Phenyl carbamate compounds for use in preventing or treating stroke

This application claims priority to and the benefit of U.S. Provisional Application No. 61/580,409 filed in the United States Patent and Trademark Office on Dec. 27, 2011, the entire contents of which are incorporated herein by reference.

A phenyl carbamate compound; a composition for treating and/or preventing stroke containing the phenyl carbamate compound or a pharmaceutically acceptable salt thereof as an active ingredient; a method of treating and/or preventing stroke comprising administering the phenyl carbamate compound or a pharmaceutically acceptable salt thereof to a patient in need of stroke treatment; and a use of the phenyl carbamate compound or a pharmaceutically acceptable salt thereof in treating and/or preventing stroke, are provided.

Approximately 15 million people worldwide suffer a stroke each year, resulting in death or sensorimotor and other defects. Stroke remains the third most common cause of death in the industrialized world behind heart disease and cancer. There are two kinds of stroke: one is ischemic stroke, caused by a blood clot that blocks or prevents the flow of blood, and the other is hemorrhagic stroke, caused by bleeding into or around the brain.

Ischemic stroke is responsible for about one third of all deaths in industrialized countries and is the major cause of serious, long-term disability in adults over the age of 45. It stands to reason that there is a need for pharmacotherapy to treat acute ischemic stroke. Considerable insights have been gained into the mechanisms of stroke and the cascade of events that occurs following stroke; there is also an improved understanding of neuronal injury and cell death.

The three main mechanisms of ischemic stroke are thrombosis, embolism, and systemic hypoperfusion (with resultant ischemia and hypoxia). In each of these types of stroke, the area of the brain that dies as a result of the lack of blood supply thereto is called an infarct. Obstruction of a cerebral artery resulting from a thrombus that has built up on the wall of a brain artery is generally called “cerebral thrombosis.” In cerebral embolism, the occlusive material blocking the cerebral artery arises downstream in the circulation (e.g., an embolus is carried to the cerebral artery from the heart). Because it is difficult to discern whether a stroke is caused by thrombosis or embolism, the term “thromboembolism” is used to cover both these types of stroke. Systemic hypoperfusion may arise as a consequence of elevated blood lactate levels, reduced hematocrit, low blood pressure, or inability of the heart to pump blood adequately.

Also, the excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by the way of a mechanism known as excitotoxicity. So, Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of a number of neurological disorders. Such as stoke, cerebral ischemia and spinal cord trauma etc.

When symptoms of stroke last less than 24 hours and the patient recovers completely, the patient is said to have undergone a transient ischemic attack (TIA). The symptoms of TIA are a temporary impairment of speech, vision, sensation, or movement. Because a TIA is often thought to be a prelude to full-scale stroke, patients having suffered a TIA are candidates for prophylactic stroke therapy with anticoagulation agents (e.g., coumarin, and heparin) or anti-platelet agents (such as aspirin and ticlopidine), for example. But, in approximately 20% to 40% of patients with stroke, the underlying etiology is not established (called “cryptogenic,” “uncertain,” or “undetermined” stroke).

Therefore, a need exists for a therapy that is effective in the treatment all types of stroke, i.e., both ischemic strokes and hemorrhagic strokes.

An embodiment provides an organic compound, i.e., phenyl carbamate compound. More particularly, the embodiment is directed to a phenyl carbamate compound of the 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. The compound has remarkably excellent treatment and/or prevention effect on stroke as well as very low toxicity. Therefore, the compounds of formula I may be useful as a drug for the treatment and/or prevention of stroke:

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,

R1 is a linear or branched alkyl group of C1-C4, for example, methyl group, ethyl group, isopropyl group, or butyl group,

A is hydrogen or a carbamoyl derivative represented by

B is hydrogen, a carbamoyl derivative represented by

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.

Another embodiment provides a pharmaceutical composition for of preventing and/or treating stroke containing a compound of 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, as an active ingredient

Another embodiment provides a method of preventing and/or treating stroke comprising administering a therapeutically 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 stroke.

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, in the prevention and/or treatment of stroke, or in the manufacture of a pharmaceutical composition for preventing and/or treating stroke.

Continuing its research work in the field of stroke, the present inventors, as results of studies on the development of anti-stroke drugs, found that a phenyl carbamate compounds of the following Chemical Formula 1 exhibits remarkably excellent anti-stroke activity in various emulation models and simultaneously has very low toxicity, to complete the invention.

An embodiment provides an organic compound, particularly, a phenyl carbamate compound, 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:

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,

R1 is a linear or branched alkyl group of C1-C4, for example, methyl group, ethyl group, isopropyl group, or butyl group,

A is hydrogen or a carbamoyl derivative represented by

B is hydrogen, a carbamoyl derivative represented by

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.

In 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-hydroxy-3-methyl-butyl-2-carbamate, 1-(2-chlorophenyl)-1-hydroxyhexyl-2-carbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-propylcarbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-isopropylcarbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclohexylcarbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-benzylcarbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-bicyclo[2,2,1]heptanecarbamate, 1-(2,4-dichlorophenyl)-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, 1-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate, 1-(2,4-dichlorophenyl)-2-hydroxyhexyl-1-carbamate, 1-(2,6-dichlorophenyl)-2-hydroxyhexyl-1-carbamate, 1-(2-fluorophenyl)-1-hydroxypropyl-2-carbamate, 1-(2-iodophenyl)-1-hydroxypropyl-2-carbamate, 1-(2-iodophenyl)-1-hydroxybutyl-2-carbamate, 1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate, and 1-(2,3-dichlorophenyl)-2-hydroxypropyl-1-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.

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.

As demonstrated in the following experimental examples, the compound of Chemical Formula 1, a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or pharmaceutically acceptable salt thereof exhibits an excellent effect on preventing and/or treating stroke. Therefore, another embodiment provides a pharmaceutical composition for preventing and/or treating stroke containing 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, as an active ingredient.

Another embodiment provides a method of preventing and/or treating stroke comprising administering a therapeutically effective amount of a phenyl alkyl 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 stroke. The method may further comprise a step of identifying the subject in need of preventing and/or treating stroke prior to the step of administering. The term “therapeutically effective amount” may refer to an amount of the active gradient capable of exhibiting the effect of preventing and/or treating stroke.

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 stroke or in the manufacture of a medicament for preventing and/or treating stroke.

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, in the prevention and/or treatment of stroke or in the manufacture of a medicament for preventing and/or treating stroke.

The stroke to be treated and/or prevented may include an ischemic stroke (for example, acute ischemic stroke, and the like) and/or a hemorrhagic stroke. In a concrete embodiment, the stroke may include a neurodegeneration associated stroke, and may not be a muscle spasm associated stroke.

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, polyvinylpirrolidine, 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 therapeutically 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 multiple sclerosis. 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 therapeutically 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 separated therefrom.

The phenyl carbamate compound of the present invention may prepared by the following reaction formula.

Reaction Formula I: Synthesis of Diol-1

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.

Reaction Formula II: Synthesis of Diol-2

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 III: Carbamation Reaction-1

As a highly selectivity form of regioisomer of single carbamate of diol having halogen substituent at phenyl ring. (Example 1˜14 and 36˜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˜115 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 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.

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 C1-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.

FIG. 1 shows the 2,3,5-triphenyltetrazolium chloride (TTC)-stained infarction area (% control) with treatment the compound example 1 on tMCAO (Transient Middle Cerebral Artery Occlusion) at various time points.

FIG. 2 illustrates coronal sections showing infract area with treatment of the compounds before tMCA occlusion, to show the neuro-prevention effect.

FIG. 3 illustrates coronal sections showing infract area with treatment of the compounds after tMCA occlusion, to show the neuro-therapeutic effect.

FIG. 4 is a graph showing the relevant size of infarct with treatment of the compounds before (A) and after (B) tMCA occlusion.

FIG. 5 illustrates coronal TTC-stained sections showing infract area with treatment of 60 mg/kg of Compound 1 or vehicle at 15 minutes after pMCA occlusion.

FIG. 6 is a graph showing the relevant size of infarct with treatment of Compound 1 at 15 minutes after pMCA occlusion.

FIG. 7 illustrates coronal TTC-stained sections showing infract area with treatment of 60 mg/kg of Compound 1 or vehicle at 1 hour after pMCA occlusion.

FIG. 8 is a graph showing the relevant size of infarct with treatment of Compound 1 at 1 hour after pMCA occlusion.

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 1-(2-chlorophenyl)-trans-1-propene

48 ml of 2-chlorobenzenaldehyde (0.42 mol) and 49.7 ml of 3-pentanone (0.47 mol) were dissolved in 600 mL of hexane in flask, and then stirred with raising the temperature. 53.6 ml of Boron trifluoride etherate (BF 3 OEt 2 , 0.42 mol) 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 (MgSO 4 ) and concentrated. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (38 g, yield 58%).

1 H NMR(400 MHz, CDCl 3 ) δ1.94(d, J=4.8 Hz, 3H), 6.24(m, 1H), 6.78(d, J=14 Hz, 1H), 7.11˜7.51(m, 4H)

Preparation Example 2

Synthesis of 1-(2-chlorophenyl)-trans-1-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 (2.9 g, yield 83%).

1 H NMR(400 MHz, CDCl 3 ) δ1.14(d, J=7.6 Hz, 3H), 2.29˜2.33(m, 2H), 6.28(dt, J=16 Hz, 6.4 Hz, 1H), 6.78(d, J=15.6 Hz, 1H), 7.13˜7.54(m, 4H)

Preparation Example 3

Synthesis of 1-(2-chlorophenyl)-3-methyl-trans-1-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 (8.0 g, yield 50˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.14(d, J=6.8 Hz, 6H), 2.25˜2.57(m, 1H), 6.20(dd, J=16 Hz, 7.2 Hz, 1H), 7.64(d, J=16 Hz, 1H), 7.12˜7.54(m, 4H)

Preparation Example 4

Synthesis of 1-(2-chlorophenyl)-trans-1-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 (10 g, yield 85%).

1 H NMR(400 MHz, CDCl 3 ) δ0.96(1, J=7.2 Hz, 3H), 1.33˜1.56(m, 4H), 2.26˜2.32(m, 4H), 6.24(dt, J=15.6 Hz, 7 Hz, 1H), 6.78(d, J=16 Hz, 1H), 7.13˜7.54(m, 4H)

Preparation Example 5

Synthesis of 1-(2,4-dichlorophenyl)-trans-1-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 (2.4 g, yield 57%).

1 H NMR(400 MHz, CDCl 3 ) δ1.95(dd, J=6.8 Hz, 1.6 Hz, 3H), 6.24(m, 1H), 6.72(d, J=15.6 Hz, 1H), 7.18˜7.44(m, 3H)

Preparation Example 6

Synthesis of 1-(2,4-dichlorophenyl)-trans-1-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 (2.1 g, yield 90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.14(d, J=7.6 Hz, 3H), 2.20˜2.33(m, 2H), 6.26(dt, J=16 Hz, 6.8 Hz, 1H), 6.70(d, J=15.6 Hz, 1H), 7.18˜7.46(m, 3H)

Preparation Example 7

Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-trans-1-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 (0.23 g, yield 10˜40%).

1 H NMR(400 MHz, CDCl 3 ) δ1.15(d, J=6.8 Hz, 6H), 2.53˜2.58(m, 1H), 6.19(dd, J=16.4 Hz, 6.8 Hz, 1H), 6.31(d, J=16.4 Hz, 1H), 7.18˜7.46(m, 3H)

Preparation Example 8

Synthesis of 1-(2,4-dichlorophenyl)-trans-1-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 (3.2 g, yield 40˜80%).

1 H NMR(400 MHz, CDCl 3 ) δ0.96(t, J=7.2 Hz, 3H), 1.38˜1.52(m, 4H), 2.25˜2.31(m, 2H), 6.22(dt, J=15.6 Hz, 6.8 Hz, 1H), 6.70(d, J=15.6 Hz, 1H), 7.18˜7.46(m, 3H)

Preparation Example 9

Synthesis of 1-(2,6-dichlorophenyl)-trans-1-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 (0.4 g, yield 10˜40%).

1 H NMR(400 MHz, CDCl 3 ) δ1.98(d, J=8 Hz, 3H), 6.23˜6.31(m, 1H), 6.40(d, J=16 Hz, 1H), 7.05˜7.32(m, 3H)

Preparation Example 10

Synthesis of 1-(2,6-dichlorophenyl)-trans-1-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 (1.2 g, yield 10˜40%).

1 H NMR(400 MHz, CDCl 3 ) δ1.17(t, J=7.6 Hz, 3H), 2.30˜2.37(m, 2H), 6.29(dt, J=16.4 Hz, 6 Hz, 1H), 6.37(d, J=16.4 Hz, 1H), 7.05˜7.32(m, 3H)

Preparation Example 11

Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-trans-1-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 (0.23 g, yield 10˜40%).

1 H NMR(400 MHz, CDCl 3 ) δ1.15(d, J=6.8 Hz, 6H), 2.53˜2.58(m, 1H), 6.19(dd, J=16.4 Hz, 6.8 Hz, 1H), 6.31(d, J=16.4 Hz, 1H), 7.05˜7.32(m, 3H)

Preparation Example 12

Synthesis of 1-(2,6-dichlorophenyl)-trans-1-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 (0.2 g, yield 10˜40%).

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

Preparation Example 13

Synthesis of 1-(2,3-dichlorophenyl)-trans-1-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 (0.2 g, yield 10˜40%).

1 H NMR(400 MHz, CDCl 3 ) δ1.94(d, J=4.8 Hz, 3H), 6.24(m, 1H), 6.78(d, J=14 Hz, 1H), 7.11˜7.51(m, 3H)

Preparation Example 14

Synthesis of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (1.5 g, Preparation Example 1) was dissolved in 30 mL of the mixture of t-BuOH/H 2 O (1:1(V/V)). At 0° C., AD-mix-α (Aldrich, U.S.A.) (13.7 g) and methane sulfone amide (CH 3 SO 2 NH 2 , 0.76 g, 0.0080 mol) 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 SO 3 ) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO 4 ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (1.65 g, yield 90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.20(d, J=6.4 Hz, 3H), 2.48(d, J=4.0 Hz 1H), 2.92(d, J=4.4 Hz, 1H), 3.93˜3.97(m, 1H), 4.97(t, J=4.8 Hz, 1H), 7.22˜7.51(m, 4H)

13 CNMR(100 MHz,CDCl 3 ) δ18.8, 71.5, 74.4, 127.1, 128.1, 128.9, 129.5, 132.6, 138.9

Preparation Example 15

Synthesis of 1-(2-chlorophenyl)-(R,R)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (2.5 g, Preparation Example 1) was dissolved in 50 mL of the mixture of t-BuOH/H 2 O (1:1(V/V)). At 0° C., AD-mix-α (Aldrich, U.S.A.) (23.5 g) and methane sulfone amide (CH 3 SO 2 NH 2 , 1.27 g, 0.013 mol) 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 SO 3 ) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO 4 ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (2.96 g, yield 90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.20(d, J=6.4 Hz, 3H), 2.48(d, J=4.0 Hz, 1H), 2.92(d, J=4.4 Hz, 1H), 3.93˜3.97(m, 1H), 4.97(t, J=4.8 Hz, 1H), 7.22˜7.51(m, 4H)

Preparation Example 16

Synthesis of the mixture of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol and 1-(2-chlorophenyl)-(R,R)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (6.53 g, Preparation Example 1) was dissolved in 45 mL of the mixture of acetone/t-BuOH/H 2 O (5:1:1 V/V). At the room temperature, N-methylmorpholine-N-oxide (7.51 g) and OsO 4 (0.54 g) 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 (MgSO 4 ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (6.42 g, yield 80%).

1 H NMR(400 MHz, CDCl 3 ) δ1.20(d, J=6.4 Hz, 3H), 2.48(d, J=4.0 Hz, 1H), 2.92(d, J=4.4 Hz, 1H), 3.93˜3.97(m, 1H), 4.97(t, J=4.8 Hz, 1H), 7.22˜7.51(m, 4H)

Preparation Example 17

Synthesis of 1-(2-chlorophenyl)-(S,S)-1,2-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 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.36 g, yield 95%).

1 H NMR(400 MHz, CDCl 3 ) δ1.01(t, J=7.4 Hz, 3H), 1.52˜1.65(m, 2H), 2.01(d, J=4.4 Hz, 1H), 2.74(d, J=5.2 Hz, 1H), 3.69˜3.75(m, 1H), 5.05(t, J=5.0 Hz, 1H), 7.23˜7.54(m, 4H)

Preparation Example 18

Synthesis of 1-(2-chlorophenyl)-(R,R)-1,2-butanediol

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 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.84 g, yield 60˜95%).

1 H NMR(400 MHz, CDCl 3 ) δ1.01(1, J=7.4 Hz, 3H), 1.52˜1.65(m, 2H), 2.01(d, J=4.4 Hz, 1H), 2.74(d, J=5.2 Hz, 1H), 3.69˜3.75(m, 1H), 5.05(t, J=5.0 Hz, 1H), 7.23˜7.54(m, 4H)

Preparation Example 19

Synthesis of the mixture of 1-(2-chlorophenyl)-(S,S)-1,2-butanediol and 1-(2-chlorophenyl)-(R,R)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.01(1, J=7.4 Hz, 3H), 1.52˜1.65(m, 2H), 2.01(d, J=4.4 Hz, 1H), 2.74(d, J=5.2 Hz, 1H), 3.69˜3.75(m, 1H), 5.05(t, J=5.0 Hz, 1H), 7.23˜7.54(m, 4H)

Preparation Example 20

Synthesis of 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(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 (0.96 g, yield 60˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.07(1, J=7.2 Hz, 6H), 1.83˜1.89(m, 1H), 1.92(d, J=5.6 Hz, 1H), 2.69(d, J=6.4 Hz, 1H), 3.53˜3.56(m, 1H), 5.22˜5.25(m, 1H), 7.23˜7.55(m, 4H)

Preparation Example 21

Synthesis of 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(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 (4.2 g, yield 60˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.07(1, J=7.2 Hz, 6H), 1.82˜1.90(m, 1H), 1.93(d, J=5.6 Hz, 1H), 2.79(d, J=6 Hz, 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 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol and 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(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 (0.8 g, yield 60˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.07(1, J=7.2 Hz, 6H), 1.83˜1.90(m, 1H), 1.92(d, J=5.6 Hz, 1H), 2.69(d, J=6.4 Hz, 1H), 3.53˜3.56(m, 1H), 5.22˜5.25(m, 1H), 7.23˜7.55(m, 4H)

Preparation Example 23

Synthesis of 1-(2-chlorophenyl)-(S,S)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.90(t, J=7.2 Hz, 3H), 1.35˜1.65(m, 6H), 2.08(d, J=4.4 Hz, 1H), 2.71(d, J=5.2 Hz, 1H), 3.78˜3.83(m, 1H), 5.04(t, J=5.0 Hz, 1H), 7.23˜7.53(m, 4H)

Preparation Example 24

Synthesis of 1-(2-chlorophenyl)-(R,R)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.91(t, J=6.6 Hz, 3H), 1.35˜1.65(m, 6H), 2.08(d, J=4.8 Hz, 1H), 2.70(d, J=5.2 Hz, 1H), 3.78˜3.83(m, 1H), 5.05(t, J=5.0 Hz, 1H), 7.23˜7.56(m, 4H)

Preparation Example 25

Synthesis of the mixture of 1-(2-chlorophenyl)-(S,S)-1,2-hexanediol and 1-(2-chlorophenyl)-(R,R)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.90(t, J=7.2 Hz, 3H), 1.26˜1.55(m, 6H), 2.08(d, J=4.4 Hz, 1H), 2.71(d, J=5.6 Hz, 1H), 3.78˜3.84(m, 1H), 5.04(t, J=3.2 Hz, 1H), 7.24˜7.55(m, 4H)

Preparation Example 26

Synthesis of 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.22(d, J=6.4 Hz, 3H), 2.10(d, J=4.4 Hz, 1H), 2.71(d, J=4.8 Hz, 1H), 3.90˜3.95(m, 1H), 4.94(t, J=5.0 Hz, 1H), 7.31(dd, J=2.0 Hz, J=8.0 Hz, 1H), 7.40(d, J=2.0 Hz, 1H), 7.49(d, J=8.4 Hz, 1H)

Preparation Example 27

Synthesis of 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.22(d, J=6.4 Hz, 3H), 2.10(d, J=4.4 Hz, 1H), 2.71(d, J=4.8 Hz, 1H), 3.90˜3.95(m, 1H), 4.94(t, J=5.0 Hz, 1H), 7.31˜7.49(m, 3H)

Preparation Example 28

Synthesis of the mixture of 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol and 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.22(d, J=6.4 Hz, 3H), 2.10(d, J=4.4 Hz, 1H), 2.71(d, J=4.8 Hz, 1H), 3.90˜3.95(m, 1H), 4.94(t, J=5.0 Hz, 1H), 7.31˜7.49(m, 3H)

Preparation Example 29

Synthesis of 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.02(1, J=7.4 Hz, 3H), 1.54˜1.61(m, 2H), 2.07(d, J=4.8 Hz, 1H), 2.74(d, J=4.8 Hz, 1H), 3.65˜3.68(m, 1H), 5.01(t, J=5.0 Hz, 1H), 7.31˜7.49(m, 3H)

Preparation Example 30

Synthesis of 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.02(1, J=7.4 Hz, 3H), 1.54˜1.61(m, 2H), 2.07(d, J=4.8 Hz, 1H), 2.74(d, J=4.8 Hz, 1H), 3.65˜3.68(m, 1H), 5.01(t, J=5.0 Hz, 1H), 7.31˜7.49(m, 3H)

Preparation Example 31

Synthesis of the mixture of 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol and 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.02(1, J=7.4 Hz, 3H), 1.54˜1.61(m, 2H), 2.07(d, J=4.8 Hz, 1H), 2.74(d, J=4.8 Hz, 1H), 3.65˜3.68(m, 1H), 5.01(t, J=5.0 Hz, 1H), 77.31˜7.49(m, 3H)

Preparation Example 32

Synthesis of 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.00(d, J=6.8 Hz, 6H), 1.60˜1.65(m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12(d, J=8.4 Hz, 1H), 4.13˜4.18(m, 1H), 5.36(t, J=7.6 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 33

Synthesis of 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.00(d, J=6.8 Hz, 6H), 1.60˜1.65(m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12(d, J=8.4 Hz, 1H), 4.13˜4.18(m, 1H), 5.36(t, J=7.6 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 34

Synthesis of the mixture of 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol and 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.00(d, J=6.8 Hz, 6H), 1.60˜1.65(m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12(d, J=8.4 Hz, 1H), 4.13˜4.18(m, 1H), 5.36(t, J=7.6 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 35

Synthesis of 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,4-dichlorophenyl)-trans-1-hexene (Preparation Example 8) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (1.1 g, yield 60˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ0.89˜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=5.2 Hz, 1H), 2.74(d, J=5.2 Hz, 1H), 3.72˜3.77(m, 1H), 4.98(t, J=4.8 Hz, 1H), 7.28˜7.50(m, 3H)

Preparation Example 36

Synthesis of 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.89˜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=5.2 Hz, 1H), 2.74(d, J=5.2 Hz, 1H), 3.72˜3.77(m, 1H), 4.98(t, J=4.8 Hz, 1H), 7.28˜7.50(m, 3H)

Preparation Example 37

Synthesis of the mixture of 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol and 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.89˜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=5.2 Hz, 1H), 2.74(d, J=5.2 Hz, 1H), 3.72˜3.77(m, 1H), 4.98(t, J=4.8 Hz, 1H), 7.28˜7.50(m, 3H)

Preparation Example 38

Synthesis of 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.10(d, J=6.4 Hz, 3H), 2.72(d, J=2.4 Hz, 1H), 3.10(d, J=8.4 Hz, 1H), 4.47˜4.54(m, 1H), 5.24(t, J=8.8 Hz, 1H), 7.18˜7.36(m, 3H)

Preparation Example 39

Synthesis of 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.10(d, J=6.4 Hz, 3H), 2.72(d, J=2.4 Hz, 1H), 3.10(d, J=8.4 Hz, 1H), 4.47˜4.54(m, 1H), 5.24(t, J=8.8 Hz, 1H), 7.18˜7.36(m, 3H)

Preparation Example 40

Synthesis of the mixture of 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol and 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,6-dichlorophenyl)-trans-1-propene (Preparation Example 9) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.91 g, yield 60˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.10(d, J=6.4 Hz, 3H), 2.72(d, J=2.4 Hz, 1H), 3.10(d, J=8.4 Hz, 1H), 4.47˜4.54(m, 1H), 5.24(t, J=8.8 Hz, 1H), 7.18˜7.36(m, 3H)

Preparation Example 41

Synthesis of 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.97(t, J=7.6 Hz, 3H), 1.26˜1.53(m, 2H), 2.64(dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14(d, J=8.4 Hz, 1H), 4.22˜4.26(m, 1H), 5.26(t, J=8.4 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 42

Synthesis of 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.97(t, J=7.6 Hz, 3H), 1.26˜1.53(m, 2H), 2.64(dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14(d, J=8.4 Hz, 1H), 4.22˜4.26(m, 1H), 5.26(t, J=8.4 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 43

Synthesis of the mixture of 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol and 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.97(t, J=7.6 Hz, 3H), 1.26˜1.53(m, 2H), 2.64(dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14(d, J=8.4 Hz, 1H), 4.22˜4.26(m, 1H), 5.26(t, J=8.4 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 44

Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene (Preparation Example 11) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.25 g, yield 60˜95%).

1 H NMR(400 MHz, CDCl 3 ) δ1.00(d, J=6.8 Hz, 6H), 1.60˜1.65(m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12(d, J=8.4 Hz, 1H), 4.13˜4.18(m, 1H), 5.36(t, J=7.6 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 45

Synthesis of 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene (Preparation Example 11) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.37 g, yield 60˜95%).

1 H NMR(400 MHz, CDCl 3 ) δ1.00(d, J=6.8 Hz, 6H), 1.60˜1.65(m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12(d, J=8.4 Hz, 1H), 4.13˜4.18(m, 1H), 5.36(t, J=7.6 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 46

Synthesis of the mixture of 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol and 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-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 11) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.47 g, yield 60˜95%).

1 H NMR(400 MHz, CDCl 3 ) δ1.00(d, J=6.8 Hz, 6H), 1.60˜1.65(m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12(d, J=8.4 Hz, 1H), 4.13˜4.18(m, 1H), 5.36(t, J=7.6 Hz, 1H), 7.17˜7.35(m, 3H)

Preparation Example 47

Synthesis of 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.85(t, J=6.8 Hz, 3H), 1.20˜1.31(m, 4H), 1.45˜1.53(m, 2H), 2.61˜2.62(m, 1H), 3.12(d, J=8.4 Hz, 1H), 4.28˜4.33(m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35(m, 3H)

Preparation Example 48

Synthesis of 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.85(t, J=6.8 Hz, 3H), 1.20˜1.31(m, 4H), 1.45˜1.53(m, 2H), 2.61˜2.62(m, 1H), 3.12(d, J=8.4 Hz, 1H), 4.28˜4.33(m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35(m, 3H)

Preparation Example 49

Synthesis of the mixture of 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol and 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ0.85(t, J=6.8 Hz, 3H), 1.20˜1.31(m, 4H), 1.45˜1.53(m, 2H), 2.61˜2.62(m, 1H), 3.12(d, J=8.4 Hz, 1H), 4.28˜4.33(m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35(m, 3H)

Preparation Example 50

Synthesis of methyl 2-(2-chlorophenyl)-(R)-2-hydroxyacetate

15 g of (R)-2-chloromandelic acid was mixed with methanol (CH 3 OH, 150 ml) and phosphorus chloride oxide (POCl 3 , 0.76 ml) in a flask by stiffing 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 SO 3 ) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO 4 ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (15.64 g, yield 95%).

1 H NMR(400 MHz, CDCl 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

N,O-dimethylhydroxylamine hydrochloride (N,O-dimethylhydroxylamine.HCl, 15.2 g) was dissolved in dichloromethane (DCM, 150 ml), and cooled to 0° C. using an ice-bath. Then, 77.7 ml 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 (15.64 g) dissolved in dichloromethane (DCM, 150 ml) 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 (HCl, 200 ml). The obtained organic layer was washed with distilled water and brine, dehydrated with anhydrous magnesium sulfate (MgSO 4 ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (14.68 g, yield 82%).

1 H NMR(400 MHz, CDCl 3 ) δ3.23(s, 3H), 3.28(s, 3H), 4.33(d, J=6.0 Hz, 1H), 5.81(d, J=5.6 Hz, 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 (0.81 g, 3.52 mmol) obtained in Preparation Example 51 was dissolved in dichloromethane (DCM), and cooled to 0° C. Imedazole (0.36 g, 5.28 mmol) was slowly added, and stirred. TBDMS-Cl (t-butyldimethylsily chloride, 0.79 g, 5.28 mmol) was slowly added. When the reaction was completed, the reaction mixture was quenched with H 2 O. The organic layer was separated and collected. The aqueous layer was extracted with CH 2 Cl 2 (300 mL), dried over MgSO 4 Concentration under vacuum provided a title compound. (0.97 g, 80˜95%).

1 H NMR(400 MHz, CDCl 3 ) δ-0.03(s, 3H), 0.14(s, 3H), 0.94(s, 9H), 2.97(s, 3H), 3.02(s, 3H), 5.83(s, 1H), 7.28˜7.60(m, 4H)

Preparation Example 53

Synthesis of 1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)propane-2-on

2-(2-chlorophenyl)-N-methoxy-(R)-2-(t-butyldimethylsiloxy)-N-methylacetamide (0.9 g) obtained in Preparation Example 52 was dissolved in tetrahydrofuran (THF), and cooled to 0° C. 3.0M methyl magnesium bromide (MeMgBr, 2.18 ml) 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 (KHSO 4 , 100 ml) and then, washed again with brine. The obtained organic layer was dehydrated with anhydrous magnesium sulfate (MgSO 4 ), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (0.69 g, yield 85˜95%).

1 H NMR(400 MHz, CDCl 3 ) δ-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 1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)-(S)-2-propanol

1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)propane-2-on (0.14 g) 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 O. The obtained organic layer was washed with H 2 O, dehydrated with anhydrous magnesium sulfate (MgSO 4 ), filtrated, and concentrated under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (0.04 g, yield 25˜33%, cis:trans=2:1).

1 H NMR(400 MHz, CDCl 3 ) δ-0.11(s, 3H), 0.11(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 1-(2-chlorophenyl)-(R,S)-1,2-propanediol

1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)-(S)-2-propanol (10.38 g) obtained in Preparation Example 54 was dissolved in methanol (CH 3 OH, 100 ml), and then, cooled to 0° C. 8M hydrochloric acid (HCl, 56.2 ml) 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, 30 ml) 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 (MgSO 4 ), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (7.05 g, yield 60˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.07(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 1-(2-chlorophenyl)-(S,R)-1,2-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 (5.04 g, yield 84%).

1 H NMR(400 MHz, CDCl 3 ) δ1.07(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 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.10(d, J=6.4 Hz, 3H), 2.72(d, J=2.4 Hz, 1H), 3.10(d, J=8.4 Hz, 1H), 4.47˜4.54(m, 1H), 5.24(t, J=8.8 Hz, 1H), 7.18˜(m, 3H)

Preparation Example 58

Synthesis of 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.10(d, J=6.4 Hz, 3H), 2.72(d, J=2.4 Hz, 1H), 3.10(d, J=8.4 Hz, 1H), 4.47˜4.54(m, 1H), 5.24(t, J=8.8 Hz, 1H), 7.18˜ (m, 3H)

Preparation Example 59

Synthesis of the mixture of 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol and 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 was conducted, except that 1-(2,3-dichlorophenyl)-trans-1-propene (Preparation Example 13) was used instead of 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (0.91 g, yield 60˜90%).

1 H NMR(400 MHz, CDCl 3 ) δ1.10(d, J=6.4 Hz, 3H), 2.72(d, J=2.4 Hz, 1H), 3.10(d, J=8.4 Hz, 1H), 4.47˜4.54(m, 1H), 5.24(t, J=8.8 Hz, 1H), 7.18˜(m, 3H)

Preparation Example 60

Synthesis of 1-(2-fluorophenyl)-trans-1-propene

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

1 H NMR(400 MHz, CDCl 3 ) δ1.94(d, J=6.8 Hz, 3H), 6.30˜6.38(m, 1H), 6.57(d, J=16 Hz, 1H), 7.00˜7.41(m, 4H)

Preparation Example 61

Synthesis of 1-(2-fluorophenyl)-(S,S)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 ) δ1.15(d, J=6.4 Hz, 3H), 2.43(d, J=3.6 Hz, 1H), 2.69(d, J=4.8 Hz, 1H), 3.90˜3.98(m, 1H), 4.78(dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50(m, 4H)

Preparation Example 62

Synthesis of 1-(2-fluorophenyl)-(R,R)-1,2-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 1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtain the title compound (3.29 g, yield 79%).

1 H NMR(400 MHz, CDCl 3 ) δ1.15(d, J=6.4 Hz, 3H), 2.43(d, J=3.6 Hz, 1H), 2.69(d, J=4.8 Hz, 1H), 3.90˜3.98(m, 1H), 4.78(dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50(m, 4H)

Preparation Example 63

Synthesis of 2-iodobenzenealdehyde

In a flask, 2-iodobenzyl alcohol (4 g, 17.09 mmol) was dissolved in dichloromethane (MC, 85 ml), and then, manganese oxide (MnO 2 , 14.86 g, 170.92 mmol) 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 (3.6 g, yield 91%).

1 H NMR(400 MHz, CDCl 3 )δ7.30˜7.99(m, 4H), 10.10(s, 1H)

Preparation Example 64

Synthesis of 1-(2-iodophenyl)-trans-1-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 (3.4 g, yield 65%).

1 H NMR(400 MHz, CDCl 3 )δ1.95(dd, J=6.8 Hz, 1.6 Hz, 3H), 6.09˜6.18(m, 1H), 6.60(dd, J=15.66 Hz, 1.8 Hz, 1H), 6.89˜7.84(m, 4H)

Preparation Example 65

Synthesis of 1-(2-iodophenyl)-trans-1-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 (8.5 g, yield 75%).

1 H NMR(400 MHz, CDCl 3 )δ1.46(t, J=7.6 Hz, 3H), 2.26˜2.34(m, 2H), 6.17(dt, J=15.6 Hz, 6.6 Hz 1H), 6.57(d, J=15.6 Hz, 1H), 6.89˜7.85(m, 4H)

Preparation Example 66

Synthesis of 1-(2-iodophenyl)-(S,S)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 )δ1.27(d, J=6.4 Hz, 3H), 2.26(br s, 1H), 2.74(br s, 1H), 3.99(t, J=6.0 Hz, 1H), 4.81(d, J=4.0 Hz, 1H), 7.01˜7.87(m, 4H)

Preparation Example 67

Synthesis of 1-(2-iodorophenyl)-(R,R)-1,2-propanediol

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

1 H NMR(400 MHz, CDCl 3 )δ1.26(d, J=6.4 Hz, 3H), 2.35(br s, 1H), 2.85(br d, J=4.0 Hz, 1H), 3.98(t, J=6.2 Hz, 1H), 4.80(dd, J=5.0, 4.4 Hz, 1H), 7.00˜7.87(m, 4H)

Preparation Example 68

Synthesis of 1-(2-iodophenyl)-(S,S)-1,2-butanediol

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

1 H NMR(400 MHz, CDCl 3 )δ1.04(t, J=7.6 Hz, 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=4.8 Hz, 1H), 7.01˜7.87(m, 4H)

Preparation Example 69

Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane

To a stirred solution of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14, 67 g, 0.35 mol) in CH 2 Cl 2 (670 ml) was added Et 3 N (200 mL, 1.43 mol) and TMSCl (113.9 mL, 0.89 mol) at 0° C. under N 2 .

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

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

Preparation Example 70

Preparation of 1-(2-chlorophenyl)-(R,R)-1,2-(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 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (8.5 g, yield 90˜120%).

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

Preparation Example 71

Preparation of 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy)propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)propane-1,2-diol (Preparation example 16) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (5.2 g, yield 90˜120%).

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

Preparation Example 72

Preparation of 1-(2-chlorophenyl)-(S,R)-1,2-(Bis-trimethylsilanyloxy)propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(S,R)-1,2-propanediol (Preparation example 56) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.4 g, yield 90˜120%).

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

Preparation Example 73

Preparation of 1-(2-chlorophenyl)-(R,S)-1,2-(Bis-trimethylsilanyloxy)propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(R,S)-1,2-propanediol (Preparation example 55) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.2 g, yield 90˜120%).

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

Preparation Example 74

Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-butanediol (Preparation example 17) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜120%).

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

Preparation Example 75

Preparation of 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-butanediol (Preparation example 18) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.5 g, yield 90˜120%).

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

Preparation Example 76

Preparation of 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy)butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-1,2-butanediol (Preparation example 19) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.0 g, yield 90˜120%).

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

Preparation Example 77

Preparation of 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 20) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title (2.7 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-0.053(s, 9H), 0.044(s, 9H), 1.07(t, J=7.2 Hz, 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 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparation example 21) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.4 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-0.053(s, 9H), 0.044(s, 9H), 1.07(t, J=7.2 Hz, 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 1-(2-chlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-3-methyl-1,2-butanediol (Preparation example 22) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-0.053(s, 9H), 0.044(s, 9H), 1.07(t, J=7.2 Hz, 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 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 23) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

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

Preparation Example 81

Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 24) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

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

Preparation Example 82

Preparation of 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-chlorophenyl)-1,2-hexanediol (Preparation example 25) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.2 g, yield 90˜120%).

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

Preparation Example 83

Preparation of 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 26) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.4 g, yield 90˜120%).

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

Preparation Example 84

Preparation of 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 38) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.4 g, yield 90˜120%).

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

Preparation Example 85

Preparation of 1-(2,3-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol (Preparation example 57) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.2 g, yield 90˜120%).

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

Preparation Example 86

Preparation of 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol (Preparation example 29) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

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

Preparation Example 87

Preparation of 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol (Preparation example 41) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

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

Preparation Example 88

Preparation of 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 32) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.7 g, yield 90˜120%).

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

Preparation Example 89

Preparation of 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparation example 44) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

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

Preparation Example 90

Preparation of 1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 90) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-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˜1.6(m, 2H), 3.72˜3.77(m, 1H), 4.98(t, J=4.8 Hz, 1H), 7.28˜7.50(m, 3H)

Preparation Example 91

Preparation of 1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparation example 47) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-0.053(s, 9H), 0.044(s, 9H), 0.85(t, J=6.7 Hz, 3H), 1.20˜1.31(m, 4H), 1.45˜1.53(m, 2H), 4.28˜4.33(m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35(m, 3H)

Preparation Example 92

Preparation of 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 27) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.2 g, yield 90˜120%).

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

Preparation Example 93

Preparation of 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 39) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.6 g, yield 90˜120%).

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

Preparation Example 94

Preparation of 1-(2,3-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol (Preparation example 58) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.9 g, yield 90˜120%).

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

Preparation Example 95

Preparation of 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol (Preparation example 30) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜120%).

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

Preparation Example 96

Preparation of 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol (Preparation example 42) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

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

Preparation Example 97

Preparation of 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparation example 33) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.5 g, yield 90˜120%).

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

Preparation Example 98

Preparation of 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparation example 45) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.4 g, yield 90˜120%).

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

Preparation Example 99

Preparation of 1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 36) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.6 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-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=4.8 Hz, 1H), 7.28˜7.50(m, 3H)

Preparation Example 100

Preparation of 1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparation example 48) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-0.053(s, 9H), 0.044(s, 9H), 0.85(t, J=6.7 Hz, 3H), 1.20˜1.31(m, 4H), 1.45˜1.53(m, 2H), 4.28˜4.33(m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35(m, 3H)

Preparation Example 101

Preparation of 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-propanediol (Preparation example 28) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.6 g, yield 90˜120%).

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

Preparation Example 102

Preparation of 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-propanediol (Preparation example 40) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

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

Preparation Example 103

Preparation of 1-(2,3-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,3-dichlorophenyl)-1,2-propanediol (Preparation example 59) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.7 g, yield 90˜120%).

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

Preparation Example 104

Preparation of 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-butanediol (Preparation example 31) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.9 g, yield 90˜120%).

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

Preparation Example 105

Preparation of 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-butanediol (Preparation example 43) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

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

Preparation Example 106

Preparation of 1-(2,4-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-3-methyl-1,2-butanediol (Preparation example 34) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.7 g, yield 90˜120%).

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

Preparation Example 107

Preparation of 1-(2,6-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-3-methyl-1,2-butanediol (Preparation example 46) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.6 g, yield 90˜120%).

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

Preparation Example 108

Preparation of 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,4-dichlorophenyl)-1,2-hexanediol (Preparation example 37) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.7 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-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=4.8 Hz, 1H), 7.28˜7.50(m, 3H)

Preparation Example 109

Preparation of 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2,6-dichlorophenyl)-1,2-hexanediol (Preparation example 49) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.2 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-0.053(s, 9H), 0.044(s, 9H), 0.85(t, J=6.7 Hz, 3H), 1.20˜1.31(m, 4H), 1.45˜1.53(m, 2H), 4.28˜4.33(m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35(m, 3H)

Preparation Example 110

Preparation of 1-(2-fluoroophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-fluoroophenyl)-(S,S)-1,2-propanediol (Preparation example 61) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

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

Preparation Example 111

Preparation of 1-(2-fulorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-fluoroophenyl)-(R,R)-1,2-propanediol (Preparation example 62) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.5 g, yield 90˜120%).

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

Preparation Example 112

Preparation of 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-iodophenyl)-(S,S)-1,2-propanediol (Preparation example 66) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.1 g, yield 90˜120%).

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

Preparation Example 113

Preparation of 1-(2-iodophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-iodophenyl)-(R,R)-1,2-propanediol (Preparation example 67) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (2.8 g, yield 90˜120%).

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

Preparation Example 114

Preparation of 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 was conducted, except that 1-(2-iodophenyl)-(S,S)-1,2-butanediol (Preparation example 68) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) to obtain the title compound (3.3 g, yield 90˜120%).

1 H NMR(400 MHz, CDCl 3 )δ-0.053(s, 9H), 0.044(s, 9H), 1.04(t, J=7.6 Hz, 3H), 1.60˜1.71(m, 2H), 3.71˜3.76(m, 1H), 4.87(d, J=4.8 Hz, 1H), 7.01˜7.87(m, 4H)