[DISCRETION]

[Invention Title]

SULFAMATE DERIVATIVE COMPOUND FOR USE IN PREVENTING OR TREATING EPILEPSY

[Technical Field]

The present invention relates to a pharmaceutical composition for treating or preventing epilepsy containing a sulfamate derivative compound and/or pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a method for treatment or prevention epilepsy comprising administering a sulfamate derivative compound in a pharmaceutically effective amount to a subject in need of treatment or prevention of epilepsy.

[Background Art]

CNS disorders nowadays concern large sections of the population. In particular on account of the increase in elderly people, the numbers of pat i ent s are i ncr eas i ng cont i nuous ly .

Epilepsy is the most common neurological disorder, affecting about 1% of the population worldwide. Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy. Using a definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is estimated at 5 to 10 people per 1000. An essential step in the diagnosis and treatment of a patient with a seizure is to determine the type of seizure that has occured. The main characteristic that distinguishes the different categories of seizure is whether the seizure activity is partial or generalized or unclassified.

For the general population there are approximately 20-70 new cases per 100,000 diagnosed each year with a 3-5% lifetime probability of developing the disease. The older established ant iepi lept ic drugs (AEDs) phenytoin, carbamazepine , clonazepam, ethosuximide, valproic acid and barbiturates are widely prescribed but suffer from a range of side effects. Furthermore, there is a significant group of patients (20-30%) that are resistant to the currently available therapeutic agents. Since 1989 several new drugs have been launched, including felbamate, gabapentin, lamotr igine, oxcarbazepine, tiagabine, topiramate, vigabartrin, zonisamide and levet iracetam. While many of new AEDs show improved efficacies and side- effect profiles, about. 30% of patients with epilepsy remain untreated. There is clearly a need for improved medication.

[Disclosure]

[Technical Problem] The o 1 der est ab 1 i shed ant iepi lept i c drugs ( AEDs ) pheny t o i n , carbamazepine, clonazepam, ethosuximide, valproic acid and barbiturates are widely prescribed but suffer from a range of side effects. Furthermore, there is a significant group of patients (20-30%) that are resistant to the currently available therapeutic agents. Since 1989 several new drugs have been launched, including felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabartrin, zonisamide and levet iracetam. While many of new AEDs show improved efficacies and side-effect profiles, about 30% of patients with epilepsy remain untreated. There is clearly a need for improved medication.

[Technical Solution]

The present invention relates to a pharmaceutical composition for treating or preventing epilepsy containing a sulfamate derivative compound and/or pharmaceutically acceptable salt thereof as an active ingredient. [Advantageous Effects]

The present inventors have discovered that the sulfamate derivatives represented by the above formula 1 provide highly enhanced anti-epileptic activity wi h significantly decreased side effects.

[Best Mode]

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

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

[Mode for Invention]

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

wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen, 'C Cs alkyl, C2-C5 alkenyl and Cg-Cio 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 car bony 1 group ^' , A is an aryl moiety or a heterocyclic moiety optionally substituted by one or more substituents selected from the group consisting of hydrogen, hydroxyl, C1 _. -C5 alkoxy, Cj- C. alkyl, C2-C5 alkenyl , Ce-Cio aryl , C1-C5 alkoxycarbonyl , carboxyl , C2-C5 acyl , C L ^~ C.5 alkyl t hi 0, cyano, nitro, amine, C1-C5 alkyl amine and halogen; R ^'J and R are each independently hydrogen or C1-C3 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 Cg-Co cycloalkyl group.

In a preferred embodiment according to the invention, an aryl moiety represents a Ce-Cio aryl group.

In a preferred embodiment according to the invention, a heterocyclic moiety represents a C3-C10 heterocyclic group.

In a preferred embodiment according to the invention, A is a phenyl optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C5 alkyl, nitro, amine and C1-C5 alkylamine or C3-C10 heterocyclic group optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C5 alkyl, and C(-rC;io aryl.

According to a concrete embodiment, R ³ and R ⁴ are each independently hydrogen or methyl .

In a preferred embodiment according to the invention, 1 and m are each independently an integer of 0-2.

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

Particular examples of the substituents represented by A in Chemical Formul 1 include the following ^' -

wherein X is each independently selected from the group consisting of hydrogen, halogen, nitro, amine, and C1-C5 alkyl; n is an integer of 0~5; and Z is selected from S, 0 or NH.

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

In a more preferred embodiment according to the invention, n 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 . "CrCs 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 wherein alkyl is as defined above.

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

The term "alkylthio" , as used herein, unless otherwise indicated, includes S-alkyl groups wherein alkyl is as defined above.

The term "alkoxycarbonyl " , as used herein, unless otherwise indicated, includes -C(0)0-alkyl 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 totally or partially unsaturated monocyclic or polycyclic carbon rings having aromaticity. The aryl group of the present invention is preferably monoaryl or biaryl. such as phenyl or naphthyl . The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nit.ro, cyano, cli alk l ami no, aminoalkyl, acyl and alkoxycarbonyl, 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-aromat i c and/or aromat i c r i ngs ) .

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

(1) ( 5-(2-ch loropheny1)-2, 2-di methy1-1, 3-d i oxo 1 an-4- yl )methyl sulfamate;

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

(3) ( 5-(2-chl oropheny1 )-2, 2-diethy1-1,3-cli oxo lan-4-yl)methyl sulfamate, ^'

(4) (3-(2-chlorophenyl )-l,4-dioxaspiro[4,4]nonan-2-yl )methyl sulfamate; (5) (3-(2-chloropheny1 )-l,4-dioxaspiro[4,5]clecan-2-yl )methyl sulfamate;

(6) (5-(2-ch1oropheny1 )-2-pheny1-1 , 3 ^~ di oxo 1 an-4-y1 )methy 1 su1 famate ;

(7) (5-(2-f 1uoropheny1 )-2 , 2-dimethy1-1 , 3 ^~ dioxo1 an-4-y1 )methy1 SLI I famate ;

(8) (5-(2-f 1uoropheny1 )-2-methyl-l ,3-dioxolan-4-yl) methyl sulfamate;

(9) (5-(2-f 1uoropheny1 ) -2 , 2-di ethy1-1 , 3-di oxo1 an-4-y1 )methy1 sul famate ^" ,

( 10) (3-(2-f 1 uoropheny1 )-1 , 4-di oxaspi ro [4 , 4]nonan-2-y1 )methy1 sul famate ;

(11) (3-(2-f 1uoropheny 1 )-1 , 4-dioxasp i ro[4 , 5] decan-2-y1 )me thy1 sulfamate;

(12) (5—(2—f 1uoropheny1 )-2-pheny1-1 , 3-dioxolan-4-y I )methy1 sul famate ;

( 13) (5-(2-i odopheny1 )- , 2-dimethy1-1 , 3-dioxo 1 an-4-y1 )methy1 sulfamate;

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

( 15) (5-(2-iodopheny1 ) -2 , 2-d i ethy1-1 , 3-di oxo1 an-4-y1 ) methy1 sulfamate;

(16) (3-(2-iodopheny1 )-l,4-dioxaspiro[4,4]nonan-2-yl ) methyl sulfamate;

( 17) (3-(2-iodopheny1 )-1 , 4-dioxaspi ro [4 , 5]decan-2-y1 )methy1 sulfamate;

( 18) (5-(2-i odopheny1 )-2-pheny1-1 , 3-di oxo1 an-4-y1 )methy1 su 1 famate ;

( 19) (5-(2 , 4-di ch1oropheny1 )-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 ioxo1 an-4-y1 )methy1 sulfamate;

(21) (5-(2 , 4-di ch1oropheny 1 )-2 , 2-di ethyl -1 , 3-cli oxo 1 an-4-y 1 )methy 1 sulfamate;

(22) (3-(2 , 4-di ch 1orophen 1 )-1 , -dioxaspi ro[4 , 4]nonan-2-yI )methy 1 sulfamate;

(23) (3-(2 , 4-di ch 1 oropheny1 )-1 , 4-dioxaspi ro[4 , 5] decan-2-y1 )methy 1 sul famate ;

(24) (5-(2 , 4-di ch 1oropheny1 )-2-pheny1 -1 , 3-di oxo 1 an-4-y 1 )methy 1 sul famate ;

(25) (5-( 2 , 6-di ch1oropheny1 ) -2 , 2-dimethyI-1 , 3-di oxo 1 an-4- yl )methyl sul famate;

(26) (5-(2 , 6-dichloropheny1 )-2-methy1-1 ,3-di oxo lan-4-yl )methyl sul famate ;

(27) (5-(2 , 6-di ch1oropheny 1 )-2 , 2-di ethy 1-1 ,3 ^~ d i oxo 1 an-4-y 1 )methy1 sulfamate; (28) (3-(2 , 6-cli ch1 oropheny1 )-1 , 4-di oxasp i ro [4 , 4]nonan-2-y1 )methy1 sulfamate;

(29) ( -(2 , 6-di ch 1 oropheny1 )-1 , 4-di oxasp i ro [4 , 5] decan-2-y I )methy1 sul famate ;

(30 ) (5-(2 , 6-di ch1 oropheny1 )-2-pheny1 -1 , 3-di oxo 1 an-4-y1 )me thy1 sul famate;

(31) (5-(2-aminopheny1 )-2,2-dimethyl-l,3-dioxolan-4-yl )methyl sul famate ;

(32) (5-(2-aminopheny1 )-2-methy1-1, 3-di oxo lan-4-yl )methyl sul famate;

(33) (5-(2-aminopheny1 )-2 , 2-cl i ethy1 -1 , 3-di oxo1 an-4-y1 )methy1 sul famate;

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

(35) (3-(2-aminopheny1 )-l ,4-dioxaspiro[4, 5]decan-2-yl )methyl sul famate ;

(36) (5-(2-ami nopheny1 )-2-pheny1-1, 3-di oxo lan-4-yl)methyl sulfamate;

(37) ( 5-(2-ni t ropheny1 )-2 , 2-dimethy1 -1 , 3-di oxo 1 an-4-y1 )methy1 sulfamate;

(38) (5-(2-ni trophenyl )-2-methyl-l ,3-dioxolan-4-yl ) methyl sulfamate;

(39) (5-(2-ni t ropheny 1 )-2 , 2-d i ethy1 -1.3-cl i oxo 1 an-4-y1 )methy1 sulfamate;

(40) (3-(2-ni trophenyl )-l ,4-dioxaspiro[4,4]nonan-2-yl )methyl sul famate ;

(41) (3-(2-ni trophenyl )-l,4-clioxaspiro[4,5]decan-2-yl )methyl sulfamate;

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

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

(44) (5-(2-methy1 pheny1 )-2 , 2-d imethy1 -1 , 3-clioxo 1 an-4-y 1 )methy 1 sul famate ;

(45) (5-(2-methylphenyl )-2-methyl-l,3-di oxo lan-4-yl )methyl sul famate ;

(46) (5-(2-methyl phenyl )-2 , 2—di ethyl -1 , 3-di oxol an-4-y1 )me hyl sul famate ;

(47) (3-(2-methylphenyl )-l,4-dioxaspiro[4,4jnonan-2-yl )methyl sulfamate;

(48) (3-(2-methy1pheny1 )-1 , 4-di oxaspi ro [4 , 5] decan-2-y1 )methy1 sulfamate;

(49 ) (5-( 2-methy1 pheny1 )-2-pheny1-1 , 3-di oxo 1 an-4-y1 )methy1 su1 famat e ;

(50) (5-(2-methy1 am inopheny1 )-2 , 2-dimethy1 -1 , 3-cli oxo 1 an-4-y1 )methy1 methyl sulfamate;

(51) (5-pheny1 -2 , 2-d i methy1 -1 , 3-di oxo 1 an-4-y1 )methy1 su 1 famate ^' .

(52 ) (5-pheny1 -2 , 2-d i ethy 1 -1 , 3-di oxo1 an-4-y1 )methy1 su 1 famat e ; (53) (3-pheny1 -1 , 4-d i oxas i ro [4 , 4]nonan-2-yl )methyl su1 famat e ;

(54) (3-pheny1 -1 , 4-di oxasp i ro [4 , 5] decan-2-y1 )methy1 sul famat e ;

(55) 2-(5-benzy1 -2 , 2-d imethy 1 -1 , 3-di oxo 1 an-4-y1 )ethy1 su 1 famate ;

(56) 2-( 5-benzy1 -2 , 2-d i ethy1-1 , 3-di oxo 1 an-4-y1 )ethy1 su 1 famat e ;

(57) 2-(3-benzy1-1 , 4-di oxaspi ro [4 , 4]nonan-2-y1 )ethy 1 su 1 famat e ;

(58) 2-(3-benzyl-l ,4 ^~ dioxaspiro[4, 5]decane-2-yl )ethyl sul famate ;

(59) (5-benzy1 -2 , 2-d imethy1 -1 , 3-di oxo 1 an-4-y1 )methy1 su 1 famate ;

(60) (5-benzy1 -2 , 2-d i ethy1 -1 , 3-di oxo 1 an-4-y1 )me thy1 su 1 famate

(61) (3-benzy1-1 ,4-dioxaspiro[4,4]nonan-2-yl )methyl sul famate

(62) (3-benzy1-1 ,4-dioxaspiro[4, 5]decan-2-yl )methyl sul famate

(63) 2-(5-pheny1 -2 , 2-dimethy1 -1 , 3-di oxo 1 an-4-y1 )ethy1 su1 famate ;

(64) 2-(5-pheny1 -2 , 2-di ethy1-1 , 3-d i oxo 1 an-4-y1 )ethy1 sul famat e ;

(65) 2-(3-phenyl-l ,4-dioxaspi ro[4, 4]nonan-2-yl )ethyl sul famate ;

(66) 2-(3-pheny1-1 , 4-di oxasp i ro [4 , 5] decan-2-y1 )ethy 1 su 1 famat e ;

(67) 2-(5-(2-chlorobenzyl)-2,2-dimethyl-l,3-dioxolan-4-yl)ethyl sul famate ;

(68) 2-(5-(2-ch1orobenzy1 )-2 , 2-cli ethy1 -1 , 3-d i oxo 1 ai-4-y1 )ethy1 sul famate;

(69) 2-(3-(2-ch lorobenzy1 )-l ,4-dioxas iro[4,4]nonan-2-y I )ethy sul famate ;

(70) 2-(3-(2-ch 1 orobenzy1 )-1 , 4-d i oxasp i ro [4 , 5] decan-2-y1 )ethy1 sul famate ^" .

(71) (5-(2-chl orobenzy1 )-2, 2-di methyl -1 ,3-di oxo lan-4-yl )methyl sul famate ;

(72) ( 5-(2-chl orobenzy 1 )-2 , 2-cl i ethy 1-1 ,3-di oxo 1 an-4-yl )methy1 sul famate;

(73) (3-(2-ch1 orobenzy1 )-1 , 4-di oxaspi ro [4 , 4]nonan-2-y1 )methy1 sul famate ;

(74) (3-(2-ch1 orobenzy 1 )-1 , -di oxaspi ro [4 , 5] decan-2-y1 )methy1 sul famate ;

(75) 2-( 5-(2-ch 1 oropheny1 )-2 , 2-dimethyl-1, 3-di oxo 1 an-4-y 1 )ethy1 sul famate ;

(76) 2-( 5-(2-ch1 oropheny1 )-2 , 2-di ethy1 -1 , 3-di oxo 1 an-4- 1 )ethy1 sul famate;

(77) 2-(3-(2-chlorophenyl )-l ,4-dioxaspi ro[4,4]nonan-2-yl )ethyl sul famate;

(78) 2-(3-(2-ch1 oropheny1 )-1 , 4-di oxaspi ro [4 , 5J decan-2-y1 )ethy1 sul famate!

(79) (5-(2,4-dichlorothiazol-5-yl)-2, 2-d imethy1-1, 3-d ioxo lan-4 yl )methyl sul famate ;

(80) (5-(2-ch1 orothi azo 1 -5-y 1 )-2 , 2-d imethy1-1 , 3-d i oxo 1 an-4 yl )methylsulfamate;

(81) ( 2 , 2-d i met hy 1 -5- ( 4-me t hy 11 hi azo 1 -5-y 1 ) - 1 , 3-d i oxo 1 an-4- y methylsLilfamate;

( 82 ) (2,2-di me t hy 1 -5- ( 2-ch 1 or o-4-me t hy 11 h i azo 1 -5-y 1 ) - 1 , 3-d i oxo 1 an-4- yOmethylsLilfamate;

( 83 ) (2,2-di me t hy 1 -5- ( t h i ophen-3-y 1 ) - 1 , 3-d i oxo 1 an-4- yDmethylsulfamate;

( 8 ) (2,2-di me thy 1 -5- ( 5-ch 1 or o t h i ophen-2-y 1 ) - 1 , 3-d i oxo 1 an-4- yl )methylsLilfamate;

( 85 ) ( 5- ( 3-ch 1 or opyr i d i n-4-y 1 ) -2 , 2-d i me t hy I - 1 , 3-d i oxo 1 an-4- yl )methylsul f amate

(86) ( 5- ( 4-ch 1 o r opyr i d i n-3-y 1 ) - 2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 an- 4- yl )methylsiilfamate;

( 87 ) ( 2 , 2-d i met hy 1 -5- (pyr i m i d i n-5-y 1 ) - 1 , 3-d i oxo 1 an-4- y methylsulf amate; and

( 88 ) (2,2-di met 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- yl )methylsul f amate.

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 anti- epileptic activity by multilateral experiments.

The term "enantiomer" as used herein, refers to one of two stereoisomers that are mirror images of each other which are non- super imposable due to the 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 C4 and C5 are diverse in stereo- conf igurat ion.

The term "diastereomer" as used herein, refers to stereoisomers that are not enantiomers, 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 and 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 can be manufactured by using a method known in the art, for example, but not limited to, salts with inorganic acids such as hydrochloric . acid, bromic 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 i cyl i c 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, lithium and potassium; or salts wit h amnion i urn i on .

In another aspect of this invention, there is provided a method for the management of epilepsy comprising administering a pharmaceutically effective amount of the compound of the present invention or 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, or treating a disease associated with epilepsy.

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 formulation, but is not limited to, includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, rubber arable, potassium phosphate, arginate, gelatin, potassium silicate, microcrystal 1 ine cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methyl eel lulose , methyl hydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oils. The pharmaceutical composition according to the present invention may further include a lubricant, a humectant, 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, subcutaneously, intramuscularly, intraperitoneal ly, transdermal ly or intra-art icular ly. More concretely, it is administered intramuscularly or intraper i toneal ly .

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 a 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 SLilf annate derivatives compound of the present invention may be prepared by the following reaction scheme.

[Reaction scheme 1] 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 d i hydroxy 1 at ion, condensation and a deprotection react ion.

[Reaction scheme 2] Synthesis of alcohol compound

Formula 2 Formula 3

Alcohol compound of formula 3 is synthesized by a reduction reaction using a reducing agent, including but not limited to, LiAl¾(Li thium aluminum hydride), NaBH ₄ ( Sodium borohydr ide) , Zn(BH ₄ )2(Zincborohydr ide) , NaH( Sodium hydride), KH(Potassium hydride), AlhVAluminum hydride), and NaOMe(Sodiumniethoxyde) in the basic condition from the Carboxylic acid compound of formula 2

[Reaction scheme 3] Synthesis of protected alcohol compound

PG

PG = Protecting group

Formula 3 Formula 4

OH of Alcohol compound of formula 3 is protected by a protecting group, including but not limited to, TMS(Tri methyl silyl), TES(Tri ethyl silyl), TIPSCTriisopropyl silyl), TBDMSCtert-butyldimethyl silyl), TBDPSCtert-butyldiphenyl silyl), Piv(Pivaloyl ) , MOMCMethoxymethyl ) , Acetyl, Benzoyl, and Ti tyl (Tr iphenylmethyl ) in the basic condition for using in the next reaction.

[Reaction scheme 4] Synthesis of diol compound

OH

PG = Protecting group OH

Formula 4 Formula 5

The asymmetric d i hydroxy 1 at 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 , K ₂ 0s0 ₂ (0H) ₄ , etc . ) , K CO.. KsFe(CN)6, N-methylmorphol ine oxide (NMO) , methane sulfone amide (CH3SO2NH2), and the like. For example, the asymmetric clihydroxylat ion. catalyst may be AD-mix-a (K ₂ 0s0 ₂ (0H)4(cat ) , K ₂ C0 ₃ , K ₃ Fe(CN) _i:i , (DHQ) PHAL(cat)) and methane sulfone amide (CH ₃ S0 ₂ NH ₂ ), or 0s0 ₄ and N- methylmorphol ine oxide (NMO), it is not limited thereto and may be appropriately selected depending on the intended purpose.

[Reaction scheme 5] Synthesis of dioxo lan-alcohol ^' compound

Formula 5 Formula 6

Diol compound of formula 5 is reacted with a ketone compouncKsuch as acetone, 3-pentanone, eye 1 opent anone , or cyclohexanone) , alkoxy compouncKsuch as dimethoxymethane, climethoxypropan, cliethoxye thane, or methoxy propene, 3-methoxypente-2-ene, 1-methoxycyclopent-l-ene, 1- methoxycyclohex-l-ene) , or aldehyde compouncKsuch as benzaldyde, eye 1 opent anecarboxaldehycle, or eye lohexaecarboxalclehycle) in the acidic condition, for example, a solution dissolved with an acid such as p-TsOH(p- toluenesul fonic acid), H ₂ S0 ₄ (Sulfuric acid), HN(¾(Nitric acid), followed by removing a protecting group to afford the Dioxolan-alcohol 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 6] 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 CrCio alkyl , or cyclic C ₃ -Cto alkyl, allyl and benzyl is synthesized by an ester i f icat ion reaction in the acidic condition from the carboxviic acid compound of formula 2.

[Reaction scheme 7] Synthesis of ester-diol compound

Formula 7 Formula 8

The asymmetric dihydroxylat ion catalyst may be one or more selected from the group consisting of a chiral ligancl (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 , K ₃ Fe(CN)(3, N-methylmorphol ine oxide (NMO) , methane sulfone amide (CH3SO2NH2), and the like. For example, the asymmetric dihydroxylat ion catalyst may be -AD-mix-a (R ₂ 0s0 ₂ (0H) ₄ (cat ) , K ₂ C0 ₃ , 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), it is not limited thereto and may be appropriately selected depending on the intended purpose. r compound

Formula 8 Formula 9

Diol compound of formula 8 is reacted with a ketone compound (such as acetone, 3-pentanone, cyclopentanone, or cyclohexanone) , an alkoxy compound (such as d i me hoxyme thane, dimethoxypropan, diethoxyethane, or methoxy propene, 3-methoxypente-2-ene , 1-methoxycyclopent-l-ene, 1- methoxycyclohex-l-ene) , or an aldehyde compound(such as benzaldyde, cyclopentanecarboxaldehyde , or cyclohexaecarboxaldehyde) in the acidic condition, for example, a solution dissolved with an acid such as p-TsOH (p-toluenesul fonic acid), H2SO4 (Sulfuric acid), HNO3 (Nitric acid) to afford the Dioxolan-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 depending on the intended purpose.

cohol compound

Formula 9 Formula 6

Dioxolan-alcohol compound of formula 6 is synthesized by a reduction reaction using a reducing agent, including but not limited to, L i A 1 H4- (Lithium aluminum hydride), NaBrU (Sodium borohydr ide) , Zn(BH ₄ )2 (Zincborohydr ide) , NaH (Sodium hydride), H (Potassium hydride), AIH3 (Aluminum hydride), and NaOMe(Socliunimethoxycle) in the basic condition from the dioxolan-ester compound of formula 9.

[Reaction scheme 10] Synthesis of Sulfamate compound

Chemical formula 6 hemical formula 1

Dioxolan-alcohol compound Sulfamate-compound

Dioxolan-alcohol compound of formula 6 is reacted with s u If amide or sulfamoyl chloride in the basic condition using a base, including but not limited to, pyridine, piperidine, and piperazine to produce the sulfamate compound of formula 1.

EXAMPLES

Preparation example 1· ^" (E)-3-(2-chLorophenyl )prop-2-en ^~ l-ol

To a 100ml round-bottomed flask, 2-Chlorocinnamic acid (5g, 7.3mmol) and THF (20ml) were added and the reaction mixture was cooled to 0 ^° C . Tri ethyl amine (4.2ml, .SO.lmmol) 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 borohydride (2.68g, 142.3mmol) in ¾0 at 0 ^° C and stirred for 2hrs, quenched with IN HCi 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, CDC1 ₃ ) 51.67(s, 1H) , 4.39(t, .1=4.0, 2H) , 6.37(dt

16.0, IH), 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 Di chl oromethane (17.5ml.) were added and the reaction mixture was cooled to 0 ^° C. Di i sopropylethylamine (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 (MgS0 ), filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the ti le compound (3.43g, 85-95%).

¾ NMR (400MHz, CDC1 ₃ ) 53.44(s, 3H) , 4.30(dd, J=8.0, 1.6, 1H), 4.73(s, 2H), 6.30C1H, 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 250m1 rouncl-bo11omed flask, equi pped with a magnetic stirrer, was filled with 80 ml of tert-butyl alcohol, 80ml of water, and K ₃ Fe(CN) ₆ (15.93g, 48.3mmol), K ₂ C0 ₃ (6.7g, 48.3mmol), (DHQD) ₂ -PHAL (0.12g, 0.16mniol), I^OsC OH)^, (ll.Smg, 0.03mmol), and Methanesul fonamide (1.53g, 16.. lmmol). Stirring at 0 ^° C . (E)-l-chloro-2-(3-(methoxymethoxy)prop-l-enyl )benzene (3.43g, 16. lmmol, 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 (Na ₂ S(¾, 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) , 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)

P epar a t i on exanip 1 e 5 : 1- ( 2-ch 1 o r opheny 1 ) -3- ( me t hoxyme t hoxy ) opane- 1 , 2-d i o 1

(E,)-l-chloro-2-(3-(methoxymethoxy)prop-l-enyl )benzene(9. Ig, Preparat ion Example 2) was dissolved in 45mL of a mixture of acetone/t-Bu0H/H ₂ 0(5 ^' - 1 : 1 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 ide (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, J=4.4, 1H), 7.23~7.61(m, 4H)

Pr epar a t i on examp 1 e 6 : ( ( 4R , 5R ) -5- ( 2-ch 1 or opheny 1 ) -2 , 2-d i me t hy 1 - 1 , 3- dioxolan-4-yl )methanol

To (lR,2R)-l-(2-chlorophenyl )-3-(methoxymethoxy)propane-l , 2-diol (3.31g, 13.4mmol, Preparation example 3), Dichloromethane 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), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (1.05g, 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 T- ((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- dioxo1 an-4-y1 )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(Preparation example 4) was used instead of (lR,2R)-l-(2-chlorophenyl )-3-(methoxymethoxy)propane-l, 2-diol (Preparat ion example 3), to obtain the title compound (l. ^' lg, 30-40%).

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, J=8.4, 1H), 7.25-7.66(m, 4H) .

Preparation example 8 ^' · (5-(2-chlorophenyl)-2,2-dimethyl-l,3-dioxolan-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(m, 4H)

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

Piper idi ne (247mg, 2.90inmol) was added to a stri ^' ied solution of ma Ionic acid (3.1g, 29.00mmol) and 2-f luoroaldehyde (3g, 24.17mmol) in pyridine at room temperature under N2 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 Na ₂ S0 , 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, CDC 13 ) δ 6.60(cl, 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%). 'Ή NMR (400MHz, CDC1 ₃ ) 61.67 (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 (Preparation example 1), to obtain the title compound (2.23g, 85-95%). ¾ NMR (400MHz, CDCl 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-l , 2—cli o1

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-l-Fluoro-2-(3-(methoxymethoxy)prop-l- enyDbenzene (Preparation 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)

( (4R, 5R)-5-(2-f 1 uoropheny1 )-2 , 2-climethy1-1 ,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 (Preparat ion example 12) was used instead of (1R, 2R)-l-(2-chlorophenyl )-3-(methoxymethoxy)propane-l,2- cliol (Preparat ion example 3), to obtain the title compound (1.73g, 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(ni, 4H)

Preparation example 14: ( IS , 2S)-1-(2-f 1 uorophenyI )-3- (methoxymethoxy)propane-1 , 2-dio1

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- (niethoxymethoxy)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 1 uoropheny1 )-2,2-dimethyl-l,3- dioxolan-4-yl )methanol

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

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

H 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 16: 2-Iodobenzenealdehyde

In a flask, 2-.iodobenzyl alcohol (4g, 17.09mmo 1 ) was dissolved in dichloromethane (MC, 85ml), and then, manganese oxide ( M11O2 , 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 title compound (3.6g, yield 75~90%) . lH NMR (400MHz, CDC 13) δ 7.30~7.99(m, 4H), lO.HXs, 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-Iodobenzene ldehyde (Preparation example 16) was used instead of 2-Fluoroaldehyde, to obtain the title compound (2.06g, 70-90%) ^L H 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 ) 61.67 (s, 1H), 4.39 (t, .1=4.0, 2H), 6.34-6.41 (m, 1H), 7.00-7.38 (m, 4H)

Preparat ion 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%).

¾ NMR (400MHz, CDC1 ₃ ) 53.44(s, 3H) , 4.30(dd, 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) ropane- 1,2-diol

The substantially same method as described in Preparation Example 3 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 NM (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 21: ((4R, ^' 5R)-5-(2-iodophenyl)-2,2-dimethyl-l,3- di oxo 1 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- 1,2-diol (Preparation example 20) 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), 5.41(d, J=8.4, 1H), 7.25~7.66(m, 4H)

Preparat ion 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(iii, 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 ion examp 1e 23 ^' · ( (4S , 5S)-5-(2- i oclopheny1 )-2 , 2-dimethy1 -1 , 3-di oxo 1 arr 4-yl )methanol

The substantially same method as described in Preparation Example 6 was conducted, except that ( IS, 2S)-.!-(2- i oclopheny1 )-3-(methoxymethoxy)propane- l,2-diol(Preparation example 22) 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 24: (E)-Methyl;-3-(2-chlorophenyl )acrylate

To a 250ml round-bo tomed flask, 2-Chlorocinnamic acid (25g, 136.9mmol) and MeOH (56ml) were added. POC 1 ₃ (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 ¾0. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgSOJ , filtered and concentrated under vacuum (26.98g, 85-97%)

^L H NMR (400MHz, CDC1 ₃ ) 53.84 (s, 3H), 6.45 (d, J=16.0, lH), 7.28-7.65 (m, 4H), 8.12 (d, 7=16.0, 1H)

Preparation example 25: ( 2R,3S) -met hy 1-3- (2-ch lor opheny 1 ) -2,3- d i hyclroxypropanoat e

A 1000ml round-bottomed flask, equipped with a magnetic stirrer, was filled with 362 ml of tert-butyl alcohol, 362ml of water, ₃ Fe(CN) ₆ (135.53g, 411.63mmol), K ₂ C0 ₃ (56.89g, 411.63mmol), (DHQ) ₂ PHAL (1.06g, 1.37mmol), ₂ 0s0 ₂ (0H) ₄ , (0. lg, 0.27mmo 1 ) , and Methanesul fonamicle (13.05g, 137.21mmol) and stirred at 0 ^° C. (E)- ethyl-3-(2-chlorophenyl)acrylate (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 H ₂ S0 ₄ /Na ₂ S0 ₄ solution (H ₂ S0 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 MgS04, 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, CDC 13 ) 57.62-7.26 (4H, m), 5.51(1H, del, 7=7.2, 2.4), 4.50UH, del. 7=5.6, 2.4), 3.86(3H, s), 3.13UH, d, .7=6.0), 2.79(1H, d, 7=7.2)

Preparat ion examp 1 e 26 : (4R, 5S)-me hyl-5-(2-chl.oropheny1 )-2 , 2-dimehty1-1.3- dioxol ne-4-carboxylate

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- Dimethoxypro ane (26ml, 211.77mmol) and p-toluenesulfonic acid (2g, 10.58nimol) was added and stirred at room temperature. The reaction mixture was quenched with H ₂ 0, extracted with DCM, washed with ¾0, 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, CDC1 ₃ ) . δ 1.63(s , 3H), 1.65(s, 3H), 3.78(s, 3H), 4.30(d, .7=7.6, 1H), 5.62(cl, 7=7.6, 1H), 7.28~7.64(m, 4H)

Preparation example 27: ( (4S, 5S)-5-(2-ch loropheny1 )-2,2-dimehtyl-1.3- dioxolane-4-yl )methanol

A solution of To a solution LAH(LiAlH ₄ 3.31g, 87.25mmol) in THF was added dropwise to a solution of (4R,5S)-methyl 5-(2-chlorophenyl )-2 ,2-dimethyl- 1, 3-di oxo lane-4-carbox late (23.6g, Preparation 26) in THF at 0 ^° C, and the mixture stirred at room temp. The reaction mixture was quenched with H20 at 0 ^° C, eel lite filtered with EtOAc, washed with EtOAc, dried over anhydrous magnesium sul fate(MgS04) , 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 ) 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)

Preparation example 28: (E)4fethy _. l-3-(2,4-dichlorophenyl)acrylate

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

¾ NMR (400MHz, CDC1 _? ,) : 63.84(s, 3H), 6.44(d, J=16, 1H), 7.28-7.33(m, 1H), 7.41(d, J=2.0, 1H), 7.55(d, /= 8.4, lH), 8.04(d, J=16, 1H) .

Preparation example 29: (2R,3S)-methyl-3-(2,4-dichlorophenyl ) ^~ 2,3- dihyclroxypropanoate

The substantially same method as described in Preparation Example 25 was conducted, except that (E)-Methyl-3-(2,4-clichlorophenyl )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, CDC1 ₃ ): 63.11(s, 1H), 3.88(s, 3H), 4.42(cl, .7=2.4, 1H), 5.43(d, J=2.0, 1H), 7.28~7.33(m, 1H) , 7.41(d, .7=2.0, 1H), 7.55(d, ./= 8.4, 1H). Preparat ion example 30: (4R,5S)-methyl-5-(2,4-dichlorophenyl )—2 , 2—di mehtyL— 1.3-dioxo 1ane-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-dihydroxypropanoate (Preparation example 25), to obtain the title compound(3.5g, 60~80%) lH NMR (400MHz, CDC1 ₃ ) ^' - 51.59(s, 3H), 1.63(cl, J=8.8, 3H), 3.78(s, 3H) , 4.25(d, 7=7.6, 1H), 5.56(d, 7=8.0, 1H) , 7.28~7.33(m, 1H), 7.41(d, 7=2.0, 1H), 7.56(d, 7= 8.4, 1H).

Preparat ion example 31 : ( (4S , 5S)-5-(2 , 4-dichloropheny1 )-2 , 2-d imehty1-1.3- dioxo 1 ane-4-y1 )methano1

The substantially same method as described in Preparation Example 27 was conducted, except that. (4R,5S)-methyl-5-(2,4-dichlorophenyl )-2, 2-dimehty1- 1.3-dioxolane-4-carboxylate(Preparat ion example 30) was used instead of (4S , 5R)-methy1 -5-(2-chloropheny1 )-2 , 2-dimehty1-1.3-di oxol ane-4-carboxy1 ate (Preparation example 26), to obtain the title compound(3.2g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 61.56(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, 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 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 I ) at 0 ^° C . The reaction mixture was added H3uOK (3.2g, 28.56mmo 1 ) 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 ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by S1O2 gel column chromatography (4.3g 4060% )

¾ NMR (400MHz, CDC13) · ^' δ 1.36(t, J=3.6, 3H) , 4.31(q, 7=3.7, 2H) , 6.61(d, 7=16, 1H), 7.21(t, J=4.2, 1H) , 7.38(d, 7=5.2, 1H) , 7.81(d, /= 16, 1H).

Preparation example 33: (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-2,3- dihydroxypropanoate The substantially same method as described in Preparation Example 25 was conducted, except that (E)-ethy1-3-(2 , 6-di ch10ropheny1 )acry1 ate

(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, CDC13) ^: δ 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 34: (4R,5S)-ethyl-5-(2,4-clichlorophenyl)-2,2-dimehtyl- 1.3-dioxol ne-4-carboxylate

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) ^~ 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. J=7.2, 3H) , 1.58(s, 3H) , 1.70(s, 3H) , 3.77(s, 3H), 4.24(q, J=7.2, 1H) , 4.95(q, J=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-dimehtyl-1.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted, except that (4R,5S)-ethyi-5-(2,6-dichlorophenyl )-2,2-dimehtyl- 1.3-dioxolane-4-carboxylate(Preparat ion example 33) was used instead of (4R , 5S)-methy1 -5-(2-ch 1oropheny1 )-2 , 2-cl i mehty1 -1.3-di oxo 1 ane-4-carboxy1 ate (Preparation example 26), to obtain the title compound(3.5g, 70-95%)

Ή NMR (400MHz, CDC1 ₃ ): 61.55(s, 3H), 1.68(s, 3H), 3.66(q, J=5.5, H ), 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 36: (2S,3R)-methyl-3-(2,4-dichlorophenyl )-2,3 ^~ d ihydroxypro anoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-Methyl-3-(2,4- dichlorophenyl )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, CDC1 ₃ ): 53.11(s, 1H) , 3.88(s, 3H), 4.42(d, .7=2.4, 1H), 5.43(d, J=2.0, 1H), 7.28~7.33(m, 1H) , 7.41(d, /=2.0, 1H), 7.55(d, 7= 8.4, 1H) .

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

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-chlorophenyl)-2,3-dihydroxypropanoate (Preparation example 25) , to obtain the title compouncl(3.2g, 60~80%) ¾ NMR (400MHz, CDC1 ₃ ): 51.59(s, 3H), 1.63(d, J=8.8, 3H) , 3.78(s, 3H), 4.25(cl, J=7.6, H), 5.56(d, 7=8.0, 1H), 7.28~7.33(m, 1H), 7.41(d, 7=2.0, Hi), 7.56(d, 7= 8.4, 1H).

Preparation example 38: ((4R,5R)-5-(2,4-clichlorophenyl )-2 , 2-climehty1—1.3- dioxol ne-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted , except that (4S , 5R)-methy1 -5-(2 , 4—di chloropheny1 )-2 , 2-dimehty1- 1.3-dioxolane-4-carboxylate(Preparat ion example 37) was used instead of (4S , 5R)-me hy1-5-(2-ch1o opheny1 )-2 , 2-dimehty1-1.3-di oxo 1 ane-4-carboxy late (Preparation example 26), to obtain the title compound(3.5g, 70-95%)

¾ NMR (400MHz, CDC13) : 61.56(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, 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- dihydroxypropanoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-ethyl-3-(2,6-dich.lorophenyl)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%) .

'Ή 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(d, 7= 8.4, 1H).¾ NMR (400MHz, CDCI ₃ ) : 6=1.21(t, 7=7.2, 3H) , 3.22(s, IH), 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).

Preparat ion examp 1e 40 : (4S , 5R)-ethy1-5-(2 , 4-di ch1oropheny1 )-2 , 2-dimehty1- 1.3-dioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 26 was conducted, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl )-2,3- dihydroxypropanoate (Preparation example 39) was used instead of (2R,3S)- methyl-3-(2-chlorophenyl)-2,3-dihyclroxypropanoate (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-1ane-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-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-dioxo 1 ane-4-carboxy1 ate (Preparat ion example 26). to obtain the title compound(5.2g, 70~95 )

H NMR (400MHz, CDC1 ₃ ): 51.55(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 ) ^~ acryl ic acid

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

H NMR (400MHz, DMS0) δ 6.52(d, j=15.6, 1H), 7.65(t, J=8.1, 1H), 7.75(t, j=7.4, 1H), 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-ni tropheny1 )acrylate

The substantially same method as described in Preparation Example 24 was conducted, except that (E)-3-(2-ni trophenyl )-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-ni trophenyl ) di hydroxypropanoate

The substantially same method as described in Preparation Example 3 was conducted, except that (E)-Methy1 -3-(2-ni tropheny1 )acry1 a te (Prepar t i on 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 ): 6=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- clioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 26 was conducted, exce t that (2S , 3R)-methy1-3-(2-ni t ropheny1 )-2 ,3 dihydroxypropanoate (Preparation example 44) was used instead of (2R,3S) ^~ methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate (Preparation example 25) , to obtain the title compounding, 60-80%) ¾ NMR (400MHz, CDC13) : 61.38(s, 3H), 1.40(s, 3H), 3.75(s, 3H), 4.49(d, ./=7.4, 1H), 5.25(d, J=7.4, 1H), 7.48~7.77(m, 3H, 8.08(m, 1H)

Preparat ion examp1e ( (4R, 5R)-5-(2-ni tropheny1 )-2 , 2-dimehty1-1.3- clioxo1 ane-4-y1. )methano1

The substantially same method as described in Preparation Example 27 was conducted, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-dimehtyl-1.3- di oxo lane-4-carboxylate (Preparation example 45) was used instead of (4S , 5R)-methy1-5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-dioxo 1 ane-4-carboxylate (Preparation example 26), to obtain the title compound( 13. lg, 70-95%)

¾ NMR (400MHz, CDC13) · ^' 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(111 , 3H) , 8.08(m, 1H).

Preparation example 47: ((4R,5R)-5-(2-aminophenyl )-2,2-dimehtyl-1.3- dioxo1 ane-4-y1 )methanol

To a stirred solution of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimehtyl-1.3- dioxolane-4-yl )methanol (Preparat ion 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 S 1 O2 gel column chromatography to give title compound (7.5g 65-85%)

¾ NMR (400MHz, CDC1 ₃ ): 61.39 (s, 3H) , 1.40 (s, 3H), 3.88 (cl, 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 trophenyl )-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)-Methyl-3-(2- chlorophenyl )acrylate(Preparat ion example 24), to obtain the title compound(21.7g, 60-80%)

¾ NMR (400MHz, CDC13)■ ^' 54.31(s, 3H), 5.44(m, 4H). 5.89(s, 1H), 7.53-7.90(m, 4H)

Preparat ion example 49: (4R,5S)-methyl-5-(2-ni trophenyl )-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)-methyl-3-(2-nitrophenyl)-2,3- dihyclroxypropanoate (Preparation example 48) was used instead of (2S,3R) ^~ methyl-3-(2-chlorophenyl )-2,3-dihydroxypropanoate (Preparat ion example 25) , to obtain the title compound(2lg, 60-90%) ¾ NMR (400MHz, CDC13) : 61.38(s, 3H), 1.40(s, 3H), 3.75(s, 3H), 4.49(d, .7=7.4, 1H), 5.25(d, 7=7.4, 1H) , 7.48~7.77(m, 3H, 8.08(m, 1H) Preparation - example 50: ( (4S,5S)-5-(2-nitrophenyl)-2,2-dimehty1-1.3- 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 (4 , 5S)-methy1-5-(2-ch1oropheny1 )-2 , 2-climehty1-1.3-dioxo 1 ane-4-carboxylate (Preparation example 26), to obtain the title compound(14g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ V- δ 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, J=7.0, 1H) , 7.55~7.86(m, 3H) , 8.08(m, 1H).

Preparation example 51: ( (4S,5S)-5-(2-aminophenyl )-2 ,2-dimehtyI-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-ni tropheny1 )-2 , 2-dimehtyl-l .3- dioxolane-4-carboxylate (Preparation example 50) was used instead of (4R, 5R)-5-(2-ni t ropheny1 )-2 , 2-dimehty1-1.3-di oxo 1 ane ^~ 4-y1 )methano 1

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

¾ NMR (400MHz, CDC1 ₃ ) ^' - δ 51.38(s, 3H), 1.40(s, 3H), 3.89(cl, .7=4.1, 2H), 4.26(dt, J=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-methylbenzenealdehyde was used instead of 2- Fluoroalclehyde, to obtain the title compound (1.5g, 70-90%) ¾ MR (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, 7= 15.1, 1H), ll.OCs, 1H).

Preparation example 53: (E)-Methyl-3-<r-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%)

¾ NMR (400MHz, CDC1 ₃ ): 62.48(s, 3H) , 3.77(s, 3H), 6.14(d, 7=15.1, 1H) , 7.00~7.10(m, 1H), 7.21~7.26(m, 3H), 8.07(d, 7= 15.1, 1H).

Preparation example 54: (2S,3R)-methyl-3-(2-methylphenyl )-2,3 ^~ dihydroxy opanoate 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 ) 62.34(s, 3H) , 2.80(s, lH), 3.65(s, 1H), 3.68(s, 3H), 4.52(cl, 7=7.0, 1H), 5.22(cl, 7=7.0, 1H), 7.19~7.39(m, 4H). Preparation example 55: (4S, 5R)-methyl-5-(2-methylphenyl)-2,2-dimehtyl-1.3- dioxolane-4-carboxylate

The substantially same method as described in Preparation Example 26 was conducted, except that (2S,3R)-niethyl-3-(2-methylphenyl )-2,3- dihydroxypropanoate (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%) lH NMR (400MHz, CDC13) : 51.27(s, 6H), 2.34(s, 3H) , 3.68(s, 3H), 5.11(cl, 7=7.0, 1H), 5.81(d, 7=7.0, H), 7.19~7.26(m, 3H) , 7.37~7.39(m, 1H).

Preparat ion example 56 : ( (4R, 5R)-5-(2-methy1phenyl )-2 , 2-dimehty1-1.3- dioxo1ane-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-dimehty 1-1.3- dioxolane-4-carboxylate (Preparation example 55) was used instead of (4R, 5S)-methyl-5-(2-chloropheny1 )-2 , 2-dimehty1-1.3-d i oxo lane-4-ca boxylate (Preparation example 26), to obtain the title compound(1.3g, 70-95%)

¾ NMR (400MHz, CDCI ₃ ) ^' · 51.27(s, 6H), 2.34(s, 3H), 3.52~3.60(m, 2H), 3.65(s, 1H), 4.36(dcl, 7=7.0, 7=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: (2 ,3S)-methyl-3-(2-methylphenyl)-2,3- dihydroxypropanoat

The substantially same method as described in Preparation Exam le 25 was conducted, except that (E)-methyl-3-o-tolyacrylate(Preparat ion example 53) was used instead of (E)-Methyl-3-(2-chlorophenyl )acrylate(Preparat ion example 24), to obtain the title compound(1.7g, 60-80%)

¾ NMR (400MHz, CDC1 ₃ ): 52.34(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—dimehty1 -1.3- dioxo 1ane-4-carboxylate

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 ): 61.27(s, 6H), 2.34(s, 3H), 3.68(s, 3H), 5.11(d, 7=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-dimehtyl-1.3- dioxolane-4-yl )methanol

The substantially same method as described in Preparation Example 27 was conduct ed , exce t that (4R , 5S)-methy1-5-(2-meth 1pheny1 )-2 , 2-dimehty1 -1.3- cli oxo lane-4-carboxylate (Preparation example 58) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl )-2, 2-d i ehty1-1.3-dioxo lane-4-carboxylate (Preparation example 26), to obtain the title compound(1.5g, 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, 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- cli oxo 1 ane-4-carboxylate

Dichloromethane (MC) was added to (2S,3R)-methyl-3-(2-chlorophenyl )-2,3- clihyclroxypropanoate(Preparat ion example 433) at room temperature. 1,1- Diethoxyethane (8ml) and p-toluenesul fonic acid (0.27g) was added and stirred at room temperature. The reaction mixture was quenched with H2O, extracted with MC, washed with ¾0, 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 (3.6g, 70-95%). lH NMR (400MHz, CDC13 ) δ 1.36(d, J=6.4, 3H) , 3.78(s, 3H) , 4.30(d, ,/=7.6, 1H), 5.07(m, 1H), 5.62(d, 7=7.6, 1H), 7.28~7.64(m, 4H)

Preparat ion example 61· ^' ((4R,5R)-5-(2-chlorophenyl )-2-mehtyl-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-chlorophenyl )-2-mehtyl-l .3- di oxo lane-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%) 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, J=7.0, 1H), 5.06(m, 1H) , 5.17(d, 7-7.0, 1H) , 7.19~7.26(m, 3H), 7.37~7.39(m, 1H).

Preparation example 62 ^' · ( (4R,5S)-methy1-5-(2-chloropheny1)-2-mehty1-1.3- dioxo1ane-4-carboxylate

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-dihydroxypropanote(Preparat ion example 54) , to obtain the title compound(2. lg, 70~95%).

¾ NMR (400MHz, CDC1 ₃ ) 6 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), 7.28~7.64(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-mehty1-1.3- dioxolane-4-carboxylate(Preparat ion example 62) was used instead of (4R , 5S)-methy1-5-(2-ch1orophenyI ) -2 , 2-dimehty1-1.3-d i oxo 1 ane-4- carboxylate(Preparat ion example 26), to obtain the title compound(3. lg, 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) , 7.19-7.26(m, 3H), 7.37~7.39(m, 1H) .

Preparation example 64: (4S, 5R)-methyl-5-(2-chlorophenyl )-2,2-diehtyl-1.3- di oxo 1 ane-4-carboxylate

3-pentanone was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3- dihyclroxypropanoate(Preparat ion example 433) at room temperature. Sulfuric acid (H2SO4) was added and stirred at room temperature. The reaction mixture was quenched with ¾(), extracted with EA, washed with H ₂ O, dried over anhydrous sodium sulfate (Na2S0 ₄ ) , filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (1.6g, 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(cl, 7=7.6, 1H), 7.22~7.60(m, 4H)

Preparation example 65: ((4R,5R)-5-(2-chlorophenyl)-2,2-diehtyl-1.3- clioxo 1 ane-4-y1 )methano1

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- dioxolane-4-carboxylate(Preparat ion example 64) was used instead of (4R , 5S)-methy1 -5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-di oxo1 ane-4-carboxy1. ate (Preparation example 26), to obtain the title compound(2. Og, 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, 7=7.6, 1H), 5.88(d, 7=7.6, 1H), 7.26~7.62(m, 4H).

Preparation example 66: (4R, 5S)-methy1-5-(2-chloropheny1 )—2 , 2—di ehty1-1.3- dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 64 was conducted, except that (2R,3S)-methyl ^~ 3-(2-chloropheny1)-2.3- dihydroxypropanote(Preparat ion example 25) was used instead of (2S.3R)- methyl-3-(2-chlorophenyl )-2.3-dihyclroxypropanote(Preparat ion example 54) , to obtain the title compound(1.4g, 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), 7.22~7.60(m, 4H)

( (4S , 5S)-5-(2-ch1oropheny1 )-2 , 2-di eht 1-1.

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-ch1oropheny1 )-2 , 2-di eht 1-1.3-dioxo1ane-4- carboxylate(Preparat ion example 64), to obtain 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 (d, 7=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- dioxaspi ro[4 ,4]nonane-2-carboxyl 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(m, 1H), 1.91-2.00(m, 3H), 3.68(s, 3H), 4.40(d, J=7.2, 1H), 5.39(d, J=7.2, 1H), 7.39~7.61(m, 4H)

Preparation example 69: ((2R,3R)-3-(2-chlorophenyl)-l,4- clioxaspi 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-chlorophenyl )-l ,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 68) was used instead of (4S , 5R)-methy1-5-(2-ch1oropheny1 )-2 , 2-di ehty1 -1.3-dioxo 1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound (1.7g, 70-95%)

H NMR (400MHz , DMS0) : 61.60~1.72(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)-methyl-3-(2-chlorophenyl )-l,4- clioxaspi ro[4 , 4]nonane-2-carboxylate

The substantially same method as described in Preparation Example 68 was conducted, except that (2R,3S)-methyl-3-(2-chlorophenyl )-2,3- clihydroxypropanoate(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(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), 7.39~7.61(m, 11; ⁾

Preparation example 71: ((2R,3R)-3-(2-chlorophenyl)-l,4- dιoxaspi ro[4 , 4]nonane-2-y1 )methano I

The substantially same method as described in Preparation Example 69 was conducted, except that (2R, 3S)-methyl-3-(2-chlorophenyl)-l,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 70) was used instead of (2S, 3R)-methy1-3-(2-chlorophenyl )-l,4-dioxaspiro[4,4]nonane-2- carboxyl ate(Preparat ion example 68), to obtain the title compound(1.8g, 70-95%)

Ί-Ι NMR (400MHz , DMS0) : 61.60~1.72(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, 3 )-methyl-3-(2-chlorophenyl )-l ,4- dioxaspiro[4,5]decane-2-carboxylate

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 ) . lH 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), 7.35~7.63(m, 4H)

Preparation example 73: ((2R,3R)-3-(2-chlorophenyl)-l,4- clioxaspiro[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- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 72) was used instead of (4S , 5R)-methy1-5-(2-ch1oropheny1 )-2 , 2-diehty1-1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.8g, 70-95%)

¾ NMR (400MHz , DMSO) : δ 1.63~1.75(m , 10H) , 3.52-3.81(m , 2H) , 3.95( , 7=8.0, 1H), 5.43(d, 7=7.6, lH) , 7.48~7.87(m, 4H) Preparation example 74: (2R, 3S)-methyl-3-(2-chlorophenyl )-l ,4- dioxaspi ro[4 , 5]decane-2-carboxylate

The substan ially same method as described in Preparation Example 72 was conducted, except that (2R,3S)-methyl-3-(2-chlorophenyl )-2 ,3- dihydroxypropanoate(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 (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(d, J=8.0, 1H) , 7.35~7.63(m, 4H)

Preparation example 75: ((2S,3S)-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)-methyl-3-(2-chlorophenyl )-l ,4- clioxaspiro[4,5]decane-2-carboxylate (Preparation example 74) was used instead of (4S , 5R)-methy1-5-(2-ch1oropheny1 )-2 , 2-di ehty1-1.3-di oxo1 ane-4- carboxylate(Preparat ion example _. 64), to obtain the title compound(1.6g, 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 76: (4S, 5R)-methy1-5-(2-chlorophen 1 )-2-pheny1-1, 3- cl i oxo1 ane-4-carboxy1 ate

The substan ially same method as described in Preparation Example 64 was conducted, except that benzaldehyde was used instead of 3-pen anone , 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(cl, 7=8.0,

1H), 5.85(d, J=8.0, 1H), 7.35~7.63(m, 4H)

Preparat i on examp1 e 77 : ( (4R, 5R)-5-(2-ch1oropheny1 )-2-pheny1-1 , 3-dioxo 1ane- 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- clioxolane-4-carboxylate (Preparation example 76) was used instead of (4S , 5R)-methy1-5-(2-ch1 oropheny1 )-2 , 2-cli ehty1 -1.3-d i oxol 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) , 3.52-3.8Km, 2H), 3.95(t, J=8.0, 1H), 5.43(d, J=7.6, 1H), 7.48~7.87(m, 4H)

Preparation example 78: (4R, 5S)-methy1-5-(2-chloropheny1 )-2-pheny1-1,3- dioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 66 was conducted, except that benzalclehycle was used instead of 3-pentanone, to obtain the title compound ( 1.9 , 50~70%) . 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), 7.35-7.63(m, 4H)

Preparat ion examp1e 79 : ( (4S, 5S)-5-(2-ch1oropheny1 )-2-pheny 1-1 , 3-dioxo1ane- 4-yl )methanol

The substantially same method as described in Preparation Example 65 was conducted, except that (2R, 3S)-methyl-3-(2-chlorophenyl )-2-pheny 1-1 ,3- dioxolane-4-carboxylate (Preparation example 78) was used instead of (4S, 5R)-methy1-5-(2-chloropheny0-2, 2-diehty1-1.3-dioxo lane-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, .7=8.0, 1H), 5.43(d, J=7.6, 1H), 7.48~7.87(m, 4H)

Preparation example 80: (E)-Methyl-3-(2-f 1noropheny1 )acrylate The substantially same method as described in Preparation Example 24 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. (6.98g, 70~90 ) ¾ NMR (400MHz, CDC1 ₃ ) 53.84 (s, 3H) , 6.45 (d, J=16.0, 1H) , 7.24-7.62 (m, 4H), 8.12 (d, 7=16.0, 1H)

Preparation example 81: (2S,3R)-methyl-3-(2-f luorophenyl )-2, 3- dihyclroxypropanoate

The substantially same method as described in Preparation Preparation Example 3 was conducted, except that (E)-Methyl -3-(2- f luorophenyl )acrylate(Preparat ion 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 ) · 5=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 luorophenyl )-2, 3- clihydroxypropanoate

The SLibs t ant ial ly same method as described in Preparation Example 25 was conducted, except that (E)-methyl-3-(2-f luorophenyl )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 ): 6=4.31(s, 3H), 5.44(m, 4H), 5.89(s, 1H) , 7.32~7.70(m, 4H)

Preparat ion exam le 83: ( (4S,5R)-methy1-5-(2-f luoropheny1 )-2-mehtyl-l .3- clioxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 60 was conducted, except that (2S,3R)-methyl-3-(2-f luorophenyl )-2,3 ^~ dihyclroxypropanoate(Preparat ion example 81) was used instead of ((2S,3R) ^~ methy1-3-(2-chlo opheny1 )-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound(3. lg, 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(d, J=7.6, 1H) , 7.29~7.67(m, 4H)

Preparat ion example 84: ((4R,5R)-5-(2-f luorophenyl )-2-mehtyl-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-mehtyl-l.3- dioxo lane-4-carboxylate (Preparation example 83) 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(3.3g, 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, J=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-1.3- dioxo1ane-4-carboxy1 ate

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) ^~ methy1-3-(2 ^~ ch1o opheny1 )-2.3 ^~ dihydroxy ropanote(Preparat ion exam 1e 433) , to obtain the title compound (2.9g, 70-95%).

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

Preparat ion example 86: ((4S,5S) ^~ 5-(2-f luorophenyl )-2-mehtyl-l .3-dioxolane- 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-mehty 1-1.3- dioxolane-4-carboxylate (Preparation example 85) was used, instead of (4R, 5S)-methyl-5-(2-chlorophenyl )-2,2-dimehtyl-l .3-dioxolane-4-carboxylate (Preparation example 26), to obtain the title compound(3.8g, 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, J=7.0, IH), 5.06(m, 1H), 5.17(d, 7=7.0, 1H), 7.19-7.4.2(m, 4H).

Preparat ion exam 1 e 87 : (4S , 5R)-methy1-5-(2-f 1uoropheny1 )-2 , 2-diehty1-1.3- clioxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 64 was conducted, except that (2S,3R)-methyl-3-(2-f 1uorophenyl )-2,3- dihydroxypropanoate(Preparat ion example 81) was used instead of (2S,3R)- methy1-3-(2-chlorophenyl )-2 ,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound (2.1g, 60~85%).

¾ NMR (400MHz, CDC13) S 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: ( (4R, 5R) ^~ 5-(2-f luorophenyl )-2 , 2-diehty1-1. 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)-methyI-5-(2-ch1oropheny1 )-2 , 2-dimehty1-1.3-dioxo 1 ane-4-carboxy late (Preparation example 26), to obtain the title compound (2.2g, 70~95 )

¾ NMR (400MHz, CDCI3) ^' · 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- dioxo 1ane-4-carboxy1ate

The substantially same method as described in Preparation Example 87 was conducted, except that (2R,3S)-methyl-3-(2-f luorophenyl )-2 ,3- dihyclroxypropanoate(Preparation example 82) was used instead of (2S,3R)- methyl-3-(2-f luorophenyl )-2.3-dihydroxypropanote (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, J=7.6, 1H), 7.20~7.61(m, 4H)

Preparation example 90: ((4S,5S)-5-(2-f luorophenyl)-2,2-diehtyl-1.3- dioxo1 ne-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-diehtyl-l.3- dioxolane-4-carboxylate (Preparation example 89) was used instead of (4S , 5R)-methy1-5-(2-f 1uoropheny1 )-2 , 2-di ehty1-1.3-dioxo1ane-4- carboxylate(Preparat ion example 87), to obtain the title compound(2.2g, 70-95%)

¾ NMR (400MHz, CDC I3 ) : δ 0.96(m. 6H) , 1.59(m, 4H), 3.66(cl, J=8.0, 2H), 5.09 (d, 7=7.6, 1H), 5.88(cl, 7=7.6, 1H), 7.23~7.62(m, 4H) .

Preparation example 91: (2S, 3R)-methyl-3-(2-f luorophenyl )-l, 4- dioxaspi r 0[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-pentanone, 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(d, J=7.2, 1H), 5.39(d, 7=7.2, 1H), 7.33~7.62(m, 4H)

Preparat ion exam 1e 92 : ( (2R, 3R)-3-(2-f 1 uoropheny1 )-1 , 4- dioxasp i ro[4 , 4]nonane-2-y1 )metha o1

The substantially same method as described in Preparation Example 65 was conducted, except that (2S, 3R)-methyl-3-(2-f 1uoropheny1 )-l ,4- dioxaspi ro[4,4]nonane-2-carboxylate(Preparat ion example 91) was used ins ead of (4S , 5R)-mettry1-5-(2-ch1oropheny1 )-2 , 2-d iehty1-1.3-d i oxo 1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.9g, 70-95%) - lH 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 o[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 luorophenyl )-2, 3- clihydroxypropanoate(Preparat ion example 82) was used instead of (2S,3R)- methyl-3-(2-f luorophenyl )-2.3 ^~ dihydroxypropanote (Preparation example 81), to obtain the title compound (1.5g, 70~95 ) .

¾ NMR (400MHz, DMSO) 61.69-1.71(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, J=7.2, 1H), 7.39~7.61(m, 4H)

Preparation example 94 ^' · ((2R,3R)-3-(2-f luorophenyl )-l, 4- dioxaspi ro[4 ,4]nonane-2-y1 )methano1

The substcintially same method as described in Preparation Example 88 was conducted, except that (2R,3S)-methyl-3-(2-f luorophenyl 4- dioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 93) was used inste d of (4S , 5R)-methy1-5-(2-f 1uoropheny1 )-2 , 2-di ehty1-1.3 ^~ di 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, J=7.6, 1H), 7.38~7.63(m, 4H)

Preparation example 95 ^' · (2S, 3R)-methyl-3-(2-f luorophenyl )-l, 4- dioxaspiro[4,5]decane-2-carboxyl te

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, DMS0) 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· ^' ( (2R, 3R)-3-(2-f 1uoropheny1 )-1 , 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-f luorophenyl)-l,4- dioxaspiro[4,5]decane-2-carboxylate(Preparation 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, 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) , 7.42~7.89(m, 4H)

Preparation example 97: (2R, 3S)-methyl-3-(2-f luorophenyl )-l,4- dioxaspi ro[4 , 5]decane-2-carboxy1 ate

The substantially same method as described in Preparation Example 95 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—fluorophenyl )-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, J=8.0, 1H), 7.32~7.64(m, 4H)

Preparation example 98: ( (2S , 3S)-3-(2-f luoropheny dioxaspiro[4 , 5]decane-2-yl )methanol

The substantially same method as described in Preparation Example 96 was conducted, except that (2R, 3S)-methyl-3-(2-f luorophenyl )-l ,4- dioxaspi ro[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%)

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), 7.33~7.67(m, 4H)

Preparat i on examp1e 5R)-methyl-5-(2-f luorophenyl )-2-phenyl-1,3- dioxo1 ane-4-carboxy1 at

The substantially same method as described in Preparation Example 87 was conducted, except that benzaldehyde was used instead of 3-pentanone, to obta in the title compound ( 1.6g, 50-70%) . ¾ NMR (400MHz, DMS0) 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), 7.33~7.64(m, 4H)

Preparation example 100: ((4R,5R)-5-(2—f uorophenyl)-2-phenyl-l,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 1uorophenyl)-2-pheny1-1, 3- dioxolane-4-carboxylate (Preparation example 99) was used instead of (4S , 5R)-methy1 -5-(2-ch1oropheny1 )-2 , 2-diehty1-1.3-dioxo1 ane-4- carboxylate(Preparat ion example 64), to obtain the title compound(1.3g, 70-95%)

¾ NMR (400MHz, DMS0) : δ 1.63-1.75(m, 10H), 3.52-3.8Km, 2H), 3.95(t, .7=8.0, 1H), 5.43(d, J=7.6, 1H), 7.43~7.85(m, 4H)

Preparation example 101: (4R, 5S)-methyl-5-(2-f luoropheny1 )-2-phenyl-l, di oxo1 ane-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%) . 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), 7.33~7.64(m, 4H)

Preparat i on exam 1 e 102 : ( (4S , 5S)-5-(2-f 1 uoropheny1 )-2-pheny1 -1 , 3-d i oxo 1 ane- 4-yl )methanol

The substantially same method as described in Preparation example 65 was conducted, except that (2R, 3S)-methyl-3-(2-f luoropheny )-2-pheny1-1,3- clioxolane-4-carboxylate (Preparation example 101) was used instead of (4S , 5R)-methy1 -5-(2-ch1 oropheny1 )-2 , 2-di ehty1 -1.3-di oxo 1 ane-4- carboxy late(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, J=8.0, 1H), 5.43(d, J=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 )-acryl ic acid (Preparation example 17)was used instead of 2-chlorocinnamic acid, to obtain the title compound. (3.2g, 70~90%) ¾ NMR (400MHz, CDC1 ₃ ) 53.84 (s, 3H) , 6.45 (cl, J=16.0, 1H), 7.01-7.35 (m, 4H), 8.09 (d, 7-16.0, IH)

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-ioclophenyl )acrylate(Preparat 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 ) ^' - 5=4.31(s, 3H), 5.44(m, 4H), 5.89(s, IH), 7.30~7.71(m, 4H).

Preparation example 105: (2R, 3S)-methyl-3-(2 ^~ iodophenyl )-2 ,3- clihyclroxypropanoate

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)-Methyl-3-(2- chlorophenyl )acrylate(Preparat ion example 24), to obtain the title compound (3.1g. 60~80%). ¾ NMR (400MHz, CDC1 ₃ ): 6=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- di oxol ne-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-chlorophenyl )-2,3-dihydroxypropanoate(Preparat ion. example 433) , to obtain the title compound (2.7g, 70-95%). lH NMR (400MHz, CDC13) 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, 1H), 7.29-7.70 (m, 4H)

Preparation example 107: ((4R,5R)-5-(2-iodophenyl)-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-iodophenyl )-2-mehtyl-l .3- dioxolane-4-carboxylate(Preparation example 106) was used instead of (4R, 5S)-methy1-5-(2-ch10ropheny1 )-2 , 2-dimenty1-1.3-dioxo 1 ane-4- carboxylate(Preparat ion example 26), to obtain the title compound (2.3g, 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, J=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- dioxol ane-4-carboxyl te

The SLibstant ial ly same method as described in Preparation example 60 was conducted, except that (2R,3S)-methyl-3-(2-iodophenyl )-2.3- dihydroxypropanote(Preparat ion example 104) was used instead of (2S,3R)- methy1-3-(2-chloropheny1 )-2.3-dihydroxypropanote(Preparat ion example 433) , to obtain the title compound (2.4g, 70-95%). lH NMR (400MHz , CDC1 ₃ ) ^' δ 1.36(d , /=6.4 , 3H) , 3.78( s , 3H) , 4.30(d , .1=7.6 , 1H), 5.07(m, 1H), 5.62(d. 7=7.6, 1H), 7.29-7.70 (m, 4H)

Preparation example 109 ^' · ((4S,5S)-5-(2-iodophenyl )-2-mehtyl-1.3-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-mehtyl-1.3- dioxolane-4-carboxylate(Preparat ion example 108) 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 (1.9g, 70-95%)

¾ NMR (400MHz , CDC1 ₃ ) ^' · 6 1.37(d , J=6.0 , 3H) , 3.62-3.70(m , 2H) , 4.36(del , J=7.0, J=7.0, 1H), 5.06(m, 1H), 5.17(d, J=7.0, 1H), 7.17~7.41(m, 4H) Preparation example 110: (4S, 5R)-methyI-5-(2-iodophenyl)-2,2-diehtyl-1.3- di oxo lane-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, 7=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- dioxolane-4-yl )methanol

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- clioxolane-4-carboxylate (Preparation example 110) was used instead of (4S , 5R)-methy 1 -5-(2-i odopheny1 )-2-mehty1 -1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 106), to obtain the title compound(2. Ig, 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, J=7.0, 1H), 7.17~7.41(m. 4H)

Preparation example 112: (4R, 5S)-inethyl-5-(2-i0dophenyl)-2,2-diehtyl-1.3- di oxo1 ane-4-carboxy1 ate

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-i odopheny1 )-2,3-dihydroxypropanoate (Preparat ion 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-1.3- clioxo1 ane-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-cliehtyl-1.3- dioxolane-4-carboxylate (Preparation example 112) was used instead of (4S , 5 )-methy1-5-(2- i odopheny1 )-2-mehty1-1.3-dioxo1 ane-4- carboxylate(Preparat ion example 106), to obtain the title compound(1.8g, 70-95%) ¾ NMR (400MHz, CDC1 ₃ ) · δ 1.37(cl, 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 114: (2S, 3R)-methyl—3—(2—iodopheny1 )-l, 4- dioxaspiro[4 , 4]nonane-2-carboxy1 ate

The substan ially same method as described in Preparation example 110 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.7g, 70-95%). LH NM (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, J=7.2, 1H), 7.19~7.44(m, 4H)

Preparation example 115: ((2R,2R)-3-(2-iodophenyl)-l,4- dioxaspiro[4,4jnoiiane-2-yl )methanol

The substantially same method as described in Preparation example 107 was conducted, except that (2S,3R)-methyl-3-(2-iodophenyl)-l,4- dioxaspiro[4,4jrionane-2-carboxylate(Preparat ion 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, 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, J=7.6, 1H), 7.20~7.45(m, 4H)

Preparation example 116· ^' (2R, 3S)-meth l-3-(2-iodophenyl )-l,4- cli oxaspi ro[4 , 4]nonane-2-carboxy1 ate

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(d, J=7.2, 1H), 7.19~7.44(m, 4H)

Preparation ^' example 117: ((2S,2S)-3-(2-iodophenyl)-l,4- di oxaspi ro[4 , 4]nonane-2-y1 )methanol

The substantially same method as described in Preparation example 107 was conducted, except that (2R,3S)-methyl-3-(2-iodophenyl )-l,4- dioxaspiro[4-,4]nonane-2-carboxylate(Preparation 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 compound(1.5g, 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, J=7.6, 1H), 7.20~7.45(m, 4H)

Preparation example 118: (2S, 3R)-methyl-3-(2-iodophenyl)-l,4- dioxaspi ro[4 , 5] decane-2-carboxy1 ate

The substantially Scime method as described in Preparation example 114 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (1.9g, 70~95%). LH 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) , 7.17~7.43(m, 4H)

Preparation example 119: ( (2R, 3R)-3-(2-iodopheny1 )-1 ,4- dioxaspi ro[4 , 5]decane-2-y1 )methano1

The substantially same method as described in Preparat ion example 107 was conducted, except that (2S,3R)-methyl-3-(2-iodopheny1 )-l ,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 118) was used instead of (4S , 5R)-methy1-5-(2-iodopheny1 )-2-mehty1—1.3-dioxo1 ane-4- carboxylate(Preparat ion example 106), 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, 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.19~7.49(m, 4H)

Preparation example 120: (2R, 3S)-methyl-3-(2-iodopheny1)-1,4- dioxaspi ro[4 , 5] decane-2-carboxy1 ate

The substantially same method as described in Preparation example 116 was conducted, except that cyclohexaiione was used instead of cyclopentanone, to obtain the title compound (2.3g, 70-95%). ¾ NMR (400MHz, DMS0) δ 1.61-1.69(m, 10H), 3.79(s, 3H), 4.33(d, J=8.0, 1H), 5.85(cl, J=8.0, 1H), 7.17~7.43(m, 4H)

Preparat i on examp le 121 : ( (2S , 3S)-3-(2-i odopheny1 )-1 , 4- di oxaspi ro[4, 5]decane-2-y1 )methano1

The substantially same method as described in Preparation example 107 was conducted, except that (2R, 3S)-methyl -3-(2- i odopheny1 )-l,4- dioxaspiro[4,5]decane-2-carboxylate(Preparation example 120) was used instead of (4S , 5R)-methy1-5-(2-i odopheny1 )-2-mehty1-1.3-di oxo1 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, 7=8.0, 1H), 5.43(d, 7=7.6, 1H), 7.19~7.49(m, 4H)

Preparation example 122: (4S, 5R)-methyl-5-(2-i odopheny1 )-2-phenyl-l,3- dioxolane-4-carboxylate

The substantially same method as described in Preparation example 118 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the i le compound(1.9g, 50~70 ) . ¾ NMR (400MHz, DMSO) 53.67(s, 3H) , 5.11(d, J=8.0, 1H), 5.8lCd, J=8.0, 1H), 6.18(s, 1H), 6.96~7.57(m, 9H)

Preparation example 123 ^' · ( (4R,5R)-5-(2-i odopheny1 )-2-pheny1-1, 3-di oxo 1 ane-4- yOmethanol

The substantially same method as described in Preparation example 107 was concluct ed , except that (4S , 5R)-methy1 -5-(2- i odopheny1 )-2-pheny 1 -1 , 3- dioxolane-4-carboxylate (Preparation example 122) was used instead of (4S , 5R)-methy1 -5-(2- i odopheny1 )-2-mehty1 -1.3-di oxo 1 ane-4- carboxylate(Preparation example 106), to obtain the title compound (1.4g, 70-95%)

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

Preparation example 124: (4R, 5S)-methyl-5-( 2- i odopheny1 )-2-pheny 1-1, 3- dioxo 1 ane-4-carboxylate

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

Preparat i on examp 1 e 125 · ^' ( (4S , 5S)-5-(2-i odopheny1 )-2-pheny1-1 , 3-d i oxo1 ane-4- yl )methanol

The substantially same method as described in Preparation example 107 was conducted, except that (4R, 5S)-methy.I-5-(2- i odopheny1 )-2-pheny1-1,3- dioxolane-4-carboxylate(Preparat ion example 124) was used instead of (4S , 5R)-methy1 -5-( 2- i odopheny1 )-2-mehty1 -1.3-di oxo 1 ne-4- carboxylate(Preparat ion example 106), to obtain the title compound(1.3g, 70~95%)

¾ NMR (400MHz, D S0): δ 3.66(d, 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 126: ((4S,5R)-methyl-5-(2,4-dichlorophenyl )-2-mehtyl- 1.3-cli oxol ane-4-carboxyl ate

The substantially same method as described in Preparation example 60 was conducted, except that (2S,3R)-methyl-3-(2,4-dichIorophenyl )-2,3- clihydroxypropanoate(Preparat ion example 36) was used instead of (2S,3R)- methy1 -3-(2-ch1oropheny1 )-2 , 3-dihydroxypropanoate(Preparat ion exanip1 e 433) , to obtain the title compound(0.9g, 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, lH), 5.62(d. 7=7.6, 1H), 7.07~7.21(m, 3H)

Preparation example 127: ((4R,5 )-5-(2,4-dichlorophenyl )-2-mehty1-1.3- clioxolane-4-yl )methanol

The substantially same method as described in Preparation example 27 was conducted, except that ((4S,5R)-methyl-5-(2,4-dichlorophenyl )-2-mehty1-1.3- dioxolane-4-carboxylate(Preparat ion example 126) was used instead of (4R, 5S)-methy1-5-(2-chloropheny1 )-2, 2-dimehty1-1.3-dioxol ane-4-carboxylate (Preparation example 26), to obtain the title compound(0.7g. 70 ^~ 95%)

H NMR (400MHz, CDC13) : δ 1.37(cl, 7=6.0, 3H), 3.62 ^~ 3.70(m, 2H), 4.

7=7.0, 7=7.0, 1H), 5.06(m, 1H) , 5.17(d, 7=7.0, 1H) , 7.08~7.39(m, 3H) .

Preparation example 128■ ^' ((4R,5S)-methyl-5-(2,4-dichlorophenyl)-2-mehtyl- 1.3-dioxo1 ane-4-carboxy1 ate

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

¾ NMR (400MHz. CDC13) δ 1.36(d, 7=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), 7.07~7.21(m, 3H) .

Preparat i on examp 1 e 129 ^' · ( (4S , 5S)-5-(2 , 4-di ch1 oropheny1 )-2-menty1 -1.3- d i oxo 1 ane-4-y1 )methano 1

The substantially same method as described in Preparation example 27 was conducted , except that (4-R , 5S)-methy 1 -5-(2 , 4-di ch10ropheny 1 )-2-mehty 1 -1.3- dioxolane-4-carboxylate(Preparat ion example 128) was used instead of (4R , 5S)-methy 1 -5-( 2-ch 1 o opheny1 )-2 , 2-d imehty1-1.3-di oxo 1 ane-4-carboxylate (Preparation example 26), to obtain the title compound( 1.5g, 70-95%) lH NMR (400MHz, CDC13) : 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) , 7.08-7.39(m, 3H).

Preparation example 130: (4S, 5R)-methyl-5-(2,4-dichloropheiiyl)-2,2-diehtyl- 1.3-di oxo 1 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 ^~ dihydroxypropanoate(Preparat ion example 36) was used instead of (2S.3R)- methy 1 -3-(2- hlorophenyl )-2,3-dihydroxypropanoate(Preparat ion example 433) , to obtain the title compound (2.2g, 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, 7=7.6, 1H), 7.12-7.37(m, 3H)

Preparation example 131· ^' ((4R,5R)-5-(2,4-dichlorophenyl)-2,2-diehtyl-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-(2,4-dichlorophenyl )-2,2-cliehtyl- 1.3-dioxolane-4-carboxylate(Preparation example 130)vvas used instead of (4R , 5S)-methy1 -5-(2-ch1 oropheny1 )-2 , 2-dimehty1 -1.3-d i oxo 1 ane-4-carboxylate (Preparation example 26), to obtain the title compoundd .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, .7=7.0, 7=7.0, 1H), 5.06(m, 1H), 5.17(d, 7=7.0, 1H) , 7.03~7.39(m, 3H).

Preparation example 132: (4R, 5S)-methyl-5-(2,4-chlorophenyl)-2,2-diehtyl- 1.3-di oxo 1 ane-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- dihydroxypropanoate (Preparation example 29) was used instead of (2S,3R) ^_ methy1 -3-( 2 , 4-cl i ch1 oropheny1 )-2 , 3-dihyclroxypropanoate (Preparation examp 1 e 36), to obtain the title compound (2.1g, 70~95 ). H 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), 7.12~7.37(m, 3H)

Preparation example 133: ((4S,5S)-5-(2,4-chlorophenyl )-2,2-diehtyl-1.3 ^~ dioxolane-4-yl )methanol

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(Preparat ion example 132) was used instead of ( (4S , 5R)-methy1-5-(2 , 4-di ch1oropheny1 )-2 , 2-di ehty1-1.3-di oxo 1 ane-4- carboxylate (Preparation example 130), to obtain the title compound (1.2g, 70-95%) .

¾ NMR (400MHz, CDC 13) : 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), 7.08~7.39(m, 3H).

Preparation example 134 ^' · (2S, 3R)-methyl-3-(2,4-chlorophenyl )-l,4- dioxaspiro[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, 7=7.2, 1H), 5.39(cl, 7=7.2, 1H), 7.03~7.36(m, 3H) Preparation example 135: ((2R,3R)-3-(2,4-chlorophenyl)-l,4- clioxaspi 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-(2,4-dichlorophenyl )-l ,4- dioxaspiro[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%) lH NMR (400MHz, DMS0) : δ 1.60-1.72(m, 4H), 1.83-1.94(m, IH), 3.52~3.65(m, 2H), 3.82-3.86(m, IH), 4.90(t, J=5.2, IH), 5.12(d, J=7.6, IH), 7.02~7.37(m,

3H)

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

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, IH) , 1.91-2.00(m, 3H), 3.68(s, 3H), 4.40(d, J=7.2, IH) , 5.39(d, J=7.2,.1H), 7 _; 03~7.36(m, 3H)

Preparation example 137: ( (2S , 3S)-3-(2 , -ch1oropheny1 )-1.4- dioxaspi ro[4 , 4]nonane-2-y1 )me hano1

The substantially same method as described in Preparation example 135 was conducted, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl )-l,4- dioxaspiro[4,.4]nonane-2-carboxylate(Preparat ion example 136) was used instead of (2S, 3R)-methyl-3-(2,4-clichlorophenyl)-l,4- dioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 134), to obtain the title compound(1.2g, 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) , 7.02~7.37(m, 3H)

Preparation example 138: (2S, 3R)-methyl-3-(2,4-chlorophenyl )-l,4- dioxaspi ro [4 , 5]decane-2-carboxy1 ate

The substantially same method as described in Preparation example 134 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compouncK l .8g, 70~95%) . lH 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) , 7.07~7.41(m, 3H)

Preparat ion exam 1e 139 : ( (2 , 3R)-3-(2 , 4-ch1o opheny1 )-1 , 4- clioxaspi ro[4,5]decane-2-yl )methanol

The substantially same method as described in Preparation example 73 was conducted, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-l,4- dioxaspiro[4,5]decane-2-carboxylate(Preparation example 138) was used instead of (2S, 3R)-methy1-3-(2-chloropheny1 )-l,4-dioxaspiro[4,5]decane-2- carboxylate(Preparat ion example 72), to obtain the title compound(1.3g, 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), 7.04-7.40(m, 3H)

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

The substantially same method as described in Preparation example 136 was conducted, except that eye1ohexanone was used instead of cyclopentanone, to obtain the title compound(1.6g, 70-95%).

^[ H 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), 7.07~7.41(m, 3H)

Preparation example 141 ^' · ( (2S , 3S)-3-(2 , 4-ch1oropheny1 )-1 , 4- dioxaspiro[4 , 5]clecane-2-y1 )methano1

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

^L H 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), 7.04~7.40(m, 3H)

Preparation example 142: (4S, 5R)-methyl-5-(2,4-chlorophenyl)-2-phenyl-l,3- di oxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 138 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the ti le 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- di oxo 1 ane-4-y1 )methano 1

The substantially same method as described in Preparation example 65 was conducted, except that (4S,5R)-methyl-5-(2,4-chlorophenyl )-2-pheny 1-1,3- d.ioxolane-4-carboxylate(Preparat ion example 142) was used instead of (4S , 5R)-methy1 -5-(2-ch1 oropheny1 )-2 , 2-di ehty1 -1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 64), 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, J=8.0, 1H), 5.43(d, J=7.6, 1H), 7.04~7.42(m, 3H)

Preparation example 144 ^' · (4R, 5S)-inethyl-5-(2,4-chlorophenyl )-2-phenyl-l ,3- cl i oxo1 ane-4-carboxy1 at e

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

¾ NMR (400MHz, DMS0) δ 1.61-1.69(m, 10H), 3.79(s, 3H), 4.33(d, J=8.0, 1H), 5.85(cl, J=8.0, 1H), 7.03~7.41(m, 3H)

Preparation example 145: ( (4S,5S)-5-(2, 4-chlorophenyl)-2-pheny 1-1,3- d i oxo1 ane-4-y1 )methano1

The SLibst ant ial ly same method as described in Preparation example 143 was conducted, except that (4R, 5S)-methyl-5-(2,4-chlorophenyl)-2-phenyl-l,3- di oxo lane-4-carboxylate (Preparation example 144) was used instead of (2S, 3R)-methy1-3-(2 , 4-ch1oropheny1 )-2-pheny1-1 , 3-dioxo1 ane-4- carboxylate(Preparat ion example 142), 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, J=7.6, 1H), 7.04~7.42(m, 3H)

Preparat ion examp1 e 146 : ( (4S, 5R)-ethy1-5-(2 , 6-di ch1oropheny1 )-2-methy1-1.3- dioxolane-4-carboxylate

The substantially same method as described in Preparation example 60 was conducted, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-2,3- dihydroxypropanoate(Preparat ion example 39) was used instead of (2S,3R)- methy1-3-(2-chloropheny1 )-2,3-dihyclroxypropanoate(Preparat ion example 433) , to obtain the title compound(1.7g, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, J=6 A , 3H), 3.78(s, 3H), 4.15(m, 2H) , 4.30(d, 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-dichlorophenyl )-2-methyl-l .3- d ioxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 27 was conducted, except that C(4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2-mehtyl-1.3- dioxolane-4-carboxylate(Preparation example 146) was used instead of (4R, 5S)-me hyl-5-(2-chloropheny1 )-2, 2-dimehty1-1.3-dioxol ane-4-carboxylate (Preparation example 26), 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(ni, 1H), 5.17(d, 7=7.0, 1H), 7.18-7.39(in, 3H).

Preparation example 148: ((4R,5S)-ethyl-5-(2,6-dichlorophenyl)-2-methyl-1.3- clioxo1 ane-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-clichlorophenyl )-2,3-dihydroxypropanoate (Preparat ion example 39), to obtain the title compound(1.8g, 70-95%). lH NMR (400MHz, CDC1 ₃ ) 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, Hi), 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- dioxolane-4-yl )methanol

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- di oxolane-4-carbox late (Preparation example 148) was used instead of ( (4S , 5R)-ethy1-5-(2 , 6-di ch1oropheny1 )-2-mehty1-1.3-dioxo 1 ane-4- carboxylate(Preparat ion example 146), to obtain the title compound (1.3g, 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, 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-dichlorophenyl)-2,2-diehtyl- 1.3-dioxo1 ane-4-carboxylate

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

¾ NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H) , 1.30(t, 7=8.0, 3H), 1.59(m, 4H) ,

4.12(m, 2H), 5.11(d, J=7.6, 1H), 5.81(d, 7=7.6, 1H), 7.08 ^~ 7.26(m, 3H)

Preparat i on examp 1e 151 : ( (4R, 5R)-5-(2 , 6-di chloropheny1 )-2 , 2-diehty1-1.3- di oxo1 ane-4-y1 )methano1

The substantially same method as described in Preparation example 147 was conducted, except that (4S,5 )-ethyl-5-(2,6-dichlorophenyl)-2,2-diehtyl- 1.3-dioxolane-4-carboxylate(Preparation example 150)was used instead of ( (4S , 5R)-ethyl-5-(2 , 6-cli chlorophenyl )-2-mehty1 -1.3-clioxo 1 ane-4-carboxy1 ate (Preparation exam le 146), 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(dcl, J=7.0. J=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-cliehtyl- 1.3-d i oxo1 ane-4-carboxy1 ate

The substantially same method as described in Preparation example 150 was conducted, except that (2R,3S)-ethyl-3-(2,6-ichlorophenyl )-2,3- clihyclroxypropanoate (Preparation example 33) was used instead of (2S,3R)- ethyl-3-(2,6-dichlorophenyl )-2,3-dihydroxypropanoate (Preparat ion example 39), to obtain the title compound(2.5g, 70~95%) lH NMR (400MHz, CDC1 ₃ ) δ 0.96(m, 6H) , 1.30(t, J=8.0, 3H), 1.59(m, 4.12(m, 2H), 5.11(d, 7=7.6, 1H), 5.81(d. 7=7.6, 1H), 7.08-7.26(m, 3H)

Preparation example 153: ((4S,5S)-5-(2,6-chlorophenyl ) ^~ 2,2-diehtyl-1.3- cli oxo 1 ane-4-y1 )methano 1

The substantially same method as described in Preparation example .151 was conducted, except that (4R,5S)-ethyl-5-(2,6-dichlorophenyl )-2,2-diehtyI- 1.3-d i oxo lane-4-carboxylate (Preparation example 152) was used instead of (4S , 5R)-et hy I—5—(2 , 6-cli ch1oropheny1 ) -2 , 2-d i ehty1 -1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 150), 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(dd, 7=7.0, 7=7.0, 1H), 5.06Cm, 1H), 5.17(d, 7=7.0, 1H), 7.07~7.29(m, 3H) .

Preparation example 154: (2S, 3R)-ethyl-3-(2,6-chlorophenyl)-l,4- cli oxasp i ro [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%). lH NMR (400MHz, DMS0) 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), S.lKcl, 7=7.2, 1H), 5.81(d, 7=7.2, 1H), 7.07~7.31(m, 3H)

Preparation example 155: ((2R,3R)-3-(2,6-chlorophenyl)-l,4- di oxasp i ro [4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 151 was conducted, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl )-l,4- di oxasp iro [4, 4]nonane-2-carboxylate (Preparation example 154) was used instead of (4S , 5R)-ethy1 -5-(2 , 6 ^~ d i ch1 oropheny1 )-2 , 2-di ehty1 -1.3-di oxo 1 ane- 4-carboxylate (Preparation example 150), to obtain the title compound (1.7g, 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, J=5.2, 1H), 5.12(d, J=7.6, 1H), 7.08~7.32(m, 3H)

Preparation example 156: (2R, 3S)-ethyl-3-(2,6-chlorophenyl )-l,4- dioxaspi ro[ , 4]nonane-2-carboxylate

The substantially same method as described in Preparation example 152 was conducted, except that eye 1opentaiione 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), 1.69-1.71(m, 4H), 1.73-1.86(m, 4H) , 4.07-4.14(m, 2H), 5.11(d, J=7.2, 1H) , 5.81(d, J=7.2, 1H), 7.07~7.31(m, 3H)

Preparation example 157: ((2S,3S)-3-(2,6-chlorophenyl)-l,4- clioxaspi 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 chIoropheny1 )-1 , 4-di oxaspi ro [4 , 4]nonane- 2-carboxylate(Preparat ion example 154), 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(cl, 7=7.6, 1H), 7.08~7.32(m, 3H)

Preparation example 158: (2S, 3R)-ethyl-3-(2,6-chlorophenyl )-l,4- dioxaspi ro [4 , 5]decane-2-carboxylate

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

^J H MR (400MHz, DMSO) 8 1.30(t, 7=7.6, 3H), 1.61~1.69(m, 10H), 4.08-4.18(d, -2H), 4.33(d, 7=8.0, 1H), 5.85(d, 7=8.0, 1H) , 7.07-7.31(m. 3H)

Preparation example 159: ( (2R, 3 )-3-(2 , 6-ch1oropheny1 )-1 , 4- dioxaspi o[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- dioxaspi o[4,5jdecane-2-carboxylate (Preparation example 158) was used insteacl of (2S , 3R)-ethy1-3-(2 , 6 ^~ dich1oropheny1 )-1 , 4-dioxaspi ro [4 , 4]nonane- 2-carboxylate (Preparation example 154), to obtain the title compound(1.7g, 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) , 7.05~7.30(m, 3H) Preparation example 160: (2R, 3S)-ethyl-3-(2,6-chlorophenyl )-l ,4- dioxas iro[4,5]decane-2-carboxylate

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

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

Preparation example 161: ( (2S ,3S)-3-(2 , 6-ch1orophen 1 )-1 , - dioxaspi ro[4 , 5jdecane-2-yl )methanol

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-. dioxo1 ane ^~ 4-carboxy1ate

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, DMS0) δ 1.30(t, J=7.6, 3H), 4.08-4.18(d, 2H), 5.13(d, J=8.0, 1H), 5.85(d. J=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- dioxo1ane-4-y1 )methano 1

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-dioxaspiro[4,5]decane-2-carboxylate (Preparation example 158), to obtain the title compound (1.6g, 70~95%)

¾ NMR (400MHz, DMS0) : 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 164: (4R, 5S)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-l,3- dioxolane-4-carboxylate

The substantially same method as described in Preparation example 160 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the title compound (1.8g, 50~70%). Τ-Ϊ NMR (400MHz, DMS0) δ 1.30(t, J=7.6, 3H), 4.08-4.18(d, 2H), 5.13(d, J=8.0, 1H), 5.85(d, J=8.0, 1H) , 6.18(s, 1H), 7.03~7.22(m, 8H)

Preparation example 165 ^' · ((4S,5S)-5-(2,6-chlorophenyl)-2-phenyl-l,3- clioxolane-4-yl )methanol

The substantially same method as described in Preparation, example 163 was conducted, except that (4R, 5S)-ethyl-5-(2,6-chlorophenyl )-2-phenyl-l ,3- dioxolane-4-carboxylate (Preparat ion' example 164) was used instead of (2S, 3 )-ethy1-3-(2 , 6-ch1oropheny1 )-2-pheny1-1 , 3-di oxo 1 ane-4- carboxylate(Preparat ion example 162), to obtain the title compound(1.4g, 70-95%)

¾ NMR (400MHz, DMS0): δ 3.50~3.79(m, 2H), 5.13(cl, J=8.0, 1H), 5.85(d, J=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- clioxo 1 ane-4-carboxy1ate

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%).

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

Preparation example 167: ((4R,5R)-5-(2-nitrophenyl )-2-mehtyl-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-ni tropheny1 )--2-mehtyl -1.3- clioxolane-4-carboxylate (Preparation example 166) was used instead of (4R, 5S)-methy1-5-(2-ch1oropheny1 )-2 , 2-climehty1-1.3-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, 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) , 7.47-8. ll(m, 4H) .

Preparation example 168: ((4R,5S)-methyl-5-(2-nitrophenyl)-2-mehtyl-1.3- di oxo1 ane-4-carboxylate

The substantially same method as described in Preparation example 160 was conducted, except that (2R,3S)-methyl-3-(2-ni trophenyl )-2,3- dihydroxypropanoateCPreparat 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. Og, 70~95%) .

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, 7=6.4, 3H), 3.78(s, 3H) , 4.30(d, 1=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- dioxolane-4-carboxylate (Preparation example 168)was used instead of (4S , 5R)-meth 1-5-(2-ni t ropheny1 )-2-mehty1-1.3-di oxo 1 ane-4- carboxylate(Preparation example 166), to obtain the title compound ( 1.6 , 70-95%)

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

Preparation example 170: (4S, 5R)-methyl-5-(2-ni trophenyl )-2,2-diehty1-1.3- di oxo1 ane-4-carboxylate

The substantially same method as described in Preparation example 150 was conducted, except that (2S,3 )-methyl-3-(2-nitrophenyl)-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, 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), 7.43~8.10(m, 4H)

Preparation example 171: ((4R,5R)-5-(2-nitrophenyl)-2,2-diehtyl-1.3- dioxo1ane-4-y1 )methano1

The substantially same method as described in Preparation example 167 was conduc ed, except that (4S, 5R)-methyl-5-(2-ni t ropheny1 )-2 , 2-diehtyl -1.3- dioxolane-4-carboxylate (Preparation example 170) was used instead of (4S , 5R)-methy1-5-(2-ni tropheny1 )-2-mehty1-1.3-dioxo 1 ane-4-carboxyl te (Preparation example 166), to obtain the title compound (1.9g, 70~95%) LH 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. Hi), 5.17(d, 7=7.0, 1H), 7.37~8.09(m. 4H)

Preparation example 172 ^' · (4R, 5S)-inethyl-5-(2-nitrophenyl)-2,2-diehtyl-1.3- dioxo1 ane-4-carboxylate

The substantially same method as described in Preparation example 170 was conducted, except that (2R,3S)-methyl-3-(2-ni tropheny1)-2,3- dihydroxypropanoate(Preparat ion example 48)was used instead of (2S,3R) ^~ methy1S ^~ (2-ni t ropheny1 )-2 , 3-dihydroxypropanoate(Preparat i on examp 1e 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(d, 7=7.6, 1H), 5.81(d, 7=7.6, 1H), 7.43-8.10(m, 4H)

Preparation example 173: ((4S,5S)-5-(2-nitrophenyl)-2,2-diehtyl-1.3- dioxo1ane-4-y1 )methano 1

The substantially same method as described in Preparation example 171 was conducted, except that (4R,5S)-methyl-5-(2-ni tropheny1 )-2 , 2-cl i ehty1-1.3- dioxolane-4-carboxylate (Preparation example 172) was used instead of (4S , 5R)-methy1-5-(2-ni t ropheny1 )-2 , 2-d i ehty1-1.3-di oxo1 ane-4- carboxylate(Preparat ion example 170), to obtain the title compound(2. Og, 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, 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- clioxaspi ro[4 , 4]nonane-2-carboxy1 ate

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

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- clioxas i ro[ , 4]nonane-2-y1 )methanol

The substantially same method as described in Preparation example 171 was conducted, except that (2S, 3R)-methyl-3-(2-ni trophenyl )-l ,4- clioxaspi ro[4,4jnonane-2-carboxylate (Preparation example 174) was used instead of (4S , 5R)-methy1-5-(2-ni t ropheny1 )-2 , 2-di ehty1 -1.3-di oxo1 ane-4- carboxy1 ate(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, J=5.2, 1H), 5.12(d, J=7.6, 1H), 7.46~8.09(m, 4H)

•Preparation example 176: (2R, 3S)-methyl-3-(2-ni trophenyl )-l ,4- clioxaspi ro[4 , 4]nonane-2-carboxy1 ate

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%) . LH NMR (400MHz, DMS0) 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(cl, .7=7.2, 1H) , 7.44~8.06(m, 4H)

Preparation example 177: ((2S,3S)-3-(2-ni trophenyl )-l, 4- dioxaspiro[4 ,4]nonane-2-yl )methanol

The substantially same method as described in Preparation example 175 was conducted, except that (2R, 3S)-methyl-3-(2-nitrophenyl)-l,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 176) was used instead of (2S, 3R)-methyl-3-(2-ni trophenyl )-l,4-dioxaspi ro[4,4]nonane-2- carboxylate(Preparat ion example 174), to obtain the title compound (2.0g, 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. 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 )-l, 4- di oxaspi ro [4 , 5]decane-2-carboxy1 ate

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

¾ 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) , 7.45-8.12(m, 4H)

Preparation example 179: ((2R,3R)-3-(2-ni trophenyl )-l, 4- dioxasp i ro[4 , 5]decane-2-y1 )methano1

The substantially same method as described in Preparation example 175 was conducted, except that (2S, 3R)-methyl-3-(2-nitrophenyl )-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%)

^L H MR (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) , 7.46~8.09(m, 4H)

Preparation example 180· ^' (.2R, 3S)-me thyl-3-(2-ni trophenyl)-1,4- dioxaspi ro [4,5] decane-2-carboxylate

The substantially same method as described in Preparation example 176 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the tit le compounding, 70-95%). lH NMR (400MHz, DMS0) δ 1.61-1.69(m, 10H) , 3.79(s, 3H) , 4.33(d, .7=8.0, 1H), 5.85(d, J=8.0, 1H), 7.45~8.12(m, 4H)

Preparation example 181 ( (2S .3S)-3-(2-ni t ropheny 1 )-1 , 4- dioxaspi ro[4 , 5]decane-2-y 1 )methanol

The substantially same method as described in Preparation example 179 was conducted, except that (2R, 3S)-methyl -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%) lH NMR (400MHz, DMSOV- 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), 7.19~7.49(m, 4H)

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

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

Preparat ion example 183 ^' · ((4R,5R)-5-(2-ni trophenyl ) ^~ 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-nitrophenyl)-2-phenyl-l,3- dioxolane-4-carboxylate(Preparat ion example 182)was used instead of (2S, 3R)-methy1-3-(2-ni trophenyl )-l ,4-dioxaspi ro[4,4]nonane-2- carboxylate(Preparat ion example 174), to obtain the title compound(1.5g, 70-95%)

H 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), 7.06-8.14(m, 9H)

Preparation example 184 ^' · (4R, 5S)-methyl-5-(2-ni trophenyl )-2-pheny1-1, 3- dioxo1ane-4-carboxylate

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

Preparat ion exam le 185: ((4S,5S)-5 ^~ (2-ni trophenyl. )-2-pheny1-1 ,3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 183 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)-methy1-3-(2-ni trophenyl )-2-pheny -1, 3-dioxolane-4- carboxylate(Preparat ion example 182), 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, 7=8.0, 1H), 6.18(s, 1H), 7.06-8.14(m, 9H)

Preparation example 186: (4S,5R)-methyl-5-(2-methylphenyl )-2-methy1-1.3- dioxo1 ane-4-carboxylate

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

¾ NMR (400MHz, CDC1 ₃ ) δ 1.36(d, J=6.4, 3H), 2.35(s, 3H), 3.68(s, 3H), 5.07(m, 1H), 5. iKd, 7=7.6, 1H), 5.82(d, 7=7.6, 1H) , 7.19-7.39 (in, 4H)

Preparation example 187: ((4R,5R)-5-(2-methylphenyl )-2-methyl-l,3dioxolane- 4-yl )methanol

The substantially 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(Preparation example 186) was used instead of (2R, 3S)-methy1 -3-(2-ni tropheny1 )-2-pheny1-1 , 3-di oxo 1 ane-4- carboxylate(Preparation example 184), to obtain the title compound (1.7g, 70-95%) lll 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), 7.17-7.41(m, 4H). ^■ Preparat ion example 188: (4R, 5S)-methy1-5-(2-methyl henyl )-2-methy1-1.3- dioxo 1 a e-4-carboxylate

The substantially same method as described in Preparation example 186 was conducted, except that (2R.3S)-methy1-3-(2-methyl henyl )-2,3- dihyclroxypropanoate(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 (1.8g, 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), . ll(cl , .7=7.6, 1H), 5.82(d, J=7.6, 1H), 7.19-7.39 (m, 4H)

Preparat ion example 189: ((4S,5S)-5-(2-methyl henyl )-2-methy1-1.3-d ioxo lane- 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-methyl henyl )-2-mehtyl-l .3-dioxolane-4- carboxylate(Preparat ion example 186), to obtain the title compound(1.6g, 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(cl, .7=7.0, 1H) , 7.17-7.41(m, 4H).

Preparation example 190: (4S, 5R)-methyl-5-(2-methylphenyl)-2,2-diethyl-1.3- dioxolane-4-carboxylate

The substan ially same method as described in Preparation example 170 was conducted, except that (2S,3R)-methyl-3-(2-methylphenyl )-2,3- clihyclroxypropanoate(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 ).

¾ 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, J=7.6, 1H), 7.00-7.17(m, 4H)

Preparation example 191: ((4R,5R-5-(2-methyl henyl )-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-diehty1 -1 ,3- dioxolane-4-carboxylate(Preparat ion example 190) was used instead of (4S , 5R)-methyt ^~ 5-(2-metby1pheny1 )-2-mehty1 -1.3-di oxo 1 ane-4- carboxylate(Preparat ion example 186), to obtain the title compound (1.7g, 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 192: (4R, 5S)-inethyl-5-(2-methylphenyl)-2,2-diethyl-1.3- dioxo1ane-4-carboxy1ate

The substantially same method as described in Preparation example 190 was conducted, except that (2R,3S)-methyl-3-(2-methylpheriyl )-2,3- clihydroxypropanoate(Preparat ion example 57) was used instead of (2S,3R)- methy1-3-(2-methylphenyl )-2,3-dihyclroxypropanoate(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), 5.11(d, J=7.6, 1H), 5.81(d, J=7.6, 1H), 7.00-7.17(m, 4H)

Preparation example 193: ((4S,5S)-5-(2-methylphenyl )-2, 2-cliethyl-l . clioxo 1ane-4-y1 )methano1

The substantially same method as described in Preparation example 191 was conducted, except that (4R, 5S)-methyl-5-(2-methyl henyl )-2,2-diehtyl-l .3- dioxolane-4-carboxylate(Preparat ion example 192) was used instead of (4S, 5R)-methy1-5-(2-methy1pheny1 )-2 , 2-cli ehty1 -1.3-di oxo1 ane-4- carboxylate(Preparat ion example 190), to obtain the title compound (1.8g-, 70-95%)

T-I NMR (400MHz, CDC 13) : δ 0.96(m, 6H), 1.59(m, 4H) , 2.37(s, 3H), 3.62 ^~ 3.70(m, 2H) , 4.36(dd, J=7.0, J=7.0, 1H) , 5.17(cl, J=7.0, 1H), 7.15-7.39(m, 4H)

Preparation example 194: (2S, 3R)-methyl-3-(2-methylphenyl )-l ,4- di oxaspiro[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, 7=7.2, 1H), 7.02~7.25(m, 4H)

Preparation example 195: ( (2R,3R)-3-(2-methy1pheny1 )-1 , - dioxaspi ro [4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 191 was conducted, except that (2S, 3R)-methy1-3-(2-methyI henyl )-l ,4- dioxaspiro[4,4]nonane-2-carboxylate(Preparat ion example 194) was used instead of (4S, 5R)-methyl-5-(2-methylphenyl)-2,2-diehtyl-1.3-dioxolaiie-4- carboxyl ate(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(d, 7=7.6, 1H), 7.02~7.25(m, 4H)

Preparation example 196· ^' (2R, 3S)-methy1-3-(2-methylphenyl )-l,4- dioxaspi 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, 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, 7=7.2, 1H), 7.02~7.25(m, 4H)

Preparation example 197: ((2S,3S)-3-(2-methylphenyl)-l,4- di oxaspi ro[4 , 4]nonane ^_ 2-y1 )methanol

The substantially same method as described in Preparation example 195 was conducted, except that (2R, 3S)-me hy1-3-(2-methy1phenyl)-1,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 196) was used insteacl of (2S , 3R)-methy1-3-(2-methy1pheny1 )-1 , 4-di oxasp i ro[4 , 4J nonane-2- carboxylate(Preparat ion example 194), to obtain the title compound(2.0g, 70-95%)

¾ NMR (400MHz, DMS0): δ 1.49-1.57(m, 4H) , 1.72-1.8Km, 4H), 2.35(s, 3H), 3.52~3.65(m, 2H) , 4.90(t. 7=5.2, 1H), 5.12(cl, 7=7.6, 1H), 7.02 ^~ 7.25(m, 4H)

Preparation example 198: (2S, 3R)-methyl-3-(2-methylphenyl)-l,4- clioxaspi 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, 7=8.0, 1H), 5.85(d, 7=8.0, 1H). 7.01 ^~ 7.30(m, 4H)

Preparation example 199: ((2R,3R)-3-(2-methylphenyl)-l,4- dioxaspiro[4,5]decane-2-yl )methanol

The substantially same method as described in Preparation example 195 was conducted, except that (2S, 3R)-methyl-3-(2-methylphenyl)-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, DMSO): 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, 7=7.6, 1H), 7.02~7.28(m, 4H)

Preparation example 200: (2R, 3S)-methyl-3-(2-methylphenyl )-l,4- dioxaspi ro[4 , 5]decane-2-carboxy1 ate

The substantially same method as described in Preparation example 196 was conducted, except that eye 1ohexanone was used instead of cyclopentanone, to obtain the title compound(2.2g, 70-95%).

¾ NMR (400MHz, DMSO) δ 1.61-1.69(m, 10H) , 2.34(s, 3H) , 3.79(s, 3H), 4.33(d, 7=8.0, 1H), 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-methyl henyl )-l ,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 200) was used instead of (2S , 3 )-methy1-3-(2-methy1pheny1 )-1 , 4-dioxaspi ro [4 , 5]decane-2- carboxylate (Preparation example 198), to obtain the title compound (1.5g, 70-95%) Tl 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, ./=7.6, 1H), 7.02~7.28(m, 4H)

Preparation example 202: (4S, 5R)-methyl-5-(2-methylphenyl )-2-phenyl-l ,3- di oxolane-4-carboxylate

The substantially same method as described in Preparation example 198 was conducted, except that benzaldehyde was used instead of eye 1 ohexanone , 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(cl, 7=8.0, 1H), 6.18(s, 1H) , 6.96-7.32(m, 9H)

Preparat ion examp1e 203 : ( (4R, 5R)-5-(2-methy1 heny1 )-2-pheny1-1 , 3-dioxo1 ane ^~ 4-yl )methanol

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

^: H NMR (400MHz, DMS0): 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 204: (4R, 5S)-methyl-5-(2-methylphenyl)-2-phenyl-l,3- dioxo Iane-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%).

Ί-Ι NMR (400MHz, DMS0) 52.33(s, 3H) , 3.67(s, 3H) , 5.11(d, 7=8.0, 1H) , 5.81(d, 7=8.0, 1H), 6.18(s, 1H), 6.96~7.32(m, 9H)

Preparation example 205 ^' · ((4S,5S)-5-(2-methylphenyl)-2-phenyl-l,3-dioxolane- 4-yl )methanol

The substantially same method as described in Preparation example 203 was conducted, except that (4R, 5S)-methy1-5-(2-methyl heny1 )-2-pheny1-1, 3- dioxolane-4-carboxylate (Preparation example 204) was used instead of (4S, 5R)-methy1-5-(2-methylphenyl )-2-pheny1-1 ,3-dioxolane-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, 7=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 )methanol

The substantially same method as described in Preparation example 47 was conducted, except that ((4R,5R)-5-(2-nitrophenyl )-2-mehtyl-1.3-dioxolane-4- yOmethanol (Preparation example 167) was used instead of ((4R,5R)-5-(2- ni tropheny1 )-2 , 2-dimehty1-1.3-di oxo1ane-4-y1 )methano1 (Preparat i on examp 1e 46), to obtain the title compound (1.5g, 65~85%)

H NMR (400MHz, CDC1 ₃ ): 6 1.37(cl, 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(cl, 7=7.0, 1H), 7.57~8.08(m, 4H).

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

The substantially same method as described in Preparation example 47 was conducted, except that ((4S,5S)-5-(2-nitrophenyl)-2-mehtyl-1.3-dioxolane-4- yl )methanol (Preparat ion example 169) was used instead of ((4R,5R) ^~ 5-(2- nitrophenyl)-2,2-dimehtyl-1.3-dioxolane-4-yl )methanol (Preparat ion example 46), to obtain the title compound( 1. lg, 65-85%)

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, lH), 5.06(m, 1H), 5.17(d, 7=7.0, 1H), 7.57~8.08(m, 4H).

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-diehtyl-1.3- dioxolane-4-yl )methanol (Preparat ion example 171) was used instead of ( (4R , 5R)-5-(2-ni tropheny1 )-2 , 2-di mehty1 -1.3-di oxo 1 ane-4- yl )methanol (Preparat ion example 46), to obtain the title compound (1.5g, 65-85%)

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

Preparat ion examp1e 209 : ( (4S , 5S)-5-(2-aminopheny1 )-2 , 2-di ehty1 -1.3- dioxo1 ane-4-y1 )methano 1

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 (Preparation example 173) was used instead of ( (4R , 5 )-5-(2-ni tropheny1 )-2 , 2-dimenty1-1.3-dioxo1 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, .7=7.0, J=7.0,- 1H), 5.17(cl, J=7.0, 1H) , 7.55~8.09(m, 4H)

Preparation example 210: ( (2R,3R)-3-(2-aminophenyl )-l ,4- dioxaspi r0[4 , 4]nonane-2-y1 )methano1

The substantially same method as described in Preparation example 47 was conducted, except that ((4R,5R)-5-(2-nitrophenyl)-l,4- clioxaspiro[4,4]nonane-2-yl )methanol (Preparation example 175) was used insteacl of ( (4R, 5R)-5-(2-ni t ropheny1 )-2 , 2-d imehty1-1.3-dioxo1 ane-4- yl )methanol (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, lH), 7.56~8.11(m, 4H)

Preparation example 211: ( (2S , 3S)-3-(2-aminopheny1 )-1 ,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- dioxaspiro[4,4]nonane-2-yl )methanol (Preparation example 177) was used ins tead of ( (4R, 5R)-5-(2-ni tropheny1 )-2 , 2-dimehty1 -1.3-di oxo 1 ane-4- yl )me hanol (Preparat ion example 46), to obtain the title compound(1.6g, 65-85%)

¾ NMR (400MHz, DMSO): δ 1.62-1.73(m, 4H), 1.82~1.95(m, 4H), 3.52~3.65(m, 2H), 4.90(t, J=5.2, 1H) 5.12(d, J=7 . 6 , 111) , 7.56-8. ll(m, 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-nitrophenyl)-l,4 ^~ dioxaspiro[4,5]decane-2-yl )methanol (Preparation example 179) was used instead of ( (4R, 5R)-5-(2-ni tropheny1 )-2 , 2-d.imehty1-1.3-di oxo1 ane-4- yDmethanol (Preparation example 46), to obtain the title compound( 1. lg, 65-85%)

¾ NMR (400MHz, DMSO): 51.61-1.75(m, 10H), 3.52~3.81(m, 2H), 3.95(t, J=8.0, 1H), 5.43(d, 7=7.6, 1H) , 7.49~8.12(m, 4H)

Preparat ion examp1e 213 · ^" ( (2S , 3S)-3-(2-aminopheny1 )-1 ,4- dioxaspi 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-nitrophenyl)-2,2-dimehtyl-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(cl, 7=7.6, 1H), 7.49-8.12(m, 4H)

exam 1 e 214: ( (4R, 5R)-5-(2-aminopheny1 )-2-pheny1 ^~ 1 , 3-dioxo 1ane- ol

The substantially same method as described in Preparation example 47 was conducted, except that ( (4R, 5R)-5-(2-ni trophenyl )-2-pheny1-1 ,3-dioxolane ^~ 4- yl )methanol (Preparat ion example 183) was used instead of ((4R,5R)-5-(2- ni trophenyl )-2, 2-dimehtyl-l .3-dioxolane-4-yl )methanol (Prepara ion example 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-aminopheny1)-2-pheny1-1, 3-di oxo lane- 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-dioxol ne-4- yOmethanol (Preparation example 185) was used instead of ((4R,5R)-5-(2- nitrophenyl)-2,2-dimehtyl-1.3-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(d, .7=8.0, 1H), 6.18(s, 1H), 7.06-8.14(m, 9H)

Preparation example 216: (E)-Methyl cinnamate

To a round-bo tomed flask, fra/js-cinnamic acid (7g, 47.25mmol) and MeOH (70mL) were added. POC I 3 (0.43mL, 4.73rnmol) 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 H2O. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgS0 ) , filtered and concentrated under vacuum (7.1g, 80-95%) lH NMR (400MHz, CDC1 ₃ ) · 63.81(s, 3H), 6.42(d, J=15.9, 1H), 7.37~7.39(m, 3H) , 7.50~7.53(m, 2H) , 7.67(d, J=15.9, 1H)

Preparation example 217: (2S, 3R)-methyl-3-phenyl-2,3-dihydroxypropanoate The substan ially same method as described in Preparation example 36 was conducted, except that (E)-Methyl cimiamate (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%) ¾ NMR (400MHz, CDC1 ₃ ): δ 2.70(bs, 1H), 3.08(bs, 1H), 3.82(s, 3H), 4.38(cl, J=2.9, 1H), 5.03(d, J=2.9, 1H), 7.30- 7.42(m, 5H)

Preparation example 218: (4S, 5R)-methyl-2,2-dimethyl-5-phenyl-l,3 ^~ cli oxo1 ane-4-carboxylate

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

¾ NMR (400MHz , CDC1 ₃ ) · δ 1.56( s , 3H) , 1.61( s , 3H) , 3.79( s , 3H) , 4.36(cl , J=7.8, Hi), 5.17(d, J=7.8, 1H), 7.-31~7.40(m, 5H)

Preparation example 219: ((4R, 5R)-5-phenyl-2,2-dimethyl-l,3-dioxolane-4- yDmethanol

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)-methyl- 5-(2-ni trophenyl )-l,3-di oxo lane-4-carboxylate (Preparation example 45), to obtain the. title compouncl(4.4g, 70~95%) ¾ NMR (400MHz, CDCl ₃ ) - 61.41(s, 3H) , 1.46(s, 3H). 2.79(bs, 1H). 3.48 ^~ 3.52(m, 1H), 3.6S~3.76(m, 2H) , 4.76(cl, .1=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 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 221: (4R, 5S)-methyl-2,2-climethyl-5-phenyl-l,3- dioxo1ane-4-carboxylate

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

Hi NMR (400MHz, CDC1 ₃ ): 61.56(s, 3H) , 1.61(s, 3H) , 3.79(s, 3H), 4.36(d, J=7.8, lH), 5.17(d, J=7.8, H), 7.31~7.40(m, 5H)

Preparation example 222: ((4S, 5S)-5-phenyl-2,2-climethyl-l,3-dioxolane-4- yOmethanol

The substantially same method as described in Preparation example 4-6 was conducted, except that (4R, 5S)-methyl-2,2-dimethyl-5-phenyl-l,3-dioxolane- 4-carboxylate(Preparat ion example 221) was used instead of (4S, 5R)-methyl- 5-(2-nitrophenyl)-l,3-dioxolane-4-carboxylate(Preparation example 45), to obtain the title compound(6.5g, 70~95 )

¾ NMR (400MHz, CDC1 ₃ ): 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-diethyl-5-phenyl-l,3-dioxolane- 4-carboxylate

The substant ial ly same method as described in Preparation example 190 was conducted, except that (2S, 3R)-methy1-3-pheny1-2,3- dihydroxypropanoate(Preparation example 217) was used instead of (2S, 3R) ^~ methyl-3-(2-methylphenyl )-2,3-dihydroxypropanoate (Preparation example 54) , to obtain the title compound(1.9g, 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 224: ((4R, 5R)-5-phenyl-2,2-diethyl-l,3-dioxolane-4- yl )methanol

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)- methy 1-2 , 2-dimethyl-5-phenyl-l , 3-dioxol ane-4-carboxyl ate(Prepara ion example 218), to obtain the title compound(1.3g, 70~95%) lH NMR (400MHz, CDC1 ₃ ): 6=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-carboxyl te

The substantially same method as described in Preparation example 223 was conducted, except that (2R, 3S)-methy1-3-pheny1-2 ,3- dihydroxypropanoate(Preparat ion example 220)was used instead of (2S, 3R)- methy 1-3-phenyI -2 ,3-clihydroxypropanoate(Preparat ion example 217), to obtain the title compound( 5.6g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =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-pheny1-2, 2-di methy1-1, 3-dioxol ane-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)- methyl-2,2-dimethyl-5-phenyl-l , 3-cioxol ane-4-carboxylate (Preparat ion example 218), to obtain the title compound(6.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.00(t. J=7.6, 1H) . 1.06(t, J=7.4, 1H) . 1.74~1.90(m, 4H) , 3.64(ddcl, 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, CDC 13) : 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. 5(m, 5H)

Preparation example 228 ^' · ((2R, 3R)-3-phenyl-l,4-dioxapiro[4,4jnonan-2- yDmethanol

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 title 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(deld, 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[4,4]nonane- 2-carboxyl te

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 )me hanol

The substantially same method as described in Preparation example 228 was conducted, except that (2R, 3S)-methyl-3-phenyl-l,4-dioxapiro[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%)

H NMR (400MHz, CDC13) : 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 231: (2S,3R)-methyl 3-phenyl-l,4-dioxapiro[4,5]decane-2- carboxylate

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 ) lH 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(d, J=7.6, 1H), 5.16(c), J=7.2, 1H), 7.31~7.44(m, 5H)

Preparation example 232: ((2R, 3R)-3-phenyl-l,4-dioxapiro[4,5jdecan-2- yl )methanol

The substantially same method as described in Preparation example 224 was conducted, except that (2S, 3R)-methyl 3-phenyl-l,4-dioxapiro[4,5]decane-2- carboxylate (Preparation example 231) was used instead of (4S, 5R)-methyl- 2 , 2-cli ethyl-5-pheny1-1 , 3-di oxo 1 ane-4-carboxy1 ate(Preparat i on examp 1 e 223) , to obtain the title compound(1. Og, 70-95%) lH 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 283: (2R, 3S)-methyl-3-phenyl-l,4-dioxa iro[4,5jdecane- 2-carboxylat

The substantially same method as described in Preparation example 229 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (1.2g, 50~75%) lH NM (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(d, 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-dioxapiro[4,5]decane-2- yOmethanol

The substantially same method as described in Preparation example 232 was conducted, except that (2R, 3S)-methyl-3-phenyl-l,4-clioxapiro[4,5jdecane-2- carboxylate(Preparat ion example 233) was used instead of (2S, 3R)-methy1-3- phenyl-l,4-dioxapiro[4,5]decane-2-carboxylate (Preparation example 231), to obtain the title compound (0.8g, 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 235: (E)-5-phenylpent-3-enoic acid

A solution of malonic acid (17.06g, 163.96mmo 1 ) in DMS0 (65mL) was treated with a solution of AcOH (O.lmL, 1.49mmol) and piperidine (0.15niL, 1.49mmo 1 ) in DMSO (4mL). The reaction solution was warmed to 65 ^° C and hydrocinnamaldehycle (lOg, 74.53mmol) was added clropwise 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 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%) lH N R (400MHz, CDC1 ₃ ): 6=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-3-en-l ^~ ol

To stirred solution of LAH (L 1 A I H4. 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(44mL) 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,i), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (7.2g, 70-90%)

^L H NMR (400MHz, CDC 13 ) · ^' 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, IH), 5.73(dt, J=4.8, 10.9, 1H), 7.17~7.31(m, 5H)

Preparat ion exam 1 e 237: (E)-1ert-butyIdimethy1 (5-pheny1pent-3- enyloxy)si 1

To a stirred solution of (E)-5-phenylpent-3-en-l-ol (Preparat ion example 236, 6.3g, 38.83mmol) in CH2CI2 was added imidazole (3.4g, 50.48mmol) 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 MgS0 ₄ , 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, CDC1 ₃ ): 6=0.00(s, 6H) , 0.84(s, 9H) , 2.21(ddd, .1=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-phenyl ent-3-enyl pivalate

To a stirred solution of (E)-5-phenylpent-3-en-l-ol (Preparation example 236, 3.8g, 23.42mmol) in CH ₂ C1 ₂ (40mL) was added pyridine (2.3mL, 28. Immo 1 ) and pivaloyl chloride (3.5mL, 28. Immo 1) at 0 ^° C under !¾. 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, CDC1 ₃ ) ^' - 6=1.17(s, 9H), 2.36(q, J=6.7, 2H), 8.34(d, J=6.8, 2H), 4.09(t, 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- pheny1pent ane-2 , 3-di 01

The substantially same method as described in Preparation example 217 was conducted, except that (E)-ter t-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(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 240: (2-((4S,5S)-5-benzyl-2,2-dimethyl-l,3-dioxolane-4- yl )ethoxy)(tert-butyl )dimethylsi lane

The substan ially same method as described in Preparation example 218 was conducted, except that (2S,3S)-5-(tert-butyldimethylsi lyloxy)-l- phenylpentane-2 ,3-diol (Preparat ion example 239) was used instead of (2R, 3S)-methyl-3-phenyl-2,3-dihydroxypropanoate(Preparat ion example 217), to obtain the title compound(9.5g, 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(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-benzy1-2,2-dimethy1-1,3-dioxolane-4- yl )ethanol

To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-dimethyl-l,3-dioxolan- 4-yl )ethoxy)(tert-butyl )dimethylsi lane (Preparation example 240, 11.5g, 32.80mmol) in THF (115mL) was slowly added tetrabutyl ammonium fluoride (TBAF , 1. OM in THF , 48.8ml , 48.8mmo1 ) 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- pheny1pentane-2 , 3-di o1

The substantially same method as described in Preparation example 220 was conducted, except that (E)-tert-butyldimethyl (5-phenyI 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 ): 6=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(m, 5H)

Preparation example 243- ^' (2-((4R,5R)-5-benzyl-2,2-dimethyl-l,3-clioxolane-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- phenylpentane-2,3-diol (Preparat ion 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(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)

Preparat i on examp 1e 244 : 2-( (4R, 5R)-5-benzy1-2 , 2-dimethy1-1 , 3-dioxo1 ane-4- yOethanol

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)(ter t-butyl )climethyl s i lane(Preparat ion . example 243) was used instead of (2-((4S,5S)-5-benzyl-2,2-dimethyl-l,3-dioxolan-4- yl )ethoxy)(tert-butyl )dimethylsi lane(Preparat ion example 240), to obtain the title compound(7.4g, 80~95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=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, 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-phenyl ent-3-enyl pivalate (Preparation example 238) was used instead of (E)-ter t-butyldimethyl (5-phenyl ent-3- enyloxy)si lane(Preparat ion example 237), to obtain the title compound(5.5g, 70-95%) ^■

¾ NMR (400MHz, CDC1 ₃ ) · ^' 5=1.16(s, 9H), 1.83-1.88(m, 2H), 2.08(d, J=4.8, H), 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 246: (2-((4S,5S)-5-benzyl-2,2-di e thyl-l,3-dioxolane-4- yDethyl pivalate

The substantially same method as described in Preparation example 223 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-dihydroxypropanoate(Preparat ion example 217), to obtain the title compound(0.9g, 70-95%)

^L H 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)

Preparation example 247: 2-((4S,5S)-5-benzyl-2,2-diethyl-l,3-dioxolane-4- yOethanol

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 ): 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) , 3.03(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)

Preparat ion example 248: (3R,4R)-3,4-dihydroxy-5-phenylpentyl pivalate

The substantially same method as described in Preparation exam le 242 was conducted, except that (E)-5-phenyl ent-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%)

Ή NMR (400MHz, CDC1 ₃ ): 5=1.16(s, 9H), 1.83~1.88(m, 2H), 2.08(d, J=4.8, H), 2.67(d, 5=5.2, 1H) , 2.80(dd, J=8.0. 13.6, 1H) , 2.92(dd, .1=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- yOethyl pivalate

The substantially same method as described in Preparation example 246 was conducted, except that (3R,4R)-3,4-dihydroxy-5-phenylpentyl pivalate(Preparat ion example 248) was used instead of (3S,4S)-3,4- dihydroxy-5-phenylpentyl pivalate (Preparation example 245), to obtain the title compound(l.lg, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=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)

Preparation example 250: 2-((4R, 5R)-5-benzyl-2,2-diethyl-l,3-dioxolane-4- yl )ethanol

The substantially same method as described in Preparation example 247 was conducted, except that (2-((4R,5R)-5-benzyl-2,2-diethyl-l,3-dioxolan-4- yOethyl pivalate(Preparat ion example 249) was used instead of (2-((4S,5S) ^~ 5-benzy1-2 , 2-diethy1-1 ,3-dioxo 1 an-4-y1 )ethy1 piva1 ate(Preparat i on examp1 e 246), to obtain the title compound (0.9g, 80~95 )

T 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 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, CDC1 ₃ ): 5=1.18(s, 9H), 1.53-1.80(m, 10H), 2.81(dd, 13.6, 1H), 3.00(dd, J=6.4, 14.0, 1H) , 3.75~3.80(m, 1H), 3.84~3.89(m, 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 )ethanol

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- yOethyl pivalate (Preparation example 251) was used instead of (2- ( (4S , 5S)-5-benzy1-2 , 2-diethy1-1 , 3-dioxo1 an-4-y1 )ethy1 pivalate (Preparat i on example 246), to obtain the title compound (0.7g, 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), l,72 ^~ 1.81(m, 4H), 2.26(t, J=5.4, 1H) , .2.80(dd, 1=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- yDethyi 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%) H 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-dioxaspiro[4.4]nonane-2- yDethanol

The substantially same method as described in Preparation example 252 was conducted, except that 2-((2R,3R)-3-benzyl-l,4-clioxaspiro[4.4]nonan-2- yDethyl pivalate (Preparation example 253) was used instead of 2-((2S,3S)- 3-benzy1-1 , 4-di oxaspi ro[4.4]nonan-2-y1 )ethy1 piva1 ate (Preparat ion examp 1e 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(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 255: 2-((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.5jdecane-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%)

H 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(dd, J=6.0, 14,0, 1H), 3.78(dt, J=3.5, 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- yl )ethanol

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- yDethyl pivalate (Preparation example 255) was used instead of 2-((2R,3R)- 3-benzy1 -1 , 4 ^~ dioxaspi ro[4.4]nonan-2-y1 )ethyl piva 1 ate (Preparat ion examp 1e 253), to obtain the title compound (l.Og, 80-95%) ll\ NMR (400MHz, CDC1 ₃ ): δ =1.34-1. 3(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 257: 2-((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.5]decane-2- yOethyl pivalate

The substantially same method as described in Preparation, example 253 was conducted, except that cyclohexanone was used instead of cvclopet none, to obtain the title compound (1.6g, 60~85 ) lH NMR (400MHz, CDC1 ₃ ) - ^' 6=1.18(s, 9H), 1.53~1.60(m, 10H), 1.61-1.66(m, 2H), 2.83(dcl, 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- yl )ethanol

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- y ethyl pivalate (Preparation example 257) was used instead of 2-((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.5]clecan-2-yl)ethyl pivalate (Preparation example 255), ^' to obtain the title compound (l.lg, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =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 acet aldehyde (5.0g, 41.61mmol) in toluene (500mL) was added methyl (t iphenylphosphoranyl 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 , 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%)

^L H NMR (400MHz, CDC1 ₃ ): 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-phenyl ent-3-enyl pivalate(Preparat ion example 238), to obtain the title compound(3.5g, 70~95 ) lH NMR (400MHz, CDC1 ₃ ): 5=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, J=1.4, 5.4, 1H), 7.23~7.34(m, 5H)

Preparat ion exam 1 e 261 : (4R , 5S)-me hy1 -5-benzy1-2 , 2-dimethy1 -1 , 3-di oxo 1 ane- 4-carboxylate

The substantially same method as described in Preparation example 240 was conducted, except that (2R, 3S)-methyl 2,3-dihydroxy-4- phenylbutanoate(Preparat ion example 260) was used instead of (2S,3S)-5 ^~ ( ter t-butyl dimethy1 s i 1y1 oxy)-1-pheny 1 pent ane-2 , 3-di o 1 (Preparati on exam Ie 239), to obtain the title compound(3. lg, 70 ^~ 95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.42(s, 3H), 1.43(s, 3H) , 3.01(dd, J=6.8, 14.4, 1H), 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-benzy1 -2, 2-dimethy1-1, 3-dioxo lan ^~ 4- yl )me hanol

The substantially same method as described in Preparation example 234 was conducted, except that (4R,5S)-methyl 5-benzyl-2,2-dimethyl-l,3-dioxol iie- 4-carboxylate(Preparat ion example 261) was used instead of (4S, 5R)-methyl- 3-phenyl-l,4-dioxapiro[4,5]decane-2-carboxylate (Preparat ion 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.l; 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 H2SO4 (O.OSlmL, 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%) LH 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(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 264: ((4S, 5S)-5-benzyl-2,2-diethyl-l,3-dioxolan-4- yOmethanol

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-benzy1-2 , 2-dimethy1-1 , 3-dioxo1 ane-4-carboxy1 ate(Preparat i on examp1 e 261), to obtain the title compound(0.8g, 70~95 )

¾ 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(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-carboxylate

The substantially same method as described in Preparation example 263 was conducted, except that cyclopetanone was used instead of 3-pantaiione, to obtain the title compound (1.3g, 60~85%)

¾ 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(d, J=7.2, 1H), 4.32 Celt , J=4.9, 7.0, IH), 7.21~7.33(m, 5H)

Preparation example 266: ((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.4]nonane-2- yOmethanol

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%)

H NMR (400MHz, CDC1 ₃ ): δ =1.57-1.88(m, 8H), 2.82(dd, J=6.6,

3.08(dd, J=6.4, 14.0, 1H), 3.27~3.33(m, 1H), 3.47~3.52(m, 1H),

1H), 4.07(q, J=6.8, 1H), 7.21~7.32(m, 5H)

Preparat ion exam 1e 267 : (2 , 3S)-methy1-3-benzy1-1 , 4-dioxaspi ro[4.5]decane- 2-carbox late

The substantially same method as described in Preparation example 265 was conducted, except that eye1ohexanone was used instead of cyclopetanone, to ob ain the title compound ( 1.5g , 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(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- yDmethanol

The substantially same method as described in Preparation example 266 was conducted, except that (2R, 3S)-methyl-3-benzyl-l,4-dioxaspiro[4.5]decane-

2-carboxylate (Preparation example 267) was used instead of (2R, 3vS)-methyl

3-benzyl-l,4-dioxaspiro[4.4]nonane-2-carboxylate (Preparation exaimple 265) , to obtain the title compound (0.8g, 70-95%)

¾ MPv (400MHz, CDC1 ₃ ): δ =1.53-1.65(m, 10H), 2.82(dd, J=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)

eparation example 269: (2S, 3R)-methyl-2,3-dihyclroxy-4-phenylbutanoate

The substantially same method as described in Preparation example 242 was conducted, except that (E)-me.thyl-4-phenylbut-2-enoate(Preparat ion example 259) was used instead of (E)-ter t-butyldimethyl (5-phenyl ent-3- enyloxy)si lane(Preparat ion example 237), to obtain the title compound(3.5g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=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, J=1.4, 5.4, 1H), 7.23~7.34(m, 5H)

Preparation example 270· ^' (4S, 5R)-methyl-5-benzyl-2,2-dimethyl-l,3- di oxo 1 ane-4-carboxylate

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%) -I 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(dcl, J=6.4, 14.0, 1H), 3.29(ddd, 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- yl )methanol

The substantially same method as described in Preparation example 262 was conducted, except, that (4S,5R)-methyl-5-benzyl-2,2-climethyl-l,3-dioxolane-

4-carboxylate (Preparation example 270) was used instead of (4R,5S)-methyl

5-benzy1-2 ,2-climethy1-1 , 3-dioxolane-4-carboxylate(Preparat ion exam le 261) , to obtain the title compound (2.7g, 70-95%)

^L H NMR (400MHz, CDC13) : 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(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, IH), 7.22~7.32(m, 5H)

Preparat ion exam 1 e 272 : (4S , 5R)-methy1-5-benzy1-2 , 2-di ethy1-1 , 3-di oxo 1 ane- 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-dihydroxy-4- phenyl butanoate (Preparation example 260), to obtain the title compound (1.5g, 50~75%) ¾ NMR (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-benzy1-2, 2-di ethyl-1,3-clioxo lan ^~ 4- yl )methanol

The substantially same method as described in Preparation example 264 was conducted, except that (4S,5R)-methyl-5-benzyl-2,2-dimethyl-l,3-dioxolane- 4-carboxylate (Preparation example 272) was used instead of (4R,5S)-methy l- 5-benzyl-2,2-dimethyl-l,3-clioxolane-4-carboxylate (Preparation example 263) , to obtain the title compound ( 1.2g , 70-95%) lH NMR (400MHz, CDC13) : 6=0.91(dt, .1=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(m, 1H), 3.78-3.82(m, 1H), 4.08-4.13(m, 1H), 7.21~7.32(m, 5H)

Preparation example 274: (2S, 3R)-methyl-3-benzyl-l,4-dioxaspiro[4.4jnonane- 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%)

Tl NMR (400MHz, CDC13) : δ =1.61-1.79(m, 5H), 1.85~1.92(m, 3H) , 3.00-3.11(ni, 2H), 3.70(s, 3H), 4.17(cl, J=7.2, 1H), 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[4.4jnonane- 2-carboxylate (Preparation example 274) was used instead of (2R, 3S)- methyl-3-benzyl-l,4-dioxaspiro[4.4]nonane-2-carboxylate (Preparat ion example 265), to obtain the title compound (l.lg, 70~95%)

¾ MR (400MHz, CDCI3) ^' · δ =1.57-1.88(m. 8H) , 2.82(del, J=6.6, 13.8, 1H), 3.08(dd, .1=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(q, J=6.8, 1H), 7.21~7.32(m, 5H).

Preparation example 276: (2S, 3R)-methyl-3-benzyl-l,4-clioxaspiro[4.5.|decane- 2-carboxy late

The substantially same method as described in 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, CDC13) : 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 277: ((2R, 3R)-3-benzyl-l,4-dioxaspiro[4.4]nonane-2- yl )methanol

The substantially same method as described in Preparation example 268 was conducted, except that (2S, 3R)-methyl-3-benzyl-l,4-dioxaspiro[4.5]clecane- 2-carboxylate (Preparation example 276) was used instead of (2R, 3S) ^~ methy1 -3-benzy1-1 , 4-di oxaspi ro [4.5] decane-2-carboxy late (Preparat ion example 267), to obtain the title compound (1.4-g, 70-95%)

H NMR (400MHz, CDC1 ₃ ): 5 =1.53-1.65(m, 10H), 2.82(dd, J=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 278 ^' · (E)-4-phenylbut-3-enoic acid

To a stirred solution of 2-phenyl acet aldehyde (5.0g, 32.3mmol) and maIonic acid (4.0g, 38.8mmol) in pyridine (25.OmL) 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 H01. The white precipitate was filtered off and dried under vacuum to produce the title compound (3.5g, 55-80%)

¾ NMR (400MHz, CDC1 ₃ ): 5=3.39(d, J=8.8, 2H), 6.31(td, J=7.9, 14.8, 1H) , 6.94(cl, J=16, 1H), ^' 7.17~7.45(m, 3H), 7.56~7.59(m, 1H)

Preparation example 279 ^' · (E)-4-phenylbut-3-en-l-ol To stirred solution of Zn(BH ₄ ) ₂ (40.0mL, 20.0mmol) in THF(40mL) was added clropwise 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 sulfate(MgS0 ₄ ) , filtered and concentrated. The crude- compound was purified by a silica gel column to produce the title compound (l.Og, 50-75%)

^] H NMR (400MHz, CDC1 ₃ ): 6=2.55(ddd, J= 4.1, 11.9, 21.5, 2H), 3.82(t, J=5.8, 2H), 6.24(tcl, 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 exam le 280 ^' · (E)-tert-butyldimethyl (4-phenylbut-3-eny loxy)si lane

The substantially same method as described in Preparation example 237 was conducted, except that (E)-4-phenyl but-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(1.7g, 80~98%)

Ή NMR (400MHz, CDC1 ₃ ): 6=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, .1=15.6, 1H), 7.13~7.24(m, 3H), 7.36(dd, .1=5.6, 12.4, 1H) , 7.53(dd, J=1.4, 7.8, 1H)

Preparation example 281: (E)-4-phen 1 but-3-eny1 pivalate

The substantially same method as described in Preparation example 238 was conducted, except that (E)-4-phenyl but-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 )

Ή NMR (400MHz, CDC1 ₃ ) ^' - 5=1.22(s, 9H), 2.57(ddd, J=1.3, 6.7, 13.5, 2H), 4.22(t, J=6.6, 2H), 6.19(tcl, 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-butyldimethylsi lyloxy)-!- pheny1butane-1 , 2-di o1

The substantially same method as described in Preparation example 239 was conducted, except that (E)-ter -butyldimethyl (4-phenylbut-3- enyloxy)si lane(Preparation example 280) was used instead of (E)-tert- butyldimethyl(5-phenylpent-3-enyloxy)si lane (Preparation example 237), to obtain the title compouncKO.Sg, 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(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 283: (3R, 4R)-3,4 ^_ dihydroxy-4-phenylbutyl 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)-ter t-butyldimethy I (4-phenylbut-3- enyloxy)si lane (Preparation example 280), to obtain the title compound(8.7g, 70-95%)

H NMR (400MHz, CDC1 ₃ ): 6=1.18(s, 9H), 1.65~1.74(m, 2H), 2.83(d, J=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(cl, J=5.6, 1H) , 7.31~7.41(m, 5H)

Preparation example 284: tert-butyl (2-((4 , 5R)-5-pheny1-2, 2-dimethyl-1, 3- dioxolan-4-yl )ethoxy)dimethylsi lane

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 ): 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, Hi), 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-phen 1-2, 2-dimethy1-1, 3-d ioxolan-4- yOethanol

The substantially same method as described in Preparation example 244 was conducted, except that tert-butyl (2-((4R, 5R)-5-pheny 1-2,2-climethyl-l, 3- dioxolan-4-yl )ethoxy)dimethylsi lane (Preparation example 284) was used instead of (2-( (4R .5R)-5-benzy1-2 , 2-d imethy1-1 , 3-di oxo 1 an-4- yl)ethoxy)(tert-butyl)dimethylsi lane(Preparat ion example 243), to obtain the title compound (1.4g, 80-95%). Ή 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, .1=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-dio1

The substantially same method as described in Preparation example 242 was conducted, except that (E)-tert-butyldimethyl (4-phenylbut-3- enyloxy)si lane(Preparat ion example 280)was used instead of (E)-tert- butyldimethyl C5-phenylpent-3-enyloxy)si lane (Preparation example 237), to obtain the title compound(0.7g, 70 ^~ 95%) lH NMR (400MHz, CDC1 ₃ ): 6=0.10(s, 3H), O.lKs, 3H), 0.92(s, 911), 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 287: (3S, 4S)-3,4-dihydroxy-4-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-phenylbut-3- enyloxy)si lane(Preparat ion example 280), to obtain the title compound( 10.4g, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=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-phenyl-2,2-dimethyl-l,3- dioxolan-4-yl )ethoxy)dimethylsi lane

The substantially same method as described in Preparation example 284 was conducted, except that (IS, 2S)-4-( tert-butyldimethyls i lyloxy)-l- phenylbutane-l,2-diol (Preparation example 286) was used instead of (1R, 2R)-4-(ter t-buty1dimethy1 s i 1y1oxy)-1-pheny1 bu ane-1 , 2-dio 1 (Preparat i on example 282), to obtain the title compound(0.7g, 70~95%)

^J" H 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 289: 2-((4S, 5S)-5-phenyl-2,2-dimethyl-l,3-dioxolan-4- yOethanol

The substantially same method as described in Preparation example 285 was conducted, except that tert-butyl (2-((4S, 5S)-5-pheny1-2, 2-dimethy1-1,3- dioxolan-4-yl )ethoxy)dimethylsi lane (Preparation example 288) was used instead of that tert-butyl (2-((4 , 5 )-5-phenyl-2,2-dimethyl-l,3-dioxolan-4- yl )ethoxy)diniethylsi lane (Preparation example 284), to obtain the title compound(0.4g, 80~95%)

^L H 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, 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(dcl, J=1.6, 7.6, 1H) Preparation example 290: 2-((4R, 5R)-2,2-diethyl-5-phenyl-l,3-dioxolan-4- yDethyl 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)—methy1—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, .1=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(cl, J=8.8, 1H) , 7.31~7.43(m, 5H)

Preparation example 291: 2-((4R, 5R)-2,2-diethyl-5-phenyl-l,3-dioxolan-4- yOethyl 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- yOethyl 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 ) : 6=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(ni, 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-dioxaspiro[4.4]nonan-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, 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, 111), 4.24(td, J=6.4, 11.2, 1H), 4.55(d, .1=8.4, 1H), 7.31~7.39(m, 5H)

Preparation example 293: 2-((2R, 3R)-3-phenyl-l,4-dioxaspiro-[4.4]nonan-2- yl )ethanol

The substantially same method as described in Preparation example 291 was conducted, except that 2-((2R, 3R)-3-phenyl-l,4-clioxaspiro[4.4]nonan-2- yOethyl pivalate(Preparat ion example 292) was used instead of that 2 ^~ ( ( S , 5S)-2 , 2-di ethy1-5-pheny1-1 , 3 ^~ di oxo 1 an-4-y1 )ethy1 p i va 1 ate( reparat ion example 290), to obtain the title compound (0.9g, 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(ni, 2H), 3.89~3.92(m, lH) , 4.59(d, J=8.4, 1H), 7.32~7.41(m, 5H)

Preparation example 294: 2-((2R, 3R)-3-phenyl-l,4-dioxaspiro[4.5]decan-2- yOethyl pivalate

The substantially same method as described in Preparation example 292 was conducted, except that eye 1ohexanone was used instead of cyclopetanone, to obtain the title compound(2. Og, 60~85%) ¾ NMR (400MHz, CDC1 ₃ V- 5=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), 4.21-4.27Cm, 1H), 4.55(d, J=8.4, 1H), 7.31~7.39(m, 5H)

Preparation example 295: 2-((2 , 3R)-3-phenyl-l,4-dioxaspiro[4.5jdecan- y ethanol

The substantially same method as described in Preparation example 293 was conducted, except that 2-((2R, 3R)-3-phenyl-l,4-dioxaspiro[4.5jclecan-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%)

^L H 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-pheny1-1, 3 ^~ dioxolan-4- yDethyl 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 (3 , 4R)-3,4- dihydroxy-4-phenylbutyl pivalate(Preparat ion example 283), to obtain the title compound(2.2g, 70-95%)

¾ NMR (4-OOMHz, CDC1 ₃ ): 5=1.00(t, 3=7 A, 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, H), 7.31 ^~ 7.43(m, 5H)

Preparation example 297: 2-((4S, 5S)-2,2-di ethyl -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%) 'Ή NM (400MHz, CDC1 ₃ ) · ^" 6=1.01(t, .1=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, J=8.8, 1H), 7.32~7.43(m, 5H)

Preparation example 298: 2-((2S, 3S)-3-phenyl-l,4-dioxaspi.ro[4.4]nonan-2- yOethyl 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%) : ¹ 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), 4.13(tcl, J=7.0, 11.1, 1H), 4.24(td, J=6.4, 11.2, 1H), 4.55(d, J=8.4, 1H) , 7.31~7.39(m, 5H)

Preparat ion exam l e 299 ^' · 2-( (2S , 3S)-3-pheny1-1 , 4-dioxaspi ro[4.4Jnonan-2- yDethanol

The substantially same method as described in Preparation example 297 was conducted, except that 2-((2S, 3S)-3-phenyl-l,4-dioxaspirol.4.4jnonan-2- vDethyl pivalate(Preparat ion example 298) was used instead of that 2-((4S, 5S).-2 , 2-diethy 1-5-pheny1-1 , 3-dioxo1 an-4-y1 )ethy1 piva1 ate(Preparat ion example 296), to obtain the title compound (07g, 80~95%)

¾ NMR (400MHz, CDC13) : δ =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-pheny1-1, 4-dioxas iro [4.5]decan-2- yDethyl pivalate

The substantially same method as described in Preparation example 298 was conducted, except that cyclohexanone was used instead of cvclopetanone, 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-dioxaspi ro[4.4]nonan-2-y1 )ethy1 piva1 ate(Preparat i on example 298), to obtain the title compound (1.2g, 80-95%)

¾ NMR (400MHz, CDCi 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 acid

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, CDC1 ₃ ): 6=3.15(dd, 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 acid(Preparat ion example 302) was used instead of that (E)-5-phenylpent-3 ^~ enoic acicKPreparat ion example 235), to obtain the title compound (4.6g, 70-90%) H NMR (400MHz, CDC1 ₃ ) · ^' 6=2.33(dq, .1=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, lH), 7.15-7.37(m, 4H)

Preparation example 304 ^' · (E)-tert-butyl (5-(2-chlorophenyl )pent ^~ 3- eny1oxy)climethyl s i 1 ane The substantially 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(dcj, 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 ) ^' · 5=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-biityldimethylsi lyloxy)-l-(2- chlorophenyl )pentane ^~ 2 ,3-diol

ci OH

OTBDMS

OH

The substantially same method as described in Preparation example 239 was conducted, except that (E)-ter t-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, CDC1 ₃ ) ^' - 5=0.11(s, 6H), 0.92(s, 9H), 1.68-1.77(m, 1H),

1.87-1.96(ni, 1H), 2.64(cl, 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 307: (2-(4S, 5S)-5-(2chlorobenzyl )-2,2-dimethyl-l,3- dioxolan-4-yl )ethoxy)(tert-butyl )climethylsi 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-( ert-buty1dimethy1 s i 1 y1oxy)-1-pheny1pentane-2 , 3-dio 1

(Preparation example 239), to obtain the title compound (3.6g, 75-90%)

¾ NMR (400MHz, CDC1 ₃ ): 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 308: 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-l,3- di oxo1 an-4-y1 )ethano 1 The substantially same method as described in Preparation exam le 241 was conducted, except that (2-(4S, 5S)-5-(2chlorobenzyl)-2,2-dimethyl-l,3- dioxolan-4-yl )ethoxy)(tert-butyl )dimethylsi lane (Preparat ion example 307) was used instead of that (2-(4S,5S)-5-benzyl-2,2-dimethyl-l,3-dioxolan-4- yl )ethoxy) ( tert-butyl ) dimethyl si lane (Preparation example 240), to obtain the title compound (3.2g, 80-95%)

¾ MMR (400MHz, CDC1 ₃ ): 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(dd, J=6.4, 14.0, 1H), 3.72(q, .1=5.5, 2H), 3.86(dt, 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- chlorophenyl ) entane-2, 3-diol

The substantially same method as described in Preparation example 242 was conducted, except that (E)-tert-butyl (5-(2-chlorophenyl )pent-3- enyloxy)dimethylsi lane (Preparation example 304) was used instead of that (E)-1er t-buty1 dimethy1 (5-pheny1pent-3 ^~ eny1oxy)s i 1 ane(Preparat i on examp1e 237), to obtain the title compound (4.4g, 90%)

¾ MR (400MHz, CDCla) - 5=0. ll(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, 5R)-5-(2chlorobenzyl)-2, 2-dimethyl-l, 3- dioxolan-4-yl )ethoxy)(tert-butyl )dimethylsi lane The substantially 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(Preparation example 309) was used instead of (2S , 3S)-5-( tert-buty1d imethy1 s i 1y1oxy)-1-(2-ch10ropheny1 )pentane-2 , 3-di 01 (Preparation example 306), to obtain the title compound (4.6g, 70~95%) ¾ NMR (400MHz, CDC1 ₃ ) ^' · 6=0.06(s, 6H), 0.91(s, 9H), 1.39(s, 3H), 1.40(s, 3H) , 1.69(q, .1=6.5, 2H) , 3.05(dq. J=5.8, 15.1, 2H), 3.70~3.80(m, 2H), 3.86~3.93(m, 1H), 8.97~4.02(m, 1H). 7.17~7.25(m, 2H). 7.36~7.38(m, 211)

Preparation example 311: 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-dimethyl-l, dioxo 1 an-4-y1 )ethano 1

The substantially same method as described in Preparation example 241 was conducted, except that (2-(4S, 5S)-5-(2chlorobenzyl )-2 , 2-dimethyl-l ,3- dioxo1 an-4-y1 )ethoxy)(tert-butyl )dimethylsi lane (Preparat ion example 307) was used instead of that (2-(4S, 5S)-5-benzyl-2, 2-dimethyl-l, 3-dioxol n-4- yl)ethoxy)(tert-butyl )dimethylsi lane (Preparation example 240), to obtain the title compound (3.0g, 80~95%)

^L H 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, IH), 2.82(dd, J=5.8, 13.8, IH), 3.01(dd, J=6.4, 14.0, IH), 3.72(q, J=5.5, 2H), 3.86(dt, J=3.2, 8.4, IH) , 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)-ter t-buty 1 (5-(2- chlorophenyl )pent-3-enyloxy)dimethylsi lane (Preparation example 304), to obtain the title compound(6. Og, 70-95%) T-I NMR (400MHz, CDC1 ₃ ) ^' - 6=1.16(s, 9H), 1.85~1.91(m, 2H) , 2.17(d, J=6.0, IH), 2.73(d, .1=5.2, IH), 2.91(dd, J=8.4, 13.6, IH) , 3.08(dd, J=5.6, 13.6, IH), 3.52~3.55(m, IH), 3.77~3.80(m, IH), 4.11~4.19(m, IH), 4.37~4.41(m, IH), 7.18~7.23(m, 2H), 7.31(dd, J=2.2, 7.0, IH), 7.36(dd, J=1.8, 7.4, IH)

Preparation example 313: 2-((4S,5S)-5-(2-chorobenzyl)-2,2-diethyl-l,3- dioxolan-4-yl )ethyl pivalate

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-phenylpentyl pivalate (Preparation example 245), to obtain the title compound(1.7g, 70-95%)

¾ NMR (400MHz, CDC1 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(cl, J=5.6, 2H) , 3.81~3.86(m, 1H), 3.94~3.99(m, H), 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- clioxo 1an-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-cliethyl-l,3- dioxolan-4-yl )ethyl pivalate (Preparation example 313) was used instead of 2-( (4S , 5S)-5-benzy1-2 , 2-di ethy1 -1 , 3-di oxo1 an-4-y1 )ethy1

pivalate(Preparat ion example 246), to obtain the title compound (0.9g, 80-95%) ; ¾ NMR (400MHz, CDC1 ₃ ): <5=0.91(clt, J=2.5, 7.5, 6H), 1.46-1.79(m, 6H), 2.42(t, J=5.6, 1H), 3.01-3.12(m, 2H), 3.79(q, J=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 315: (3R,4R)-3,4-dihydroxy-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-buty1 (5-(2- ch1 orophenyl )pent-3-enyloxy)climethy] si lane (Preparation example 304), to obtain the title compound (4.4g, 70~95%) ¾ NMR (400MHz, CDCl ₃ ) - 6=0. ll(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 316: 2-((4R, 5R)-5-(2-chlorobenzyl)-2,2-diethyl-l,3- dioxolan-4-yl )ethyl pivalate

The substantially same method as described in Preparation example 313 was conducted, except that (3R, 4R)-3,4-dihydroxy-5-(2chlorophenyl )penty I 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%)

¾ NMR (400MHz, CDC1 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 317: 2-((4R, 5R)-5-(2-chlorobenzyl)-2,2-dimethyl-l,3- dioxo1an-4-y1 )ethano1

The substantially same method as described in Preparation example 314 was conducted, except that 2-((4R, 5R)-5-(2-chGrobenzy l)-2,2-d i et hy l - l,3- dioxolan-4-yl )ethyl pivalate (Preparation example 316) was used instead of 2-( (4S , 5S)-5-(2-chorobenzy1 )-2 , 2-di ethy1-1 , 3-di oxo 1 an-4-y1 )ethy1 pivalate(Prepara 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), 1.46-1.79(m. 6H), 2.42(t, J=5.6, 1H), 3.01-3.12(m, 2H), 3.79(q, J=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- di oxaspi ro[4.4]nonan-2-y1 )ethy1 piva1ate

The substantially same method as described in Preparation example 313 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the ti le 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), 3.03~3.11(ni, 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-chlorobenzyl )-l ,4- clioxaspiro[4.4]nonan-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-l,3-dioxolan-4- yOethyl pivalate(Preparat ion example 316), to obtain the title compound (0.7g, 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 320: 2-((2R, 3R)-3-(2-chlorobenzyl)-l,4- dioxaspiro[4.4]nonan-2-yl)ethyl pivalate

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 ): 5=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), 7.18~7.25(m, 2H), 7.34~7.39(m, 2H)

Preparation example 321: 2-((2R, 3R)-3-(2-chlorobenzyl)-l,4- dioxaspi ro[4.4.1nonan-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-ch1orobenzy 1 )-1 , 4-dioxaspi ro [4.4J nonan-2- yDethyl pivalate (Preparation example 318), to obtain the title compound. (0.8g, 80-95%) lH 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(ni, 2H) , 7.34~7.39(m, 2H)

Preparation example 322: 2-((2S, 3S)-3-(2-chlorobenzyl)-l,4- di oxaspi ro[4.5]decan-2-y1 )ethyI piva1ate

The substantially same method as described in Preparation example 318 was conducted, except that cvclohexanone was used instead of cyclopetanone, to ■obtain the title compound (l.lg, 60 ^~ 85%)

¾ NMR (400MHz, CDC13) ^' · 5=1.21(s. 9H), 1.58-1.61(m, 8H), 1.77(q, J=6.8, 211), 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- clioxaspiro[4.5]decan-2-yl )ethanol

The substantially same method as described in Preparation example 321 was conducted, . except that 2-((2S, 3S)-3-(2-chlorobenzyl )-l ,4- dioxaspiro[4.5]decan-2- l )ethyl pivalate (Preparation example 322) was used instead of 2-((2R, 3 )-3-(2-chlorobenzyl)-l,4-dioxaspiro[4.4]nonan-2- yDethyl pivalate (Preparation example 320), to obtain the title compound (0.7g, 80-95%)

¾ NMR (400MHz, CDCI ₃ ) : 6 =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-((2 , 3R)-3-(2-chlorobenzyl)-l,4- dioxaspiro[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%) lH NMR (400MHz, CDC1 ₃ ): 6=1.21(s, 9H), 1.58~1.61(m, 8H), 1.77(q, J=6.8, 2H), 3.07(d, 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 )ethano1

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-dioxas i ro[4.5jdecan-2- yOethyl pivalate (Preparation example 322), to obtain the title compound (0.9g, 80-95%)

¾ 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, Hi), 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 acet aldehyde was used instead of phenyl acet aldehyde, to obtain the title compound (5.0g, 65~85%)

¾ NMR (400MHz, CDC1 ₃ ) ^' - 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) , 7.12~7.28(m, 4H)

Preparation example 327 ^' · (2R, 3S)-methyl-4-(2chlorophenyl)-2,3- di hydroxybut anoate

The substantially same method as described in Preparation example 260 was conducted, except that (E)--methy1-4-(2-chlorophenyl )but-2- enoate(Prepara 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%)

¾ NMR (400MHz, CDC1 ₃ ) ^" · δ =3.08-3.17(m, 2H), 3.84(s, 3H), 4.12(eld, J=1.6, 5.2, IH), 4.28~4.34(m, lH), 7.20~7.27(m, 2H) , 7.33-7.36(m, 1H) , 7.39~7.41(m, 1H)

Preparation example 328: (4R, 5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl- 1, 3-di oxolane-4-carboxylate

The substantially same method as described in Preparation example 261 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-dihydroxy-4-phenylbutanoate(Preparation example 260), to obtain the title compound(0.6g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.45(s, 3H) , 1.49(s, 3H) , 3.11(dcl, J=7.6, 14.4 1H), 3.35(dd, J=4.4, 14.4, 1H), 3.74(s, 3H) , 4.30(cl, J=7.6, 1H), 4.50(dt, J=4.0, 7.6, 1H), 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- dioxo1 an-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 (4 .5S)-methyl 5-benzy1 -2 , 2-dimethy1-1 ,3-di oxo 1 ane-4- carboxylate(Preparat ion example 261), to obtain the title compound(0.5g, 70~95%)

¾ NMR (400MHz, CDC1 ₃ ) · ^' 6=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)

Preparat ion exam le 330 : (4R, 5S)-methyl-5-(2-chlorobenzy1 )-2 , 2-di ethyl -1 , 3- di oxo1ane-4-carboxy1 ate

The substantially same method as described in Preparation example 263 was conducted, except that (2R, 3S)-methyl-4-(2chlorophenyl. )-2 ,3- dihydroxybutanoate(Preparation example 327) was used instead of (2R, 3S)- methyl 2,3-dihydroxy-4-phenylbutanoate(Preparation example 260), to obtain the title compound(0.8g, 50~75%) ¾ NMR (400MHz, CDC1 ₃ ): 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, 1H), 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- dioxolane-4-carboxylate (Preparation example 330) was used instead of (4R, 5S)-methy1-5-(2-ch1orobenzy1 )-2 , 2-dimethy1-1 , 3-di oxo 1 ane-4- carboxylate(Preparat ion example 328), to obtain the title compound(0.6g, 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, .1=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(ddcl, 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- dioxaspi ro[4.4]nonane-2-carboxyI ate

The substantially same method as described in Preparation example 330 was conducted, except that cyclopetanone was used instead of 3-pantanone, to obtain the title compound (0.8g, 60-85%)

Ή NMR (400MHz, CDC1 ₃ ): 5 =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 333: ((2S, 3S)-3-(-2chlorobenzyl )-l ,4- clioxaspiro[4.4]nonan-2-yl )methanol

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 i stead of (4R,5S)-methyl-5-(2-chlorobenzyl )-2,2-dimethyl-l,3-dioxolane-4- carboxylate (Preparation example 330), to obtain the title compound (0.6g, 70-95%)

¾ NMR (400MHz, CDC13) : 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(m, 1H), 3.87~3.91(m, 1H), 4.19(q, .1=6.8, 1H), 7.19~7.26(m, 2H) , 7.34~7.40(m, 2H)

Preparation example 334: (2R,3S)-methyl-3-(2-chloroben.zyl )-l,4- di oxaspi ro[4.5]decane-2-carboxy1 ate

The substantially same method as described in Preparation example 332 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (0.5g, 60-85%)

¾ NMR (400MHz, CDC1 ₃ ) · 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)-methy1 -3-(2-chlorobenzy1 )-1,4- dioxaspiro[4.5]decane-2-carboxylate(Preparation example 334) was used instead of (2R, 3S)-methyl-3-(2-chlo obenzy1 )-l ,4-dioxas iro[4.4]nonane-2- carboxylate(Preparat ion example 332), to obtain the title compound(0.5g, 70-95%) Ή NMR (400MHz, CDC1 ₃ ): δ =1.38-1.45(m, 2H), 1.58~1.63(m, 8H), 1.84(q, .7=4.3, 1H), S.lKdcld, J=7.9, 15.9, 22.1, 2H), 3.43(ddd, .1=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 ) dihydroxybutaiioate

The substantially same method as described in Preparation example 269 was conducted, except that (E)-methyl-4-(2-chioropheny 1 )but-2- enoate(Preparat ion example 326) was used instead of (E)-niethyl-4-phenylbi.it- 2-enoate(Preparat ion example 259), to obtain the _. title compound(3.5g, 70-95%)

Ή NMR (400MHz, CDC1 ₃ ): δ =3.08-3.17(m, 2H) , 3.84(s, 3H) , 4.12(dd, J=1.6, 2, 1H), 4.28~4.34(m, 1H) , 7.20~7.27(m, 2H) , 7.33~7.36(m, 1H) , 7.39~7.41(m

Preparation example 337: (4S, 5R)-methyl-5-(2-chlorobenzyl )-2 ,2-dimethyl- 1, 3-dioxolane-4-carboxylate

The substan ially same method as described in Preparation example 328 was conducted, except that (2S, 3R)-methyl-4-(2chlorophenyl)-2,3- dihydroxybutanoate(Preparation example 336) was used instead of (2R, 3S) ^~ methyl-4-(2chlorophenyl )-2 ,3-dihydroxybutanoate(Preparat ion example 327) , 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(.del, J=6.2, 13.8, 1H), 3.07(dcl, J=6.4, 14.0, 1H), 3.29(ddd, 3=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. .1=7.1, 1H), 7.22-7.32(m, 5H)

Preparation example 338 ^" · ((4R, 5R)-5-(-2chlorobenzyl)-2,2-dimethyl-l,3- dioxo1an-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-dimethyl-l,3- dioxolane-4-carboxylate (Preparation example 337) was used instead of (2R, 3S)-methyl-3-(2-chlorobenzyl )-l,4-dioxas iro[4.5]decane-2- carboxylate(Preparation example 334), to obtain the title compound (2.7g, 70-95%) .

¾ MR (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, .1=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 339 ^' · (4S, 5R)-methyl-(5-2-chlprp)benzyl-2,2-diethy -l .3- d i oxo1 ane-4-carboxy1ate

The substantially same method as described in Preparation example 330 was conducted, except that (25, 3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation example 336) was used instead of that (2R, 3S)-methyI-4- (2chlorophenyl )-2,3-dihydroxybutanoate (Preparation example 327), to obtain the title compound (0.6g, 50-75%) LH NMR (400MHz, CDC1 ₃ ): 6=0.93(t, J=7.4. 6H), 1.67-1.74(ra, 4H) , 3.10(dd, J=8.0, 14.4, lH), 3.35(dd, J=4.0, 14.4, 1H), 3.73(s, 3H), 4.27(d, .1=8.4, 1H), 4.42~4.47(ni, 1H), 7.18~7.26(m, 2H), 7.37~7.40(m, 2H)

Preparation example 340 ^' · ((4R, 5R)-5-(2-chlorobenzyl )-2 , 2-di ethyl-l , 3- clioxo1 an-4-y1 )methano1

The substantially same method as described in Preparation example 338 was conducted, except that (4S, 5R)-methyl-(5-2-chlprp)benzyl-2,2-diethyI-l,3- dioxolane-4-carboxylate (Preparation example 339) was used instead of (4S , 5R)-metby1 -5-(2-ch 1 robenzy1 )-2 , 2-dimethy1 -1 , 3-dioxo 1 ane-4-carboxylate (Preparation example 337), to obtain the title compound (0.5g, 70~95%) lH MR (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, 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, 1H), 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- di oxaspi ro[4.4]nonane-2-carboxylate

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%) lH NMR (400MHz, CDC1 ₃ ): δ =1.65-1.80(m, 5H) , 1.89-2.00(m, 311), 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)-1.4- di oxaspi ro[4.4Jnonan-2-y1 )methano1

The substantially same method as described in Preparation example 340 was conducted, except that (2S, 3R)-methyl-3-(2-chlorobenzyl )-l,4- dioxaspiro[4.4]nonane-2-carboxylate (Preparation example 341) was used instead of that (4S, 5R)-methyl-(5-2-chlprp)benzyl-2,2-diethyl-l,3- clioxolane-4-carboxylate(Preparat ion example 339), to obtain the title compound(0.4g, 70-95%) ^l H NMR (400MHz, CDC1 ₃ ) : δ =1.69-1.74(m, 3H) , 1.77-1.85(m, 5H), 3. lKclcld, J=6.3, 14.1, 31.3. 2H), 3.42~3.48(m, 1H), 3.61~3.66(m, 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- di oxaspi ro[ .5]decane-2-carboxyl ate

The substantially same method as described in Preparation example 341 was conducted, except that cyclohexanone was used instead of cyclopetanone, to obtain the title compound (0.9g, 60-85%)

¾ NMR (400MHz, CDC1 ₃ ): δ =1.54-1.77(m, 10H) , 3.12(dd, .1=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 344: ((2R, 3R)-3-(2-chlorobenzyl )-l ,4- dioxaspir0[4.5] decan-2-y1 )methano1

The substantially same method as described in Preparation example 342 was conducted, except that (2S, 3R)-methyl-3-(2-chlorobenzyl )-l,4- dioxaspiro[4.5]decane-2 ^~ carboxylate (Preparation example 343) was used 1ns ead of (2S , 3R)-metb 1 -3-(2-ch1orobenzy1 )-1 , 4-d ioxas i r0 [4.4Jnonane-2- carboxylate (Preparation example 341), to obtain the title compound (0.7g, 70-95%)

H NMR (400MHz, CDC13) ^: 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 phenyl acetaldehyde, 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-3-en-l-ol

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 acicKPreparat ion example 278), to obtain the title compound (1.2g, 55-80%)

¾ NMR (400MHz, CDC1 ₃ ): 5=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(m, 3H), 7.36(dd, .1=1.2, 8.0, 1H), 7.52(dd, J=1.6, 9.2, 1H)

Preparat ion example 347: (E)-tert-butyldimethyl(4-(2-chlorophenyl )but ^~ 3- enyloxy)si l ne 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-pheny1but-3-en-l-ol (Preparat ion example 279), to obtain the title compoiindd. 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 substan ially same method as described in Preparation example 281 was conducted, except that (E)-4-(2-chloropheny1 )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 ): 6=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, 1H), 6.86(d, J=16.0, 1H), 7.22~7.26(m, 2H), 7.38(dd, 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- ch10ropheny1 )butane-1 , 2-di01

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- butyklimethyl (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(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-clihydroxy-4-(2-chloropheny1 )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-butyldimethy1 (4-2- chlorophenyl )but-3-enyloxy)si lane (Preparation example 347), to obtain the title compound(3.2g, 70-95%)

^L H 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 ) dimethy1-1 , 3-dioxo 1an ^~ 4-y1 )ethoxy)dimethy1 si 1ane

The substantially same method as described in Preparation example 284 was conducted, except that (1R, 2R)-4-(tert-butyldimethylsi l oxy)-l-(2- chlorophenyl)butane-l,2-cliol(Preparation example 349) was used instead of ( 1R, 2R)-4-(tert-buty1 dimethy1 s i 1y1 oxy)-1-pheny1butane-1 , 2-d io1

(Preparation example 282), to obtain the title compound (0.8g, 70-95%)

Ή 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 352: 2-((4R, 5R)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- dioxolan-4-yl )ethanol

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-buty1 (2-( (4R, 5R)-5-pheny1 -2 , 2-dimethy1-1 , 3-d i 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 ) - 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(tcl, 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 358 ^' · (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-butyldimethyl (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 compound(0.7g, 70-95%)

H 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 ^~ 4.4Km, 1H), 5 ^' .05(t, J=5.0, 1H), 7.23~7.39(m, 3H) , 7.54(cld, 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)-tert-butyldimethyl (4-(2- chlorophenyl )but-3 ^~ enyloxy)si lane (Preparation example 347), to obtain the title compound(3. Og, 70-95%)

¾ NMR (400MHz, CDC1 ₃ ): 5=1.19(s, 9H), 1.76-1.84(m, 111), 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-1 ,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-butyldimethyl si lyloxy)-l-(2- chlorophenyl )butane-l,2-diol (Preparation example 353) was used instead of 1R , 2R)-4-( tert-buty1dimethy1 s i 1y1oxy)-1-(2-ch1oropheny1 )butane-1 , 2-di 01 (Preparation example 349), to obtain the title compound(0.7g, 70-95%) LH 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 356· ^' 2-((4S, 5S)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- dioxo1an-4-yΓ)ethano1

The substantially same method as described in Preparation example 352 was conducted, except that tert-butyl (2-((4S, 5S)-5-(2-chlorophenyl )-2 ,2- dimethyl-1 ,3-dioxolan-4-yl )ethoxy)dimethylsi lane(Preparat ion example 355) was used instead of that tert-butyl (2-((4R,5R)-5-(2-chlorophenyl )-2, 2- dimethyl-l,3-dioxolan-4-yl)ethoxy)dimethyl si. lane (Preparation example 351), to obtain the title compound (0.3g, 80-95%).

¾ MR (400MHz, CDGls): 6=1.56(s, 3H) , 1.62(s, 3H). 1.92-2.0 (in, 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, .7=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- dioxolan-4-yl )ethyl pival ate

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 pivalate(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, J=7.6, 2H) , 1.84~1.90(m, 2H), 2.00~2.07(m, 2H) , 3.85(clt, J=3.7, 8.5, 1H), 4.14~4,27(m, 2H), 5.17(cl, 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- dioxolan-4-yl)ethyl pivalate

The substan ially same method as described in Preparation example 291 was conducted, except that 2-((4R, 5R)-2,2-diethyl-5-(2-chlorophenyl)-1.3- di oxo1 an-4-y1 )ethyl pivalate (Preparation example 357) was used instead of 2-( (4R , 5R)-2 , 2-d i ethy1-5-pheny1-1 , 3-d i oxo 1 an-4-y1 )ethy1 pivalate(Preparation example 290), to obtain the title compound (0.6g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): 6=1.02(t, .1=7.4, 3H), 1.08(t, 1=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), 3.76~8.95(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 eye lopetanone was used instead of 3-pantanone, to obtain the title compound (0.8g, 60~85%)

¾ NMR (400MHz, CDC1 ₃ ): 5=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, .1=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-chlorophenyl )-1.4- 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- dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 359) was used instead of that 2-((4R, 5R)-2,2-diethyl-5-(2-chl0rophenyl)-l,3-clioxolan-4- y ethyl pivalate (Preparation example 357), to obtain the title compound (0.5g, 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 361: 2-((2R, 3R)-3-(2-chlorophenyl)-l,4- dioxaspiro[4.5]decan-2-yl )ethyl pivalate

The substantially same method as described in Preparation example 359 was conducted, except that eye 1ohexanone was used instead of eye lopetanone, to obtain the title compound (l.Og, 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(dd, J=1.4, 7.8, 1H)

Preparation example 362: 2-((2R, 3R)-3-(2-chlorophenyl )-l ,4- dioxaspi ro[4.5]decan-2-y1 )ethano 1

The substantially same method as described in Preparation example 360 was conducted, except that 2-((2 , 3R)-3-(2-chlorophenyl)-l,4- dioxaspi ro[4.5]decan-2-yl )ethyl pivalate (Preparation example 361) was used instead of that 2-((2R, 3R)-3-(2-chlorophenyl)-l,4-dioxas iro[4.4]nonan-2- yDethyl pivalate(Preparat ion example 359), to obtain the title compound (0.6g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ) ^' - δ =1.42-1.50(m, 2H), 1.63-1.77(m, 5H), 1.82~1.89(m, 5H), 2.41(q, .1=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 363: 2-((4S, 5S)-2,2-diethyl-5-(2-chlorophenyl)-l,3- dioxolan-4-yl )ethyl 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 350), to obtain the title compound (0.7g, 70-95%).

¾ NMR (400MHz, CDC1 ₃ ): 6=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, .1=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- dioxolan-4-yl )ethanol

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-di oxo1 an-4-y1 )ethy1 piva 1 ate (Preparation example 357), to obtain the title compound (0.5g, 80-95%)

¾ NMR (400MHz, CDC1 ₃ ): δ =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(dd, J=1.8, 7.8, 1H)

Preparation example 365: 2-((2S, 3S)-3-(2-chloropheny1 )-l ,4- dioxaspi ro[4.4]nonan-2-y1 )ethy1 piva1ate

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, 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, .1=1.6, 8.0, 1H)

Preparation example 366· ^' 2-((2S, 3S)-3-(2-ch1oropheny1 )-1 , 4- dioxaspi 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-chloropheiiyl )-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-dioxolan-4- yDethyl pivalate (Preparation example 363), to obtain the title compound (0.4g, 80 ^~ 95%)

^] 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(cl, J=8.0, 1H) , 7.24-7.29(m, 1H), 7.32~7.38(m, 2H), 7.60(cld, J=1.8, 7.8, 1H)

Preparation example 367: 2-((2S, 3S)-3-(2-chlorophenyl)-l,4- dioxaspiro[4.5jdecan-2-yl )ethyl pivalate

The substan ially same method as described in Preparation example 366 was conducted, except that cyclohexanone 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(dd, J=1.4, 7.8, 1H)

Preparation example 368: 2-((2R, 3R)-3-(2-chlorophenyl)-l,4- dioxaspi r0[4- .5]decan-2-y1 )ethano1

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 NM (400MHz, CDCI ₃ ) : δ =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 hr . 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 and evaporated under reduced pressure. The crude compound was purified by silica gel column to produce the title compound (4.94 g, 70-90%). lH NMR (400 MHz, CDC13) δ 7.57 (dd, J = 7.76, 2, 1H) , 7.42-7.13 (m, 3H), 7.05 (d, = 16 Hz, 1H), 6.37-6.30 (m, 1H) , 4.62 (s, 2H) , 4.26 (dd, J = 6, 1.6, 2H). Preparat ion examp le 370 ^' · ( ± )-2-(benzyloxyme hy 1 )-3-(2-c loropheny 1 )oxi rane

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 CI ₂ (110 mL) was added 3-chloroperoxybenzoic acid (70-75 , 8 g, 33 mole) 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 organic layer was washed with sat ^' NaHCOs, 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 (4.3 g, 60-80%).

¾ NMR (400 MHz, CDCI ₃ ) δ 7.42-7.24 (m, 9H) , 4.68 (cl, / = 14.8, 2H), 4.18 (cl, ./= 2 Hz, 1H), 3.96 (dd, J = 11.6, 2.8 Hz, 1H) , 3.69-3.64 (m, 1H), 3.14 (qt, .7= 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 so 1 ut i on of ( ± ) -2- ( benzy 1 oxyme t hy 1 ) -3- ( 2- chlorophenyl )oxirane(Preparat ion example 370, 4.3 g, 15.6 mmole) 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 TLC 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) ^L H NMR (400 MHz, CXI 3 ) δ 7.55-7.22 (m, 9H), 5.41 (t, J = 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)¾ NMR (400 MHz, CDC13) δ 7.46-7.24 (m, 9H), 6.31 (d, /= 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 (d, J = 5.2 Hz, -OH), 2.10 (s, 3H) .

Preparat ion 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 niL) and H ₂ 0 (4 niL) was added K2CO3 (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 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 (2.4 g. 80-95 ).

¾ NMR (400 MHz, CDC13) 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 ( 111 , 3H, -OH), 3.02 (d, ./= 5.2 Hz, -OH).

Preparation example 373 ^' · (±)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2- dimethy1-1 , 3-dioxo 1ane

To a solution of ( + )-3-(benzyloxy)-l-(2-chlorophenyl)propane-l,2-diol (Preparation example 372, 2.4 g, 8.2 mmole) in CH2C I 2 (40 niL) was added p- oluenesul fonyl chloride (15.2 g, 0.08 mmole), and 2,2-climethoxypropan (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 H2O 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 and evaporated under reduced pressure. The crude compound was purified by silica gel column to produce the title compound (2.2 g, 75~90 %) .

¾ NMR (400 MHz, CDC13 ) δ 7.61 (dd, J = 7.4, 1.6 Hz, 1H) , 7.35-7.16 (m, 8H), 5.63 (d, J = 6.8, 1H) , 4.88-4.78 (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-l,3-dioxolan-4- yl )methanol (SR & RS mixture)

To a solution of (± )-4-(benzyl oxymethy1 )-5-(2-chlorophenyl )-2, 2- dimethyl—1 ,3 -cli oxo lane (Preparation example 375, 2.2 g, 6.6 mmole) 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 consumption 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 %).

H NMR (400 MHz, CDC 13) 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 (m, 2H), 1.66 (s, 3H), 1.53 (s, 3H).

Preparation example 375: (2R,3R)-2-(benzyloxymethyl )-3-(2- oxi rane

To a solution of (£ ^' )-l-(3-(benzyloxy)prop-l-enyl )-2- chlorobenzene(Preparat ion example 369, 4.16 g, 18.58 mmole) and 1 , 2 ;4, 5-di - Hsopropyl idene-β -D-erythra-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 K ₂ C0 ₃ -AcOH in 4 X 10 ⁴ M ac|. EDTA, buffer pH = 8.0) (185 mL) and Bu ₄ NHS0 ₄ (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 K ₂ C0 ₃ (13.6 g, 98.47 mmole) in ¾0 (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 H ₂ 0 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 MgSGv and evaporated under reduced pressure The crude compound was purified by silica ge column to produce the title compound (2.9 g, 50-65 ) . i NMR (400 MHz, CDC13 ) 53.14 (qt, J = 2.4 Hz, 1H). 3.69-3.64 (m, 1H), 3.96 ( eld , ./= 11.6, 2.8 Hz, 1H), 4.18 (d, J = 2 Hz, 1H), 4.68 (d, J = 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' NaHC0 ₃ 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 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 (d, /= 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-cliol

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, .7 =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-chloropheny1 )- 1 , 3-di oxo1 ane

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 (Preparat ion 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 %).

^L H 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 (del, J = 7.4, 1.6 Hz, 1H) .

Preparation example 379: ((4R, 5S)-5-(2-chlorophenyl)-2, 2-dimethyl-l, 3- di oxo1an-4-y1 )methano1

The substant ial ly same method as described in Preparation example 374 was conducted, except that ((4R, 5S)-4-(benzyloxymethyl )-5-(2-chlorophenyl )- 2, 2-dimethyl-l, 3-di oxolane (Preparation example 378) was used instead of that ( ± )-4-(benzyloxymethyl )-5-(2-chlorophenyl )-2, 2-dimethyl-l ,3 - di oxolane (Preparation example 373), to obtain the title compound (0.58 g, 80-100 %) .

^X R 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 (d, J = 6.8 Hz, 1H), 7.35- 7.16 (m, 8H), 7.61 (dd, 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(6.6niL, 32.9mmol) and Lithiumhydroxide (0.79mL, 3 .9mmo1 ) , 4A molecular sieve 5g at room temperature under N ₂ . 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%) Ή NMR (400MHz, DMSO) : δ = 1.22(q, 7=12.5, 3H) , 4.23(q, 7=7.0, 2H), 6.54(d, J= 16, 1H), 7.54(d, 7= 16, 1H) .

Preparation example 381: (2S,3S)-ethyl 3-(2,4-dichlorothiazol-5-yl)-2,3- dihydroxypropanoate

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, 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 382: (4S,5S)-ethyl 5-(2,4-dichlorothiazol-5- climethy1-1 ,3-dioxo 1ane-4-carboxylate

The substantially same method as described in Preparation example 26 was conducted, except that (2S,3S)-ethyl 3-(2,4-dichlorothiazol-5-yl)-2,3- dihydroxypropanoate (Preparation example 381) was used instead of (2S,3R)- methyl-3-(2-chlorophenyl )-2,3 ^~ dihydroxypropanoate (Preparat ion example 25) , to obtain the title compound (0.13g, 65-80%)

¾ NMR (400MHz, DMSO): 6= 1.20(t, J=7.2, 3H), 1.42(s, 3H), 1.49(s, 3H), 4.18(m, 2H), 4.66(d, J= 6.8, 1H), 5.44(d, 7= 6.8, 1H) . Pre arat ion examp1e 383 : ( (4R, 5S)-5-(2 , 4-di ch1orothi azo1-5-y1 )-2 , 2-dimeth 1- l,3-dioxolan-4-yl )methanol

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-dioxol.ane-4-carboxylate(Preparation example 382) was used instead of (4S , 5R)-methy1-5-(2-ch1 oropheny1 )-2 , 2-climehty1 -1.3-di oxo 1 ane ^~ 4- carboxylate (Preparation example 26), 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, 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- clihydroxypropanoate

The substantially same method as described in Preparation Example 381 was conducted, except that (DHQ) ₂ -PHAL was used instead ^' of (DHQD) ₂ -PHAL, to obtain the title compound(3.9g, 50-70%).

T-l 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(dd, 7= 2.6, 7= 5.8, 1H) , 6.03(d, 7= 7.6, 1H), 6.37(cl, .7= 5.6, 1H)..

Preparation example 385: (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2- dimethy1-1 , 3-dioxo1ane-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)- ethy1 3-( 2 , 4-d i ch1 orothi azo1 -5-y1 )-2 , 3-d ihydroxypropanoat e(Preparat i on example 381),- to obtain the title compound(0.13g, 65-80%).

¾ NMR (400MHz, DMS0): δ= 1.20(t, J=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-dichlorothiazol-b-yl)-2,2- dimethyl-l,3-dioxolan-4-yl )methanol

The substantially same method as described in Preparation Example 383 was conducted, except that (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2- dimethyl-l,3-dioxolane-4-carboxylate (Preparation example 385) was used instead of (4S, 5S)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-l,3- dioxolane-4-carboxylate(Preparat ion example 382), to obtain the title compound(0.05g. 50~70%) .

¾ NMR (400MHz, D S0): 5= 1.42(d, 7=6.0, 6H), 3.59(m, 1H), 3.67(m, H ), 3.97(m, 1H), 5.04(t, J= 5.4, 1H) , 5.10(d, J= 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-chlorothiazole-5-carbadehyde was used instead of 2,4-dichlorothiazole-5-carbadehyde, to obtain the title compound (4.7g, 80-95%)

¾ NMR (400MHz, DMS0) : δ= 1.25(t, J=7.0, 3H) , 4.19(q, 7=7.2, 2H), 6.40(d, 7= 16, 1H), 7.81(d, 7= 16, 1H) , 8.11(s. 1H)

Preparation example 388: (2S,3S)-ethyl-3-(2-chlorothiazol-5-yl )-2,3- di hydroxypropanoate

The substantially same method as described in Preparation Example 381 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(4. lg, 50-70%). lH NMR (400MHz, DMS0) : δ= 1.20(t, 7=7.0, 3H), 4.12(q, 7=7.2, 2H), 5.18(d, 7= 1.6. 1H), 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- d imethy1 -1 , 3-di oxo 1 ane-4-carboxylate

The substantially same method as described in Preparation Example 382 was conducted, except that (2S, 3S)-ethyl 3-(2-chlorothiazol-5-y.l )-2,3- dihydroxypropanoate(Prepara ion example 388) was used instead of (2S, 3S)- ethy1 3-(2 , 4-di ch1orothi azo1-5-y1 )-2 , 3-dihydroxypropanoate(Preparat i on example 381), to obtain the title compound(l.Og, 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- dioxo 1 an-4-y1 )methano1

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-1 ,3-dioxolane-4-carboxylate(Preparat ion example 389) was used instead of (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-l,3- cli oxo lane-4-carboxylate (Preparation example 385), to obtain the title compound(0.84g, 70~90%) ..

¾ NMR (400MHz, DMSO) : δ= 1.40(d, 7=2.0, 6H), 3.59(cj, .1=4.7, 2H), 3.94(m, 1H), 5.06(t, 7=6.6, 1H) , 5.09(cl, 7= 0.8, 1H) , 7.69(s, 1H).

Preparation example 391: (2R, 3R)-ethyl 3-(2-chlorothiazol-5-yl)-2,3- dihyclroxypropanoate

The substantially same method as described in Preparation Example 384 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(Preparat ion example 380), to obtain the title compound(3.9g, 50-70%).

¾ NM (400MHz, DMS0) : 6= 1.20(t, 7=7.0, 3H), 4.12(q, 7=7.2, 2H), 5.18(d, 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- dime hy1-1 , 3-di oxo1 ane-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- dihyclroxypropanoateCPreparat 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, 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 393 ^' · (4S, 5 )-5-(2-chlorothiazol-5-yl)2,2-dimethyl-l,3- d ioxo 1 an-4-y1 )methano1

The substantially same method as described in Preparation Example 386 was conducted, except that (4R, .5R)-ethyl-5-(2-chlorothiazol-5-yl )-2,2- dimethyl-l,3-dioxolane-4-carboxylate(Preparat ion example 392) was used instead of (4R, 5R)-ethyl 5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-l,3- dioxolane-4-carboxylate (Preparation example 385), to obtain the title compound(0.60g, 70-90%).. lll NMR (400MHz, DMS0): δ= 1.40(d, 7=2.0, 6H), 3.59(q, J=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 394: (E)-ethyl-3-(4-methylthiazol-5-yl)acrylate

The substantially same method as described in Preparation Example 380 was conducted, except that 4-methylthiazole-5-carbadehyde was used instead of 2,4-dichlorothiazole-5-carbadehyde, to obtain the title compound (15g, 80-95%) ¾ NMR (400MHz, DMS0): δ= 1.25(t. 7=7.0, 3H) , 1.45(s 3H), 4.19(q, 7=7.0, 2H), 6.12(d, 7= 16, 1H), 7.77(d, 7= 16, 1H), 9.09(s, 1H).

Preparation example 395· ^' (2S,3S)-ethyl-3-(4-methyl thiazol-5-yl )-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 2 was conducted, except that (E)-ethyl-3-(4-methlythiazol ^_ 5- yl )acrylate(Preparat ion example 394) was used instead of (E)-ethyl-3 ^~ (2,4- dichlorothiazol-5-y] )acrylate(Preparat ion example 381), to obtain the title compound(4.0g, 50-70%). lH NMR (400MHz , DMS0) ^' · δ = 1.11( t , 7=7.0 , 3H) , 1.43( s , 3H) , 4.04(m , 2H) , 5.11(t, ./= 3.8, 1H), 5.70(d, J=20.7, 1H), 5.92(d, J= 4.0, 1H), 6.81(s, 1H), 8.86(s, 1H).

Preparation example 396: (4S,5S)-ethyl-5-(4-methylthiazol-5- dimethy1 -1 , 3-di oxo 1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 382 was conducted, except that (2S, 3S)-ethyl-3-(4--methylthiazol-5-yl)-2,3- dihydroxypropanoateCPreparat ion example 395) was used instead of (2S, 3S)- ethy1 3-(2 , 4-di ch 1 orothi azo 1 ^~ 5-y1 )-2 , 3 ^~ dihydroxyp opanoat e(Preparat i on example 381), to obtain the title compound(2.6g, 55~70%).

^L H 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, /= 14.0, 1H), 5.53(d, /= 7.2, 1H), 9.01(s, 1H).

Preparation example 397: (4R, 5S)-5-(4-methylthiazol-5-yl)2,2-dimethyl-l,3- dioxolan-4-yl )methanol

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, 5R)-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%) .. H 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, 7=5.4, 1H), 5.17(d, 7= 8.4, 1H), 8.98(s, 1H).

Preparation example 398: (2R, 3R)-ethyl-3-(4-methylthiazol-5-yl)-2,3- dihydroxypropanoate

The substantially same method as described in Preparation Example 384 was conducted, except that (E)-ethyl-3-(4-methyl thi azo 1-5- yl )acrylate(Preparat 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 , DMSO) : δ = 1.11( t , 7=7.0 , 3H) , 1.43(s , 3H) , 4.04(m , 2H) , 5.11(t, 7= 3.8, 1H), 5.70(cl, 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-dioxo1 an.e-4-cafboxy1ate

The substantially same method as described in Preparation Example 382 was conducted, except that (2R, 3R)-ethyl-3-(4-methylthiazol-5-yl)-2,3- dihydroxypropanoateCPreparat ion example 398) was used instead of (2S, 3S)- ethy1 3-(2 , 4-di ch1orothi azo1 -5-y1 )-2 , 3-dihydroxypropanoate(Prepar ti on example 381), to obtain the title compound(5. Og, 65~80%) .

¾ NMR (400MHz , DMSO) : δ = 1.17( t , 7=3.6 , 3H) , 1.43(S , 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, 7= 7.2, 1H), 9.01(s, 1H). Preparation example 400: (4S, 5R)-5-(4-methylthiazol-5-yl)2,2-dimethyl-l,3- clioxo1 an-4-y1 )methano1

The substantially same method as described in Preparation Example 386 was conducted, except that (4R, 5R)-ethyl-5-(4-methyl thiazol-5-yl )-2,2- dimethy1-1 , 3-di oxo 1 ane-4-carboxy1 ateCPreparat i on examp 1 e399) was used instead of (4R, 5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-climethyl-l,3- dioxolane-4-carboxylate (Preparation example 385), to obtain the title compound(4. lg, 70-90%).

¾ NMR (400MHz, DMS0) : δ= 1.42(cl, 7=7.6, 6H) , 2.36(s, 3H), 3.58(m. 2H), 3.80(cl, .7=3.2, 1H), 5.02(t, 7=5.4, 1H) , 5.17(d, 7= 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-dioxo1 ane-4-carboxylate

To a stirred solution of (4R, 5S)-5-(4-methyl thiazol-5-yl )2.2-dimethyl- 1 , 3-dioxo lan-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 CC Li (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 , 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%)

^L H NMR (400MHz, DMS0) : δ= 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(cl, 7= 8.4, 1H) . Preparation example 402: (4S, 5R)-ethyl-5-(2-chloro-4-methyl thiazol-5- yl )-2 , 2-dimethy1-1 , 3 ^~ di oxolane-4-carboxy1 ate

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- di oxo 1 n-4-yl )methanol (Preparat ion example 400) was used instead of (4R, 5S)-5-(4-methy11hi azo1 -5-y1 )2 , 2-dimethy1 -1 , 3-di oxo1 an-4- yOmethanol (Preparat ion example 397), to obtain the title compound(1.5g, 70-90%) .

¾ NMR (400MHz, DMS0): δ= 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, J= 8.4, 1H).

Preparation example 403: (E)-ethyl 3-(thiophen-3-yl )acrylate

To a stirred solution of tr iethylphosphnoacetate(5.36ml , 26.7mmo 1 ) in THF(40ml) was added to t-BuOK(3g,26.7mmol ) dropwise at rt and stirred at this temperature for 30min. Then thiophene-3-carbaklehyde (8g, 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%).

¾ NMR (400MHz, CDC13) : δ =1.34(t , 7=7.2, 3H), 4.26(q, 7=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, J=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(Preparat ion example 380), to obtain the title compound(6. Og, 60-80%) . ^l H NMR (400MHz, CDC1 ₃ ): 5=1.34(t, J=7.2, 3H), 4.26(q, J=7.2, 2H), 4.65(d, 7=5.5, 1H), 5.13(d, j=5.5, 1H), 6.93(dcl, J=6.09, j=1.32, 1H), 7.47(dd, j=6.09, J=1.73, IH), 7.88(dd, J=1.73, j=1.32, 1H)

Preparation example 405: (4R,5S)-ethyl 2,2-dimethyl-5-(thiophen-3-yl )-l,3- clioxo1 ane-4-carboxylate

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-di ch1orothi azo1 -5-y1 )-2 , 3-dihydroxypropanoate(Preparat i on examp1 e 381), to obtaiivthe title compound(3. Og, 65~80%) .

^] H NMR (400MHz, CDC1 ₃ ): 6=1.18(t, j=7.1, 3H) , 1.41(S, 3H), 1.43(S, 3H) , 4.16(q, .1=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, 1=1.7, 1H), 7.90(dd, J=1.7. j=1.3, IH) Preparation example 406: ((4S,5S)-2,2-dimethyl-5-(thiophen-3-yl)-l,3- dioxo1 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-dichlorothiazol-5-yl )-2,2-dimethyl-l,3-dioxolane-4- carboxylate (Preparation example 385), to obtain the title compound(2.2g, 70-90%) .

^] H NMR (400MHz, CDC1 ₃ ): 6=1.39 (S, 3H), 1.42 (S, 3H) , 3.47-3.6 (m,2H.) 3.84~3.88(m.lH) 4.82 (d, J=7.0, 1H) , 6.93 (dd, J=6.1, .1=1.3, 1H), 7.47 (del, ^* J=6.1, J=1.7, 1H,), 7.89 ( del, 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-carbaldehycle 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, 7=7.2, 3H) , 4.20(q, .7=7.2, 2H), 6.13(d, .7=15.6, 1H), 6.89 (cl, 7=4, 1H), 7.65(d, 7=15.6, 1H), 7.83(cl, 7=4.2, 1H)

Preparation example 408: (2R,3S)-ethyl 2,3-dihydroxy-3-(5-chlorothiophen-2- yl )propanoate

The substantially same method as described in Preparation Example 404 was conducted, except that (E)-ethyl 3-(5-chlorothiophen-2-yl )acryl ate (Preparation example 407) was used instead of (E)-ethyl 3-(thiophen-3- yOacrylate (Preparation example 403), to obtain the title compound(2.8g, 60-80%) .

¾ NMR (400MHz, CDC1 ₃ ) 61.34(t, .7=7.2 ,3H), 2.76(d, J=8.4,1H), 3.32(d, J=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- y1 )-1 , 3 ^~ di oxo1 ane-4-carboxylate

The substantially same method as described in Preparation Example 4-05 was conducted, except that (2R,3S)-ethyl 2,3-dihydroxy-3-(5-chlorothiophen-2- yl )propanoate(Preparation example _. 408) was used instead of (2R,3S)-ethyl 2,3-dihydroxy-3-(thiophen-3-yl )propanoate(Preparat ion 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(cl, 7=7.2 1H), 6.81(q, 7=4 1H), 6.88(cl, 7=3.2 1H)

Preparat ion example 410· ^' ((4S,5S)-2,2-dimethyl-5-(5-chlorothiophen-2-yl )- 1 , 3-dioxo1 n-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- carboxylateCPreparat ion example 405), to obtain the title compound(0.8g, 70-90%).

¾ NMR (400MHz, CDC 13 )■ ^' 6=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)

Preparatio example 411· ^' 3-chloroi son i cot inaldehyde

To a 250 ml round-bottomed flask, LDA (11ml, 22.02mmol) was added to 3- chloropyr icli edg, 8.80mmol) in THF(20 ml) dropwise at -78 ^° C and stirred at same temperature for l~2hr. Then DMF(822//.P, , 10.56mmol )was added and stirred at room temperature for Ihr. 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, CDC 13 ) δ 7.73 (d, J = 8.0, 1H) 8.71 (cl, J = 4.0, 1H) 8.81 (s, 1H) 10.52 (s, 1H) Preparation example 412: (E)-ethyl 3-(3-chl or opyr idiii-4-yl ) aery late

3-chloroisonicotinaldehyde (Preparation example 411, 0.54g, 3.79mmol) was dissolved in benzene. At the room temperature, triethyl phosphoacetate (753 f , 3.79mmol) and potassium tert-but oxide (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%) .

^L H 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 (cl, J = 16.0, 1H) 7.97 (d J = 8.0, 1H) 8.51 (d, J - 4.0, 1H) 8.66 (s, 1H)

Preparation example 413: Ethyl 3-(3-chloropyr idin-4-yl )-2, ^' 3~ dihydroxypropanoate

(E)-ethyl 3-(3-chloropyr idin-4-yl )acrylate(Preparat ion example 412, 0.57g, 2.69mmol) was dissolved in the mixture of ac tone( 11.4ml ) /water (2.3ml )/t- BuOH(2.3ml). NM0(0.47g, 4.03mmol), Osmium tetroxide (13.6mg, 0.05mmol) 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, CDC 13 ) 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- dioxolane-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(Preparat ion example 413) was used instead of (2R,3S)- ethyl 2, 3-dihydroxy-3-(thiophen-3-yl )propanoate(Preparat ion example 404), to obtain the title compound(5.26g, 70~90 ) .

¾ NMR (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)

Preparation example 415: (5-(3-chloropyridin-4-yl)-2,2-dimethyl-l,3- dioxo 1an-4-y1 )methano1

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—climethy1-5-( thi ophen-3-y1 )-1 , 3-di oxo1 ane-4- carboxylate(Preparat ion example 405), to obtain the title compouncKO.18g, 70-90%) . ¾ 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 ,1H) 7.57(cl, J = 6.0, 1H) 8.57 (d, J = 12, 2H)

Preparation example 416· ^' 4-chloroisonicot inalclehyde

The substantially same method as described in Preparation Example 411 was conducted, except that Ethyl 4-chloropyr idine was used instead of 3- chloropyr idine, to obtain the title compound(3.0g, 60~80%) .

¾ NMR (400MHz, CDC1 ₃ ): 6=7.45(d, J=5.2, 1H), 8.70(d, .7=5.2, 1H), 9.06(s, 1H), 10.52(s, 1H)

Preparat ion example 417: (E)-ethyl 3-(4-chloropyr idin-3-yl )acrylate

The substantially sanie method as described in Preparation Example 412 was conducted, except that Ethyl 4--chloronicotinealdehyde(Preparat ion example 416) was used instead of 3-chloroisonicot inaldehyde(Preparat ion example 411), to obtain the title compound(4.0g, 70~90%) .

¾ NMR (400MHz, CDC1 ₃ ): 5=1.37(t, .7=7.0, 3H), 4.33(q, .7=6.6, 2H), 6.57(d,

7=16.4, ,1H), 7.39 (cl, J=5.2, 1H), 7.98(cl, 7=16.0, 1H) , 8.49(d, 7=5.2, 1H), 8.82(s, 1H) .

Preparation example 418: Ethyl 3-(4-chloropyridin-3-yl)-2,3- dihydroxypropanoate

The substan ially 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-chloropyridin- 4-yl )acrylate(Preparat ion example 412), to obtain the title compound(2.4g, 60-80%) .

¾ NMR (400MHz, CDC13) ^' ■ 5=1.34(t, 7=7.2, 3H), 4.35(q, 7=7.0, 2H), 4.45(d, J=2.4, 1H), 5.49 (d, J=2.0, 1H), 7.32(d, 7=5.2, 1H) , 8.46(cl, 7=4.4, 1H), 8.79(s, 1H)

Preparation example 419 ^' · Ethyl 5-(4-chloropyi ^' idin-3-yl)-2,2-dimethyl-l,3- dioxo1 ane-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(Preparation example 418) was used instead of Ethyl 3- (3-chloropyr idin-4-yl )-2 ,3-dihydroxypropanoate(Preparat ion example 413) , to obtain the title compound(1.3g, 70~90%).

¾ NMR (400MHz, CDC13) : 6=1.25(t, 7=7.2 3H), 1.59(s,3H), 1.64(s, 3H), 4.22 (q, 7=8.27 2H) , 4.37(d, 7=7.6, IH); 5.56(d, 7=7.6, 1H), 7.31(d, 7=5.2, 1H), 8.48(d, 7=5.2, IH), 8.78(s,lH)

Preparation example 420 ^' · (5-(4-chloropyridin-3-yl)-2,2-dimethyl-l,3- dioxo1 an-4-y1 )methano1

The substantially same method as described in Preparation Example 415 was conducted, except that Ethyl 5-(4-chloropyridin-3-yl)-2,2-climethyl-l,3- dioxolane-4-carboxylate(Preparat ion example 419) was used instead of Ethyl 5-(3-ch1oropyr i din-4-y1 )-2 , 2-dimethy1 -1 , 3-dioxo1 ane-4- .

carboxylate(Preparat ion example 414), to obtain the title compound(0.8g, 70-90%) .

¾ NMR (400MHz, CDC1 ₃ ): 6 =1.56(s,3H) , 1.63(s,3H), 1.64(s. 3H) , 3.73-3.77 (m, 2H), 3.95 ^~ 3.99(m, 2Ά) , 5.39(d, .7=8.4, 1H) , 7.32(d, 7=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 imicline (5 g, 31.4 mmol) in DMF (75 m( was added ethyl acrylate (9.5 mi, 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 ¾0 then extracted with 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 sul fate(MgSC )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, CDC1 ₃ ) δ 1.38 (t, J = 6.8, 3H), 4.29-4.35 (m, 1H), 6.61 (d, J= 17.2, 1H), 7.63 (cl, J= 16.4, 1H), 8.90 (s, 2H), 9.22 (s, 1H) . Preparation example 422: Ethyl 3--(pyrimiclin-5-yl)-2,3-dihydroxypropanoate

The substantially 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-chloropyr idin-3- yl )acrylate(Preparat ion example 417), to obtain the title compound ( 1.6g , 40-60%) .

¾ NMR (400 MHz, CDC1 ₃ ) δ 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 423: Ethyl 2,2-dimethyl-5-(pyrimidin-5-yl )-l,3- di oxo 1 ane-4-carboxy1 ate

The substantially same method as described in Preparation Example 419 was conducted, except that Ethyl 3-(pyr imidin-5-yl )-2 ,3 ^~ dihydroxypropanoate(Preparat ion example 422) was used instead of Ethyl 3- (4-chloropyr idin-3-yl )-2,3-dihydroxypropanoate(Preparat ion example 418) , to obtain the title compound(0.97g, 40~60%).

¾ NMR (400 MHz, CDC1 ₃ ) δ 1.30 (t, / = 7.2, 3H) , 1.55 (s, 3H), 1.61 (s, 3H), 4.25-4.32 (in, 1H) , 4.35 (d, /= 8.0, 1H) , 5.18 (d, /= 7.6, 1H) , 8.82 (s, 2H), 9.20 (s, 1H).

Preparat i on examp 1 e 424 : (2 , 2-d imethy1 -5-(pyr imi d in-5-y1 )-1 , 3-di oxo 1 an-4- yOmethanol

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--carboxyiate(Preparat ion example 423) was used instead of Ethyl 5- (4- ch 1 or opyr i d i n-3-y 1 ) -2 , 2-d i me t hy 1 - 1 , 3-d i oxo 1 ane-4-c ar boxy 1 at e ( Pr epar a t i on example 419), to obtain the title compound (0.65g, 70-90%).

Ή 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 imidine was used instead of 5- bromopyr imidine, to obtain the title compound ( 9.7g, 50-70%).

'H NMR (400 MHz, CDC1 ₃ ) δ 1.37 (t, J = 6.8, 3H), 4.32 (qt , J = 7.2, 2H), 6.59 (d, J = 16.4, 1H), 7.60 (d, J= 16.4, 1H) , 8.77 (s, 2H) .

Preparation example 426 ^' · Ethyl 3-(2-chloropyr imidin-5-yl )-2,3 ^~ d i hydr oxypr opanoat e

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, J= 7.2, 1H) , 8.72 (s, 2H) . Preparation example 427: Ethyl 2,2-dimethyl-5-(2-chloropyrimidin-5-yl)-l,3- d i oxo 1 ane-4- car boxy late

The substantially same method as described in Preparation Example 423 was conducted, except that Ethyl 3-(2-chloropyrimidin-5-yl)-2,3- dihyclroxypropanoate(Preparat ion example 426) was used instead of Ethyl 3- (pyrimidin-5-yl )-2,3-dihydroxypropanoate(Preparat ion example 422), to obtain the title compound (0.98g, 40-60%).

*H NMR (400 MHz, CDC 13 ) δ 1.32 (t, / = 7.2 3H), 1.55 (s, 3H), 1.60 (s. 3H), 4.27-4.34 (m, 3H), 5.19 (d, /= 7.6, 1H), 8.71 (s, 2H) .

Preparat ion example 428 ^' · (2,2-dimethyl-5-(2-chloropyr imidin-5-yl )-l ,3- d i oxo 1 an-4- 1 ) me t hano 1

The substantially same method as described in Preparation Example 424 was conducted, except that Ethyl 2,2-dimethyl-5-(2-chloropyr imidin-5-yl )-l,3- dioxolane-4-carboxylate(Preparat ion example 427) was used instead of Ethyl 2 , 2-d i me t hy 1 -5- ( y r i m i cl i n-5-y 1 ) - 1 , 3-d i oxo 1 ane-4-c ar boxy 1 a t e ( Pr epar a t i on example 423), to obtain the title compound (0.71g, 70-90%).

Ή NMR (400 MHz, CDC 13 ) δ 1.54 (s, 3H), 1.56 (s, 3H), 2.21 (s, -OH), 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 hyclroxypropan-2-y1 acetate

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, CDC1 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, J = 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 %) . ^l H NMR (400 MHz, CDC1 ₃ ) 53.02 (d, /= 5.2 Hz, 1H). 3.55-3.42 (m. 3H, -OH), 4.18-4.13 (m, 1H), 4.46 (d, J= 6 Hz, 2H), 5.28 (t, J =4.8 Hz, 1H), 7.35- 7.19 (m, 8H), 7.50 (del, /= 7.6, 1.2 Hz, 1H).

Preparation example 431: (4S, 5R)-4-(benzyloxymethyl )-5-(2-chloropheny1 )- 2 , 2-dimethy1-1 , 3-dioxo1ane

The substantially same method as described in Preparation example 373 was conducted, except that (1R, 2S)-3-(benzyloxy)-l-(2-chlorophenyl )propane- l,2-diol(Preparation example 430) was used instead of that ( + )-3 ^~ (benzyloxy)-l-(2-chlorophenyl)propane-l,2-diol (Preparat ion 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 (del, J = 7.4, 1.6 Hz, 1H).

Preparation example 432: ((4S, 5R)-5-(2-chlorophenyl )-2 ,2-dimethyl-l ,3- clioxo1an-4-y1.)metha.no1 The substantially same method as described in Preparation example 374 was conducted, except that ((4S, 5R)-4-(benzyloxymethyl )-5-(2-chloropheny 1 )- 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 oxolane (Preparation example 373), to obtain the title compound (0.82 g, 80-100 %).

¾ NMR (400 MHz, CDC13) 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 (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- dihyclroxypropanoate

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 ecompouncK 14.2g, 70-90%) ^l H NMR (400MHz, CDC13) 6 2.79(d, j=7.2, 1H), 3.13(d, J=6.0, 1H) , 3.86(s, 3H), 4.50(dd, .1=5.6, 2.4, 1H), 5.51(dd, J=7.2, 2.4, 1H), 7.62-7.26 (m, 4H) Table 1: Example of sulfamate compound (A = Phenyl)

A =

No n 1 m R ¹ R ² R ³ R ⁴ Chiral-1 Chiral-2 Phenyl

1 2-Cl 1 0 0 Me Me H H R R

2 2-Cl 1 0 0 Me Me H H S S

3 2-Cl 1 0 0 Me Me H H Rac . ( syn) Rac . (syn)

Rac. (ant i Rac . (ant i

4 2-Cl 1 0 0 Me Me H H

) )

5 2-Cl 1 0 0 Me H H H R R

6 2-Cl 1 0 0 Me H H H S S

7 2-Cl 1 0 0 Et Et H H R R

8 2-Cl 1 0 0 Et Et H H S S

9 2-Cl 1 0 0 Cyclopentyl H H R R

10 2-Cl 1 0 0 Cyclopentyl H H S S

11 2-Cl 1 0 0 Cyc 1ohexy1 H H R R

12 2-Cl 1 0 0 Cyclohexyl H H S S

Methylbenzen

13 2-Cl 1 0 0 H H R R e

Methylbenzen

14 2-Cl ^' 1 0 0 H H S S e

15 2-F 1 0 0 Me Me H H R R

16 2-F 1 0 0 Me Me H H S S

17 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 Cyclopentyl 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 1 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 Methylbenzen

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 Cyclopentyl H H S S

2,4-Cl 2 0 0 Cyc 1ohexy1 H H R R

2,4-Cl 2 0 0 Cyc 1ohexy1 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 Cyc 1ohexy1 H H R R

2,6-Cl 2 0 0 Cyc1ohexy1 H H S S

Methylbenzen

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- H2 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 Cyclopentyl H H R R

2-NH2 1 0 0 Cyclopentyl H H S S

2-NH2 1 0 0 Cyc 1ohexy1 H H R R

2- H2 1 0 0 Cyc1ohexy1 H H S S

Methylbenzen

2-NH2 1 0 0 H H R R e

Methylbenzen

2-NH2 1 0 0 H H S S e

2-N02 1 0 0 Me Me H H R R 78 2-N02 1 0 0 Me Me H H S S

79 2-N02 1 0 0 Me H H H R R

80 2-N02 1 0 0 Me H H H S S

81 2-N02 1 0 0 Et Et H H R R

82 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 Cy c 1 ohexy 1 H H R R

86 2-N02 1 0 0 Cyclohexyl H H S S

Methyl benzen

87 2-N02 1 0 0 H H R R e

Methyl benzen

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 Cyclohexyl H H R R

100 2-Me 1 0 0 Cyclohexyl 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 ^' Cyc 1 ohexy1 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 Cyclohexyl 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

185 H 1 0 1 Cyclohexyl H H R R

136 H 1 0 1 Cyclohexyl H H S S

137 2-Cl 1 1 1 Me Me H H R R

138 2-Cl 1 1 1 Me Me H H S S

139 2-Cl 1 1 1 Et Et H H R R

140 2-Cl 1 1 1 Et Et H H S S 141 2-Cl 1 1 1 Cyclopentyl H H R R

142 2 CI 1 1 1 Cyclopentyl H H S S

143 2-Cl 1 1 1 Cyc 1ohexy1 H H R R

144 2-Cl 1 1 1 Cyclohexyl H H S S

145 2-Cl 1 1 0 Me Me H H R R

146 2-Cl 1 1 0 Me Me H H S S

147 2-Cl 1 1 0 Et Et H H R R

148 2-Cl 1 1 0 Et Et H H S S

149 2-Cl 1 1 0 Cyclopentyl H H R R

150 2-Cl 1 1 0 Cyclopentyl H H S S

151 2-Cl 1 1 0 Cyc 1 ohexy1 H H R R

152 2-Cl 1 1 0 Cyclohexyl H H S S

153 2-Cl 1 0 1 Me Me H H R R

154 2-Cl 1 0 1 Me Me H H S S

155 2-Cl 1 0 1 Et Et H H R R

156 2-Cl 1 0 1 Et Et H H S S

157 2-Cl 1 0 1 Cyclopentyl H H R R

158 2-Cl 1 0 1 Cyclopentyl H H S S

159 2-Cl 1 0 1 Cyclohexyl H H R R

160 2-Cl 1 0 1 Cyc 1 ohexy1 H H S S

161 2-Cl 1 0 0 Me Me H H R S

162 2-Cl 1 0 0 Me Me H H S R 177=:= 2-Cl 1 0 0 Me Me H H S S

*· Sodium salt

Table 2: Example of sulfamate compouncKA = Heterocyclic ring)

No A X n 1 m R ¹ R ² R ³ R ⁴ Chiral-1 Chiral-2

16 2,4-

Thiazole 2 0 0 Me Me H H R S

3 Cl

16 2,4-

Thiazole 2 0 0 Me Me H H S R

4 Cl

16

Thiazole 2-Cl 1 0 0 Me Me H H R S 5

16

Thi zole 2-Cl 1 0 0 Me Me H H S R 6

16

Thiazole 4-Me 1. 0 0 Me Me H H R S 7

16

Th i azo 1 e 4-Me 1 0 0 Me Me H H S R

8

2-

16

Thiazole Cl, 2 0 0 Me Me H H R S 9

4-Me

2-

17

Thi azole Cl, 2 0 0 Me Me H H S R

0

4-Me

17

Thiophene H 1 0 0 Me Me H H S S 1

17

Thiophene 2-Cl 1 0 0 Me Me H H S R 2 17

Pyr i cli ne 3-Cl 1 0 0 Me Me H H Rac . (syn) Rac . (syn) 3

17

Pyr i cli ne 4-Cl 1 0 0 Me Me H H Rac . (syn) Rac. (syn)

4

17 Pyr iinidin

H 1 0 0 Me Me H H Rac. (syn) Rac . (syn) 5 e

17 Pyr imi din

2-Cl 1 0 0 Me Me H H Rac . ( syn ) Rac . (syn)

6 e

Example 1-1 : ((4R,5R)-5-(2-chlorophenyl )-2,2-dimethyl-l,3-dioxolan-4- yDniethyl 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, 17.3mniol) was added dropwise and stirred at room temperature for 6 hours. ((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-l,3-dioxolan-4-yl)m ethanol

(Preparation example 6, 1.05g, 4.3mmol) in Ν,Ν-dimethyl acet 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 H2O, extracted with EtOAc, and washed with ¾0. The organic layer was dried over anhydrous magnesium sulfate (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. CDC13) δ 1.57 (s, 3H), 1.63 (s, 3H) , 4.11-4.10 ( 111 , 1H), 4.53-4.42 (m, 2H) , 4.88 (s, 2H), 5.37 (d, J = 8.4, 1H) , 7.28-7.56 (in, 4H)

Example 1-2: ((4R,5R)-5-(2-chlorophenyl )-2,2-dimethyl-l,3-dioxolan-4- yOmethyl sulfamate To a 100 mL RB flask, ((4R,5 )-5-(2-chlorophenyL)-2,2-dimethyl-l,3- di oxo 1 an-4-y1 )methanol (Preparation example 6, 10.0 g, 41.2mmol), 50 ml of toluene, 7.92 g (82.4 mmol) of sulfamide 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 Preparation 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

sul famate 5.17(d, / = 7.0,

1H), 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), benzy1-2,2- Prepara 3.96-4.21(m, 2H), dimethyl-1,3- t ion 4.42(dt, / - 7.02,

113

dioxolan-4- examp1e J = 3.27, 1H), yl )ethyl 241 5.17(d, / ^' = 7.0, sul famate 1H), 7.62~7.64(m,

2H), 7.77~7.90(m, 2H)

^D 5 1.27(s, 6H), 1.40(s, 3H),

2-((4R, 5 )-5- 2.0(s, 2H), benzy1-2,2- Prepara 3.96~4.21(m, 2H), dimethyl-1 ,3- t ion 4.42(dt, J = 7.02,

114

dioxolan-4- example J = 3.27, 1H), yOethyl 244 5.17(d, J - 7.0, sul famate 1H), 7.62~7.64(m,

2H), 7.77~7.90(m, 2H). c6 0.90(t, J = 8.0, 6H), 1.59(q,

2-((4S, 5S)-5- / = 8.0, 4H), benzy1-2,2- Prepara 2.0(s, 2H), diethyl-1,3- tion

115 3.96-4.21(m, 2H) , dioxolan-4- examp1e 4.42(dt, J = 7.02, yl )ethyl 247 / = 3.27, 1H), sul famate 5.17(d, ./ = 7.0,

1H), 7.62~7.64(ni, 2H), 7.77~7.90(m,

DMS0

Example 65: Sodium ((((4R, 5R)-5-(2-aminophenyl)-2,2-dimethyl-l,3-dioxolan- 4-y1 )methy1 su1 fony1 )ami de

To stirred solution of ((4R,5R)-5-(2-aminophenyl)-2,2-dimethy.l-l,3- di oxo1 an-4-y1 )methyl sul famate(Example 63, 5.5g) in distilled water (55ml ) was added. IN NaOH(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(200ml) 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, DMSO) 6 1.42(s, 3H), 1.46(s, 3H), 3.79~3.81(m, 2H), 3.99~4.00(m, 1H) , 4,94(d, 7=8.4, 1H), 6.59-7.16(m, 4H).

Example 66· ^" Sodium ((((4S, 5S)-5-(2-aminophenyl)-2,2-dimethyl-l,3-dioxolan- 4-yl)methyl sul fony 1 )amide

The substantially same method as described in example 65 was conducted, except that ( (4R, 5R)-5-(2-aminopheny1 )-2 , 2-climethy1-1 , 3-dioxo 1 an-4- yOmethyl sul famate(Example 64)was used instead of ((4R,5R)-5-(2- aminopheny I )-2 , 2-dimeth 1-1 , 3-dioxo1 an-4-y1 )methy1 su1 famate(Examp 1e 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) , 3.99~4.00(m, 1H) , 4.94(d, J=8.4, 1H) , 6.59-7.16(m, 4H).

Example 89: ((4R, 5R)-5-(2-nitrophenyl)-2-oxo-l,3-dioxolan-4-yl)methyl sul famate

To a stirred solution of ((4R, 5R)-5-(2-nitrophenyl)-2,2-dimethyl-l,3- di oxo1 an-4-y1 )methyl sul famate(Exam le 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. NaHCC , dried over MgSC , 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 ₎ 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%) ^l H NMR (400MHz, CDC 13 ) δ 2.0(s, 2H), 4.08~4.33(m, 2H) , 4.72(dt, J = 7.02, 7= 3.27, 1H), 5,47(d, 7= 7.0, H ) , 7.62~7.64(m, 2H), 7.77~7.90(m, 2H).

Example 90: ((4S, 5S)-5-(2-ni troplienyl )-2-oxo-l ,3-dioxolan-4-yl )methyi sul famate

The substantially same method as described in example 89 was conducted, except that ((4S, 5S)-5-(2-ni trophenyl )-2,2-dimethyl-l,3-dioxolan-4- yOmethyl sul f amate(Example 78) was used instead of ((4R, 5R)-5 ^~ (2- n i t r opheny 1 ) -2 , 2-cl i met hy 1 - 1 , 3-d i oxo 1 n-4-y 1 )met hy 1 su 1 f am t e ( Ex amp 1 e 77 ) , to obtain the title compound(0.9g, 50-80%)

Ti NMR (400MHz, CDC 13 ) δ 2.0(s, 2H), 4.08~4.33(m, 2H) , 4.72(dt, 7 = 7.02. J = 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-dioxolan-4- yOmethyl methyl sul famate

To a stirred solution of ((4R, 5R)-5-(2-aminophenyl)-2,2-dimethyl-l,3- dioxolan-4-yl)methyl sul famate(Exam le 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 ₄ (0.085g, 2.25mmol) at 0 ^° C . The resulting mixture was diluted with EtOAc, washed with water, dried over MgS0 , filtered, and concentrated under reduced pressure. The crude product was purified by Si(¾ gel column chromatography to obtain the title compound (0.3g, 30~50%)

¾ NMR (400MHz, CDC1 ₃ ) 51.40(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)

Examp1e 104 ^' · ( (4S , 5S)-5-(2-methy1aminopheny1 )-2 , 2 ^~ climethy1-1 , 3-clioxo1 an-4- yl )methyl methyl sul famate

The substantially same method as described in example 103 was conducted, except that ((4S, 5S)-5-(2-aminophenyl)-2,2-dimethyl-l,3-dioxolan-4- yDmethyl sul famate(Exam le 64) was used instead of ((4R, 5R)-5-(2- aminopheny1 )-2 , 2-dimethy1 -1 , 3-dioxo1 an-4-y1 )methy1 su1 famate(Examp1e 63) , to obtain the title compound(0.5g, 50-80%) ¾ NMR (400MHz, CDC1 ₃ ) 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(cl, 7=7.0, 1H) , 6.99~7.20(m, 4H)

Example 177: sodium ((((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-l,3-dioxolan- 4-yl )methoxy)sul fonyl )amide

To a stirred solution of ((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-l,3- dioxolan-4-yl )methyl sulfamate (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 NMR (400 MHz, DMS0-d ₆ ) δ 1.43 (s, 3H) , 1.50 (s, 3H), 3.77 (del, J=7.2, 11.2, 1H), 3.87 (dd, J=2.8, 11.2, 1H) , 3.99-4.03 (m, 1H), 5.09 (d, .7=8.4, 1H), 7.35-7.47 (m, 3H) , 7.61 (dd, J=1.8, 7.4, 1H)

Biological Experimental Example. 1: Measurement of Anti-epilepsy activity (MES-test)

In the MES test (Ref., G. Villetti et al . Neuropharmacology 40(2001) 866- 878), an electrical stimulus (mice: 50mA, 60Hz, 0.2sec, and rats: 150mA, 60Hz, 0.2sec in the test animal) supplied by an 11A Shocker (II TC Life Science Company) was delivered through corneal electrodes. All mice or rats assigned to any electroshock at peak time were treated with each test compound sample which was dissolved in 20% tween 80 prepared by saline solvent applied orally before the test. If the test animal' s stretching of its hind limb in a straight line wasn' t observed in the MES test, this results indicated that the test sample had anti-epilepsy activity. Three doses of the test sample were administered orally to 9-18 animals (3-6 mice per close) for evaluating the respective closes at which 50% of the animals were protected from seizure (ED50). The ED50 value (median effective close) was calculated by Litchfield and fficoxon log-probit method which is a dose- response relationship. The test results are shown in the following Table 4-5. Experimental animals, male ICR mice and male SD rats, were purchased from OrientBio, Samtako, or Nara Biotech, Korea, and housed in cages (4-5 mice or 3 rats per cage) for 4-5 days. The range of mice body weight was between 19 and 25 grams and range of rats body weight was between 100 and 130 grams. [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.

[Results] The results of anti-epileptic activity of the sulfamate derivative compounds measured in the above Experimental Example are shown in the following Tables 4 and 5. In Tables 4 and 5, the ED50 is represented by the concentration where the compound shows 50% of anti-epileptic activity compared to the vehicle only (100%).

[Table 4] Results of the measurements of anti-epileptic activity of the sulfamate derivative compounds

Examp 1 e mMES(po)

No.

ED50(mg/kg) Peak Time

1 6.5 0.5hr

2 9.0 lhr

3 14.0 4hr

4 50 ^a (33%) lhr

6 50 ³ (33%) lhr

8 50 ^b (100%) 1.2,4hr

10 30 ^a (66%) l,2hr 12 50 ^b (100%) l,2,4hr

15 50 (100%) 1,2, 4hr

16 50 ^a (100%) l,2,4hr

27 27.6 lhr

28 15.0 lhr

40 49.2 4hr

52 50 ^a (100%) l,2,4hr

66 12.3 lhr

70 50 ^a (100%) l,2,4hr

72 14.2 2hr

74 14.5 2hr

76 50 ^a (66%) lhr

90 9.2 2hr

92 50 ^a (100%) 1 , 2hr

104

50 ^a (66.6%) 4h ^'

106 30 ^a (100%) 4h

108

50 ^a (100%) 2,4h

110 9 ^a (33.3%) 4h

112

50 ^a (100%) l,2h

114

80 ^a (33.3%) 2h

116

150 ^a (33.3%) lh

118

80 ^a (66.6%) 2h 120 l,2,4h

80 ^a (66.6%)

122 l,2h

50 ^a (100%)

124 lh

50 ^a (100%)

126 2h

50 ^a (100%)

128 4h

50 ^a (100%)

130 2h

50 ^a (33.3%)

132 l,2h

80 ^a (33.3%)

134 1,2, 4h

50 ^a (100%)

136 4h

50 ^a (100%)

138 4h

80 ^a (33.3%)

140 lh

50 ^a (33.3%)

142 lh

80 ^a (33.3%)

144 l,2,4h

100 ^a (33.3%)

146 50 ^a (66.6%) 2,4h

148 lh

50 ^a (33.3%)

150 2h

50 ^a (100%)

152 2h

50 ^a (66.6%)

154 4h

50 ^a (100%)

156 l,2h

80 ^a (100%)

158 2h

50 ^a (100%)

160

80 ^a (66.6%) 4h

161

100 ^a (100%) 2,4h 162

100 ^a (100%) l,2h

163

50 " (50%) l,2h

164

50 ^a (100%) 4h

165

100 ^a (100%) 2,4h

166

100 ^a (100%) l,2h

167

100 ^a (100%) l,2,4h

168

100 ^a (100%) l,2,4h

169

30 ^a (100%) Ih

170

100 ^a (100%) l,2,4h

171

43.3 4h

172

30.2 4h

173

100 ^a (100%) 1,2, 4h

174

100 ^a (100%) l,4h

175

100 ^a (100%) l,2h

176

100 ^a (100%) 2h

# a ^' - Injection amount (mg/kg) , Protect ion%(3 mice); b - Injection amount (mg/kg) , Protect ion%(4 mice), %= the percentage of anti-epileptic activity compared to the vehicle only (100%), respec ively.

[Table 5] Results of the measurements of anti-epileptic activity of the sulfamate derivative compounds

. Example rMES(po)

No.

ED50(mg/kg) Peak Time 1 1.2 Ih

2 3.5 4h

4 5.2 lh

15 50 ^b (66.6%)

16 7.7 lh

28 32.7 4h

66 11.8 4h

72 1.0 4h

90 1.1 2h

163 6.5 4h

164 13.2 2h

166 1.9 4h

168 4.9 4h

169 15 ^a (100%)

172 4.7 4h

177 3.5 ^a (100%)

# a- ^' Injection amount (mg/kg) , Protect ion%(3 rats); b- ^' Injection amount (mg/kg) , Protect ion%(6 rats), %- the percentage of ant i—epi lept ic activity compared to the vehicle only (100%), respectively.

Biological Expe imental Example 2: Li thium-pi locarpine induced epilepsy test(LI-PIL0 test)

Prevention test Male Spr ague-Daw ley rats (purchased from Orient Bio Inc. Korea) of body weight 175 grams were used for these studies and 3 rats per cage were housed for 4-5 days. On the day prior to SE, rats received 127 mg/kg lithium chloride (Sigma, St. Louis, MO, U.S.A.) intraper i toneal ly (i.p.). Approximately 18-20 h following this treatment, rats were given an i.p. injection of 43 mg/kg pilocarpine (Sigma). An i.p. injection of 2 mg/kg methyl -scopolamine (Sigma) was administered 30 min prior to pilocarpine to block the effects of the muscarinic agonist on peripheral cholinergic receptors. Test drugs were dissolved in 20% tweenSO (Sigma). The drugs were administered intraperitoneal ly (i.p.) in a volume of 2ul/g body weight. Pharmacological effects of all of the test materials were evaluated to compare test groups (n=6) with a control group (n=6). Control group was administered vehicle only. The efficacy was measured 0.5, 1, 2, or 4 hours after the administration of the test material. The time point that the most animals were protected was defined as peak time and the ED50 was determined at peak time. The animals were then transferred to observation cages and observed continuously for 90 min. Seizure was elicited in approximately 95% of the control group. Protection was defined as complete absence of seizure grade 3 ^~ 5 (Racine scale; Racine, 1972) over the 90-min observation period. The effective dose of the compound necessary to protect 50% of the animals against seizures compared to controls (i.e. ED50) was determined by a curve fitting program (Excel 2007, Microsoft).

Intervent ion Male Spr ague -Daw ley rats (purchased from Orient Bio Inc. Korea) of body weight 175 grams were used for these studies and 3 rats per cage were housed for 4-5 days. On the clay prior to SE, rats received 127 mg/kg lithium chloride (Sigma, St. Louis, M0, U.S.A.) intraper i toneal ly (i.p.). Approximately 18-20 h following this treatment, rats were given an i.p. injection of 43 mg/kg pilocarpine (Sigma). An i.p. injection of 2 mg/kg methyl-scopolamine (Sigma) was administered 30 min prior to pilocarpine to block the effects of the muscarinic agonist on peripheral cholinergic receptors. Test drugs were dissolved in 20% tweenSO (Sigma). The drugs were administered intravenously (i.v.) in a volume of 2ul/g body weight at SE onset. Pharmacological effects of all of the test materials were evaluated to compare test groups (n=3-6) with a control group (n=3-6). Control group was administered vehicle only. The animals were then transferred to observation cages and observed continuously for 90 min. Seizure was elicited in approximately 95% of the control group. Protection was defined as complete absence of seizure grade 3~5 (Racine scale; Racine, 1972) over the 90-min observation period. The effective dose of the compound necessary to protect 50% of the animals against seizures compared to controls (i.e. ED50) was determined by a curve fitting program (Excel 2007, Microsoft).

[Results]

The results of Li thium-pi locarpine induced epilepsy test of the sulfamate derivative compounds measured in the above Experimental Example are shown in the following Tables 6. In Tables 6, the ED50 is represented by the concentration where the compound shows 50% of Li thium-pi locarpine induced epilepsy test compared to the vehicle only (100%).

[Table 6] Results of test compounds' efficacy against 1 i thium-pi locarpine induced seizure (Rats)

Ant i -ep i 1 ept ogenes i s Therapeutic effect

(rat/ip)

Example No. (min, rat/Iv)

ED50(mg/kg) Peak Time(h) ED50(mg/kg)

1 150 ^h (50%) 2h

2 97.1 4h 89.0

100 ^b

15 0.5h

(66.6%) 100 ^b

lh

(16.6%)

100 ^b

0.5h

(33.3%)

100 ^b (50%) 2h

150 ^b (16.6%) 2h

28 154.4 lh

167 30 ^a (100%) lh

# a- ^' Injection amount (mg/kg) , Protect ion%(3 rats); b- ^' Injection amount (mg7 kg) , Protect ion%(6 rats), %= the percentage of anti-epileptic activity compared to the vehicle only (100%), respectively.

[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.