^' [Xth] log = [vFr] log + ky where |.vFr] is the force of the last von Frey used, k - 0.2249 which is the average interval (in log units) between the von Frey monofilaments, and y is a value that depends upon the pattern of withdrawal responses (Dixon, 1980). If an animal did not respond to the highest von Frey hair (15 g), then the paw was assigned a value of 18.4 g.

All animals were fasted 18 h before the administration of the compounds. The antiallodynic effect of the compounds were evaluated at the various dose (n=5~6), orally administrated in a volume of 5 ul/g, bw in a vehicle of 30% (v/v) PEG 400 or 20% (v/v) Tween 80 or Saline. The test was performed at the peak time of efficacy (1 hr) after compound administration.

The relative values compared to the sham group (% control) were calculated and shown in Table 5, which show an antiallodynic effect of the test compounds on SNL model in rats.

(Table 5) Antiallodynic effect of the compound of examples on SNL mode 1

106 "50 (25.4%, 0.5h)

118 90 (38.3%, 0.5h)

122 ^# 50 (64.1%, 0.5h)

138 ^# 90 (71.4%, 0.5h)

146 ^# 90 (45.8%, 0.5h)

the concentration administered and effect (%) compared to that of control treated with vehicle only

Experimental Example 3: Writhing Test

To examine the pain relief effect of the sulfamate derivative compounds, a writhing test was conducted in general pain animal model referring to Fischer, L.G. et al . (2008).

ICR mice (male, 24-28g; Orient Bio, Korea) were habituated before test in test room for 1 hour. Animals were fasted 2 hr , before administration of compounds. Compounds was orally administered at the dose of 20 mg/kg, 10 ul/g, bw (n=3~5/group) . All compounds were dissolved in a vehicle of 30% (v/v) PEG 400 or 20% (v/v) Tween 80. The control group was treated the vehicle without compounds.

One hour after the administration of Compounds, 0.6% acetic acid at the close of 10 ul/g, bw was injected into the mice. Animals were habituated in the cage for 5 min. 5 min after habituation, the number of writhes (abdominal constriction) for 15 min was counted referring to Korzeniewska- Rybicka, I. et al . (1998) and compared with that of a control.

The relative values compared to the control (% control) were calculated and shown in Table 6

(Table 6) Effect of the compound of examples in writhing test

15 20 (74.4%, 0.5h)

27 50 (48.2%, 0,5h)

28 ^# 90 (66.0%, 0.5h)

72 50 (38.1%, lh)

76 ^# 90 (40.5%, 0.5h)

106 ^# 50 (26.4%, lh)

108 ^# 90 (23.9%, lh)

112 90 (14.0%, 0.5h)

122 ^# 50 (48.8%, lh)

128 ^# 50 (44.6%, lh)

134 ^# 50 (9.6%, 0.5h)

136 50 (49.8%, 0.5h)

138 ¾0 (35.8%, 0.51O

140 90 (47.5%, lh)

154 "90 (73.8%, 0.51O

156 ^# 90 (23.9%, 110 the concentration administered and effect (%) compared to that of control treated with vehicle only

Experimental Example 4: Evaluation of Ant ia 1 lodynic Activity on Post operative-induced pain model.

Male Sprague-Dawley rats (Orient Bio, Korea), 300-320g, total of 201 rats were used (details in Table 7). Rats were habituated at least 3 days before surgery and free access to food and water (room temperature and humidity were maintained at 24 + 2 ^" C and 50 + 10%, respectively). The process of performing the post-operation model' s surgery was adapted from Brennan et al (1996). At first, rats with allodynia (threshold valueless than 8 g) were excluded in Pre-von Frey Test. During the post-operation surgery, rats were anesthetized under gaseous anesthesia with 2% isoflurane. Rats were laid face down on a plate fixed at 37 ^° C to prevent against hypothermia. The ipsi lateral plantar aspect (left side) of the hind paw was prepared in a sterile manner with a 10% povidone- iodine solution. A longitudinal incision (1 cmXFigure 2-A) was made with a blade (number 11) through the skin and fascia of the ipsi lateral plantar aspect of the foot, starting from 0.5 cm below the proximal edge of the heel and extending toward the toes. Rats' plantar muscles were elevated and incised longitudinally (Figure 2-B). After hemostasis with gentle pressure, the skin was opposed with 2 mattress sutures (4-0 Dafilon) (Figure 2-C) . The wound site was covered with a 10% povidone- iodine solution gauze and injected with antibiotics (gentamicin, 8mg/kg, ip). The sutures were removed under halothane anesthesia approximately 30 hours later, at the end of post-operative day 1.

After 2-3 days of recovery, rats with a good response (threshold less than 4 g) in Pre-von Frey Test were selected. According to this response, we made three groups with each group having equal average responses- ^' Group 1, post-operation and drug treated; Group 2, post-operation and vehicle treated; Group 3, no post-operation and vehicle treated. In this study, Group 3 was the sham control (positive) group. The group 2 was used to check for possible failures to generate post-operative pain.

For efficacy measure, the threshold value of group C was assigned

100% efficacy, and the percentage of the threshold values of group A compared to group C (for each different dose level) were calculated as the efficacies. Base on these efficacy values, ED50 was calculated using log fitting. If there was no clear ED50, then we marked the percent efficacy at the highest tested dose or larger than highest tested dose.

For pain threshold test, all animals were placed in a stainless steel meshed chamber and habituated, for 30 min in the test box. The tactile sensitivity of the ipsi lateral hind paw was measured using the up-and-down method (Dixon, 1980) with seven von Frey monofilaments (0.4, 1, 2, 4, 6, 8, and 15 g) using 3 trials. The 50% paw withdrawal threshold for each paw was calculated using the following formula: [Xth] log = [vFr] log + ky, where [vFr] is the force of the last von Frey filament used, k = 0.2249 which is the average interval (in log units) between the von Frey monofilaments, y which is a value that depends upon the pattern of withdrawal responses, and Xth which is the threshold value (Dixon, 1980). If an animal did not respond to the highest von Frey hair (15 g) , then the threshold value was assigned as 18.4.

Drugs were dissolved 30% PEG400 for example 2, 0.9% saline for Pregabalin, 20% TweenSO for Tylenol, 0.9% saline for Topiramate. These vehicles were selected depending on the compound' s solubility. Intraperitoneal injection (5 μΐ/g) was done for all drugs.

The relative values compared to the sham ( control) were calculated and shown in Table 8, which show an ant ial lodynic effect of the compound of examples on Post operation-induced pain model in rats.

Table 7. Number of animal s used in thi s study

Overall experimental timeline is depicted in Figure 1 and more detailed procedures are explained in the following sections.

(Table 8) Antiallodynic effect of the compound of examples on Post operation-induced pain model

the concentration administered and effect (%) compared to that of control treated with vehicle only Experimental Example 5 ^' · Evaluation of Ant ial lodynic Activity on Streptozotocin (STZ)- induced Diabetic Pain Model.

Male, _. Spr ague-Daw ley rats (200-220 g, Nara Bio, Korea) were habituated for 1 week before surgery and allowed free access to food and water throughout the experimentation. Room temperature and humidity were maintained at 24 + 2 ^° C and 50+10%, respectively.

STZ- induced diabetic pain model was established with a modified method of Rakieten et al. (1963) and Bert rand Aubel et al . (2004). All animals were fasted 4 to 6 hr prior to STZ injection. STZ (signia, USA) was dissolved in 20 mM sodium citrate buffer, pH 5.5 (sigma, USA) and intraper i toneal ly injected at 75 mg/kg, 4ul/g, bw into the rats. Sham controls were injected with same volume of 20 mM sodium citrate buffer, pH 5.5 and vehicle controls were identical to STZ model, except for administration of vehicles. Rats were supplied with 10% sucrose water for 2 days against sudden hypoglycemia. 3 days later, the induction of diabetes was checked by measurement of tail vein blood glucose levels with a blood glucose meter. (Life Scan One Touch Ultra, USA). If blood glucose was not >300 mg/dl by 72 hr, the rat was excluded from the diabetic group.

Tactile sensitivity (Mechanical allodynia) was evaluated using von

Frey monofilaments before and after treatment of the compound of Examples and animals were used withdrawal threshold value was less than 4g. One week after surgery, diabetic animals (n=6), sham controls (n=12), and vehicle control (n=18) were tested for tactile sensitivity with von Frey monofilaments 3 trials in each animal. All Animals were placed in a stainless steel mashed chamber and habituated for 30 min in the test box. The tactile sensitivity for ipsi lateral hind paw was measured using the up- and-down method (Dixon, 1980) with seven von Frey monofilaments (0.4, 1, 2, 4, 6, (S, and 15 g) to 3 trials. Tactile sensitivity test was followed by Dixon' s method (Dixon, 1980). The 50% paw withdrawal threshold for each paw was calculated using the following formula ^' - [Xth] log = [vFr] log + ky where [vFr] is the force of the last von Frey used, k = 0.2249 which is the average interval (in log units) between the von Frey monofilaments, and y is a value that depends upon the pattern of withdrawal responses (Dixon, 1980). If an animal did not respond to the highest von Frey hair (15 g) , then the paw was assigned a value of 18.4 g.

The ant ial lodynic effect of the compound of examples was evaluated at the dose of 10, 30 and 60 mg/kg (n=6), intraper i toneal ly administrated in a volume of 5 ul/g, bw in a vehicle of 30% (v/v) PEG. The test was performed at the peak time of efficacy (0.5hr) after compound aclministrat ion.

The relative values compared to the sham (% control) were calculated and shown in Table 9, which show an antiallodynic effect of the compound of examples on STZ- induced pain model in rats.

(Table.9) Antiallodynic effect of the compound of examples on STZ- induced pain model Experimental Example 6: Hot -plate Test

To examine the pain relief effect of the sulfamate derivative compounds, a hot-plate test was conducted in general pain animal model referring to Current Protocols in Neuroscience ; Behavioral Neuroscience Unit 8.9.

ICR mice (male, 30-35g; Orient Bio, Korea) were habituated before test in test room for 1 hour. Animals were fasted 2 hr before administration of compounds. Compounds were orally administered at the dose of 150 mg/kg, 10 ul/g, bw (n=7~10/group) . All compounds were dissolved in a vehicle of 30% (v/v) PEG 400 or 20% (v/v) Tween 80. The control group was treated the vehicle without compounds.

0.5 hr after the aclministrat ion of compounds, the mice were put on a hot plate pre-heated to 55+l ^° C (Hu, X. et al, 2008), and then, measured as the withdrawal latency (cut-off time: 30 sec) time until the point when each mouse was taking off a paw from the plate, shaking, licking a paw or hind leg, or jumping from the plate. The relative values compared to the control (% control) were calculated and shown in Table 10.

(Table 10) Effect of the compound of examples in hot-plate test. 15 112.6 (0.5h)

16 116.3 (lh)

28 "100 (126.4%)

the concentration administered and effect (%) compared to that of control treated with vehicle only

Experimental Example 7· ^' Evaluation of Ant ial lodynic Activity on Vincrist ine-Induced Pain Model.

Male, Spr ague-Daw ley rats (300-320 g, Nara Bio, Korea) were habituated for 1 week before surgery and allowed free access to food and water throughout the experimentation. Room temperature and humidity were maintained at 24±2 ^° C and 50+10%, respectively.

Vincristine was established by the procedure of Natsuko et al . (2001) with minor modifications. Vincristine was intravenously infused continuously for 14 days using a mini-osmotic pump as follows. Vincristine sulfate solution (Hospira, Australia) was diluted with 0.9% saline to 80 ug/kg, final dose. The pumps (Alzet Model 2002, USA) were filled with the vincristine solution. and primed by incubation at 37 ^° C for 4 h before the infusion. Briefly, animal under gaseous anesthesia with isoflurane a. 4:4 flow ratio of NO2. Catheter made from PE-60 tube was inserted into an external jugular vein in rat. Sham controls were prepared in the same manner as expose of the external jugular vein, but, not cut down of external jugular vein and vehicle control groups were identical to vincristine i fusion model , except for administration of vehicles.

Tactile sensitivity (Mechanical allodynia) was evaluated using von Frey monofilaments before and after treatment, and animals were used withdrawal threshold value was less than 4g. One week after surgery, vincrist ine-infused animals (11=6), sham-operated animals (n=12) and vehicle-operated (n=18) animals were tested for tactile sensitivity with von Frey monofil ments 3 trials in each animal. All Animals were placed in a stainless steel mashed chamber and habituated for 30 min in the test box. The tactile sensitivity for- ipsi lateral hind paw was measured using the up- and-down method (Dixon, 1980) with seven von Frey monofilaments (0.4, 1, 2, 4, 6, 8, and 15 g) to 3 trials. Tactile sensitivity test was followed by Dixon' s method. The 50% paw withdrawal threshold for each paw was calculated using the following formula: [Xth] log = [vFr] log + Ay where [vFr] is the force of the last von Frey used, k = 0.2249 which is the average interval (in log units) between the von Frey monofilaments, and y is a value that depends upon the pattern of withdrawal responses (Dixon, 1980). If an animal did not respond to the highest von Frey hair (15 g) , then the paw was assigned a value of 18.4 g.

The ant ial lodynic effect of the compound of the examples was evaluated at the dose of 1, 5 and 10 mg/kg (n=6), intraper i toneal ly administrated in a volume of 5 ul/g, bw in a vehicle of 30% (v/v) PEG. The test was performed at the peak time of efficacy (0.5hr) after compound administration.

The relative values compared to the sham (% control) were calculated and shown in Table 11, which show an ant ial lodynic effect of the compound of examples on vincristine-induced pain model in rats.

(Table 11) Ant ial lodynic effect of the compound of examples Vincristine-induced pain model

Experimental Example 8- Tai 1-f 1 ick Test .

To examine the pain relief effect of the sulfamate compounds, a tail- flick test was conducted in general pain animal model referring to Current Protocols in Neuroscience; Behavioral Neuroscience Unit 8.9.

ICR mice (male, 25-30g; Orient Bio, Korea) were habituated before test in test room for 1 hour. Animals were fasted 2 hr before administration of compounds. Each of Compound was orally administered at the dose of .150 mg/kg, 10 ul/g, bw (n=7~10/group) . All compounds were dissolved in a vehicle of 30% (v/v) PEG 400 or 20% (v/v) Tween 80. The control group was treated the vehicle without compounds.

After the administration of compounds, the mice tail were put on a tail-flick analgesia meter. To avoid tissue damage, maximal exposure time to pain stimuli was restricted to 15 s. The withdrawal latency was measured as the time to the point when each mouse response to the stimulus. The relative values compared to the control (% control) were calculated.

The relative values compared to the sham were calculated and shown in Table 12, which show effect of the compound of examples on tail-flick test in rats.

(Table 12) Effect of the compound of examples in tail-flick test.

the concentration administered and effect compared to that of control treated with vehicle only

[Statistical Analysis]

The obtained results are shown as mean+sem. The difference between the groups was statistically analyzed by ANOVA, and then, further examined by Dunnett' s test or Bonferroni test. If p is less than 0.05, it was determined that the difference between the groups had. statistical significance.