[Title of the Invention]

PHENYL CARBAMATE COMPOUNDS FOR USE IN PREVENTING OR TREATING EPILEPSY OR EPILEPSY-RELATED SYNDROME [Technical Field]

The present invention provides a pharmaceutical composition for preventing and/or treating a epilepsy or epilepsy-related syndrome, for example an intractable epilepsy or its related syndrome such as drug-resistant epilepsy, comprising the phenyl carbamate compound as an active ingredient, and a use of the phenyl carbamate compound for preventing and/or treating epilepsy or epilepsy-related syndrome.

[Related Art]

Epilepsy and its related syndromes may be classified according to whether the associated seizures are partial or generalized, and whether the etiology is idiopathic or symptomatic/cryptogenic. Several important syndromes can be further grouped according to age of onset and prognosis.

Epilepsy is a chronic brain disease in which epileptic seizures are the predominant feature. Generally, most epilepsies and diseases associated therewith are difficult to treat, since epilepsies are not etiologically elucidated. Thus, administration of an antiepileptic agent is a common approach toward suppressing epileptic seizures or inhibiting propagation of focal seizures to other portions.

The older established antiepileptic drugs (AEDs) such as phenytoin carbamazepine, clonazepam, ethosuximide, valproic acid and barbiturates are widely prescribed but suffer from a range of side effect. Furthermore, there is a significant group of patients (20-30%) that are resistant to the currently available therapeutic agents. Fifty million people in the world have epilepsy, and there are between 16 and 51 cases of new-onset epilepsy per 100,000 people every year. A community-based study in southern France estimated that up to 22.5% of patients with epilepsy have drug-resistant epilepsy. Patients with drug-resistant epilepsy have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life.

One study showed that the use-dependent blockade of the fast sodium current in dentate granule cells by carbamazepine was lost in hippocampi resected from patients with carbamazepine-resistant temporal-lobe epilepsy, although this finding did not extend to lamotrigine, which has a pharmacologic action similar to that of carbamazepine. Altered expression of subtypes of the γ-aminobutyric acid type A (GABAA) receptor has also been observed in patients with drug-resistant temporal-lobe epilepsy. Whether these changes result in reduced sensitivity to antiepileptic drugs that act on the receptor is unknown.

Since 1989 several new drugs have been launched, including felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topimarate,vigabartrin,zonisamide and levetiracetam. While many of new drugs AEDs show improved efficacies and side-effect profiles, patients with intractable epilepsy remain untreated. Because of the need to individualize therapy, no rigid set of guidelines can be applied to determine medical intractability. There is still a need for improved medication.

[SUMMARY OF THE INVENTION]

An embodiment provides a pharmaceutical composition for the prevention and the treatment of an epilepsy or a epilepsy-related syndrome, for example an intractable epilepsy or its related syndrome such as drug-resistant epilepsy, comprising a phenyl carbamate compound of the following Chemical Formula 1 , an enantiomer or a diastereomer thereof, or a mixture of enantiomers or diastereomer s; or a pharmaceutically acceptable salt thereof.

Another embodiment is to provide a method of preventing and/or treating an epilepsy or a epilepsy-related syndrome in a subject comprising administering a pharmaceutically effective amount of a phenyl carbamate compound represented by Chemical Formula 1 ; a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof, to the subject in need.

Still other embodiment is to provide a phenyl carbamate compound represented by Chemical Formula 1 ; a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of epilepsy or the manufacture of a pharmaceutical composition for preventing and/or treating an epilepsy or a epilepsy-related syndrome.

[DETAILED DESCRIPTION OF THE EMBODIMENTS]

Continuing its research work in the field of epilepsy, the present inventors, as results of studies on the development of the drugs useful for prevention and/or treatment of an epilepsy or a epilepsy-related syndrome, found that a substituted phenyl carbamate compounds of the following Chemical Formula 1 exhibits remarkably excellent anti-epilepsy activity in various emulation models and simultaneously has very low toxicity, and completed the invention.

Therefore, an embodiment provides a pharmaceutical composition for prevention and/or treatment of an epilepsy or a epilepsy-related syndrome, comprising an organic compound, i.e., phenyl carbamate derivatives, more particularly, a phenyl carbamate compound represented by following Chemical Formula 1 ; a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

wherein,

X is a halogen, for example, chlorine, fluorine, iodine, or bromine,

n, that means the number of substituent X, is an integer from 1 to 5, for example, 1 or

2,

Rl is a linear or branched alkyl group of C1-C4, for example, methyl group, ethyl group, isopropyl group, or butyl group,

H

A is hydrogen or a carbamoyl derivative represented by ® ,

B is hydrogen, a carbamoyl derivative represented by _s trialkyl silyl groups (e.g., a trimethyl silyl (TMS) group, a triethyl silyl (TES) group, a triisopropyl silyl (TIPS) group, t-butyl dimethyl silyl (TBDMS) group, and the like), trialkylaryl silyl groups (wherein the total number of alkyl and aryl groups is three; e.g., a t-butyl diphenyl silyl (TBDPS) group and the like), or a trialkyl silyl ether group, wherein each alkyl group may be independently selected from the group consisting of linear, branched, or cyclic C1-C4 alkyl groups, and each aryl group may be independently selected from the group consisting of C5- C8 aryl groups, preferably a phenyl group,

A and B are not carbamoyl derivatives at same time, and R2 and R3 may be the same as or different from each other, and independently selected from the group consisting of hydrogen, a linear or branched alkyl group of C1-C4, for example C1-C3, a cycloalkyl group of C3-C8, for example C3-C7, and benzyl group, and more specifically, R2 and R3 may be the same as or different from each other, and independently selected from the group consisting of hydrogen, methyl group, propyl group, isopropyl group, cyclopropyl group, cyclohexyl group, bicycloheptane group, and benzyl group.

Preferably, in Chemical Formula 1 , A is hydrogen and B is carbamoyl group, or A is a carbamoyl group and B is hydrogen.

In the embodiment, in Chemical Formula 1 ,

if X is F or Br, A and B are not hydrogen at the same time,

if X is chlorine and n is 1 and A and B are hydrogen at the same time, Rl is a C2-C4 linear or branched alkyl group,

if X is chlorine and n is 1, Rl is methyl, isopropyl or butyl, and

if X is bromine located at 4-postion of the aromatic ring and n is 1, Rl is methyl, propyl, isopropyl or butyl, and

if A is the carbamoyl represented by , B is hydrogen, Rl is ethyl, and n is 2 at the same time, two X are located at 2 and 3 positions, 2 and 4 positions, 2 and 5 positions, or 3 and 5 positions of the aromatic ring.

In a concrete embodiment, the phenyl carbamate compound may be selected from the group consisting of:

1- (2-chlorophenyl)- 1 -hydroxypropyl-2-carbamate,

1- '2-chlorophenyl)- 1 -hydroxybutyl-2-carbamate,

1- ^2-chlorophenyl)- 1 -hy droxy-3 -methyl -butyl -2-carbamate,

1- (2-chlorophenyl)- 1 -hydroxyhexyl-2-carbamate,

1- ^2-chlorophenyl)- l-hydroxypropyl-2-N-methylcarbamate,

1- (2-chlorophenyl)- l-hydroxypropyl-2-N-propylcarbamate,

1- (2-chlorophenyl)- l-hydroxypropyl-2-N-isopropylcarbamate,

1- (2-chlorophenyl)- l-hydroxypropyl-2-N-cyclopropylcarbamate,

1- (2-chlorophenyl)- l-hydroxypropyl-2-N-cyclohexylcarbamate,

1- (2-chlorophenyl)- l-hydroxypropyl-2-N-benzylcarbamate,

1- (2-chlorophenyl)- l-hydroxypropyl-2-N-bicyclo[2,2,l]heptanecarbamate,

1- ,4-dichlorophen yl)- 1 -hydroxypropyl-2-carbamate, 1 -(2,6-dichlorophenyl)- 1 -hydroxypropyl-2-carbamate,

1 -(2,4-dichlorophenyl)- 1 -hydroxybutyl-2-carbamate,

1 -(2,6-dichlorophenyl)- 1 -hydroxybutyl-2-carbamate

1 -(2,4-dichlorophenyl)- 1 -hydroxy-3-methyl-butyl-2-carbamate,

1 -(2,6-dichlorophenyl)- 1 -hydroxy-3-methyl-butyl-2-carbamate,

1 -(2,4-dichlorophenyl)- 1 -hydroxyhexyl-2-carbamate,

1 -(2,6-dichlorophenyl)- 1 -hydroxyhexyl-2-carbamate,

1 -(2-chlorophenyl)-2-hydroxypropyl- 1 -carbamate,

1 -(2-chlorophenyl)-2-hydroxypropyl- 1 -N-methylcarbamate,

1 -(2-chlorophenyl)-2-hydroxypropyl- 1 -N-propylcarbamate,

1 -(2-chlorophenyl)-2-hydroxypropyl- 1 -N-isopropylcarbamate,

1 -(2-chlorophenyl)-2-hydroxypropyl- 1 -N-cyclopropylcarbamate,

1 -(2-chlorophenyl)-2-hydroxypropyl- 1 -N-cyclohexylcarbamate,

1 -(2-chlorophenyl)-2-hydroxypropyl- 1 -N-benzylcarbamate,

1 -(2,4-dichlorophenyl)-2-hydroxypropyl- 1 -carbamate,

1 -(2,6-dichlorophenyl)-2-hydroxypropyl- 1 -carbamate,

1 -(2,4-dichlorophenyl)-2-hydroxybutyl- 1 -carbamate,

1 -(2,6-dichlorophenyl)-2-hydroxybutyl- 1 -carbamate,

1 -(2,4-dichlorophenyl)-2-hydroxy-3-methyl-butyl- 1 -carbamate,

l-(2,6-dichlorophenyl)-2-hydroxy-3 -methyl-butyl- 1 -carbamate,

1 -(2,4-dichlorophenyl)-2-hydroxyhexyl- 1 -carbamate,

l -(2,6-dichlorophenyl)-2-hydroxyhexyl-l -carbamate,

1 -(2-fluorophenyl)- 1 -hydroxypropyl-2-carbamate,

1 -(2-iodophenyl)- 1 -hydroxypropyl-2-carbamate,

1 -(2-iodophenyl)- 1 -hydroxybutyl-2-carbamate,

l-(2,3-dichlorophenyl)-l -hydroxypropyl-2-carbamate, and

l-(2,3-dichlorophenyl)-2-hydroxypropyl-l -carbamate.

In another concrete embodiment, the compound may not include 1 -(2-chlorophenyl)- 1 ,2-propanediol, 1 -(2-chlorophenyl)- 1 -hydroxybutyl-2-carbamate, and 1 -(2,6- dichlorophenyl)- 1 -hydroxybutyl-2-carbamate.

In this compound, 2 chiral carbons exist at positions 1 and 2 from phenyl group substituted with X; thus, the compound may exist in the form of an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers, as well as a racemate. In an embodiment, the phenyl carbamate compound is selected from the group consisting of:

1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(S)-2-carbamate,

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-carbamate,

racemate of l-(2-chlorophenyl)-(S)-l -hydroxypropyl-(S)-2-carbamate and l-(2- chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-carbamate,

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(S)-2-carbamate,

1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(R)-2-carbamate,

1 -(2-chlorophenyl)-(S)- 1 -hydroxybutyl-(S)-2-carbamate,

racemate of l-(2-chlorophenyl)-(S)-l-hydroxybutyl-(S)-2-carbamate and l-(2- chlorophenyl)-(R)- 1 -hydroxybutyl-(R)-2-carbamate,

l-(2-chlorophenyl)-(S)-l -hydroxy-3-methyl-butyl-(S)-2-carbamate,

racemate of l-(2-chlorophenyl)-(S)-l-hydroxy-3-methyl-butyl-(S)-2-carbam ate and

1 -(2-chlorophenyl)-(R)- 1 -hydroxy-3-methyl-butyl-(R)-2-carbamate,

1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(S)-2-N-methylcarbamate,

1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(S)-2-N-propylcarbamate,

1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(R)-2-N-isopropylcarbamate,

1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(R)-2-N-cyclopropylcarbamate,

1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(R)-2-N-cyclohexyl carbamate,

1 -(2-chlorophenyl)-(R)-l -hydroxypropyl-(R)-2-N-methylcarbamate,

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-propylcarbamate,

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-isopropylcarbamate,

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-cyclopropylcarbamate,

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-cyclohexyl carbamate,

racemate of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(S)-2-N-methylcarbama te and

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-methylcarbamate

racemate of l-(2-chlorophenyl)-(S)-l -hydroxypropyl-(S)-2-N-propylcarbamate and

1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-propylcarbamate,

racemate of 1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(S)-2-N-isopropylcarbamate and 1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-isopropylcarbamate,

racemate of 1 -(2-chlorophenyl)-(S)- 1 -hydroxypropyl-(S)-2-N-cyclopropylcarbamate and 1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-cyclopropylcarbamate,

racemate of 1 -(2-chlorophenyl)-(S)-l -hydroxypropyl-(S)-2-N-cyclohexylcarbamate and 1 -(2-chlorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-N-cyclohexylcarbamate,

1 -(2-fluorophenyl)-(S)- 1 -hydroxypropyl-(S)-2-carbamate,

1 -(2-fluorophenyl)-(R)- 1 -hydroxypropyl-(R)-2-carbamate,

1 -(2-iodophenyl)-(S)-l -hydroxypropyl-(S)-2-carbamate,

l-(2-iodophenyl)-(R)-l-hydroxypropyl-(R)-2-carbamate, and

1 -(2-iodophenyl)-(S)- 1 -hydroxybutyl-(S)-2-carbamate.

Alternatively, the compound may be in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt may include an additional salt of acid or base, and its stereochemical isomer. For example, the compound may be in the form of an additional salt of an organic or inorganic acid. The salt may not be specially limited, and include any salts that maintain the activities of their parent compounds, with no undesirable effects, in the subject, when they are administered to the subject. Such salts may include inorganic and organic salts, such as salts of acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzene sulfonic acid, benzoic acid, stearic acid, lactic acid, bicarbonic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium edetate, carbonic acid, chlorobezoic acid, citric acid, edetic acid, toluenesulfonic acid, fumaric acid, gluceptic acid, esilic acid, pamoic acid, gluconic acid, methyl nitric acid, malonic acid, hydrochloric acid, hydroiodic, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, mucic acid, naphthylic acid, muconic acid, p- nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, salicylic acid, sulfamic acid, sulfanilic acid, methane sulfonic acid, and the like.

The additional salts of base may include salts of akali metal or alkaline earth metal, such as salts of ammonium, lithium, sodium, potassium, magnesium, calcium, and the like; salts having an organic base, such as benzathine, N-methyl-D- glucamine, hydrabamine, and the like; and salts having an amino acid such as arginine, lysine, and the like. In addition, these salts may be converted to a released form by treating with a proper base or acid. Reaction Formula I: Synthesis of Diol-1

trans olefin Diol

A diol compound used in the synthesis of the carbamate compound may be synthesized by dihydroxylation of a trans-olefin compound. A diol compound having optical activity may be synthesized using a sharpless asymmetric dihydroxylation catalyst.

PG = Protecting Group

Protected alcohol Diol

As indicated in the Reaction Formula II, the optically active substance of diol may also be synthesized using an reduction reagent after synthesizing a hydroxy-ketone compound using Haloro-Mandelic acid. In the Reaction Formula II, PG may be Trialkyl Silyl group(TMS, TES, TIPS, TBDMS, TBDPS), Ether group [MOM(Mothoxymethyl ether), MEM(2- Methoxyethoxymethyl ether), BOM(Benzyloxymethyl ether). MTM(Methylthiomethyl ether), SEM(2-(Trimethylsilyl)ethoxymethyl ether), PMBM(p-Methoxybenzyl ether), THP(Tetrahydropyranyl ether), Allyl ether, Trityl ether, Ester group [Ac(acetate), Bz(Benzoate), Pv(Pivaloate), Cbz(Benzyl carbonate), BOC(t-Butyl carbonate), Fmoc(9- Fulorenylmethyl)carbaonate, Alloc(Allyl Carbonate), Troc(Trichloroehtyl carbonate), or p- Methoxybenzoate, Methyl carbonate, and so on.

Reaction Formula I: Synthesis of Diol- 1

trans olefin Diol

A diol compound used in the synthesis of the carbamate compound may be synthesized by dihydroxylation of a trans-olefin compound. A diol compound having optical activity may be synthesized using a sharpless asymmetric dihydroxylation catalyst.

As indicated in the Reaction Formula II, the optically active substance of diol may also be synthesized using a reduction reagent after synthesizing a hydroxy-ketone compound using Haloro-Mandelic acid. In the Reaction Formula II, PG(protecting group) may be selected from the group consisting of trialkyl silyl group(e.g., a trimethyl silyl (TMS) group, a triethyl silyl (TES) group, a triisopropyl silyl (TIPS) group, t-butyl dimethyl silyl (TBDMS) group, and the like), trialkylaryl silyl groups (wherein the total number of alkyl and aryl groups is three; e.g., a t-butyl diphenyl silyl (TBDPS) group and the like), ester group[Ac(acetate), Bz(benzoate), Pv(pivaloate), Cbz(benzyl carbonate), BOC(t-butyl carbonate), Fmoc(9- fluoroenylmethyl)carbaonate, Alloc(allyl Carbonate), Troc(trichloroethyl carbonate), p- methoxybenzoate, methyl carbonate, and so on] and the like, wherein each alkyl group may be independently selected from the group consisting of linear, branched, or cyclic C1 -C4 alkyl groups, and each aryl group may be independently selected from the group consisting of C5-C8 aryl groups, preferably a phenyl group.

Reaction Formula HI: Carbamation reaction- 1

As a highly selectivity form of regioisomer of single carbamate of diol having halogen substituent at phenyl ring. (Example 1 to 14 and 36 to 67 are synthesized by reaction formula III)

Reaction Formula IV: Carbamation reaction-2

Two substances in the form of regioisomers of a single carbamate of diol having halogen substituent at phenyl ring may be separated by flash column chromatography to obtain two kinds of single carbamate compounds. (Example 15-35 and 68-1 15 are synthesized by reaction formula IV)

Reaction Formula V: Protection reaction

In the Reaction Formula V, PG(protecting group) may be selected from the group consisting of trialkyl silyl group(e.g., a trimethyl silyl (TMS) group, a tri ethyl silyl (TES) group, a triisopropyl silyl (TIPS) group, t-butyl dimethyl silyl (TBDMS) group, and the like), trialkylaryl silyl groups (wherein the total number of alkyl and aryl groups is three; e.g., a t- butyl diphenyl silyl (TBDPS) group and the like), ester group [Ac(acetate), Bz(benzoate), Pv(pivaloate), Cbz(benzyl carbonate), BOC(t-butyl carbonate), Fmoc(9- fluoroenylmethyl)carbaonate, Alloc(allyl Carbonate), Troc(trichloroethyl carbonate), p- methoxybenzoate, methyl carbonate, and so on] and the like, wherein each alkyl group may be independently selected from the group consisting of linear, branched, or cyclic C1 -C4 alkyl groups, and each aryl group may be independently selected from the group consisting of C5-C8 aryl groups, preferably a phenyl group.

In the Reaction Formula IV and V, R4 and R5 may be the same as or different from each other, and independently selected from the group consisting of hydrogen, a linear or branched alkyl group of C1 -C4, for example C 1 -C3, a cycloalkyl group of C3-C8, for example C3-C7, and benzyl group, and more specifically, R4 and R5 may be the same as or different from each other, and independently selected from the group consisting of hydrogen, methyl group, propyl group, isopropyl group, cyclopropyl group, cyclohexyl group, bicycloheptane group, and benzyl group.

Two substances in the form of regioisomers of a single carbamate of diol having halogen substituent at phenyl ring may be separated by flash column chromatography to obtain two kinds of single carbamate compounds.

Another embodiment provides a method of prevention and/or treatment of a an epilepsy or a epilepsy-related syndrome, comprising administering a pharmaceutically effective amount of a phenyl carbamate compound represented by Chemical Formula 1 ; a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof, to a subject in need of preventing and/or treating drug-resistant epilepsy or drug-resistant epilepsy-related symptom. The method can be applied for preventing and/or treating drug-resistant epilepsy or drug- resistant epilepsy-related symptom.

The method may further comprise a step of identifying the subject in need of preventing and/or treating an epilepsy or a epilepsy-related syndrom, prior to the step of administering. Another embodiment provides a phenyl carbamate compound represented by Chemical Formula 1 ; a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of an epilepsy or a epilepsy-related syndrome.

Another embodiment provides a use of a phenyl carbamate compound represented by Chemical Formula 1 ; a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing and/or treating an epilepsy or a epilepsy-related syndrome.

In an embodiment, the present invention relates to a therapeutic or preventive agent for epilepsy and epilepsy-related syndrome, preferable an intractable epilepsy and its related syndrome.

The characteristics of intractable epilepsy include 1) high occurrence of partial seizure followed by a generalized seizure (particularly temporal lobe epilepsy); 2) high occurrence of symptomatic epilepsy caused by an organic lesion in the brain; 3) long-term absence of treatment from the onset to consultation of a specialist and high occurrence of seizures; and 4) high occurrence of status epilepticus in the anamnesis. In other words, the temporal lobe is likely to be a portion of the brain responsible for intractable epilepsy. It is indicated that epilepsy becomes more intractable by changing of the nature thereof and evolving as acquired seizures are repeated.

Intractable epilepsy is categorized into three clinical types, i.e., (a) localization- related epilepsies and syndromes, (b) generalized epilepsies and syndromes, and (c) epilepsies and syndromes undetermined, whether focal or generalized.

Examples of (a) localization-related epilepsies and syndromes include temporal lobe epilepsies, frontal lobe epilepsies, and multi-lobe epilepsies. Temporal lobe epilepsies and frontal lobe epilepsies are typical examples of intractable epilepsy. Multi-lobe epilepsies are considered to be caused by two or more lobes.

Examples of (b) generalized epilepsies and syndromes include myoclonic epilepsy.

Examples of (c) epilepsies and syndromes undetermined, whether focal or generalized, include severe myoclonic epilepsy, which exhibits a variety of seizure types. In particular, tonic-clonic seizures frequently occur, to thereby often lead to status epilepticus. Thus, special treatment conducted by a specialist for epilepsy is strongly required (Masako WATANABE, et al., Igakuno Ayumi, 183(1): 103-108, 1997).

Seizures associated with intractable epilepsy are categorized into a variety of types, e.g., tonic seizures, tonic-clonic seizures, atypical absence seizures, atonic seizures, myoclonic seizures, clonic seizures, simple partial seizures, complex partial seizures, and secondary generalized seizures. Of these, for tonic and atonic seizures, attention must be paid to injuries resulting from falls.

In addition, complex partial seizures may cause a behavior-caused accident during disturbance of consciousness. In intractable epilepsies, "complex partial seizures" associated with temporal lobe epilepsies and frontal lobe epilepsies occur at relatively high frequency in adults. Although said seizures occur at low frequency in children, the seizures are also intractable as in the case of adults (Progress of Epileptology, No. 2, Haruo AKIMOTO and Toshio YAMAUCHI, Iwanami Gakujutsu Shuppan, 1991 , p 51-85).

In the present description, the term "intractable epilepsy" refers to epilepsies or seizures associated therewith corresponding to the following four epilepsies or seizures associated therewith:

(1) epilepsies difficult to treat in which suppression of seizures associated therewith cannot be controlled through a conventional pharmaceutical treatment (Masako WATANABE, et al., Igaku-no Ayumi, 183(1): 103-108, 1997);

(2) epilepsies corresponding to the following (a) to (c): (a) localization-related epilepsies such as temporal lobe epilepsis and cortical epilepsis; (b) generalized epilepsies and myoclonic epilepsy; and (c) epilepsies and syndromes undetermined, whether focal or generalized, such as severe myoclonic epilepsy;

(3) seizures associated with the above-described intractable epilepsis including tonic seizures, tonic-clonic seizures, atypical absence seizures, atonic seizures, myoclonic seizures, clonic seizures, simple partial seizures, complex partial seizures, and secondary generalized seizures; and

(4) epilepsies such as epilepsies following brain surgery, traumatic epilepsies, and relapsed epilepsies following surgery for epilepsy.

The antiepileptic agent of the present invention is effective for the above four types of intractable epilepsies. Of these, the antiepileptic agent of the present invention is particularly effective for localization-related epilepsies corresponding to (2) (a); seizures such as secondary generalized seizures, complex partial seizures and status epilepticus corresponding to (3) and status epilepticus; and epilepsies following brain surgery, traumatic epilepsies, and relapsed epilepsies following surgery for epilepsy corresponding to (4). The antiepileptic agent of the present invention has a possibly excellent effect to epilepsies such as localization-related epilepsies, temporal lobe epilepsies, and cortical epilepsies.

"Temporal lobe epilepsy," which is one type of intractable epilepsy, is an epilepsy having a seizure focus in the temporal lobe, and is categorized under symptomatic and localization-related epilepsies, which also include frontal lobe epilepsies, parietal lobe epilepsies, and occipital lobe epilepsies, based on the international classification of epilepsy.

The syndromes of temporal lobe epilepsy vary in accordance with a focus-localized site and type of seizure propagation, in that the temporal lobe has an anatomically complex structure including neocortex, allocortex, and paleocortex. Temporal lobe epilepsy, as previously defined as a psychomotor seizure, mostly causes complex partial seizures as clinically observed seizures, and also causes simple partial seizures, secondary generalized seizures, and combinations thereof.

Simple partial seizures include autonomic and mental symptoms and sensory symptoms such as olfaction, audition, or vision, sometimes concomitant with symptoms of experiences such as deja-vu and jamais-vu. Complex partial seizures often exhibit motion stopping followed by eating-function automatism, and are divided into amygdala- hippocampus seizures and lateral temporal lobe seizures according to localization. In the case of temporal lobe epilepsy, 70-80% of the seizures are hippocampus seizures, in which aura, motion stopping, lip automatism, and clouding of consciousness are successively developed to result in amnesia. When the focus is in the amygdala, there are caused autonomic symptoms such as dysphoria in the epigastrium; phobia; and olfactory hallucination. Lateral temporal lobe seizures include auditory illusion, hallucination, and a dreamy state, and disturbance of speech when the focus is in the dominant hemisphere. Temporal lobe epilepsy exhibits a long-term psychosis-like state in addition to other symptoms and recognition-and- memory disorder more frequently than do other epilepsies (Medical Dictionary, Nanzando). Treatment of temporal lobe epilepsy is carried out through pharmacotherapy employing a maximum dose of a combination of drugs, or through surgical treatment.

"Cortex epilepsy, which is one type of intractable epilepsy, is an epilepsy having a focus in the cerebral cortex, and is classified as symptomatic epilepsy belonging to localization-related (focal) epilepsies and syndromes in the international classification of epilepsy. In the international classification, seizures associated with cortex epilepsy are classified as simple partial seizures, which are partial seizures without reduction of consciousness. Accordingly, an electroencephalogram taken during a seizure associated with cortex epilepsy (not always recorded on the scalp) exhibits localized contralateral electric discharge from the corresponding cortical field. The cortex epilepsy is classified as temporal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy.

"Traumatic epilepsy," which is one type of intractable epilepsy, in a broad sense, is divided into two epilepsies, i.e., "early epilepsy" and "late epilepsy." "Early epilepsy" is caused through stimulation of the brain induced by convulsion within a week after suffering a trauma, and is not a true epilepsy. In contrast, "late epilepsy" is a true epilepsy that is caused one or more weeks after suffering a trauma. Most of the traumatic epilepsies are caused by formation of a focus at a traumatically damaged portion of the cortex, and they are considered to be typical examples of partial epilepsies.

"A secondary generalized seizure," which is one of the symptoms associated with intractable epilepsy, is one type of partial seizure, which exhibit a clinical syndrome and an electrocephalogram feature observed as excitation of neurons that shows initiation of a seizure in a limited portion of one cerebral hemisphere. The secondary generalized seizure is initiated as a simple partial seizure (without impairment of consciousness) or a complex partial seizure (with impairment of consciousness), and develops to general convulsion induced through secondary generalization. The main symptom thereof is convulsion such as a tonic-clonic seizure, a tonic seizure, or a clonic seizure.

"A complex partial seizure," which is one of the symptoms associated with intractable epilepsy, refers to a partial seizure with impairment of consciousness, and is similar to a seizure that has conventionally been called a psycho-motor seizure or a seizure associated with temporal lobe epilepsy. In the international classification draft (1981), the complex partial seizure is defined as a seizure with impairment of consciousness exhibiting an electrocephalogram during a seizure in which unilateral or bilateral electric discharge attributed to a focus in a diffuse or a temporal or front-temporal portion.

Clinically, an epileptic seizure results from a sudden and abnormal electrical discharge originating from a collection of interconnected neurons in the brain or elsewhere in the nervous system. Depending on the type of epilepsy involved, the resulting nerve cell activity may be manifested by a wide variety of clinical symptoms such as uncontrollable motor movements, changes in the patient's level of consciousness and the like. Epilepsy and epileptic seizures and syndromes may be classified in a variety of ways (See, The Treatment of Epilepsy, Principles & Practice, Third Edition, Elaine Wyllie, M.D. Editor, Lippincott Williams & Wilkins, 2001). However, as used herein the terms; "epilepsy", "epileptic seizures" and "epileptic syndromes" are meant to include all known types of epileptic seizures and syndromes including; partial seizures, including simple, complex and partial seizures evolving to generalized tonic-clonic convulsions and generalized seizures, both convulsive and nonconvulsive and unclassified epileptic seizures.

Patients with epilepsy whose seizures do not successfully respond to antiepileptic drug (AED) therapy are considered to have drug-resistant epilepsy (DRE). This condition is also referred to as intractable, medically refractory, or pharmacoresistant epilepsy. The International League Against Epilepsy (ILAE) defines drug resistant epilepsy as a failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.

As used herein, the term "anti-epileptic drug(s)" or "AED(s)" generally encompasses pharmacological agents that reduce the frequency or likelihood of a seizure. There are many drug classes that comprise the set of antiepileptic drugs (AEDs), and many different mechanisms of action are represented. For example, some medications are believed to increase the seizure threshold, thereby making the brain less likely to initiate a seizure. Other medications retard the spread of neural bursting activity and tend to prevent the propagation or spread of seizure activity. Some AEDs, such as the Benzodiazepines, act via the GABA receptor and globally suppress neural activity. However, other AEDs may act by modulating a neuronal calcium channel, a neuronal potassium channel, a neuronal NMDA channel, a neuronal AMPA channel, a neuronal metabotropic type channel, a neuronal sodium channel, and/or a neuronal kainite channel. The phrase "Anti-epileptic drugs that block sodium channels", "sodium-channel-blocking AEDs" used herein refers to anti-epileptic drugs that block sodium channels. The sodium-channel-blocking AEDs can be selected from the group consisting of topiramate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, zonisamide, felbamate, ethosuximide, and valproate (valproic acid), as well as other existing or new AEDs which may be identified to block sodium channels in the future.

As used herein, the terms "subject" or "patient" are used herein interchangeably and as used herein, refer to a human being, who has been the object of treatment, observation or experiment.

The pharmaceutical composition may be formulated in various forms for oral or parenteral administration. For example, the pharmaceutical composition may be formulated in the oral administration form, such as a tablet, pill, soft or hard capsule, liquid, suspension, emulsion, syrup, granules, elixirs, and the like. In addition to the active ingredient, the oral administration form may further include pharmaceutically acceptable and conventional components, for example, a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, and the like; a lubricant such as silica, talc, stearic acid, magnesium or calcium salt thereof, polyethyleneglycol, and the like. In the case that the oral administration form is a tablet, it may further include a binder such as magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvmylpirrolidine, and the like; and optionally include one or more additives selected from the group consisting of a disintegrant such as starch, agar, arginic acid or sodium salt thereof, an absorbent, a colorant, a flavoring, a sweetener, and the like. Alternatively, the pharmaceutical composition may also be formulated in a parenteral administration form, which can be administered by subcutaneous injection, intravenous injection, intramuscular injection, injection into thoracic cavity, and the like. In order to formulate the parenteral administration form, the pharmaceutical composition may be prepared as a solution or suspension wherein the active ingredient is dissolved in water together with a stabilizer and/or a buffering agent, and such solution or suspension formulation may be prepared as a dosage form in ample or vial.

The pharmaceutical composition may be sterilized, and/or include further additives such as a preservative, a stabilizer, a hydrating agent, an emulsification accelerator, a salt and/or buffering agent for osmoregulation, and the like, and/or further therapeutically effective ingredients. The pharmaceutical composition may be formulated by any conventional method for mixing, granulating, coating, and the like.

The pharmaceutical composition may be administered to a mammal including human, in the pharmaceutically effective amount of 0.01 to 750 mg/kg(body weight), preferably 0.1 to 500 mg/kg(body weight) per one day, based on the active ingredient. The pharmaceutically effective amount may refers to an amount capable of exhibiting a desired effect, i,e., an effect of treating and/or preventing epilepsy. The pharmaceutically effective amount may be administered through oral or parenteral pathway (e.g., an intravenous injection, an intramusclular injection, etc.), one or two or more times per one day.

The pharmaceutically effective amount and the administration pathway of the present pharmaceutical composition may be properly adjusted by a person skilled in the relevant field considering the conditions of the subject (patient), desired effects, and the like. The subject may be a mammal including human or cells and/or tissues obtained therefrom. [BREIF DESCRIPTION OF DRAWINGS ]

Fig. 1 is a graph showing the measurement results of benzodiazepine-resistant electrographic status epilepsy model of l -(2-chlorophenyl)-(S)-l-hydroxypropyl-(S)-2- carbamate (compound 1) in the test(Rats). [EXAMPLE]

The present invention is further explained in more detail with reference to the following examples. These examples, however, should not be interpreted as limiting the scope of the present invention in any manner.

Preparation Example 1: Synthesis of l-(2-chlorophenyl)-trans-l-propene

48ml of 2-chlorobenzenaldehyde (0.42mol) and 49.7ml of 3-pentanone (0.47mol) were dissolved in 600mL of hexane in flask, and then stirred with raising the temperature. 53.6ml of Boron trifluoride etherate (BF ₃ OEt ₂ , 0.42mol) was added to the resultant under reflux conditions. When the reaction was completed, water was added thereto. After layer separation, the obtained organic layer was washed twice with 1M sodium hydroxide solution (1M NaOH), and then the separated organic layer was washed with water. The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ) and concentrated. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (38g, yield 58%). Ή NMR(400MHz, CDC1 ₃ ) 51.94(d, J=4.8Hz, 3H), 6.24(m, 1H), 6.78(d, J=14Hz, 1H), 7.1 1-7.5 l(m, 4H)

Preparation Example 2: Synthesis of l-(2-chlorophenyl)-trans-l-butene

The substantially same method as described in Preparation Example 1 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (2.9g, yield 83%).

Ή NMR(400MHz, CDC1 ₃ ) 61.14(d, J=7.6Hz, 3H), 2.29~2.33(m, 2H), 6.28(dt, J=16Hz, 6.4Hz, 1H), 6.78(d, J=15.6Hz, 1H), 7.13~7.54(m, 4H)

Preparation Example 3: Synthesis of l-(2-chlorophenyl)-3-methyl-trans-l- butene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,6-dimethyl-heptan-4-one was used instead of 3-pentanone, to obtain the title compound (8.0g, yield 50-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.14(d, J=6.8Hz, 6H), 2.25~2.57(m, 1 H), 6.20(dd,

J=16Hz, 7.2Hz, 1H), 7.64(d, J=16Hz, 1H), 7.12~7.54(m, 4H)

Preparation Example 4: Synthesis of l-(2-chlorophenyl)-trans-l-hexene

The substantially same method as described in Preparation Example 1 was conducted, except that 6-undecanone was used instead of 3-pentanone, to obtain the title compound (l Og, yield 85%).

lH NMR(400MHz, CDC1 ₃ ) 60.96(t, J=7.2Hz, 3H), 1.33~1.56(m, 4H), 2.26~2.32(m, , 4H), 6.24(dt, J=15.6Hz, 7Hz, 1H), 6.78(d, J=16Hz, 1H), 7.13~7.54(m, 4H)

Preparation Example 5: Synthesis of l-(2,4-dichlorophenyl)-trans-l-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,4-dichlorobenzenaldehyde was used instead of 2-chlorobenzenaldehyde, to obtain the title compound (2.4g, yield 57%).

Ή NMR(400MHz, CDC1 ₃ ) 61.95(dd, J=6.8Hz, 1.6Hz, 3H), 6.24(m, 1H), 6.72(d, J=15.6Hz, 1 H), 7.18~7.44(m, 3H)

Preparation Example 6: Synthesis of l-(2,4-dichlorophenyl)-trans-l-butene The substantially same method as described in Preparation Example 5 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (2. lg, yield 90%).

Ή NMR(400MHz, CDC1 ₃ ) 81.14(d, J=7.6Hz, 3H), 2.20~2.33(m, 2H), 6.26(dt, J=16Hz, 6.8Hz, 1H), 6.70(d, J=15.6Hz, 1H), 7.18~7.46(m, 3H)

Preparation Example 7: Synthesis of l-(2,6-dichlorophenyl)-3-methyl-trans-l- butene

The substantially same method as described in Preparation Example 5 was conducted, except that 2,6-dimethyl-heptan-4-one was used instead of 3-pentanone, to obtain the title compound (0.23g, yield 10-40%).

Ή NMR(400MHz, CDC1 ₃ ) 51.15(d, J=6.8Hz, 6H), 2.53~2.58(m, 1H), 6.19(dd, J=16.4Hz, 6.8Hz, 1H), 6.31(d, J=16.4Hz, 1H), 7.18~7.46(m, 3H)

Preparation Example 8: Synthesis of l-(2,4-dichlorophenyl)-trans-l-hexene

The substantially same method as described in Preparation Example 5 was conducted, except that 6-undecanone was used instead of 3-pentanone, to obtain the title compound (3.2g, yield 40-80%).

Ή NMR(400MHz, CDC1 ₃ ) 60.96(t, J=7.2Hz, 3H), 1.38~1.52(m, 4H), 2.25-2.3 l(m, 2H), 6.22(dt, J=15.6Hz, 6.8Hz, 1H), 6.70(d, J=15.6Hz, 1H), 7.18~7.46(m, 3H)

Preparation Example 9: Synthesis of l-(2,6-dichlorophenyl)-trans-l-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,6-dichlorobenzenaldehyde was used instead of 2-chlorobenzenaldehyde, to obtain the title compound (0.4g, yield 10-40%).

Ή NMR(400MHz, CDC1 ₃ ) 61.98(d, J=8Hz, 3H), 6.23-6.3 l(m, 1H), 6.40(d, J=16Hz, 1H), 7.05~7.32(m, 3H)

Preparation Example 10: Synthesis of l-(2,6-dichIorophenyl)-trans-l-butene

The substantially same method as described in Preparation Example 9 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (1.2g, yield 10-40%).

Ή NMR(400MHz, CDC1 ₃ ) 51.17(t, J=7.6Hz, 3H), 2.30~2.37(m, 2H), 6.29(dt, J=16.4Hz, 6Hz, 1H), 6.37(d, J=16.4Hz, 1H), 7.05~7.32(m, 3H)

Preparation Example 11: Synthesis of l-(2,6-dichlorophenyl)-3-methyl-trans-l- butene

The substantially same method as described in Preparation Example 9 was conducted, except that 2,6-dimethyl-heptan-4-one was used instead of 3-pentanone, to obtain the title compound (0.23g, yield 10-40%).

Ή NMR(400MHz, CDC1 ₃ ) 51.15(d, J=6.8Hz, 6H), 2.53~2.58(m, 1H), 6.19(dd, J=16.4Hz, 6.8Hz, 1H), 6.31(d, J=16.4Hz, 1H), 7.05~7.32(m, 3H)

Preparation Example 12: Synthesis of l-(2,6-dichlorophenyl)-trans-l-hexene

The substantially same method as described in Preparation Example 9 was conducted, except that 6-undecanone was used instead of 3-pentanone, to obtain the title compound (0.2g, yield 10-40%).

Ή NMR(400MHz, CDC1 ₃ ) δ0.99(ΐ, J=7.2Hz, 3H),1.14-1.59(m, 4H), 2.30~2.36(m, 2H), 6.24(dt, J=16Hz, 6.6Hz, 1H), 6.38(d, J=16.4Hz, 1H), 7.05~7.33(m, 3H)

Preparation Example 13: Synthesis of l-(2,3-dichlorophenyI)-trans-l-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2,3-dichlorobenzenaldehyde was used instead of 2-chlorobenzenaldehyde, to obtain the title compound (0.2g, yield 10-40%).

1H NMR(400MHz, CDC1 ₃ ) 61.94(d, J=4.8Hz, 3H), 6.24(m, 1 H), 6.78(d, J=14Hz, 1H), 7.1 1~7.51 (m, 3H)

Preparation Example 14: Synthesis of l-(2-chlorophenyl)-(S,S)-l,2-propanediol

l-(2-chlorophenyl)-trans- l -propene(1.5g, Preparation Example 1) was dissolved in 30mL of the mixture of t-BuOH/H ₂ 0 (1 : 1 (V/V)). At 0 ^° C , AD-mix-a (Aldrich, U.S.A.) (13.7g) and methane sulfone amide (CH ₃ S0 ₂ NH ₂ , 0.76g, 0.0080mol) were added thereto and stirred for overnight. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na ₂ S0 ₃ ) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (1.65g, yield 90%).

1H NMR(400MHz, CDC1 ₃ ) 61.20(d, J=6.4Hz, 3H), 2.48(d, J=4.0Hz 1H), 2.92(d, J=4.4Hz, 1 H), 3.93~3.97(m, 1H), 4.97(t, J=4.8Hz, 1H), 7.22~7.51 (m, 4H)

¹³ CNMR(100MHz,CDCl ₃ ) 518.8, 71.5, 74.4, 127.1 , 128.1 , 128.9, 129.5, 132.6, 138.9

Preparation Example 15: Synthesis of l-(2-chlorophenyl)-(R,R)-li2-propanediol

l -(2-chlorophenyl)-trans- l -propene (2.5g, Preparation Example 1) was dissolved in 50mL of the mixture of t-BuOH/H ₂ 0 (1 : 1 (V/V)). At 0 ^° C , AD-mix-a (Aldrich, U.S.A.) (23.5g) and methane sulfone amide (CH ₃ S0 ₂ NH ₂ , 1.27g, 0.013mol) were added thereto and stirred for overnight. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na ₂ S0 ₃ ) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (2.96g, yield 90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.20(d, J=6.4Hz, 3H), 2.48(d, J=4.0Hz, 1H), 2.92(d, J=4.4Hz, 1 H), 3.93~3.97(m, 1H), 4.97(t, J=4.8Hz, 1H), 7.22~7.51 (m, 4H)

Preparation Example 16: Synthesis of the mixture of l-(2-chlorophenyl)-(S,S)- 1,2-propanediol and l-(2-chlorophenyl)-(R,R)-l,2-propanedioI

l -(2-chlorophenyl)-trans-l -propene(6.53g, Preparation Example 1) was dissolved in 45mL of the mixture of acetone/t-BuOH/H ₂ 0(5: l : l V/V). At the room temperature, N- methylmorpholine-N-oxide (7.5 l g) and OsO 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 methylenechloride (MC). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (6.42g, yield 80%).

Ή NMR(400MHz, CDC1 ₃ ) 61.20(d, J=6.4Hz, 3H), 2.48(d, J=4.0Hz, 1H), 2.92(d, J=4.4Hz, 1 H), 3.93~3.97(m, 1H), 4.97(t, J=4.8Hz, 1H), 7.22~7.51 (m, 4H)

Preparation Example 17: Synthesis of l-(2-chlorophenyl)-(S,S)-l,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1 -(2-chlorophenyl)-trans- 1 -butene(Preparation Example 2) was used instead of l -(2-chlorophenyl)-trans-l -propene(Preparation Example 1 ), to obtain the title compound (0.36g, yield 95%).

Ή NMR(400MHz, CDC1 ₃ ) 51.01(t, J=7.4Hz, 3H), 1.52~1.65(m, 2H), 2.01(d, J=4.4Hz, 1H), 2.74(d, J=5.2Hz, 1H), 3.69~3.75(m, 1H), 5.05(t, J=5.0Hz, 1H), 7.23~7.54(m, 4H)

Preparation Example 18: Synthesis of l-(2-chlorophenyl)-(R,R)-lj2-butanedioI

The substantially same method as described in Preparation Example 15 was conducted, except that 1 -(2-chlorophenyl)-trans- 1 -butene(Preparation Example 2) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.84g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 61.01(t, J=7.4Hz, 3H), 1.52~1.65(m, 2H), 2.01(d, J=4.4Hz, 1H), 2.74(d, J=5.2Hz, 1H), 3.69~3.75(m, 1H), 5.05(t, J=5.0Hz, 1H), 7.23~7.54(m, 4H)

Preparation Example 19: Synthesis of the mixture of l-(2-chlorophenyl)-(S,S)- 1,2-butanediol and l-(2-chlorophenyl)-(R,R)-l,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2-chlorophenyl)-trans-l-butene(Preparation Example 2) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (5.1g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.01(t, J=7.4Hz, 3H), 1.52~1.65(m, 2H), 2.01(d, J=4.4Hz, 1H), 2.74(d, J=5.2Hz, 1H), 3.69~3.75(m, 1H), 5.05(t, J=5.0Hz, 1H), 7.23~7.54(m, 4H)

Preparation Example 20: Synthesis of l-(2-chlorophenyl)-3-methyI-(S,S)-l,2- butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2-chlorophenyl)-3 -methyl-trans- 1 -butene(Preparation Example 3) was used instead of 1 -(2-chlorophenyl)-trans- 1 -propene(Preparation Example 1), to obtain the title compound (0.96g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 51.07(t, J=7.2Hz, 6H), 1.83~1.89(m, 1H), 1.92(d, J=5.6Hz, 1H), 2.69(d, J=6.4Hz, 1H), 3.53~3.56(m, 1H), 5.22~5.25(m, 1H), 7.23~7.55(m, 4H)

Preparation Example 21: Synthesis of l-(2-chlorophenyl)-3-methyl-(R,R)-l,2- butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l-(2-chlorophenyl)-3 -methyl-trans- l-butene(Preparation Example 3) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (4.2g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.07(t, J=7.2Hz, 6H), 1.82~1.90(m, 1H), 1.93(d, J=5.6Hz, 1H), 2.79(d, J=6Hz, 1H), 3.53~3.57(m, 1H), 5.23~5.25(m, 1H), 7.23~7.54(m, 4H)

Preparation Example 22: Synthesis of the mixture of l-(2-chlorophenyl)-3- methyI- -l ,2-butanediol and l-(2-chlorophenyl)-3-methyl-(R,R)-l ,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2-chlorophenyl)-3 -methyl-trans- l-butene(Preparation Example 3) was used instead of l-(2-chlorophenyl)-trans-l -propene(Preparation Example 1), to obtain the title compound (0.8g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.07(t, J=7.2Hz, 6H), 1.83~1.90(m, 1H), 1.92(d, J=5.6Hz, 1H), 2.69(d, J=6.4Hz, 1H), 3.53-3.56(m, 1H), 5.22~5.25(m, 1H), 7.23-7.55(m, 4H) Preparation Example 23: Synthesis of l-(2-chlorophenyl)-(S,S)-l,2-hexanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2-chlorophenyl)-trans-l-hexene(Preparation Example 4) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.37g, yield 90%).

1H NMR(400MHz, CDC1 ₃ ) 50.90(t, J=7.2Hz, 3H), 1.35~1.65(m, 6H), 2.08(d, J=4.4Hz, IH), 2.71(d, J=5.2Hz, IH), 3.78~3.83(m, IH), 5.04(t, J=5.0Hz, IH), 7.23~7.53(m, 4H)

Preparation Example 24: Synthesis of l-(2-chIorophenyl)-(R,R)-l _? 2-hexanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l -(2-chlorophenyl)-trans-l-hexene(Preparation Example 4) was used instead of l-(2-chlorophenyl)-trans-l -propene(Preparation Example 1), to obtain the title compound (4.2g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 50.91(t, J=6.6Hz, 3H), 1.35~1.65(m, 6H), 2.08(d, J=4.8Hz, IH), 2.70(d, J=5.2Hz, IH), 3.80~3.83(m, IH), 5.05(t, J=5.0Hz, IH), 7.24~7.56(m, 4H)

Preparation Example 25: Synthesis of the mixture of l-(2-chlorophenyl)-(S,S)- 1,2-hexanediol and l-(2-chlorophenyl)-(R,R)-l,2-hexanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l -(2-chlorophenyl)-trans-l-hexene(Preparation Example 4) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (7.9g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 50.90(t, J=7.2Hz, 3H), 1.26~1.55(m, 6H), 2.08(d, J=4.4Hz, 1H), 2.71(d, J=5.6Hz, 1H), 3.78-3.84(m, 1H), 5.04(t, J=3.2Hz, 1H), 7.24~7.55(m, 4H)

Preparation Example 26: Synthesis of l-(2,4-dichlorophenyl)-(S,S)-l,2- propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2,4-ichlorophenyl)-trans-l-propene(Preparation Example 5) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.33g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 61.22(d, J=6.4Hz, 3H), 2.10(d, J=4.4Hz, 1H), 2.71(d, J=4.8Hz, 1H), 3.90~3.95(m, 1H), 4.94(t, J=5.0Hz, 1H), 7.31(dd, J=2.0Hz, J=8.0Hz, 1H), 7.40(d, J=2.0Hz, 1H), 7.49(d, J=8.4Hz, 1H)

Preparation Example 27: Synthesis of l-(2,4-dichlorophenyl)-(R,R)-l,2- propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l-(2,4-ichlorophenyl)-trans-l-propene(Preparation Example 5) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.45g, yield 60-95%).

1H NMR(400MHz, CDC1 ₃ ) 51.22(d, J=6.4Hz, 3H), 2.10(d, J=4.4Hz, 1H), 2.71(d, J=4.8Hz, 1H), 3.90~3.95(m, 1H), 4.94(t, J=5.0Hz, 1H), 7.31~7.49(m, 3H)

Preparation Example 28: Synthesis of the mixture of l-(2,4-dichlorophenyl)- (S,S)-l,2-propanediol and l-(2,4-dichlorophenyl)-(R,R)-l,2-propanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2,4-ichlorophenyl)-trans-l-propene(Preparation Example 5) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.45g, yield 60-95%).

1H NMR(400MHz, CDC1 ₃ ) 61.22(d, J=6.4Hz, 3H), 2.10(d, J=4.4Hz, 1H), 2.71(d, J=4.8Hz, 1H), 3.90~3.95(m, 1H), 4.94(t, J=5.0Hz, 1H), 7.31~7.49(m, 3H)

Preparation Example 29: Synthesis of l-(2,4-dichlorophenyl)-(S,S)-l,2- butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2,4-dichlorophenyl)-trans-l-butene(Preparation Example 6) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.32g, yield 90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.02(t, J=7.4Hz, 3H), 1.54~1.61(m, 2H), 2.07(d, J=4.8Hz, 1H), 2.74(d, J=4.8Hz, 1H), 3.65~3.68(m, 1H), 5.01(t, J=5.0Hz, 1H), 7.31~7.49(m, 3H)

Preparation Example 30: Synthesis of l-(2,4-dichlorophenyl)-(R,R)-lj2- butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l-(2,4-dichlorophenyl)-trans-l-butene(Preparation Example 6) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.43g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 51.02(t, J=7.4Hz, 3H), 1.54~1.61(m, 2H), 2.07(d, J=4.8Hz, 1 H), 2.74(d, J=4.8Hz, 1H), 3.65~3.68(m, 1H), 5.01 (t, J=5.0Hz, 1H), 7.31~7.49(m, 3H)

Preparation Example 31: Synthesis of the mixture of l-(2,4-dichlorophenyl)- (S,S)-l,2-butanediol and l-(2,4-dichlorophenyl)-(R,R)-l,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l -(2,4-dichlorophenyl)-trans-l -butene(Preparation Example 6) was used instead of 1 -(2-chlorophenyl)-trans- 1 -propene(Preparation Example 1), to obtain the title compound (0.33g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.02(t, J=7.4Hz, 3H), 1.54~1.61 (m, 2H), 2.07(d, J=4.8Hz, 1H), 2.74(d, J=4.8Hz, 1H), 3.65~3.68(m, 1H), 5.01 (t, J=5.0Hz, 1H), 77.31~7.49(m, 3H) Preparation Example 32: Synthesis of l-(2,4-dichlorophenyI)-3-methyl-(S,S)-l,2- butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l -(2,4-dichlorophenyl)-3-methyl-trans-l-butene(Preparation Example 7) was used instead of l -(2-chlorophenyl)-trans-l -propene(Preparation Example 1), to obtain the title compound (0.25g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 51.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1 H), 2.35(d, J=4.0Hz, 1 H), 3.12(d, J=8.4Hz, 1H), 4.13~4.18(m, 1 H), 5.36(t, J=7.6Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 33: Synthesis of l-(2,4-dichlorophenyl)-3-methyl-(R,R)- 1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l -(2,4-dichlorophenyl)-3 -methyl -trans- l-butene(Preparation Example 7) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.36g, yield 60-95%).

lH NMR(400MHz, CDC1 ₃ ) 61.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1H), 2.35(d, J=4.0Hz, 1H), 3.12(d, J=8.4Hz, 1H), 4.13~4.18(m, 1H), 5.36(t, J=7.6Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 34: Synthesis of the mixture of l-(2,4-dichlorophenyi)-3- methyl- -l ,2-butanediol and l-(2,4-dichlorophenyl)-3-methyl-(R,R)-l ,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2,4-dichlorophenyl)-3-methyl-trans-l-butene(Preparation Example 7) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.26g, yield 60-95%).

Ή NMPv(400MHz, CDC1 ₃ ) 51.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1H), 2.35(d, J=4.0Hz, 1H), 3.12(d, J=8.4Hz, 1H), 4.13~4.18(m, 1H), 5.36(t, J=7.6Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 35: Synthesis of l-(2,4-dichlorophenyl)-(S,S)-l,2- hexanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2,4-dichlorophenyl)-trans-l-hexene(Preparation Example 8) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (l . lg, yield 60-90%). 1H NMR(400MHz, CDC1 ₃ ) 50.89~0.93(m, 3H), 1.30~1.39(m, 2H), 1.49~1.52(m, 2H), 1.56~1.62(m, 2H), 2.05(d, J=5.2Hz, IH), 2.74(d, J=5.2Hz, IH), 3.72~3.77(m, IH), 4.98(t, J=4.8Hz, I H), 7.28~7.50(m, 3H) Preparation Example 36: Synthesis of l-(2,4-dichlorophenyI)-(R,R)-l>2- hexanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l -(2,4-dichlorophenyl)-trans- l -hexene(Preparation Example 8) was used instead of l -(2-chlorophenyl)-trans-l -propene(Preparation Example 1), to obtain the title compound (1.2g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 60.89~0.93(m, 3H), 1.30~1.39(m, 2H), 1.49~1.52(m, 2H), 1.56~1.62(m, 2H), 2.05(d, J=5.2Hz, IH), 2.74(d, J=5.2Hz, IH), 3.72~3.77(m, IH), 4.98(t, J=4.8Hz, IH), 7.28~7.50(m, 3H)

Preparation Example 37: Synthesis of the mixture of l-(2,4-dichlorophenyl)- (S,S)-l,2-hexanediol and l-(2,4-dichlorophenyl)-(R,R)-l)2-hexanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l -(2,4-dichlorophenyl)-trans-l -hexene(Preparation Example 8) was used instead of l -(2-chlorophenyl)-trans- l -propene(Preparation Example 1 ), to obtain the title compound (0.67g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 50.89~0.93(m, 3H), 1.30~1.39(m, 2H), 1.49~1.52(m, 2H), 1.56~1.62(m, 2H), 2.05(d, J=5.2Hz, IH), 2.74(d, J=5.2Hz, IH), 3.72~3.77(m, IH), 4.98(t, J=4.8Hz, IH), 7.28~7.50(m, 3H)

Preparation Example 38: Synthesis of l-(2,6-dichlorophenyl)-(S,S)-l,2- propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2,6-dichlorophenyl)-trans-l-propene(Preparation Example 9) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.9g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.10(d, J=6.4Hz, 3H), 2.72(d, J=2.4Hz, 1H), 3.10(d, J=8.4Hz, 1H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7.36(m, 3H)

Preparation Example 39: Synthesis of l-(2,6-dichlorophenyI)-(R,R)-l,2- propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l -(2,6-dichlorophenyl)-trans-l-propene(Preparation Example 9) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.84g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.10(d, J=6.4Hz, 3H), 2.72(d, J=2.4Hz, 1H), 3.10(d, J=8.4Hz, 1H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7.36(m, 3H)

Preparation Example 40: Synthesis of the mixture of l-(2,6-dichlorophenyl)- (S,S)-l _? -propanediol and l-(2,6-dichlorophenyl)-(R,R)-l _? 2-propanedioI

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2,6-dichlorophenyl)-trans-l-propene(Preparation Example 9) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.9 lg, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.10(d, J=6.4Hz, 3H), 2.72(d, J=2.4Hz, 1H), 3.10(d, J=8.4Hz, 1H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7.36(m, 3H)

Preparation Example 41: Synthesis of l-(2,6-dichlorophenyl)-(S,S)-l,2- butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2,6-dichlorophenyl)-trans-l-butene(Preparation Example 10) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (1.23g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 60.97(t, J=7.6Hz, 3H), 1.26~1.53(m, 2H), 2.64(dd,

J=0.8Hz, J=4.0Hz, 1H), 3.14(d, J=8.4Hz, 1H), 4.22~4.26(m, 1H), 5.26(t, J=8.4Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 42: Synthesis of l-(2,6-dichlorophenyl)-(R,R)-l,2- butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l-(2,6-dichlorophenyl)-trans-l-butene(Preparation Example 10) was used instead of l -(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.96g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 50.97(t, J=7.6Hz, 3H), 1.26~1.53(m, 2H), 2.64(dd, J=0.8Hz, J=4.0Hz, 1H), 3.14(d, J=8.4Hz, 1H), 4.22~4.26(m, 1H), 5.26(t, J=8.4Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 43: Synthesis of the mixture of l-(2,6-dichlorophenyl)- (S,S)-l,2-butanediol and l-(2,6-dichlorophenyl)-(R,R)-l,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2,6-dichlorophenyl)-trans-l-butene(Preparation Example 10) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.86g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 50.97(t, J=7.6Hz, 3H), 1.26~1.53(m, 2H), 2.64(dd, J=0.8Hz, J=4.0Hz, 1H), 3.14(d, J=8.4Hz, 1H), 4.22~4.26(m, 1H), 5.26(t, J=8.4Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 44: Synthesis of l-(2,6-dichlorophenyl)-3-methyl-(S,S)-l,2- butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1 -(2, 6-dichlorophenyl)-3 -methyl-trans- l-butene(Preparation Example 1 1) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.25g, yield 60-95%).

Ή NMR(400MHz, CDCI3) 51.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1H), 2.35(d, J=4.0Hz, 1H), 3.12(d, J=8.4Hz, 1H), 4.13~4.18(m, 1H), 5.36(t, J=7.6Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 45: Synthesis of l-(2,6-dichlorophenyl)-3-methyl-(R,R)- 1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l -(2,6-dichlorophenyl)-3-methyl-trans-l-butene(Preparation Example 1 1) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.37g, yield 60-95%).

Ή NMR(400MHz, CDC1 ₃ ) 81.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1H), 2.35(d, J=4.0Hz, 1H), 3.12(d, J=8.4Hz, 1H), 4.13~4.18(m, 1H), 5.36(t, J=7.6Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 46: Synthesis of the mixture of l-(2,6-dichlorophenyl)-3- methyl-(S,S)-l,2-butanediol and l-(2,6-dichIorophenyl)-3-methyl-(R,R)-l ₅ 2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1 -(2, 6-dichlorophenyl)-3 -methyl -trans- 1 -butene(Preparation Example 1 1) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.47g, yield 60-95%).

1H NMR(400MHz, CDC1 ₃ ) 51.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1 H), 2.35(d, J=4.0Hz, 1H), 3.12(d, J-8.4Hz, 1H), 4.13~4.18(m, 1H), 5.36(t, J=7.6Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 47: Synthesis of l-(2,6-dichlorophenyl)-(S,S)-l,2- hexanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l -(2,6-dichlorophenyl)-trans-l-hexene(Preparation Example 12) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.36g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 50.85(t, J=6.8Hz, 3H), 1.20-1.3 l(m, 4H), 1.45~1.53(m, 2H), 2.61~2.62(m, 1H), 3.12(d, J=8.4Hz, 1H), 4.28~4.33(m, 1H), 5.25(t, J=8.4Hz, 1H), 7.18~7.35(m, 3H)

Preparation Example 48: Synthesis of l-(2,6-dichlorophenyl)-(R,R)-l,2- hexanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l -(2,6-dichlorophenyl)-trans-l -hexene(Preparation Example 12) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.58g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 60.85(t, J=6.8Hz, 3H), 1.20-1.3 l(m, 4H), 1.45~1.53(m, 2H), 2.61~2.62(m, 1H), 3.12(d, J=8.4Hz, 1H), 4.28~4.33(m, 1H), 5.25(t, J=8.4Hz, 1H), 7.18~7.35(m, 3H)

Preparation Example 49: Synthesis of the mixture of l-(2,6-dichlorophenyI)- (S,S)-l,2-hexanediol and l-(2,6-dichlorophenyl)-(R,R)-l,2-hexanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2,6-dichlorophenyl)-trans-l-hexene(Preparation Example 12) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.62g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 50.85(t, J=6.8Hz, 3H), 1.20-1.3 l(m, 4H), 1.45-1.53(m, 2H), 2.61~2.62(m, 1H), 3.12(d, J=8.4Hz, 1H), 4.28-4.33(m, 1H), 5.25(t, J=8.4Hz, 1H), 7.18~7.35(m, 3H)

Preparation Example 50: Synthesis of methyl 2-(2-chIorophenyl)-(R)-2- hydroxyacetate

15g of (R)-2-chloromandelic acid was mixed with methanol (CH ₃ OH, 150ml) and phosphorus chloride oxide (POCl ₃ , 0.76ml) in a flask by stirring using a magnetic stirrer at the room temperature for 6 hours. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na ₂ S0 ₃ ) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (15.64g, yield 95%).

Ή NMR(400MHz, CDC1 ₃ ) δ 3.59(d, J=5.2, 1H), 3.79(t, J=6.0, 3H), 5.59(d, J=5.2, 1H), 7.28~7.43(m, 4H)

Preparation Example 51: Synthesis of 2-(2-chlorophenyl)-(R)-2-hydroxy-N- methoxy-N-methylacetamide

Ν,Ο-dimethylhydroxylamine hydrochloride (Ν,Ο-dimethylhydroxyIamine.HCl, 15.2g) was dissolved in dichloromethane (DCM, 150ml), and cooled to 0 ^° C using an ice- bath. Then, 77.7ml of 2.0M trimethylaluminium in hexane was slowly added thereto in drop- wise manner for 30 minutes. Thereafter, the ice-bath was removed, and the obtained product was stirred at the room temperature for 2 hours. Methyl-2-(2-chlorophenyl)-(R)-2- hydroxyacetate(15.64g) dissolved in dichloromethane(DCM, 150ml) was added in drop-wise manner thereto at the room temperature for 30 minutes, and subjected to reflux for 12 hours. When the reaction was completed, the obtained product was cooled to 0 ^° C , and washed by a slow drop-wise addition of hydrochloric acid (HC1, 200ml). The obtained organic layer was washed with distilled water and brine, dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (14.68g, yield

82%).

Ή NMR(400MHz, CDC1 ₃ ) 63.23(s, 3H), 3.28(s, 3H), 4.33(d, J=6.0Hz, 1H), 5.81(d, J=5.6Hz, 1H), 7.23~7.42(m, 4H)

Preparation Example 52: Synthesis of 2-(2-chlorophenyl)-N-methoxy-(R)-2-(t- butyl dimethlysiloxy)-N-methylacetamide

2-(2-chlorophenyl)-(R)-2-hydroxy-N-methoxy-N-methylacetamide (0.81g, 3.52mmol) obtained in Preparation Example 51 was dissolved in dichloromethane (DCM), and cooled to 0 ^° C . Imedazole (0.36g, 5.28mmol) was slowly added, and stirred. TBDMS-Cl (t-butyldimethylsily chloride, 0.79g, 5.28mmol) was slowly added. When the reaction was completed, the reaction mixture was quenched with H ₂ 0. The organic layer was separated and collected. The aqueous layer was extracted with CH ₂ C1 ₂ (300mL), dried over MgS0 ₄ . Concentration under vacuum provided a title compound. (0.97g, 80~95%).

. Ή NMR(400MHz, CDC1 ₃ ) 6-0.03(s, 3H), 0.14(s, 3H), 0.94(s, 9H), 2.97(s, 3H), 3.02(s, 3H), 5.83(s, 1H), 7.25~7.60(m, 4H)

Preparation Example 53: Synthesis of l-(2-chlorophenyl)-(R)-l-(t- butyldimethyl-siloxy)propane-2-on

2-(2-chlorophenyl)-N-methoxy-(R)-2-(t-butyldimethylsiloxy)-N - methylacetamide(0.9g) obtained in Preparation Example 52 was dissolved in tetrahydrofuran(THF), and cooled to 0 ^° C . 3.0M methyl magnesium bromide (MeMgBr, 2.18ml) solution in ether was added thereto in drop- wise manner for 30 minutes, and the obtained product was stirred at 0 ^° C . When the reaction was completed, diethylether was added thereto. The obtained product was washed with 10%(w/v) potassium hydrogen sulfate (KHS0 _4; 100ml) and then, washed again with brine. The obtained organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (0.69g, yield 85~95%).

Ή NMR(400MHz, CDC1 ₃ ) 5-0.3(s, 3H), 0.14(s, 3H), 0.94(s, 9H), 2.18(s, 3H), 5.50(s, 1H), 7.27~7.56(m, 4H)

Preparation Example 54: Synthesis of l-(2-chlorophenyl)-(R)-l-(t- butyldimethyl-siloxy)-(S)-2-propanol

1 -(2-chlorophenyl)-(R)- 1 -(t-butyldimethyl-siloxy)propane-2-on(0.14g) obtained in Preparation Example 53 was dissolved in ether, and cooled to -78 ^" C . Zinc borohydride(Zn(BH ₄ ) ₂ ) was slowly added thereto and the obtained product was stirred. When the reaction was completed, the obtained product was washed by H ₂ 0. The obtained organic layer was washed with H ₂ 0, dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (0.04g, yield 25-33%, cis : trans = 2 : 1).

Ή NMR(400MHz, CDC1 ₃ ) 5-0.11(s, 3H), 0.1 l (s, 3H), 0.93(S, 9H), 1.07(d, J=6.4 3H), 2.05(d, J=6.4 1H), 4.01~4.05(m, 1H), 5.18(d, J=4.0, 1H), 7.20~7.56(m, 4H))

Preparation Example 55: Synthesis of l-(2-chiorophenyI)-(R,S)-l,2- propanediol

1 -(2-chlorophenyl)-(R)- 1 -(t-butyldimethyl-siloxy)-(S)-2-propanol( 10.38g) obtained in Preparation Example 54 was dissolved in methanol (CH ₃ OH, 100ml), and then, cooled to 0 ^° C . 8M hydrochloric acid(HCl, 56.2ml) was slowly added in drop-wise manner to the obtained product, and then, the obtained product was warmed to the room temperature, and stirred for 15 hours. When the reaction was completed, the obtained product was cooled to 0 ^° C . 5N sodium hydroxide (NaOH, 30ml) was slowly added thereto, and the obtained product was subjected to vacuum concentration. The obtained product was diluted with ethylacetate. The obtained organic layer was washed with distilled water, dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (7.05g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.07(d, J=6.8, 3H), 2.01(d, J=5.6, 1H), 2.61 (s, 1H), 4.21~4.27(m, 1H), 5.24(d, J=3.6, 1H), 7.22~7.64(m, 4H) Preparation Example 56: Synthesis of l-(2-chlorophenyl)-(S,R)-l _? 2-propanediol

The substantially same method as described in Preparation Example 50-55 was conducted, except that (S)-2-chloromandelic acid was used instead of (R)-2-chloromandelic acid, to obtain the title compound (5.04g, yield 84%).

Ή NMR(400MHz, CDC1 ₃ ) 61.07(d, J=6.8, 3H), 2.00(d, J=5.6, 1H), 2.54(d, J=3.6, 1H), 4.22~4.26(m, 1H), 5.25(t, J=3.2, 1H), 7.22~7.65(m, 4H)

Preparation Example 57: Synthesis of l-(2,3-dichlorophenyl)-(S,S)-l,2- propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2,3-dichlorophenyl)-trans-l-propene(Preparation Example 13) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.9g, yield 60-90%).

Ή NMPv(400MHz, CDC1 ₃ ) 51.10(d, J=6.4Hz, 3H), 2.72(d, J=2.4Hz, 1H), 3.10(d, J=8.4Hz, 1H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18- (m, 3H)

Preparation Example 58: Synthesis of l-(2,3-dichlorophenyl)-(R,R)-lj2- propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that l-(2,3-dichlorophenyl)-trans-l-propene(Preparation Example 13) was used instead of l-(2-chlorophenyl)-trans-l-propene(Preparation Example 1), to obtain the title compound (0.84g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.10(d, J=6.4Hz, 3H), 2.72(d, J=2.4Hz, 1H), 3.10(d, J=8.4Hz, 1H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18- (m, 3H)

Preparation Example 59: Synthesis of the mixture of l-(2,3-dichlorophenyl)- (S,S)-l,2-propanedioI and l-(2,3-dichlorophenyI)-(R,R)-l,2-propanediol

The substantially same method as described in Preparation Example 16 was conducted, except that l-(2,3-dichlorophenyl)-trans-l-propene(Preparation Example 13) was used instead of l -(2-chlorophenyl)-trans-l -propene(Preparation Example 1), to obtain the title compound (0.9 lg, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.10(d, J=6.4Hz, 3H), 2.72(d, J=2.4Hz, 1H), 3.10(d, J=8.4Hz, 1H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~(m, 3H)

Preparation Example 60: Synthesis of l-(2-fluorophenyl)-trans-l-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2-fiuorobenzenaldehyde was used instead of 2-chlorobenzenealdehyde, to obtain the title compound (6.67g, yield 61%).

Ή NMR(400MHz, CDC1 ₃ ) 51.94(d, J=6.8Hz, 3H), 6.30~6.38(m, 1H), 6.57(d, J=16Hz, 1H), 7.00~7.41(m, 4H)

Preparation Example 61: Synthesis of l-(2-fluorophenyl)-(S,S)-l,2-propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l-(2-fluorophenyl)-trans-l-propene (Preparation Example 60) was used instead of l-(2-chlorophenyl)-trans-l-propene (Preparation Example 1), to obtain the title compound (6.46g, yield 78%).

Ή NMR(400MHz, CDC1 ₃ ) 51.15(d, J=6.4Hz, 3H), 2.43(d, J=3.6Hz, lH), 2.69(d, J=4.8Hz, 1H), 3.90~3.98(m, 1H), 4.78(dd, J=4.4, 7.2Hz, 1H), 7.04~7.50(m, 4H)

Preparation Example 62: Synthesis of l-(2-fluorophenyl)-(R,R)-l,2-propanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1 -(2-fluorophenyl)-trans- 1 -propene (Preparation Example 60) was used instead of l-(2-chlorophenyl)-trans-l -propene (Preparation Example 1), to obtain the title compound (3.29g, yield 79%).

Ή NMR(400MHz, CDC1 ₃ ) 51.15(d, J=6.4Hz, 3H), 2.43(d, J=3.6Hz, 1H), 2.69(d, J=4.8Hz, 1H), 3.90~3.98(m, 1H), 4.78(dd, J=4.4, 7.2Hz, 1H), 7.04~7.50(m, 4H)

Preparation Example 63: Synthesis of 2-iodobenzenealdehyde

In a flask, 2-iodobenzyl alcohol (4g, 17.09mmol) was dissolved in dichloromethane (MC, 85ml), and then, manganese oxide (Mn0 ₂ , 14.86g, 170.92mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6g, yield 91%).

'H NMR(400MHz, CDCl ₃ )57.30~7.99(m, 4H), 10.10(s, 1H)

Preparation Example 64: Synthesis of l-(2-iodophenyl)-trans-l-propene

The substantially same method as described in Preparation Example 1 was conducted, except that 2-iodobenzenealdehyde (Preparation Example 63) was used instead of 2- chlorobenzenealdehyde, to obtain the title compound (3.4g, yield 65%).

lH NMR(400MHz, CDCl ₃ )61.95(dd, J=6.8Hz, 1.6Hz, 3H), 6.09-6.18(m, 1H), 6.60(dd, J=l 5.66Hz, 1.8Hz, 1H), 6.89~7.84(m, 4H) Preparation Example 65: Synthesis of l-(2-iodophenyl)-trans-l-butene

The substantially same method as described in Preparation Example 64 was conducted, except that 3-heptanone was used instead of 3-pentanone, to obtain the title compound (8.5g, yield 75%).

Ή NMR(400MHz, CDCl ₃ )51.46(t, J=7.6Hz, 3H), 2.26~2.34(m, 2H), 6.17(dt, J=l 5.6Hz, 6.6Hz 1 H), 6.57(d, J=15.6Hz, 1H), 6.89~7.85(m, 4H)

Preparation Example 66: Synthesis of l-(2-iodophenyl)-(S,S)-l,2-propanediol

The substantially same method as described in Preparation Example 14 was conducted, except that l -(2-iodophenyl)-trans-l -propene (Preparation Example 64) was used instead of 1 -(2-chlorophenyl)-trans- 1 -propene (Preparation Example 1), to obtain the title compound (3.4g, yield 88%).

Ή NMR(400MHz, CDCl ₃ )61.27(d, J=6.4Hz, 3H), 2.26(br s, 1 H), 2.74(br s, 1H),

3.99(t, J=6.0Hz, 1H), 4.81 (d, J=4.0Hz, 1 H), 7.01~7.87(m, 4H)

Preparation Example 67: Synthesis of l-(2-iodorophenyi)-(R,R)-l _> 2-propanediol

The substantially same method as described in Preparation Example 15 was conducted was conducted, except that l -(2-iodophenyl)-trans-l -propene (Preparation Example 64) was used instead of l -(2-chlorophenyl)-trans-l -propene (Preparation Example 1), to obtain the title compound (7.4g, yield 84%).

Ή NMR(400MHz, CDCl ₃ )61.26(d, J=6.4Hz, 3H), 2.35(br s, 1 H), 2.85(br d, J=4.0Hz, 1H), 3.98(t, J=6.2Hz, 1 H), 4.80(dd, J=5.0, 4.4Hz, 1 H), 7.00~7.87(m, 4H)

Preparation Example 68: Synthesis of l-(2- iodophenyl)-(S,S)-l,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted was conducted, except that l-(2-iodophenyl)-trans-l-butene (Preparation Example 65) was used instead of l-(2-chlorophenyl)-trans-l-propene (Preparation Example 1), to obtain the title compound (9.5g, yield 84%).

Ή NMR(400MHz, CDCl ₃ )51.04(t, J=7.6Hz, 3H), 1.60~1.71(m, 2H), 2.07(br s, 1H), 2.74(br s, 1H), 3.71~3.76(m, 1H), 4.87(d, J=4.8Hz, 1H), 7.01~7.87(m, 4H)

Preparation Example 69 : Preparation of l-(2-chlorophenyl)-(S,S)-l,2-(Bis- trimethylsilanyloxy) propane

To a stirred solution of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4, 67g, 0.35mol) in CH ₂ C1 ₂ (670ml) was added Et ₃ N (200mL, 1.43mol) and TMSC1

(113.9mL, 0.89mol) at 0°C under N ₂ . The reaction mixture was allowed to stir at 0°C for 3hr. The reaction mixture was quenched with H ₂ 0 (650mL) at 0°C. The organic layer was separated and collected. The aqueous layer was extracted with CH ₂ C1 ₂ (300mL), dried over MgS0 ₄ . Concentration under vacuum provided a crude product. 104.18g ( 117.44%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.15(d, J=5.6Hz, 3H), 3.977-3.918(m, 1H), 4.973(d, J=6.4Hz, 1H), 7.207~7.165(m,lH), 7.321~7.245(m, 2H), 7.566~7.543(m, 1H)

Preparation Example 70 : Preparation of l-(2-chIorophenyI)-(R,R)-l _» 2-(Bis- trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1 -(2-chlorophenyl)-(R,R)- 1 ,2-propanediol(Preparation example 15) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (8.5g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.15(d, J=5.6Hz, 3H), 3.977~3.918(m, 1H), 4.973(d, J=6.4Hz, 1H), 7.21~7.54(m,4H)

Preparation Example 71 : Preparation of l-(2-chlorophenyl)— l,2-(Bis- trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)propane-l,2-diol(Preparation example 16)was used instead of l -(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4) to obtain the title compound (5.2g, yield 90-120%).

1H NMR(400MHz, CDCl ₃ )8-0.053(s, 9H), 0.044(s, 9H), 1.15(d, J=5.6Hz, 3H), 3.977-3.918(m, 1H), 4.973(d, J6.4Hz, 1H), 7.21-7.54(m,4H)

Preparation Example 72 : Preparation of l-(2-chlorophenyl)-(S,R)-l,2-(Bis- trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-(S,R)-l ,2-propanediol(Preparation example56)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4) to obtain the title compound (3.4g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.15(d, J=5.6Hz, 3H), 3.977-3.918(m, 1H), 4.973(d, J=6.4Hz, 1H), 7.21~7.54(m,4H)

Preparation Example 73 : Preparation of l-(2-chlorophenyl)-(R,S)-l,2-(Bis- trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-(R,S)-l ,2-propanediol(Preparation example55)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3.2g, yield 90-120%).

1H NMR(400MHz, CDCl ₃ )8-0.053(s, 9H), 0.044(s, 9H), 1.15(d, J=5.6Hz, 3H), 3.977-3.918(m, 1H), 4.973(d, J=6.4Hz, 1H), 7.21~7.54(m,4H)

Preparation Example 74 : Preparation of l-(2-chIorophenyl)-(S,S)-l,2-(Bis- trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-(S,S)-l,2-butanediol(Preparation example 17)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3.6g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.01(t, J=7.4Hz, 3H), 1.52~1.65(m, 2H), 3.69~3.75(m, 1H), 5.05(t, J=5.0Hz, 1H), 7.23~7.54(m,4H)

Preparation Example 75 : Preparation of l-(2-chlorophenyl)-(R,R)-l,2-(Bis- trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-(R,R)-l,2-butanediol(Preparation example 18)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4) to obtain the title compound (3.5g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.01(t, J=7.4Hz, 3H), 1.52~1.65(m, 2H), 3.69~3.75(m, 1H), 5.05(t, J=5.0Hz, 1H), 7.23~7.54(m,4H) Preparation Example 76 : Preparation of l-(2-chlorophenyl)-l,2-(Bis- trimethylsilanyloxy) butane

CI OTMS

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-l ,2-butanediol(Preparation example 19)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (3.0g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.01(t, J=7.4Hz, 3H), 1.52~1.65(m, 2H), 3.69~3.75(m, 1H), 5.05(t, J=5.0Hz, 1H), 7.23~7.54(m,4H)

Preparation Example 77 : Preparation of l-(2-chlorophenyl)-3-methyl-(S,S)- l,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-3-methyl-(S,S)-l,2-butanediol(Preparation example20)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4) to obtain the title (2.7g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.07(t, J=7.2Hz, 6H), 1.83~1.89(m, 1H), 3.53~3.56(m, 1H), 5.22~5.25(m, 1H), 7.23~7.55(m,4H)

Preparation Example 78 : Preparation of l-(2-chlorophenyl)-3-methyl-(R,R)- l,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-3-methyl-(R,R)-l,2-butanediol(Preparation example21)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (2.4g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.07(t, J=7.2Hz, 6H), 1.83~1.89(m, 1H), 3.53~3.56(m, 1H), 5.22~5.25(m, 1H), 7.23~7.55(m,4H)

Preparation Example 79 : Preparation of l-(2-chlorophenyl)-3-methyl-l,2- (Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-3 -methyl- 1 ,2-butanediol(Preparation example22)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4) to obtain the title compound (2.8g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )8-0.053(s, 9H), 0.044(s, 9H), 1.07(t, J=7.2Hz, 6H), 1.83~1.89(m, 1H), 3.53-3.56(m, 1H), 5.22~5.25(m, 1H), 7.23-7.55(m,4H)

Preparation Example 80 : Preparation of l-(2-chlorophenyl)-(S,S)-l,2-(Bis- trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-(S,S)-l ,2-hexanediol(Preparation example23)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (3.1g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 0.90(t, J=7.2Hz, 3H), 1.35~1.65(m, 6H), 3.78-3.83(m, 1H), 5.04(t, J=5.0Hz, 1H), 7.23~7.53(m,4H)

Preparation Example 81 : Preparation of l-(2-chlorophenyl)-(S,S)-l,2-(Bis- trimethylsilanyloxy)-hexane The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-(R,R)-l ,2-hexanediol(Preparation example24)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (3.3g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 0.90(t, J=7.2Hz, 3H), 1.35~1.65(m, 6H), 3.78~3.83(m, 1H), 5.04(t, J=5.0Hz, 1H), 7.23~7.53(m,4H)

Preparation Example 82 : Preparation of l-(2-chlorophenyl)-(S,S)-l,2-(Bis- trimethylsiIanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-chlorophenyl)-l,2-hexanediol(Preparation example25)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3.2g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.90(t, J=7.2Hz, 3H), 1.35~1.65(m, 6H), 3.78~3.83(m, 1H), 5.04(t, J=5.0Hz, 1H), 7.23~7.53(m,4H)

Preparation Example 83 : Preparation of l-(2,4-dichlorophenyl)-(S,S)-l,2- (Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l ,2-propanediol(Preparation example26)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation examplel4) to obtain the title compound (2.4g, yield 90~120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.22(d, J=6.4Hz, 3H), 3.90~3.95(m, 1H), 4.94(t, J=5.0Hz, 1H), 7.31(dd, J=2.0Hz, J=8.0Hz, 1H), 7.40(d, J=2.0Hz, 1H), 7.49(d, J=8.4Hz, 1H)

Preparation Example 84 : Preparation of l-(2,6-dichlorophenyl)-(S,S)-l,2- (Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl (S,S)-l ,2-propanediol(Preparation example38)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (3.4g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.10(d, J=6.4Hz, 3H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.13~7.36(m, 3H)

Preparation Example 85 : Preparation of l-(2,3-dichlorophenyl)-(S,S)-l,2- (Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,3-dichlorophenyl)-(S,S)-l,2-propanediol(Preparation example57)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation examplel4) to obtain the title compound (2.2g, yield 90~120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.10(d, J=6.4Hz, 3H,), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7,22(m, 3H)

Preparation Example 86 : Preparation of l-(2,4-dichlorophenyl)-(S,S)-l,2- (Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l,2-butanediol(Preparation example29)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3. lg, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.02(t, J=7.4Hz, 3H), 1.54~1.61(m, 2H), 3.65~3.68(m, 1H), 5.01(t, J=5.0Hz, 1H), 7.31~7.49(m, 3H) Preparation Example 87 : Preparation of l-(2,6-dichlorophenyI)-(S,S)-l,2- (Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l ,2-butanediol(Preparation example41)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (2.8g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.97(t, J=7.6Hz, 3H), 1.26~1.53(m, 2H), 4.22~4.26(m, IH), 5.26(t, J=8.4Hz, IH), 7.17~7.35(m, 3H)

Preparation Example 88 : Preparation of l-(2,4-dichlorophenyl)-3-methyl- (S,S)-l,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-3-methyl-(S,S)-l ,2-butanediol(Preparation example32)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (2.7g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.00(d, J=6.8Hz, 6H), 1.60~1.65(m, IH), 4.13~4.18(m, IH), 5.36(t, J=7.6Hz, IH), 7.30~7.53(m, 3H)

Preparation Example 89 : Preparation of l-(2,6-dichlorophenyl)-3-methyl- (S,S)-l,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-3-methyl-(S,S)-l ,2-butanediol(Preparation example44)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation exampleH) to obtain the title compound (3.3g, yield 90-120%).

'H NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.00(d, J=6.8Hz, 6H), 1.60~1.65(m, IH), 4.13~4.18(m, IH), 5.36(t, J=7.6Hz, IH), 7.17~7.35(m, 3H)

Preparation Example 90 : Preparation of l-(2,4-dichlorophenyl)-(S,S)-l,2- (Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l,2-hexanediol(Preparation example90)was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation exampleH) to obtain the title compound (3.6g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.89~0.93(m, 3H), 1.30-1.39(m, 2H), 1.49-1.52(111, 2H), 1.56~1.6(m, 2H), 3.72~3.77(m, IH), 4.98(t, J=4.8Hz, IH), 7.28~7.50(m, 3H)

Preparation Example 91 : Preparation of l-(2,6-dichlorophenyl)-(S,S)-l,2- (Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l ,2-hexanediol(Preparation example47)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation exampleH) to obtain the title compound (2.8g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.85(t, J=6.7Hz, 3H), 1.20~1.31(m, 4H), 1.45~1.53(m, 2H), 4.28~4.33(m, IH), 5.25(t, J=8.4Hz, IH), 7.18~7.35(m, 3H)

Preparation Example 92 : Preparation of l-(2,4-dichlorophenyl)-(R,R)-l,2- (Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l,2-propanediol(Preparation example27)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation examplel4) to obtain the title compound (2.2g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.22(d, J=6.4Hz, 3H), 3.90~3.95(m, 1H), 4.94(t, J=5.0Hz, 1H), 7.31~7.49(m, 3H)

Preparation Example 93 : Preparation of l-(2,6-dichlorophenyl)-(R,R)-l,2- (Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l ,2-propanediol(Preparation example39)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation exampleH) to obtain the title compound (2.6g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )8-0.053(s, 9H), 0.044(s, 9H), 1.10(d, J=6.4Hz, 3H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7.36(m, 3H)

Preparation Example 94 : Preparation of l-(2,3-dichlorophenyl)-(R,R)-l,2- (Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l -(2,3-dichlorophenyl)-(R,R)-l,2-propanediol(Preparation example58)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation exampleH) to obtain the title compound (2.9g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.10(d, J=6.4Hz, 3H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7.22(m, 3H) Preparation Example 95 : Preparation of l-(2,4-dichIorophenyl)-(R,R)-l _> 2-(Bis- trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l ,2-butanediol(Preparation example30)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (3.6g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.02(t, J=7.4Hz, 3H), 1.54~1.61(m, 2H), 3.65~3.68(m, IH), 5.01(t, J=5.0Hz, IH), 7.31~7.49(m, 3H)

Preparation Example 96 : Preparation of l-(2,6-dichlorophenyl)-(R,R)-l)2- (Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l,2-butanediol(Preparation example42)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3.3g, yield 90-120%).

1H NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.97(t, J=7.6Hz, 3H), 1.26~1.53(m, 2H), 4.22~4.26(m, IH), 5.26(t, J=8.4Hz, IH), 7.17~7.35(m, 3H)

Preparation Example 97 : Preparation of l-(2,4-dichlorophenyI)-3-methyl- (R,R)-l,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-3-methyl-(R,R)-l ,2-butanediol(Preparation example33)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation examplel4) to obtain the title compound (3.5g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1H), 4.13~4.18(m, 1H), 5.36(t, J=7.6Hz, 1H), 7.30~7.53(m, 3H)

Preparation Example 98 : Preparation of l-(2,6-dichlorophenyl)-3-methyl- (R,R)-l _> 2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l -(2,6-dichlorophenyl)-3-methyl-(R,R)-l ,2-butanediol(Preparation example45)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3.4g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.00(d, J=6.8Hz, 6H), 1.60~1.65(m, 1H), 4.13~4.18(m, 1H), 5.36(t, J=7.6Hz, 1H), 7.17~7.35(m, 3H)

Preparation Example 99 : Preparation of l-(2,4-dichlorophenyl)-(R,R)-l _» 2- (Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l ,2-hexanediol(Preparation example36)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14) to obtain the title compound (3.6g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.89~0.93(m, 3H), 1.30~1.39(m, 2H), 1.49~1.52(m, 2H), 1.56~1.62(m, 2H), 3.72~3.77(m, 1H), 4.98(t, J=4.8Hz, 1H), 7.28~7.50(m, 3H)

Preparation Example 100 : Preparation of l-(2,6-dichlorophenyl)-(R,R)-l,2- (Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l ,2-hexanediol(Preparation example48)was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation exampleH) to obtain the title compound (3.3g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.85(t, J=6.7Hz, 3H), 1.20-1.3 l(m, 4H), 1.45-1.53(m, 2H), 4.28~4.33(m, 1H), 5.25(t, J=8.4Hz, 1H), 7.18-7.35(m, 3H)

Preparation Example 101 : Preparation of l-(2,4-dichlorophenyl)-l,2-(Bis- trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-l,2-propanediol(Preparation example28)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation exampleH) to obtain the title compound (2.6g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.22(d, J=6.4Hz, 3H), 3.90~3.95(m, 1H), 4.94(t, J=5.0Hz, 1H), 7.31~7.49(m, 3H)

Preparation Example 102 : Preparation of l-(2,6-dichlorophenyi)-l,2-(Bis- trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-l,2-propanediol(Preparation example40)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4) to obtain the title compound (3.1g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.10(d, J=6.4Hz, 3H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7.36(m, 3H) Preparation Example 103 : Preparation of l-(2,3-dichlorophenyl)-l,2-(Bis- trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,3-dichlorophenyl)-l,2-propanediol(Preparation example59)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation examplel4) to obtain the title compound (2.7g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.10(d, J=6.4Hz, 3H), 4.47~4.54(m, 1H), 5.24(t, J=8.8Hz, 1H), 7.18~7.22(m, 3H)

Preparation Example 104 : Preparation of l-(2,4-dichlorophenyl)-l,2-(Bis- trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-l ,2-butanediol(Preparation example31)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (2.9g, yield 90-120%).

1H NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.02(t, J=7.4Hz, 3H), 1.54~1.61(m, 2H), 3.65~3.68(m, 1H), 5.01(t, J=5.0Hz, 1H), 7.31~7.49(m, 3H)

Preparation Example 105 : Preparation of l-(2,6-dichlorophenyl)-l,2-(Bis- trimethylsilanyloxy)-butane

'The substantially same method as described in Preparation Example 69 was conducted, except that l -(2,6-dichlorophenyl)-l,2-butanediol(Preparation example43)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3.1g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 0.97(t, J=7.6Hz, 3H), 1.26~1.53(m, 2H), 4.22~4.26(m, IH), 5.26(t, J=8.4Hz, IH), 7.17~7.35(m, 3H)

Preparation Example 106 : Preparation of l-(2,4-dichlorophenyI)-3-methyl- l,2-(Bis-trimethylsilanyIoxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-3 -methyl- l,2-butanediol(Preparation example34)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation exampleH) to obtain the title compound (2.7g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.00(d, J=6.8Hz, 6H), 1.60~1.65(m, IH), 4.13~4.18(m, IH), 5.36(t, J=7.6Hz, IH), 7.30~7.53(m, 3H)

Preparation Example 107 : Preparation of l-(2,6-dichlorophenyl)-3-methyI- l,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1 -(2, 6-dichlorophenyl)-3 -methyl- l,2-butanediol(Preparation example46)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation exampleH) to obtain the title compound (2.6g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.00(d, J=6.8Hz, 6H), 1.60~1.65(m, IH), 4.13~4.18(m, IH), 5.36(t, J=7.6Hz, IH), 7.17~7.35(m, 3H)

Preparation Example 108 : Preparation of l-(2,4-dichlorophenyl)-l,2-(Bis- trimethylsilanyloxy)-hexane The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,4-dichlorophenyl)-l,2-hexanediol(Preparation example37)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4) to obtain the title compound (3.7g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.89~0.93(m, 3H), 1.30~1.39(m, 2H), 1.49~1.52(m, 2H), 1.56~1.62(m, 2H), 3.72~3.77(m, IH), 4.98(t, J=4.8Hz, IH), 7.28~7.50(m, 3H)

Preparation Example 109 : Preparation of l-(2,6-dichIorophenyl)-l,2-(Bis- trimethyisilanyIoxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2,6-dichlorophenyl)-l,2-hexanediol(Preparation example49)was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation examplel4) to obtain the title compound (3.2g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 0.85(t, J=6.7Hz, 3H), 1.20-1.3 l(m, 4H), 1.45-1.53(m, 2H), 4.28~4.33(m, IH), 5.25(t, J=8.4Hz, IH), 7.18~7.35(m, 3H)

Preparation Example 110 : Preparation of l-(2-fluoroophenyl)-(S,S)-l,2-(Bis- trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-fluoroophenyl)-(S,S)-l,2-propanediol(Preparation example61)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation examplel4) to obtain the title compound (2.8g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.15(d, J=6.4Hz, 3H), 3.90~3.98(m, IH), 4.78(dd, J=4.4, 7.2Hz, IH), 7.04~7.50(m, 4H)

Preparation Example 111 : Preparation of l-(2-fulorophenyl)-(R,R)-l _> 2-(Bis- trimethylsiIanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-fluoroophenyl)-(R,R)-l ,2-propanediol(Preparation example62)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation exampleH) to obtain the title compound (2.5g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.15(d, J=6.4Hz, 3H), 3.90~3.98(m, 1H), 4.78(dd, J=4.4, 7.2Hz, 1H), 7.04~7.50(m, 4H)

Preparation Example 112 : Preparation of l-(2-iodophenyl)-(S,S)-l,2-(Bis- trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-iodophenyl)-(S,S)-l ,2-propanediol(Preparation example66)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation exampleH) to obtain the title compound (3.1 g, yield 90- 120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.27(d, J=6.4Hz, 3H), 3.99(t, J=6.0Hz, 1H), 4.81(d, J=4.0Hz, 1H), 7.01~7.87(m, 4H)

Preparation Example 113 : Preparation of l-(2-iodophenyl)-(R,R)-l,2-(Bis- trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-iodophenyl)-(R,R)-l,2-propanediol(Preparation example67)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation exampleH) to obtain the title compound (2.8g, yield 90-120%).

Ή NMR(400MHz, CDCl ₃ )5-0.053(s, 9H), 0.044(s, 9H), 1.26(d, J=6.4Hz, 3H), 3.98(t, J=6.2Hz, 1H), 4.88(d, J=4.4Hz, 1H), 7.00~7.87(m, 4H)

Preparation Example 114 : Preparation of l-(2-iodophenyI)-(S,S)-l,2-(Bis- trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that l-(2-iodophenyl)-(S,S)-l ,2-butanediol(Preparation example68)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14) to obtain the title compound (3.3g, yield 90-120%).

1H NMR(400MHz, CDCl ₃ )6-0.053(s, 9H), 0.044(s, 9H), 1.04(t, J=7.6Hz, 3H),

1.60-1.71 (m, 2H), 3.71~3.76(m, 1H), 4.87(d, J=4.8Hz, 1H), 7.01~7.87(m, 4H)

Example 1 : Preparation of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(S)-2- carbamate(l)

To a stirred solution of crude l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane(preparation example69, 104g, 0.31mol) in toluene (670mL) was added by

Chlorosulfonyl isocynate(62.5mL, 0.71mol) at 0°C. The reaction mixture was stirred for 2hr.

The reaction mixture was quenched with ice water and then was stirred by additional cold H ₂ 0 (500mL) for 2hr. After separation of organic layer, the aqueous was adjusted pH2~3 with sat. NaHCO ₃ (400mL) and extracted with EtOAc (300mL x3). The EtOAc layer was washed with sat. NaHC0 ₃ (500mL) and H ₂ O(500mL). The organic phase was treated with Charcol for 1.5hr. The organic phase was filtered with Cellite, dreid over MgS0 ₄ . Filterion and concentration under vacuum provided the title compound of white solid(yield 85%(71.1g), ee = 99.9% MP = 83~84°C, [ ] _D =+57.8(c=0.25, MeOH))

Ή NMR(400MHz, CDC1 ₃ ) 51.24(d, j=6.4, 3H), 2.91(d, J=4.8, 1H), 4.68(br s, 2H), 5.06~5.09(m, 1H), 5.18~5.21(m, 1H), 7.23~7.39(m, 3H), 7.55(dd, J=1.6, J=7.8, 1H) C NMR(100MHz, CDC1 ₃ ) 516.4, 73.1, 75.0, 127.0, 128.4, 129.1 , 129.5, 132.7, 138.0, 156.6

Example 2: Preparation of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(R)-2- carbamate(2)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-(R,R)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example70)was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (5.7g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 51.24(d, J=6.4, 3H), 2.91(d, J=4.8, 1H), 4.68(br s, 2H), 5.06~5.09(m, 1H), 5.18~5.21(m, 1H), 7.23~7.39(m, 3H), 7.55(dd, J=1.6, J=7.8, 1H)

Example 3: Preparation of l-(2-chlorophenyl)-l-hydroxypropyl-2- carbamate(3)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example71)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (3.8g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.24(d, J=6.4, 3H), 2.9 l(d, J=4.8, 1H), 4.68(br s, 2H), 5.06-5 ,09(m, 1H), 5.18~5.21(m, 1H), 7.23~7.39(m, 3H), 7.55(dd, J=1.6, J=7.8, 1H)

Example 4: Preparation of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(R)-2- carbamate(4)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-(S,R)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example72)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.4g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.24(d, J=6.4, 3H), 2.91(d, J=4.8, 1H), 4.68(br s, 2H), 5.06~5.09(m, 1H), 5.18~5.21(m, 1H), 7.23~7.39(m, 3H), 7.55(dd, J=1.6, J=7.8, 1H)

Example 5: Preparation of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(S)-2- carbamate(S)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-(R,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example73)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.3g, yield 60-90%).

Ή NMR(400MHz, CDCI3) 51.24(d, J=6.4, 3H), 2.91(d, J=4.8, 1H), 4.68(br s, 2H), 5.06~5.09(m, 1H), 5.18~5.21(m, 1H), 7.23~7.39(m, 3H), 7.55(dd, J=1.6, J=7.8, 1H)

Example 6: Preparation of l-(2-chlorophenyl)-(S)-l-hydroxybutyl-(S)-2- carbamate(6)

The substantially same method as described in Example 1 was conducted, except that l-(2- chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation example74)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.6g, yield 60-90%).

'H NMR(400MHz, CDC1 ₃ ) 60.96(t, J= 7.4HZ, 3 H), 1.57-1.73(m, 2H), 3.01(d, J = 5.6Hz, 1H), 4.74(br s, 2H), 4.95(dt, J = 7.2, 8.8Hz, 1H), 5.23(t, J= 5.6Hz, 1H), 7.22~7.54(m, 4H)

Example 7: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxybtyl-(R)-2- carbamate(7)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-(R,R)-l,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 75) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.5g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.94(t, J=7.4Hz, 3H), 1.53~1.73(m, 2H), 2.92(s, 1H), 4.78(br s, 2H), 4.91~4.96(m, 1H), 5.22(d, J=5.5Hz, 1H), 7.20~7.54(m, 4H)

Example 8: Synthesis of l-(2-chlorophenyI)-l-hydroxybutyl-2-carbamate(8)

The substantially same method as described in Example 1 was conducted, except that

1- (2-chlorophenyl)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 76) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.9g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.97(t, J=7Hz, 3H), 1.58~1.74(m, 2H), 2.94(d, J=6Hz, 1H), 4.69(br s, 2H), 4.94~4.99(m, 1H), 5.24(t, J=6Hz, 1H), 7.23~7.56(m, 4H)

Example 9: Synthesis of l-(2-chlorophenyl)-(S)-l-hydroxy-3-methyl-butyl-(S)-

2- carbamate(9)

The substantially same method as described in Example 1 was conducted, except that 1 -(2-chlorophenyl)-3-methyl-(S,S)- 1 ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 77) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.7g, yield 60-90%). Ή NMR(400MHz, CDC1 ₃ ) 61.01 (d, J = 6.4Hz, 3H), 1.09(d, J= 6.8Hz, 3H), 2.06(m, 1H), 2.75(d, J = 6.8Hz, 1H), 4.58(br s, 2H), 4.85~4.88(m, 1H), 5.34~5.37(m, 1H),

7.22~7.33(m, 2H), 7.35~7.37(m, 1H), 7.51~7.53(m, 1H)

Example 10: Synthesis of l-(2-ch!orophenyl)-(R)-l-hydroxy-3-methyl-butyl- (R)-2-carbamate(10)

The substantially same method as described in Example 1 was conducted, except that 1 -(2-chlorophenyl)-3-methyl-(R,R)- 1 ,2-(Bis-trimethylsilanyloxy)butane (Preparation

Example 78) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.6g, yield 60~90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.01(d, J= 6.8Hz, 3H), 1.09(d, J= 6.8Hz, 3H), 2.06(m, 1H), 2.73(d, J= 6.8Hz, 1H), 4.57(br s, 2H), 4.85~4.88(m, 1H), 5.34~5.37(m, 1H),

7.24~7.30(m, 2H), 7.35~7.37(m, 1H), 7.51~7.53(m, lH)

Example 11: Synthesis of l-(2-chIorophenyl)-l-hydroxy-3-methyl-butyl-2- carbamate(ll)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-3-methyl-l,2-(Bis-trimethylsilanyloxy)but ane (Preparation Example 79) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.7g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.00(d, J=6.4Hz, 3H), 1.09(d, J=6.4Hz, 3H), 2.08(m, 1H), 2.76(d, J=6.0Hz, 1H), 4.59(br s, 2H), 4.87(dd, J=7.2Hz, 4.4Hz, 1H), 5.36(t, J=4.6, 1H), 7.23~7.54(m, 4H)

Example 12: Synthesis of l-(2-chIorophenyl)-(S)-l-hydroxyhexyI-(S)-2- carbamate(12)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 80) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.3g, yield 60-90%).

'H NMR(400MHz, CDC1 ₃ ) 60.88(t, J= 7Hz, 3H), 1.33~1.42(m, 4H), 1.53-1.71 (m, 2H), 2.89(d, J = 5.6Hz, 1H) 4.64(br s, 2H), 5.04(dt, J= 5.0, 9.0Hz, 1H), 5.20(t, J= 5.6Hz, 1 H), 7.23~7.55(m, 4H)

Example 13: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxyhexyI-(R)-2- carbamate(13)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-(R,R)-l ,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 81) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.2g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.89(dd, J=5Hz, 3H), 1.28~1.43(m, 4H), 1.52~1.58(m, 1H), 1.65~1.72(m, 1H), 2.90(d, J=6Hz, 1H), 4.64(br s, 2H), 5.01~5.06(m, 1H), 5.22(t, J=6Hz, 1H), 7.22~7.56(m, 4H) hesis of l-(2-chlorophenyl)-l-hydroxyhexyl-2-carbamate(14)

The substantially same method as described in Example 1 was conducted, except that l-(2-chlorophenyl)-l ,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 82) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.1 g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.88(dd, J=5Hz, 3H), 1.31~1.43(m, 4H), 1.63~1.70(m, 1H), 1.52~1.60(m, 1H), 3.06(d, J=6Hz, 1H), 4.75(br s, 2H), 5.00~5.05(m, 1H), 5.21(t, J=6Hz, 1H), 7.22~7.55(m, 4H)

Example 15: Synthesis of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(S)-2-N- methylcarbamate(15)

l-(2-chlorophenyl)-(S,S)-l,2-propanediol(2.4g) obtained in Preparation Example 14, tetrahydrofuran (THF, 12ml), and carbonyldiimidazole (CDI, 3.12g) were put into a flask and stirred at the room temperature. After approximately 3 hours, methylamine solution(CH ₃ NH ₂ , 4ml(33% in EtOH)) was added thereto. When the reaction was completed, the obtained product was washed with 1M HC1 solution and ethylacetate (EA). The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgS0 ₄ ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography, to obtain the title compound (1.6g, yield 51%).

Ή NMR(400MHz, CDC1 ₃ ) 81.03~1.25(m, 3H), 2.76(s, 3H), 3.34(s, 1H), 4.80(br s 1H), 5.04(t, J=12.5Hz, 1H), 5.14(s, 1H), 7.20~7.53(m, 4H)

Example 16: Synthesis of l-(2-chlorophenyl)-(S)-l-hydroxypropyI-(S)-2-N- propylcarbamate 16)

The substantially same method as described in Example 15 was conducted, except that propylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (0.79g, yield 25%).

1H NMR(400MHz, CDC1 ₃ ) 50.90(t, J=6.8Hz, 3H), 1.20(d, J=5.96Hz, 3H), 1.49(dd, J=14.2Hz, 2H), 3.11(d, J=6.28Hz, 2H), 3.34(s, 1H), 4.84(br s, 1H), 5.05(t, J=5.88Hz, 1H), 5.14(s, 1H), 7.22~7.53(m, 4H)

Example 17: Synthesis of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(R)-2-N- isopropylcarbamate(l 7)

The substantially same method as described in Example 15 was conducted, except that isopropylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (1.5g, yield 41%).

Ή NMR(400MHz, CDC1 ₃ ) 61.14(dd, J=6.5Hz, 6H), 1.19(d, J=6.4Hz, 3H), 3.21(s, 1H), 3.73~3.82(m, 1H), 4.59(br s, 1H), 5.01~5.07(m, 1H), 5.14(t, J=5.8Hz, 1H), 7.20~7.53(m, 4H)

Example 18: Synthesis of l-(2-ch!orophenyl)-(S)-l-hydroxypropyl-(R)-2-N- cyclopro lcarbamate(18)

The substantially same method as described in Example 15 was conducted, except that cyclopropylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (2.2g, yield 43%).

Ή NMR(400MHz, CDC1 ₃ ) 60.50~0.56(m, 2H), 0.74(d, J=7.21Hz, 2H), 1.25(s, 3H), 2.56~2.61 (m, 1H), 3.72(s, 1H), 4.98(br s, 1H), 5.05-5. l l (m, 1H), 7.16(s, 1H), 7.23~7.54(m, 4H)

Example 19: Synthesis of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(R)-2-N- cyclohexyl carbamate(19)

The substantially same method as described in Example 15 was conducted, except that cyclohexylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (l .lg, yield 26%).

Ή NMR(400MHz, CDC1 ₃ ) 51.06~1.40(m, 7H), 1.56~1.61(m, 2H), 1.69~1.71(m, 2H), 1.87~1.94(m, 2H), 3.19(d, J=4.32Hz, 1H), 3.45(s, 1H), 4.64(br s 1H), 5.02~5.07(m, 1H), 5.14(t, J=6.08Hz, 1H) 7.20~7.53(m, 4H)

Example 20: Synthesis of l-(2-chlorophenyI)-(S)-l-hydroxypropyl-(S)-2-N- benzyl carbamate(20)

The substantially same method as described in Example 15 was conducted, except that benzylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (1.2g, yield 18%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.27(d, J=10Hz, 3H), 3.12(d, J=5Hz, 1H), 4.37(d, J=6Hz, 2H), 5.12~5.19(m, 3H), 7.15~7.56(m, 9H)

Example 21: Synthesis of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(S)-2- N- bicyclo[2,2,l]heptanescarbamate(21)

The substantially same method as described in Example 15 was conducted, except that 2-aminonorbornane was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (1.7g, yield 32%).

1H NMR(400MHz, CDC1 ₃ ) 51.08~1.35(m, 9H), 1.65(br s, 1H), 1.75~1.71(m, 1H), 2.14~2.24(m, 1H), 2.27~2.30(m, 1H), 3.23~3.29(m, 1H), 3.47~3.52(m, 1H), 4.67(br s, 1H), 5.01~5.09(m, 1H), 5.12~5.18(m, 1H), 7.22~7.55(m, 4H)

Example 22: Synthesis of l-(2-chIorophenyl)-(R)-l-hydroxypropyl-(R)-2- N- methylcarbamate(22)

The substantially same method as described in Example 15 was conducted, except that 1 -(2-chlorophenyl)-(R,R)- 1 ,2-propanediol(Preparation example 15) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (3.36g, yield 60%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.20(d, J-6.8Hz, 3H), 2.80(d, J=4.8Hz, 3H), 3.20(d, J=4.4Hz, 1H), 4.75(br s, 1H), 5.03~5.09(m, 1H), 5.14~5.17(m, 1 H), 7.22~7.55(m, 4H)

Example 23: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(R)-2- N- propylcarbamate(23)

The substantially same method as described in Example 22 was conducted, except that propylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (3.1g, yield 53%).

Ή NMR(400MHz, CDC1 ₃ ) 60.92(t, J=7.6Hz, 3H), 1.21(d, J=6.4Hz, 3H), 1.51(m, 2H), 3.09-3.14(m, 2H), 3.28(d, J=4.4Hz, l H), 4.82(br s, 1H), 5.03~5.09(m, 1H), 5.14~5.17(m, 1H), 7.22~7.55(m. 4H)

Example 24: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(R)-2- N- isoprop lcarbamate(24)

The substantially same method as described in Example 22 was conducted, except that isopropylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (0.16g, yield 27%).

Ή NMR(400MHz, CDC1 ₃ ) 50.88~1.16(m, 6H), 1.19~1.26(m, 3H), 3.34(s, lH), 3.71~3.78(m, 1H), 4.62(br s, 1H), 5.03(t, J=5.8Hz, 1H), 5.13(d, J=4.9Hz, 1H), 7.20~7.53(m, 4H)

Example 25: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(R)-2- N- cyclopro lcarbamate(25)

The substantially same method as described in Example 22 was conducted, except that cyclopropylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (3.7g, yield 60%).

Ή NMR(400MHz, CDC1 ₃ ) 50.49~0.54(m, 2H), 0.74(d, J=7.2Hz, 2H), 1.22(s, 3H), 2.55~2.60(m, 1H), 3.16(s, 1H), 5.00(s, 1H), 5.04-5. l l(m, 1H), 5.16(s, 1H), 7.23~7.54(m, 4H)

Example 26: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(R)-2- N- cyclohexyl carbamate(26)

The substantially same method as described in Example 22 was conducted, except that cyclohexylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (1.9g, yield 28%).

Ή NMR(400MHz, CDC1 ₃ ) 51.05~1.38(m, 8H), 1.58~1.70(m, 3H), 1.85~1.95(m, 2H), 3.39~3.47(m, 1H), 3.56(s, 1H), 4.79(br s, 1H), 5.01~5.07(m, 1H), 5.14(t, J=5.2Hz, 1H), 7.20~7.54(m, 4H)

Example 27: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(R)-2- N- benzylcarbamate(27)

The substantially same method as described in Example 22 was conducted, except that benzylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (0.52g, yield 19%).

Ή NMR(400MHz, CDC1 ₃ ) 51.25(d, J=6Hz, 3H), 1.64(s, 1H), 3.13(d, J=4.4Hz, 1H), 4.37(d, J=5.6Hz, 2H), 5.12~5.19(m, 2H), 7.23~7.55(m, 9H)

Example 28: Synthesis of l-(2-chlorophenyl)-(R)-l-hydroxypropyl-(R)-2- N- bicyclo[2,2,l]heptanecarbamate(28)

The substantially same method as described in Example 22 was conducted, except that 2-aminonorbornane was used instead of methylamine solution(CH ₃ NH2 in EtOH), to obtain the title compound (1.7g, yield 20~50%).

Ή NMR(400MHz, CDC1 ₃ ) 61.08~1.35(m, 9H), 1.65(br s, 1H), 1.75~1.71(m, 1H), 2.14~2.24(m, 1H), 2.27~2.30(m, 1H), 3.23~3.29(m, 1H), 3.47~3.52(m, 1H), 4.67(br s, 1H), 5.01~5.09(m, 1H), 5.12-5.18(m, 1H), 7.22~7.55(m, 4H)

Example 29: Synthesis of l-(2-chlorophenyl)-l-hydroxypropyl-2- N- methylcarbamate 29)

The substantially same method as described in Example 15 was conducted, except that l-(2-chlorophenyl)-l ,2-propanediol(Preparation example 16) was used instead of l-(2- chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (2.6g, yield 45%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.21(d, J=6Hz, 3H), 2.81(d, J=5Hz, 3H), 3.14(d, J=4Hz, 1H), 4.72(br s, 1H), 5.07(dd, J=6Hz, 1H), 5.16(t, J=6Hz, 1H), 7.22~7.56(m, 4H)

Example 30: Synthesis of l-(2-chlorophenyl)-l-hydroxypropyl-2- N- propylcarbamate(30)

The substantially same method as described in Example 29 was conducted, except that propylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (l .Og, yield 17%).

1H NMR(400MHz, CDC1 ₃ ) δ 0.92(t, J=7Hz, 3H), 1.21(d, J=6Hz, 3H), 1.53(dd, J=7Hz, 2H), 3.13(dd, J=7Hz, 2H), 3.28(d, IH), 4.82(S, IH), 5.06(dd, J=7Hz, IH), 5.16(t, J-5Hz, IH), 7.21~7.56(m, 4H)

Example 31: Synthesis of l-(2-chlorophenyI)-l-hydroxypropyl-2- N- isoprop lcarbamate(31)

The substantially same method as described in Example 29 was conducted, except that isopropylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (0.54g, yield 16%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.16(dd, J=6Hz, 6H), 1.21(d, J=6Hz, 3H), 3.23(d, J=6Hz, IH), 3.75-3.84(m, IH), 4.61(br s, IH), 5.06(t, J=6Hz, IH), 5.16(t, J=6Hz, IH), 7.22~7.56(m, 4H)

Example 32: Synthesis of l-(2-chlorophenyl)-l-hydroxypropyl-2- N- cyclopropylcarbamate(32)

The substantially same method as described in Example 29 was conducted, except that cyclopropylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (l .Og, yield 17%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.50(t, J=6Hz, 2H), 0.77(t, J=3Hz, 2H), 1.12(d, J=7Hz, 53~2.59(m, IH), 3.22(d, J=4Hz, IH), 5.08(dd, J=6Hz, IH), 5.15(S, IH), 7.22~7.55(m, 4H)

Example 33: Synthesis of l-(2-chlorophenyl)-l-hydroxypropyl-2- N- cyclohex lcarbamate(33)

The substantially same method as described in Example 29 was conducted, except that cyclohexylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (2.2g, yield 33%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.07~1.17(m, 3H), 1.21(d, J=6Hz, 3H), 1.29~1.42(m, 3H), 1.72(dd, J=6Hz, 2H), 1.92(dd, J=6Hz, 2H), 3.26(d, J=4Hz, IH), 3.46(t, J=4Hz, IH), 4.68(d, J=6Hz, IH), 5.07(dd, J=6Hz, IH), 5.16(t, J=6Hz, IH), 7.22~7.55(m, 4H)

Example 34: Synthesis of l-(2-chlorophenyl)-l-hydroxypropyl-2- N- benzylcarbamate(34)

The substantially same method as described in Example 29 was conducted, except that benzylamine was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (1.3g, yield 19%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.25(d, J=6Hz, 3H), 3.16(d, J=4Hz, IH), 4.36(d, J=6Hz, 2H), 5.14(dd, J=6Hz, 3H), 7.23~7.56(m, 9H), yield: 19%(1.3g)

Example 35: Synthesis of l-(2-chlorophenyl)-l-hydroxypropyl-2- N- bicyclo[2,2,l]heptanecarbamate(35)

The substantially same method as described in Example 29 was conducted, except that 2-aminonorbornane was used instead of methylamine solution(CH ₃ NH ₂ in EtOH), to obtain the title compound (1.7g, yield 20-50%).

1H NMR(400MHz, CDC1 ₃ ) δ1.08~1.35(ιη, 9H), 1.65(br s, 1H), 1.75~1.71(m, 1H), 2.14~2.24(m, 1H), 2.27~2.30(m, 1H), 3.23~3.29(m, 1H), 3.47~3.52(m, 1H), 4.67(br s, 1H), 5.01~5.09(m, 1H), 5.12~5.18(m, 1H), 7.22~7.55(m, 4H)

Example 36: Synthesis of l-(2,4-dichlorophenyl)-(S)-l-hydroxypropyl-(S)-2- carbamate(36)

The substantially same method as described in Example 1 was conducted, except that l -(2,4-dichlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 83) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (1.8g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.22(d, J= 6.4Hz, 3H), 4.16(br t, 1H) 4.96(br t, 3H), 5.07(t, J= 4.8Hz, 1H), 7.23~7.52(m, 3H)

Example 37: Synthesis of l-(2,6-dichlorophenyl)-(S)-l-hydroxypropyl-(S)-2- carbamate(37)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy)pr opane (Preparation Example 84) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2.6g, yield 60-90%)

Example 38 : Synthesis of l-(2,3-dichlorophenyI)-(S)-l-hydroxypropyI-(S)-2- carbamate(38)

The substantially same method as described in Example 1 was conducted, except that l-(2,3-dichlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy)pr opane (Preparation Example 85) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (1.4g, yield 60-90%)

'H NMR(400MHz, CDC1 ₃ ) 61.15(d, J= 6.4Hz, 3H), 3.66(d, J= 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J = 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H),

Example 39: Synthesis of l-(2,4-dichlorophenyl)-(S)-l-hydroxybutyl-(S)-2- carbamate(39)

CI OH

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 86) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2.3g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 60.96(t, J = 7.4Hz, 3H), 1.58~1.74(m, 2H), 2.98(d, J = 5.6Hz, 1H) 4.68(br s, 2H), 5.59(dt, J= 5.2, 8.8Hz, 1H), 5.19(t, J= 5.4Hz, 1H), 7.30~7.50(m, 3H)

Example 40: Synthesis of l-(2,6-dichlorophenyl)-(S)-l-hydroxybutyI-(S)-2- carbamate(40)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 87) was used instead of 1 -(2-chlorophenyl)-(S , S)- 1 ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (1.7g, yield 60-90%).

'H NMR(400MHz, CDC1 ₃ ) 60.92(t, J= 7.4Hz, 3H), 1.30~1.38(m, 1H), 1.57~1.64(m, 1 H), 3.74(d, J= 9.2Hz, 1H), 4.80(br s, 2H), 5.40~5.50(m, 2H), 7.17~7.34(m, 3H)

Example 41: Synthesis of l-(2,4-dichlorophenyl)-(S)-l-hydroxy-3-methyl- butyl-(S -2-carbamate(41)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-3-methyl-(S,S)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 88) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.9g, yield 60-90%).

'H NMR(400MHZ, CDCI3) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1 H), 4.85(br s, 2H), 5.40~5.43(m, 1 H), 5.49~5.54(m, 1 H), 7.30~7.50(m, 3H)

Example 42: Synthesis of l-(2,6-dichlorophenyI)-(S)-l-hydroxy-3-methyl- butyl-(S)-2-carbamate(42)

The substantially same method as described in Example 1 was conducted, except that 1 -(2,6-dichlorophenyl)-3-methyl-(S,S)- 1 ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 89) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.4g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1H), 4.85(br s, 2H), 5.40~5.43(m, 1H), 5.49~5.54(m, 1H), 7.16~7.33(m, 3H)

Example 43: Synthesis of l-(2,4-dichlorophenyl)-(S)-l-hydroxyhexyl-(S)-2- carbamate(43)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy)he xane (Preparation Example 90) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2.2g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 60.89(t, J= 3.6Hz, 3H), 1.28~1.42(m, 4H), 1.52~1.59(m, 1H), 1.64~1.71(m, 1H), 2.98(d, J= 5.6Hz, 1H), 4.67(br s, 2H), 4.96~5.00(m, 1H), 5.17(t, J= 5.6Hz, 1H), 7.30~7.49(m 3H)

Example 44: Synthesis of l-(2,6-dichlorophenyI)-(S)-l-hydroxyhexyl-(S)-2- carbamate(44)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy)he xane (Preparation Example 91) was used instead of l -(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2. lg, yield 60-90%)

'H NMR(400MHz, CDC1 ₃ ) 60.84(t, J = 7.0Hz, 3H), 1.20~1.35(m, 4H), 1.36~1.41(m, 1H), 1.59~1.63(m, 1H), 3.71(d, J= 10.0Hz, 1H), 4.74(br s, 2H), 5.40~5.44(m, 1H),

5.52~5.57(m, 1H), 7.17~7.35(m, 3H)

Example 45: Synthesis of l-(2,4-dichlorophenyl)-(R)-l-hydroxypropyl-(R)-2- carbamate(45)

The substantially same method as described in Example 1 was conducted, except that 1 -(2,4-dichlorophenyl)-(R,R)- 1 ,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 92) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (1.2g, yield 60-90%),

1H NMR(400MHz, CDC1 ₃ ) 61.22(d, J = 6.4Hz, 3H), 4.16(br t, 1H) 4.96(br t, 3H), 5.07(t, J= 4.8Hz, 1H), 7.23~7.52(m, 3H)

Example 46: Synthesis of l-(2,6-dichlorophenyl)-(R)-l-hydroxypropyl-(R)-2- carbamate(46)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l,2-(Bis-trimethylsilanyloxy)pr opane (Preparation Example 93) was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (1.7g, yield 60~90%),

Ή NMR(400MHz, CDC1 ₃ ) 61.15(d, J= 6.4Hz, 3H), 3.66(d, J= 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J= 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H),

Example 47: Synthesis of l-(2,3-dichlorophenyl)-(R)-l-hydroxypropyl-(R)-2- carbamate(47)

The substantially same method as described in Example 1 was conducted, except that l-(2,3-dichlorophenyl)-(R,R)-l,2-(Bis-trimethylsilanyloxy)pr opane (Preparation Example 94) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.0g, yield 60-90%)

Ή NMR(400MHz, CDC1 ₃ ) 81.15(d, J = 6.4Hz, 3H), 3.66(d, J = 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J= 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H),

Example 48: Synthesis of l-(2,4-dichlorophenyl)-(R)-l-hydroxybutyl-(R)-2- carbamate(48)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 95) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2.3g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 60.96(t, J= 7.4Hz, 3H), 1.58~1.74(m, 2H), 2.98(d, J = 5.6Hz, 1H) 4.68(br s, 2H), 5.59(dt, J= 5.2, 8.8Hz, 1H), 5.19(t, J= 5.4Hz, 1H), 7.30~7.50(m, 3H)

Example 49: Synthesis of l-(2,6-dichlorophenyl)-(R)-l-hydroxybutyl-(R)-2- carbamate(49)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 96) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2.5g, yield 60-90%).

'H NMR(400MHz, CDCI3) 60.92(t, J = 7.4Hz, 3H), 1.30~1.38(m, 1H), 1.57~1.64(m, 1H), 3.74(d, J= 9.2Hz, 1H), 4.80(br s, 2H), 5.40~5.50(m, 2H), 7.17~7.34(m, 3H)

Example 50: Synthesis of l-(2,4-dichlorophenyl)-(R)-l-hydroxy-3-methyl- butyl-(R)-2-carbamate(50)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-3-methyl-(R,R)-l,2-(Bis-trimethylsila nyloxy)butane (Preparation Example 97) was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.8g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1H), 4.85(br s, 2H), 5.40~5.43(m, 1H), 5.49~5.54(m, 1H), 7.30~7.50(m, 3H)

Example 51: Synthesis of l-(2,6-dichlorophenyl)-(R)-l-hydroxy-3-methyl- butyl-(R)-2-carbamate(51)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-3-methyl-(R,R)-l,2-(Bis-trimethylsila nyloxy)butane (Preparation Example 98) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.6g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1H), 4.85(br s, 2H), 5.40~5.43(m, 1H), 5.49~5.54(m, 1H), 7.16~7.33(m, 3H)

Example 52: Synthesis of l-(2,4-dichlorophenyl)-(R)-l-hydroxyhexyl-(R)-2- carbamate(52)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l,2-(Bis-trimethylsilanyloxy)he xane (Preparation Example 99) was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2.5g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 60.89(t, J= 3.6Hz, 3H), 1.28~1.42(m, 4H), 1.52~1.59(m, 1H), 1.64~1.71(m, 1H), 2.98(d, J= 5.6Hz, lH), 4.67(br s, 2H), 4.96-5.00(m, 1H), 5.17(t, J= 5.6Hz, 1H), 7.30~7.49(m, 3H)

Example 53: Synthesis of l-(2,6-dichlorophenyl)-(R)-l-hydroxyhexyl-(R)-2- carbamate(53)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l,2-(Bis-trimethylsilanyloxy)he xane (Preparation Example 100) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane

(Preparation example69) to obtain the title compound (2.4g, yield 60-90%).

'H NMR(400MHz, CDC1 ₃ ) 60.84(t, J = 7.0Hz, 3H), 1.20~1.35(m, 4H), 1.36~1.41(m, 1H), 1.59~1.63(m, 1H), 3.71(d, J= 10.0Hz, 1H), 4.74(br s, 2H), 5.40~5.44(m, 1H),

5.52~5.57(m, 1H), 7.17~7.35(m, 3H)

Example 54: Synthesis of l-(2,4-dichlorophenyl)-l-hydroxypropyl-2- carbamate(54)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-l ,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 101) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.7g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.22(d, J- 6.4Hz, 3H), 4.16(br t, 1H) 4.96(br t, 3H), 5.07(t, J= 4.8Hz, 1H), 7.23~7.52(m, 3H)

Example 55: Synthesis of l-(2,6-dichlorophenyl)-l-hydroxypropyl-2- carbamate(55)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-l,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 102) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.4g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 61.15(d, J= 6.4Hz, 3H), 3.66(d, J= 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J= 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H),

Example 56: Synthesis of l-(2,3-dichlorophenyl)-l-hydroxypropyl-2- carbamate(56)

The substantially same method as described in Example 1 was conducted, except that l-(2,3-dichlorophenyl)-l ,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 103) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsiIanyloxy) propane (Preparation example69) to obtain the title compound (1.6g, yield 60-90%).

Ή NMPv(400MHz, CDC1 ₃ ) 51.15(d, J = 6.4Hz, 3H), 3.66(d, J = 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J= 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H),

Example 57: Synthesis of l-(2,4-dichlorophenyl)-l-hydroxybutyl-2- carbamate(57)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-l,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 104) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.7g, yield 60-90%).

Ή NMPv(400MHz, CDC1 ₃ ) 60.96(t, J= 7.4Hz, 3H), 1.58~1.74(m, 2H), 2.98(d, J = 5.6Hz, 1H) 4.68(br s, 2H), 5.59(dt, J= 5.2, 8.8Hz, 1H), 5.19(t, J= 5.4Hz, 1H), 7.30~7.50(m, 3H)

Example 58: Synthesis of l-(2,6-dichlorophenyl)-l-hydroxybutyl-2- carbamate(58)

The substantially same method as described in Example 1 was conducted, except that 1 -(2, 6-dichlorophenyl)-l ,2-(Bis-trimethylsilanyloxy) butane (Preparation Example 105) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.4g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 60.92(t, J= 7.4Hz, 3H), 1.30~1.38(m, 1H), 1.57~1.64(m, 1H), 3.74(d, J= 9.2Hz, 1H), 4.80(br s, 2H), 5.40~5.50(m, 2H), 7.17~7.34(m, 3H)

Example 59: Synthesis of l-(2,4-dichlorophenyl)-l-hydroxy-3-methyl-butyl-2- carbamate(59)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-3 -methyl- l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 106) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.9g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 61.00(t, J = 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1H), 4.85(br s, 2H), 5.40~5.43(m, 1H), 5.49~5.54(m, 1H), 7.30~7.50(m, 3H)

Example 60: Synthesis of l-(2,6-dichlorophenyl)-l-hydroxy-3-methyI-butyl-2- carbamate(60)

The substantially same method as described in Example 1 was conducted, except that 1 -(2, 6-dichlorophenyl)-3 -methyl- l,2-(Bis-trimethylsilanyloxy) butane (Preparation Example 107) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.7g, yield 60-90%). Ή NMR(400MHz, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1H), 4.85(br s, 2H), 5.40~5.43(m, 1H), 5.49~5.54(m, 1H), 7.16~7.33(m, 3H)

Example 61: Synthesis of l-(2,4-dichloropheny.)-l-hydroxyhexyl-2- carbamate(61)

The substantially same method as described in Example 1 was conducted, except that l-(2,4-dichlorophenyl)-l,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 108) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.6g, yield 60-90%).

'H NMR(400MHz, CDC1 ₃ ) 60.89(t, J = 3.6Hz, 3H), 1.28~1.42(m, 4H), 1.52~1.59(m, 1H), 1.64~1.71(m, 1H), 2.98(d, J= 5.6Hz, 1H), 4.67(br s, 2H), 4.96~5.00(m, 1H), 5.17(t, J= 5.6Hz, 1H), 7.30~7.49(m, 3H)

Example 62: Synthesis of l-(2,6-dichlorophenyl)-l-hydroxyhexyl-2- carbamate(62)

The substantially same method as described in Example 1 was conducted, except that l-(2,6-dichlorophenyl)-l,2-(Bis-trimethylsilanyloxy)hexane (Preparation Example 109) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.5g, yield 60-90%).

lH NMR(400MHz, CDC1 ₃ ) 60.84(t, J = 7.0Hz, 3H), 1.20-1.35(m, 4H), 1.36~1.41(m, 1H), 1.59-1.63(m, 1H), 3.71(d, J = 10.0Hz, 1H), 4.74(br s, 2H), 5.40~5.44(m, 1H),

5.52~5.57(m, 1H), 7.17~7.35(m, 3H)

Example 63: Synthesis of l-(2-fluorophenyI)-(S)-l-hydroxypropyl-(S)-2- carbamate(63)

The substantially same method as described in Example 1 was conducted, except that l -(2-fluorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 110) was used instead of l-(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.8g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.19(d, J=5.2Hz, 3H), 2.93(d, J=4.4Hz, 1H), 4.71(br s, 2H), 4.99~5.06(m, H), 7.04~7.48(m, 4H)

Example 64: Synthesis of l-(2-fluorophenyl)-(R)-l-hydroxypropyl-(R)-2- carbamate(64)

The substantially same method as described in Example 1 was conducted, except that l-(2-fluorophenyl)-(R,R)-l ,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 111) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.6g, yield 60-90%).

1H NMR(400MHz, CDC1 ₃ ) 51.19(d, J=5.2Hz, 3H), 2.93(d, J=4.4Hz, 1H), 4.71(br s, 2H), 4.99~5.06(m, H), 7.04~7.48(m, 4H)

Example 65: Synthesis of l-(2-iodophenyl)-(S)-l-hydroxypropyl-(S)-2- carbamate(65)

The substantially same method as described in Example 1 was conducted, except that l-(2-iodophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 112) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.2g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.27(d, J=6.4Hz, 3H), 3.09(br s, 1H), 4.83(br s, 2H), 5.00~5.10(m, 2H), 7.00~7.76(m, 4H)

Example 66: Synthesis of l-(2-iodophenyI)-(R)-l-hydroxypropyI-(R)-2- carbamate(66)

The substantially same method as described in Example 1 was conducted, except that l-(2-iodophenyl)-(R,R)-l ,2-(Bis-trimethylsilanyloxy)propane (Preparation Example 113) was used instead of l -(2-chlorophenyl)-(S,S)-l,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (1.7g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 51.27(d, J=6.4Hz, 3H), 2.95(d, J=3.6Hz, 1H), 4.73(br s, 2H), 5.01~5.11(m, 2H), 7.01~7.86(m, 4H)

Example 67: Synthesis of l-(2-iodophenyl)-(S)-l-hydroxybutyl-(S)-2- carbamate(67)

The substantially same method as described in Example 1 was conducted, except that l-(2-iodophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy)butane (Preparation Example 114) was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-(Bis-trimethylsilanyloxy) propane (Preparation example69) to obtain the title compound (2.1 g, yield 60-90%).

Ή NMR(400MHz, CDC1 ₃ ) 61.27(d, J=6.4Hz, 3H), 3.09(br s, 1H), 4.83(br s, 2H), 5.00~5.10(m, 2H), 7.00~7.76(m, 4H)

Example 68: Synthesis of l-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-l- carbamate(68)

O

11

CI O NH ₂

OH l-(2-chlorophenyl)-(S,S)-l,2-propanediol(2.33g, Preparation example 14) obtained in Preparation Example 14, tetrahydrofuran (THF, 12ml), and carbonyldiimidazole (CDI, 3.04g) were put into a flask and stirred at the room temperature. After approximately 3 hours, ammonia solution (NH ₄ OH, 4ml) was added thereto. When the reaction was completed, the obtained product was washed with 1M HCl solution and ethylacetate (EA). The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgSC^), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography, to obtain the title compound (0.28g, yield 10~30%).

^! H NMR(400MHz, CDC1 ₃ ) 61.24(d, J= 6.8Hz, 3H), 2.13(d, J= 4.4Hz, 1H),

4.12~4.16(m, 1H), 4.85(br s, 2H), 5.98(d, J= 5.6Hz, 1H), 7.24~7.43(m, 4H)

Example 69: Synthesis of l-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-l- carbamate(69)

The substantially same method as described in Example 68 was conducted, except that l-(2-chlorophenyl)-(R,R)-l ,2-propanediol (Preparation Example 15) was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-propanediol (Preparation example 14) to obtain the title compound (0.77g, yield 16%).

Ή NMR(400MHz, CDC1 ₃ ) 61.24(d, J= 6.4Hz, 3H), 2.04(d, J= 4.8Hz, 1H), 4.1 1~4.18(m, 1H), 4.74(br s, 2H), 6.00(d, J= 5.6Hz, 1H), 7.24~7.43(m, 4H)

Example 70: Synthesis of l-(2-chlorophenyl)-2-hydroxypropyl-l-carbamate(70)

O

u

CI 0 NH ₂

The substantially same method as described in Example 68 was conducted, except that l-(2-chlorophenyl)-(R,R)-l ,2-propanediol (Preparation Example 16) was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-propanediol (Preparation example 14) to obtain the title compound (0.16g, yield 10-30%). 1H NMR(400MHz, CDC1 ₃ ) 61.24(d, J = 6.4Hz, 3H), 2.04(d, J = 4.8Hz, 1H), 4.11~4.18(m, 1H), 4.74(br s, 2H), 6.00(d, J = 5.6Hz, 1H), 7.24~7.43(m, 4H)

Example 71: Synthesis of l-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-l- N- methylcarbamate(71)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 15, to obtain the title compound (0.70g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 51.21(d, J=6.4Hz, 3H), 2.80(d, J=4.8Hz, 3H), 3.12(s, 1H), 4.09~4.16(m, 1H), 4.86(br s, 1H), 5.99(d, J= 6.0Hz, 1H), 7.23~7.40(m, 4H)

Example 72: Synthesis of l-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-l- N- methylcarbamate(72)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 22, to obtain the title compound (0.69g, yield 10-30%).

1H NMR(400MHz, CDC1 ₃ ) 51.21(d, J=6.4Hz, 3H), 2.80(d, J=4.8Hz, 3H), 3.12(s, 1H), 4.09~4.16(m, 1H), 4.86(br s, 1H), 5.99(d, J= 6.0Hz, 1H), 7.23~7.40(m, 4H)

Example 73: Synthesis of l-(2-chlorophenyl)-2-hydroxypropyl-l- N- methylcarbamate(73)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 29, to obtain the title compound (0.73g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.22(d, J=6Hz, 3H), 2.15(d, J=4Hz, IH), 2.81(d, J=5Hz, 3H), 4.12(dd, J=6Hz, IH), 4.83(br s, IH), 6.00(d, J=6Hz, IH), 7.23-7.4 l(m, 4H)

Example 74: Synthesis of l-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-l- N- propylcarbamate(74)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 16, to obtain the title compound (0.15g, yield 10-30%).

1H NMR(400MHz, CDC1 ₃ ) δ 0.9 l(t, J=7Hz, 3H), 1.22(d, J=6Hz, 3H), 1.52(dd, J=7Hz, 2H), 2.23(d, J=4Hz, IH), 3.09~3.21(m, 2H), 4.09~4.17(m, IH), 4.93(s, IH), 5.99(d, J=6Hz, IH), 7.23~7.47(m, 4H)

Example 75: Synthesis of l-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-l- N- propylcarbamate(75)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 23, to obtain the title compound (0.04g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.91(t, J=7Hz, 3H), 1.22(d, J=6Hz, 3H), 1.52(dd, J=7Hz, 2H), 2.23(d, J=4Hz, IH), 3.09~3.21(m, 2H), 4.09~4.17(m, IH), 4.93(s, IH), 5.99(d, J=6Hz, IH), 7.23~7.47(m, 4H)

Example 76: Synthesis of l-(2-chlorophenyl)-2-hydroxypropyl-l- N- propylcarbamate(76)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 30, to obtain the title compound (0.15g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.9 l (t, J=7Hz, 3H), 1.22(d, J=6Hz, 3H), 1.52(dd,

J=7Hz, 2H), 2.23(d, J=4Hz, 1H), 3.09~3.21 (m, 2H), 4.09~4.17(m, 1H), 4.93(s, 1H), 5.99(d, J=6Hz, 1H), 7.23~7.47(m, 4H)

Example 77: Synthesis of l-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-l- N- isopropylcarbamate(77)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 17, to obtain the title compound (0.42g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 51.10(d, J=6.0Hz, 3H), 1.15~1.19(m, 6H), 2.41 (s, 1H),

3.76~4.08(m, 1 H), 4.34(s, 1 H), 4.83(br s 1H), 5.95(d, J=5.3Hz, 1H), 7.19~7.39(m, 4H)

Example 78: Synthesis of l-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-l- N- isopropylcarbamate(78)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 24, to obtain the title compound (0.5g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 51.13(d, J=6Hz, 3H), 1.20(dd, J=9.2Hz, 6H), 2.23(s, 1H), 3.77~3.82(m, 1H), 4.10(s, 1H), 4.76(br s, 1 H), 5.98(d, J=5.6Hz, 1 H), 7.23~7.41 (m, 4H) Example 79: Synthesis of l-(2-chlorophenyl)-2-hydroxypropyl-l- N- isoprop lcarbamate(79)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 31 , to obtain the title compound (0.09g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.14(d, J=6Hz, 3H), 1.21(dd, J=6Hz, 6H), 2.16(d, J=5Hz, 1H), 3.81 (t, J=6Hz, 1H), 4.11(d, J=5Hz, 1H), 4.73(br s, 1H), 5.98(d, J=5Hz, 1H), 7.24-74 l(m, 4H)

Example 80: Synthesis of l-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-l- N- cyclopropylcarbamate(80)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 18, to obtain the title compound (0.53g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 50.53~0.60(m, 2H), 0.74(s, 2H), 1.21(d, J=6.0Hz, 3H), 2.19(s, 1H), 2.59(s, 1H), 4.11~4.15(m, 1H), 5.13(br s, 1H), 5.99(d, J=5.20Hz, 1H), 7.23~7.40(m, 4H)

Example 81: Synthesis of l-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-l- N- cyclopropylcarbamate(81)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 25, to obtain the title compound (0.58g, yield 10%).

Ή NMR(400MHz, CDC1 ₃ ) 50.53~0.60(m, 2H), 0.74(s, 2H), 1.21(d, J=6.0Hz, 3H), 2.19(s, IH), 2.59(s, I H), 4.11~4.15(m, IH), 5.13(br s, IH), 5.99(d, J=5.20Hz, IH), 7.23~7.40(m, 4H)

Example 82: Synthesis of l-(2-chlorophenyl)-2-hydroxypropyl-l- N- cyclopropylcarbamate(82)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 32, to obtain the title compound (0.38g, yield 14%).

Ή NMR(400MHz, CDC1 ₃ ) δ 0.71(s, 2H), 1.19(d, J=6Hz, 3H), 2.45(S, IH), 2.57(S, IH), 4.08~4.12(m, IH), 5.26(s, IH), 5.97(d, J= Hz, IH), 7.22~7.54(m, 4H)

Example 83: Synthesis of l-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-l- cyclohexylcarbamate(83)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 19, to obtain the title compound (0.24g, yield 10-30%),

Ή NMR(400MHz, CDC1 ₃ ) 61.10~1.39(m, 7H), 1.61(s, 3H), 1.71~1.74(m, 2H), 1.87(d, J=11.2Hz, IH), 2.48(d, J=10.8Hz, IH), 3.46(t, J=4Hz, IH), 4.10~4.11 (m, IH), 4.80(br s IH), 5.97(d, J=5.6Hz, IH), 7.23~7.41(m, 4H) Example 84: Synthesis of l-(2-ch!orophenyl)-(R)-2-hydroxypropyl-(R)-l- N- cyclohexylcarbamate(84)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 26, to obtain the title compound (0.35g, yield 10%).

1H NMR(400MHz, CDC1 ₃ ) 61.10~1.39(m, 7H), 1.61(s, 3H), 1.71~1.74(m, 2H),

1.87(d, J=11.2Hz, 1H), 2.48(d, J=10.8Hz, 1H), 3.46(t, J=4Hz, 1H), 4.10~4.11(m, 1H), 4.80(br s 1H), 5.97(d, J=5.6Hz, 1H), 7.23~7.41(m, 4H)

Example 85: Synthesis of l-(2-chlorophenyl)-2-hydroxypropyl-l- cyc!ohex lcarbamate(85)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 33, to obtain the title compound (0.26g, yield 10%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.12~1.19(m, 3H), 1.22(d, J=6Hz, 3H), 1.27~1.37(m,

1H), 1.71(t, J=6Hz, 2H), 1.86-1.88(m, 1H), 1.97~2.00(m, 1H), 2.18(d, J=4Hz, 1H), 3.47(S, 1H), 4.12(t, J=6Hz, 1H), 4.78(S, 1H), 5.97(d, J=6Hz, 1H), 7.23~7.40(m, 4H)

Example 86: Synthesis of l-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-l- benzylcarbamate(86)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 20, to obtain the title compound (0.19g, yield 10-30%).

lH NMR(400MHz, CDC1 ₃ ) δ 1.23(d, J=6Hz, 3H), 2.16(d, J=4Hz, 1H), 4.12(t, J=6Hz,. 1H), 4.31~4.44(m, 2H), 5.22(br S, 1H), 6.04(d, J=6Hz, 1H), 7.27~7.42(m, 9H)

Example 87: Synthesis of l-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-l- N- benzylcarbamate(87)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 27, to obtain the title compound (0.07g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.23(d, J=6Hz, 3H), 2.16(d, J=4Hz, 1H), 4.12(t, J=6Hz, 1H), 4.31~4.44(m, 2H), 5.22(br S, 1H), 6.04(d, J=6Hz, 1H), 7.27~7.42(m, 9H)

Example 88: Synthesis of l-(2-chlorophenyl)-2-hydroxypropyl-l- N- benzylcarbamate(88)

A regioisomer of monocarbamate was separated and purified by conducting the silica gel column chromatography as described in Example 34, to obtain the title compound (0.2 lg, yield 14%).

Ή NMR(400MHz, CDC1 ₃ ) δ 1.23(d, J=6Hz, 3H), 2.16(d, J=4Hz, 1H), 4.12(t, J=6Hz, 1H), 4.31~4.44(m, 2H), 5.22(br S, 1H), 6.04(d, J=6Hz, 1H), 7.27~7.42(m, 9H)

Example 89: Synthesis of l-(2,4-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-l- carbamate(89)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l,2-propanediol(Preparation example 26)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.05g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 61.13(d, J= 6.8Hz, 3H), 2.49(d, J= 4.0Hz, 1H), 4.66~4.74(m, 1H), 4.76(br s, 2H), 6.20(d, J= 8.8Hz, 1H), 7.30(d, J=8.4Hz, 1H), 7.39(d, J=2.0Hz, 2H), 7.50(dd, J=8.4Hz, 2.0Hz, 1H)

Example 90: Synthesis of l-(2,6-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-l- carbamate(90)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 38)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.07g, yield 24%).

Ή NMR(400MHz, CDC1 ₃ ) 61.13(d, J = 6.8Hz, 3H), 2.49(d, J = 4.0Hz, 1H), 4.66~4.74(m, 1H), 4.76(br s, 2H), 6.20(d, J = 8.8Hz, 1H), 7.25~7.40(m, 3H)

Example 91: Synthesis of l-(2,3-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-l- carbamate(91)

The substantially same method as described in Example 68 was conducted, except that l-(2,3-dichlorophenyl)-(S,S)-l,2-propanediol(Preparation example 57)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.08g, yield 10-30%).

^! Η ΝΜΙ (400ΜΗζ, CDC1 ₃ ) 51.15(d, J= 6.4Hz, 3H), 3.66(d, J= 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J = 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H), Example 92: Synthesis of l-(2,4-dichIorophenyl)-(S)-2-hydroxybutyl-(S)-l- carbamate(92)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l,2-butanediol(Preparation example 29)was used instead of l -(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.07g, yield 10-30%).

1H NMR(400MHz, CDC1 ₃ ) 60.77(t, J = 7.4Hz, 3H), 0.92~1.01(m, 1H), 1.18~1.28(m, 1H), 4.06-4.13(m, 1H), 4.96(d, J= 6.0Hz, 1H), 5.91(d, J= 8.8Hz, 1H), 6.4(br s, 2H), 7.30~7.50(m, 3H)

Example 93: Synthesis of l-(2,6-dichIorophenyl)-(S)-2-hydroxybutyl-(S)-l- carbamate(93)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l,2-butanediol(Preparation example 41)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.1 1 g, yield 29%).

'H NMR(400MHz, CDC1 ₃ ) 80.77(t, J= 7.4Hz, 3H), 0.92-1.01 (m, 1H), 1.18-1.28(m, 1H), 4.06-4.13(m, 1H), 4.96(d, J=6.0Hz, 1H), 5.91(d, J=8.8Hz, 1H), 6.4(br s, 2H),

7.25~7.40(m, 3H)

Example 94: Synthesis of l-(2,4-dichlorophenyl)-(S)-2-hydroxy-3-methyl-butyl- (S)-l-carbamate(94)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-3-methyl-(S,S)-l,2-butanediol(Prepara tion example 32)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (O.Olg, yield 10-30%).

'H NMR(400MHz, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, I H), 3.67~3.69(m, IH), 4.96(d, J=6.0Hz, IH), 5.91(d, J=8.8Hz, IH), 6.42(br s, 2H), 7.30~7.50(m, 3H)

Example 95: Synthesis of l-(2,6-dichIorophenyl)-(S)-2-hydroxy-3-methyI-butyI- (S)-l-carbamate(95)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-3-methyl-(S,S)-l,2-butanediol(Prepara tion example 44)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.03g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, IH), 3.67~3.69(m, IH), 4.96(d, J=6.0Hz, IH), 5.91(d, J=8.8Hz, IH), 6.42(br s, 2H), 7.25~7.40(m, 3H)

Example 96: Synthesis of l-(2,4-dichlorophenyl)-(S)-2-hydroxyhexyl-(S)-l- carbamate(96)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-(S,S)-l ,2-hexanediol(Preparation example 35)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.2 lg, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 60.85(t, J=7.2Hz, 3H), 1.18~1.33(m, 4H), 1.48~1.55(m, 2H), 2.35(d, J=4.4Hz, IH), 4.45~4.50(m, IH), 4.76(br s, 2H), 6.21(d, J=8.4Hz, IH),

7.30~7.50(m, 3H) Example 97: Synthesis of l-(2,6-dichlorophenyl)-(S)-2-hydroxyhe: carbamate(97)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-(S,S)-l ,2-hexanediol(Preparation example 47)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.06g, yield 29%).

Ή NMR(400MHz, CDC1 ₃ ) 80.85(t, J= 7.2Hz, 3H), 1.18~1.33(m, 4H), 1.48~1.55(m, 2H), 2.35(d, J= 4.4Hz, 1H), 4.45~4.50(m, 1H), 4.76(br s, 2H), 6.21(d, J=8.4Hz, 1H), 7.16~7.34(m, 3H)

Example 98: Synthesis of l-(2,4-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-l- carbamate(98)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l,2-propanediol(Preparation example 27)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.04g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 61.13(d, J=6.8Hz, 3H), 2.49(d, J=4.0Hz, 1H),

4.66~4.74(m, 1H), 4.76(br s, 2H), 6.20(d, J=8.8Hz, 1H), 7.30~7.50(m, 3H)

Example 99: Synthesis of l-(2,6-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-l- carbamate(99)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l ,2-propanediol(Preparation example 39)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.09g, yield 10-30%).

¹ H NMR(400MHz, CDC1 ₃ ) 61.13(d, J= 6.8Hz, 3H), 2.49(d, J= 4.0Hz, 1H), 4.66~4.74(m, 1H), 4.76(br s, 2H), 6.20(d, J = 8.8Hz, 1H), 7.25~7.40(m, 3H)

Example 100: Synthesis of l-(2,3-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-l- carbamate(lOO)

The substantially same method as described in Example 68 was conducted, except that l-(2,3-dichlorophenyl)-(R,R)-l ,2-propanediol(Preparation example 58)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.25g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 61.15(d, J= 6.4Hz, 3H), 3.66(d, J= 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J= 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H),

Example 101: Synthesis of l-(2,4-dichlorophenyl)-(R)-2-hydroxybutyl-(R)-l- carbamate(lOl)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l ,2-butanediol(Preparation example 30)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation examplel4), to obtain the title compound (0.08g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 60.77(t, J = 7.4Hz, 3H), 0.92~1.01(m, 1H), 1.18~1.28(m, 1H), 4.06-4.13(m, 1H), 4.96(d, J= 6.0Hz, 1H), 5.91(d, J= 8.8Hz, 1H), 6.4(br s, 2H), 7.30-7.50(m, 3H) Example 102: Synthesis of l-(2,6-dichlorophenyl)-(R)-2-hydroxybutyl-(R)-l- carbamate(102)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l ,2-butanediol(Preparation example 42)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.09g, yield 10-30%). Ή NMR(400MHz, CDC1 ₃ ) 60.77(t, J= 7.4Hz, 3H), 0.92~1.01(m, 1H), 1.18~1.28(m, 1H), 4.06~4.13(m, 1H), 4.96(d, J= 6.0Hz, 1H), 5.91(d, J= 8.8Hz, 1H), 6.4(br s, 2H), 7.25~7.40(m, 3H)

Example 103: Synthesis of l-(2,4-dichlorophenyl)-(R)-2-hydroxy-3-methyl- butyl-(R)-l-carbamate(103)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-3-methyl-(R,R)-l,2-propanediol(Prepar ation example 33)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.0 lg, yield 10-30%).

'H NMR(400MHz, CDCI ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1H), 4.96(d, J=6.0Hz, 1H), 5.91(d, J=8.8Hz, 1H), 6.42(br s, 2H), 7.30~7.50(m, 3H)

Example 104: Synthesis of l-(2,6-dichlorophenyl)-(R)-2-hydroxy-3-methyl- butyl-(R)-l-carbamate(104)

The substantially same method as described in Example 68 was conducted, except that l -(2,6-dichlorophenyl)-3-methyl-(R,R)-l ,2-propanediol(Preparation example 45)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation exampleH), to obtain the title compound (O.Olg, yield 10-30%).

'H NMR(400MHZ, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, 1H), 3.67~3.69(m, 1H), 4.96(d, J=6.0Hz, 1H), 5.91(d, J=8.8Hz, 1H), 6.42(br s, 2H), 7.25~7.40(m, 3H)

Example 105: Synthesis of l-(2,4-dichlorophenyl)-(R)-2-hydroxyhexyl-(R)-l- carbamate(105)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-(R,R)-l ,2-hexanediol(Preparation example 36)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.2 lg, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 60.85(t, J=7.2Hz, 3H), 1.18~1.33(m, 4H), 1.48~1.55(m, 2H), 2.35(d, J=4.4Hz, 1H), 4.45~4.50(m, 1H), 4.76(br s, 2H), 6.21(d, J=8.4Hz, 1H), 7.30~7.50(m, 3H)

Example 106: Synthesis of l-(2,6-dichlorophenyl)-(R)-2-hydroxyhexyl-(R)-l- carbamate(106)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-(R,R)-l,2-hexanediol(Preparation example 48)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.12g, yield 10-30%). Ή NMR(400MHz, CDC1 ₃ ) 60.85(t, J = 7.2Hz, 3H), 1.18~1.33(m, 4H), 1.48~1.55(m, 2H), 2.35(d, J= 4.4Hz, 1H), 4.45~4.50(m, 1H), 4.76(br s, 2H), 6.21(d, J= 8.4Hz, 1H), 7.16~7.34(m, 3H)

Example 107: Synthesis of l-(2,4-dichlorophenyl)-2-hydroxypropyl-l- carbamate(107)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-l ,2-propanediol(Preparation example 28)was used instead of 1- (2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.05g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 51.13(d, J=6.8Hz, 3H), 2.49(d, J=4.0Hz, 1H),

4.66~4.74(m, 1H), 4.76(br s, 2H), 6.20(d, J=8.8Hz, 1H), 7.30~7.50(m, 3H)

Example 108: Synthesis of l-(2,6-dichlorophenyl)-2-hydroxypropyl-l- carbamate(108)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-l,2-propanediol(Preparation example 40)was used instead of 1- (2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.06g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 61.13(d, J= 6.8Hz, 3H), 2.49(d, J = 4.0Hz, 1H),

4.66~4.74(m, 1H), 4.76(br s, 2H), 6.20(d, J= 8.8Hz, 1H), 7.25~7.40(m, 3H)

Example 109: Synthesis of l-(2,3-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-l- carbamate(109)

The substantially same method as described in Example 68 was conducted, except that l-(2,3-dichlorophenyl)-l ,2-propanediol(Preparation example 59)was used instead of 1- (2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.02g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 61.15(d, J= 6.4Hz, 3H), 3.66(d, J= 9.2Hz, 1H), 4.73(br s, 2H), 5.43(t, J= 9.0Hz, 1H), 5.62~5.69(m, 1H), 7.18~7.22(m, 3H),

Example 110: Synthesis of l-(2,4-dichlorophenyl)-2-hydroxybutyI-l- carbamate(llO)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-l ,2-butanediol(Preparation example 31)was used instead of l-(2- chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.07g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 60.77(t, J=7.4Hz, 3H), 0.92-1.01(m, 1H), 1.18~1.28(m, 1H), 4.06~4.13(m, 1H), 4.96(d, J=6.0Hz, 1H), 5.91(d, J=8.8Hz, 1H), 6.4(br s, 2H),

7.30-7.50(m, 3H)

Example 111: Synthesis of l-(2,6-dichlorophenyl)-2-hydroxybutyI-l- carbamate(lll)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-l,2-butanediol(Preparation example 43)was used instead of l-(2- chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.1 Og, yield 10-30%). 1H NMR(400MHz, CDC1 ₃ ) 60.77(t, J = 7.4Hz, 3H), 0.92-1.01 (m, IH), 1.18~1.28(m, lH), 4.06~4.13(m, IH), 4.96(d, J= 6.0Hz, IH), 5.91(d, J= 8.8Hz, IH), 6.4(br s, 2H), 7.25~7.40(m, 3H)

Example 112: Synthesis of l-(2,4-dichlorophenyI)-2-hydroxy-3-methyl-butyI-l- carbamate(112)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-3 -methyl- 1 ,2-propanediol(Preparation example 34)was used instead of l-(2-chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.04g, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 81.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, IH), 3.67~3.69(m, IH), 4.96(d, J=6.0Hz, IH), 5.91(d, J=8.8Hz, IH), 6.42(br s, 2H), 7.30~7.50(m, 3H)

Example 113: Synthesis of l-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-l- carbamate(113)

The substantially same method as described in Example 68 was conducted, except that 1 -(2, 6-dichlorophenyl)-3 -methyl- 1 ,2-propanediol(Preparation example 46)was used instead of l-(2-chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.0 lg, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 61.00(t, J= 7.2Hz, 6H), 1.73~1.79(m, IH), 3.67~3.69(m, IH), 4.96(d, J=6.0Hz, IH), 5.91(d, J=8.8Hz, IH), 6.42(br s, 2H), 7.25~7.40(m, 3H)

Example 114: Synthesis of l-(2,4-dichlorophenyl)-2-hydroxyhexyl-l- carbamate(114)

The substantially same method as described in Example 68 was conducted, except that l-(2,4-dichlorophenyl)-l,2-hexanediol(Preparation example 37)was used instead of l-(2- chlorophenyl)-(S,S)-l,2-propanediol(Preparation example 14), to obtain the title compound (0.2 lg, yield 10-30%).

Ή NMR(400MHz, CDC1 ₃ ) 50.85(t, J=7.2Hz, 3H), 1.18~1.33(m, 4H), 1.48~1.55(m, 2H), 2.35(d, J=4.4Hz, 1H), 4.45~4.50(m, 1H), 4.76(br s, 2H), 6.21(d, J=8.4Hz, 1H), 7.30~7.50(m, 3H)

Example 115: Synthesis of l-(2,6-dichlorophenyl)-2-hydroxyhexyI-l- carbamate(115)

The substantially same method as described in Example 68 was conducted, except that l-(2,6-dichlorophenyl)-l ,2-hexanediol(Preparation example 49)was used instead of l-(2- chlorophenyl)-(S,S)-l ,2-propanediol(Preparation example 14), to obtain the title compound (0.12g, yield 10-30%).

lH NMR(400MHz, CDC1 ₃ ) 60.85(t, J= 7.2Hz, 3H), 1.18~1.33(m, 4H), 1.48~1.55(m, 2H), 2.35(d, J= 4.4Hz, 1H), 4.45~4.50(m, 1H), 4.76(br s, 2H), 6.21(d, J= 8.4Hz, 1H), 7.16~7.34(m, 3H)

Compounds 1 to 115 produced in Examples 1 to 1 15 were summarized in following Tables 1 and 2.

(Table 1) Compounds 1 to 67 having the structure of Chemical Formula 1 where 'A' is a carbamoyl derivative and 'B' is H

(Table 2) Compounds 68 to 1 15 having the structure of Chemical Formula 1 where and 'B' is a carbamoyl derivative

108 CI 2(2,6-) Rac. Rac. Me H H

109 CI 2(2,3-) Rac. Rac. Me H H

110 CI 2(2,4-) Rac. Rac. Et H H

1 11 CI 2(2,6-) Rac. Rac. Et H H

112 CI 2(2,4-) Rac. Rac. Isopropyl H H

113 CI 2(2,6-) Rac. Rac. Isopropyl H H

114 CI 2(2,4-) Rac. Rac. Butyl H H

115 CI 2(2,6-) Rac. Rac. Butyl H H

Example 116: Lithium-pilocarpine induced status epilepticus model

Prevention study

Male Sprague-Dawley rats (purchased from Orient Bio Inc. Korea) of body weight 200-23 Og were used for these studies and housed 4-5 rats per a cage for 4-5 days. On the day prior to status epilepsy (SE), rats received 127 mg/kg lithium chloride (Sigma, St. Louis, MO, U.S.A.) intraperitoneally (i.p.). Approximately 18-20 h following this treatment, the rats were given 43 mg/kg pilocarpine (Sigma) intraperitoneally. 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. The test drug was administered intraperitoneally (i.p.) in a volume of 2ul/g body weight. Pharmacological effects of all the test materials were evaluated to compare the test groups (n=6) with a control group (n=6). Control group was administrated vehicle, only. The peak time was determined by administration test material's random dose for 0.5, 1 , 2, 4 hour. The time that the most protect was defined peak time and ED50 was determined by other dose administration at peak time. The animals were then transferred to observation cages and observed continuously for 90 min. The seizure activity was elicited in approximately 95% of control group. Protection was defined as a complete absence of seizure grade 4~5 based on Racine scale (Racine, 1972) over the 90-min observation period. The effective dose of compound necessary to protect against seizures to 50% of controls (i.e. ED50) was determined by log probit analysis using SPSS software program (SPSS Inc.). The obtained results are shown in following Table 3.

Intervention Study

Male Sprague-Dawley rats (purchased from Orient Bio Inc. Korea) of body weight 200-230g were used for these studies and housed 4-5 rats per a cage for 4-5 days. On the day prior to SE, rats received 127 mg/kg lithium chloride (Sigma, St. Louis, MO, U.S.A.) intraperitoneally (i.p.). Approximately 18-20 h following this treatment, the rats were given 43 mg/kg pilocarpine (Sigma) intraperitoneally. 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. The effects of the test compounds dissolved in 30% Poly Ethylene Glycol 400 (Acros Organics, Geel, Belgium) or 20% Tween80 were studied at various times or 30min after the occurrence of the first motor seizure or SE onset. The drug was administered intraperitoneally in a volume of 2 ul/ g body weight. Pharmacological effects was evaluated to compare the test groups with a control group (n=8). Control group was administrated vehicle, only. The obtained results are shown in following Table 4. (Reference; Racine R.J. (1972). Modification of seizure activity by electrical stimulation: II Motor seizure. Electroenceph. Clin. Neurophysiol. 32: 281-294.)

(Table 3) Measurement results of Lithium-pilocarpine induced status epilepticus of compounds in the test (Rats)

a: Injection amount (mg/kg), Protection% = the percentage of prevention activity compared to the vehicle only, respectively.

(Table 4) Measurement results of Lithium-pilocarpine induced status epilepticus of compounds in the test (Rats)

a: Injection amount (mg/kg),

Protection% = the percentage of prevention activity compared to the vehicle only, respectively. Example 117: Potential pharmacological therapies for benzodiazepine-resistant status epilepticus The lithium-pilocarpine model is used to study the effects of test compounds on the electrographic properties of benzodiazepine-resistant SE. Adult rats are implanted for electroencephalogram (EEG) recordings, and then pretreated with lithium chloride (127 mg/kg, 24 h) and scopolamine bromide (1 mg/kg; 30 min) prior to the administration of pilocarpine (50 mg/kg). Either thirty or sixty minutes after the development of the first motor seizure, the animals receive diazepam (10 mg/kg). Ten minutes after diazepam, the experimental group is given the test compound and the control group given vehicle. Typically, 8 animals comprise a "Trial" where 2 animals are controls (i.e., vehicle only) and 6 animals receive the test compound, although this varies depending on the number animals that actually experience SE. In order to have an adequate number of replications, two (or even more) Trials are conducted. When needed, additional control animals are derived from other temporally adjacent Trials using the same protocol. The obtained results are shown in following Fig. 1 and Table 5.

Fig. 1 showed the measurement results of benzodiazepine-resistant electrographic status epilepsy model of l-(2-chlorophenyl)-(S)-l-hydroxypropyl-(S)-2-carbamate (compound 1) in the test(Rats). A graph summarizing the percent change in EEG power over time. Only animals that underwent pilocarpine-induced status epilepticus and had an acceptable EEG signal were included in the analysis. In addition, the vehicle group includes historical controls derived from other temporally adjacent trials. The data are the mean(solid line) and 95% confidence intervals(shaded) of model predictions for each of the treatments normalized to the power at the time of the injection of test compound/vehicle. Differences between the groups were assessed using the non-parametric Mann- Whitney U-teat. The dashed lines represent the time points at which a significant difference was found between the two groups(p<0.05).

(Table 5) Measurement results of benzodiazepine-resistant status epilepticus of l-(2- chlorophenyl)-(S)-l-hydroxypropyl-(S)-2-carbamate (compound 1) in the test

Example 118 : Lamotrigene-resistant amygdala kindled model

Two group(n=8~10 group) of rats(i.e., vehicle-and LTG-treated) are kindled according to the following protocol. A bipolar stimulating electrode is stereotactically implanted into the left amygdale(AP+5.7mm, ML+4.5, dv +2.0 from intra-aural zero) of adult male Sprague-Dawley rats(250~300g) under ketamine-xylazine anesthesia. Three anchor screws are attached to the skull and the electrode assembly anchored to the skull with dental acrylic cement. After the incision is closed with sutures, the animal receives a single dose of Bicillin(60,000 unit, i.m.) and is returned to animal's home cage in the animal quarters. Animals are kindled according to the procedure described by Postma et. al.(LTG treatment during amygdale-kindled seizure development fails to inhibit seizures and diminishes subsequent anticonvulsant efficacy. Epilepsia 41 : 1514-21 ,2000). Briefly, after one week, animals are stimulated at an initial stimulation intensity of lOO Amps. The stimulus intensity increases in 50 uAmp increments until an afterdischarge(AD)of 4 sec or greater is elicited. The kindling stimulus necessary to evoke an AD is then administered daily until all animals in both treatment groups display consistent stage 4 or 5 seizures on the Racine scale(Racine RJ Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281-94,1972). Prior to each kindling stimulation rats receive a single dose of either vehicle(0.5% methylcellulose) or LTG(5mg kg of LTG suspended in vehicle) by intraperitoneal(i.p.) administration. Previous studies have shown that this dose of LTG dose not modify the development of kindling(Postma et al.2000;Srivastava,AKea Proceedings of the AES Annual Meeting, Boston, Massachusetts, Epilepsia 44 Suppl 9:42,2003) but does lead to a LTG-resistant state. One week after all animals are kindled, both groups will receive a challenge dose of LTG(15mg/kg) to confirm LTG sensitivity(vehicle-treated control animals) and LTG resistance(LTG-treated experimental group). After a washout period of 3~4 days, both groups are challenged with a single dose(demonstrated to produce minimal behavioral impairment) of an investigational AED. Rats in both treatment groups are then challenged with the kindling stimulus at the predetermined time-to-peak effect of the investigational AED. The obtained results are shown in following Table 6.

(Table 6) Measurement results of lamotrigene-resistant amygdala kindled rat of 1 -(2- chlorophenyl)-(S)-l-hydroxypropyl-(S)-2-carbamate (compound 1) in the test

Example 119 : Minimal Clonic Seizure (6Hz) Test

Some clinically useful AEDs are ineffective in the standard MES and scPTZ tests but still have anticonvulsant activities in vivo. In order to identify potential AEDs with this profile, compounds may be tested in the minimal clonic seizure (6Hz or 'psychomotor') test (Barton et al., 2001). Like the maximal electroshock (EMS) test, the minimal clonic seizure (6Hz) test is used to assess a compound's efficacy against electrically induced seizures but used a lower frequency (6Hz) and longer duration of stimulation (3s).

Test compound was pre-administrated to mice via i.p. injection. At varying times, individual mice (four per time point) are challenged with sufficient current delivered through corneal electrodes to elicit a psychomotor seizure in 97% of animals (32 mA or 44mA for 3s) (Toman et al., 1952). Untreated mice will display seizures characterized by a minimal clonic phase followed by stereotyped, automatistic behaviors described originally as being similar to the aura of human patients with partial seizures. Animals not displaying this behavior are considered protected. The test may be evaluated quantitatively by measuring the response at varying doses at a determined time of peak effect (TPE). The obtained results are shown in following Table 5(Reference;Barton M.E., Klein B.D., Wolf H.H. and White H.S. (2001) Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy, Epilepsy Res. 47: 217-227./Toman J.E., Everett G.M. and Richards R.K. (1952), The search for new drugs against epilepsy. Tex. Rep. Biol. Med. 10: 96-104.)

when the current is increased to twice the CC97 (i.e., 44 mA), most AEDs loose their efficacy, and only few AEDs, including levetiracetam (at high doses), valproate, and novel AEDs such as brivaracetam and retigabine, allow complete protection against the 6-Hz seizures. Based on these observations, it was suggested that the 6-Hz stimulation may provide a useful and rather inexpensive model of therapy-resistant limbic seizures(Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs(2011), Seizure 20, 359-368, Wolfgang Loscher).

(Table 7) Measurement results of 6Hz-induced seizure of l-(2-chlorophenyl)-(S)-l- hydroxypropyl-(S)-2-carbamate (Compound 1) in the test(Mice)

Example 120 : MES(maximal electroshock seizure) 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 1 1A Shocker(IITC Life Science Company) was delivered through corneal electrodes. All mice assigned to any electroshock at peak time (0.25, 0.5, 1 , 2, 4hr) were treated with each test compound sample which was dissolved in 30% PEG400 or 20%Tween80 prepared by saline solvent applied to oral before the test. If the test animal stretching their hind limb in a straight line weren't observed in the MES test, the results indicate that the test sample had an anti-excitation activity. Three doses of the test sample were administered orally to over 18 mice (6 mice per dose) for evaluating the respective doses at which 50% of the animals are protected from seizure (ED50). The value of ED50 (median effective dose) is calculated by Litchfield and Wicoxon log-probit method which is a dose-response relationship. Then, the test results are shown in following Table 3. Experimental animal, male ICR mice and male SD rats, were purchased from OrientBio or Nara biotech, Korea, and housed 4-5 mice per a cage for 4-5 days. The range of mice body weight was used between 19 and 26 grams. The obtained results are shown in following Table 8.

Neurotoxicity

The measurement of neurotoxicity of the test compounds was conducted by the method of Dunham and Miya [Dunham, N.W. and Miya, T.S. 1957. A note on a simple apparatus for detecting neurological deficit in rats and mice. J. Am. Pharm. Assoc. (Baltimore) 46: 208-209]. In the method, motor abilities of the test animals can be determined by observing whether the test animals can walk without falling from a rotator, thereby determining the value of neurotoxicity of each compound. Term "TD50" means the respective dose of the test compound at which 50% of the test animal exhibit neurotoxicity. They were pre-trained on the rotarod (Rotarod; Columbus instrument, rota-max, USA) at 6 rpm for 5 min 24 hr prior to the test. The peak time was determined by administration test material's random dose for 0.5, 1, 2, 4 hour. To evaluate the minimal neurotoxicity of the compound, the mice were placed on the Rotarod (rod circle; 3 Cm) at 6rpm and the test animal fails to maintain walking once or more during 1 minute, it can be regarded that the test animal exhibits neurotoxicity. The ratio of TD50 to ED50 (TD50/ED50) is called as a protective index, and useful as a parameter for comparison of pharmaceutical efficacy and neurotoxicity. The obtained results are shown in following Tables 8 and 9. [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.

(Table 8) Measurement results of anti-epilepsy activity of compounds in the test animals (Mice)

38 91.4 2

39 41.2 1

40 46.9 -

42 35.2 0.5

43 100 ^a (25%) -

44 100 ^a (75%) -

46 35.2 1

63 50 ^a (100%) -

65 50 ^a (100%) -

67 100 ^a (100%) - a: Injection amount(mg/kg),

Protection %= the percentage of activity compared to the vehicle only. (Table 9) Measurement results of neurotoxicity of compounds in the test

Example 121 : PTZ(Pentylenetetrazol) test

The obtained results are shown in following Tables 8 and 9. In this experiment, administered intraperitoneally(i.p.) or orally to test animals (Mouse; ICR, and Rats; SD); Experimental animal, male SD rats, were purchased from OrientBio or Nara biotech, Korea, and housed 4-5 mice per a cage for 4-5 days. The range of mice body weight was used between 19 and 26 grams and range of rats body weight was used between 100 and 130 grams. After Peak time (0.5, 1, 2 and 4hr) from the administration, from the administration, PTZ (Pentylenetetrazol) was administered subcutaneously in the concentration capable of inducing 97% intermittent convulsions (mice & rats: 90-110 mg/kg»bw, 2jUJ2/g). If clonic seizure was not observed for at least 3 seconds in the PTZ administered animal, it can be considered that the test compound has nonconvulsive seizure activity. The median effective dose (ED50) is determined using 6 animals per a concentration (total three different concentrations), and calculated by Litchfield and Wicoxon log-probit method which is a dose-response relationship. The obtained results are shown in following Tables 10 and 11.

(Table 10) Measurement results of anti-nonconvulsive seizure activity of compounds in the test animals (Mice)

PTZ test (ip) in Mice

Compound No.

ED50(mg/kg) Peak Time (h)

1 15.8 2

2 38.8 0.5

3 15.3 0.5

4 26.7 0.5

5 15.0 0.5

6 17.9 0.5

8 ^a 20.4 (50%)

9 ^a 20.4 (33.3%) -

12 ^a 20.4 (33.3%) -

13 ^a 20.4 (50%) -

14 ^a 20.4 (16.7%) -

23 ^a 20.4 (50%) -

25 ^a 20.4 (66.7%) -

29 ^a 20.4 (33.3%) -

30 ^a 20.4 (33.3%) -

31 ^a 20.4 (83.3%) -

32 ^a 20.4 (16.7%) -

36 ^a 20.4 (33.3%) -

37 25.7 0.25

38 ^a 20.4 (50%) -

39 24.3 0.5 40 ^a 20.4 (33.3%) -

42 ^a 20.4 (50%) -

44 ^a 20.4 (33.3%) -

45 ^a 20.4 (16.7%) -

46 ^a 20.4 (50%) -

63 ^a 20.4 (50%) -

65 ^a 20.4 (100%) -

67 23.1 0.5

a: Injection amount (mg/kg),

Protection % (Mice)

*: Peak Time (h)

(Table 11) Measurement results of anti-nonconvulsive seizure activity of compounds in the test animals (Rats)

b: Injection amount (mg/kg),

Protection % (Rats)

*: Peak Time (h)