JPH0832657B2 - Optically active ethers and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention provides a compound represented by formula (I): (In the formula, R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms, and R'is an alkyl group having 1 to 15 carbon atoms or Indicates a group. Here, A is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2, and * is an asymmetric carbon. ) Is represented by the formula (1) and the production method thereof.

<Prior Art> The optically active ethers represented by the general formula (I) are novel compounds that have not been described in any literature, and have been known not only about their production methods but also about their usefulness as compounds. Has not been done.

<Problems to be Solved by the Invention> The optically active ethers represented by the general formula (I) are also useful as intermediates for medicines, agricultural chemicals, etc., but especially organic electronic materials, especially intermediates of novel liquid crystalline substances. , Which can be introduced into a novel liquid crystalline substance (II) by a method represented by the following formula, and the substance has very excellent properties as a ferroelectric liquid crystal.

(Here, Ar represents a phenylene group, a biphenylene group, a heterocyclic group, or the like, Y represents an alkyl group or an alkoxyl group, and the like. R, R ', l, and * have the same meanings as described above.) Among the optically active ethers of formula (I) are
It can also be used as a liquid crystal substance itself.

<Means for Solving the Problems> The present invention provides such a novel and useful optically active ether represented by the general formula (I).

The optically active ethers represented by the general formula (I) are represented by the general formula (III) (In the formula, R'is an alkyl group having 1 to 15 carbon atoms or Indicates a group. Here, A is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2, and * is an asymmetric carbon. ) Is represented by the general formula (IV) R—X (IV) (wherein R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms, X is a halogen atom or —OSO). ₂ R
Indicates. Here, R represents a lower alkyl group or an phenyl group which may be substituted).

This reaction is usually carried out in the presence of a basic substance, and examples of the basic substance include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as lithium, sodium and potassium, sodium ethylate, Examples thereof include alkali metal alcoholates such as sodium methylate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and butyllithium.

Such basic substances are optically active alcohols (III)
However, the upper limit is not particularly limited, but it is preferably 1,1 to 5 equivalents.

Examples of the alkylating agent used in this reaction include halides such as chloride, bromide, and iodo having an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms as described below, or sulfuric acid esters (methanesulfonic acid). Ester, ethanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc.).

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxy. Butyl, methoxypentyl, methoxyhexyl, methoxyheptyl, methoxyoctyl, methoxynonyl, methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyheptyl, ethoxyoctyl, ethoxynonyl, ethoxydecyl, Propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhex Le, propoxy octyl, propoxy decyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, Butokishipenchiru, Butokishihekishiru, Butokishihepuchiru, Butokishinoniru,
Pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyoctyl, pentyloxydecyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl,
Hexyloxypentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, heptyloxymethyl, heptyloxyethyl, heptyloxypropyl, heptyloxypentyl, octyloxymethyl, octyloxyethyl, decyloxymethyl, decyloxy Ethyl, decyloxypropyl.

The amount of such an alkylating agent to be used is 1 equivalent times or more with respect to the optically active alcohol (III),
Usually, it is in the range of 1 to 5 equivalent times.

Examples of the reaction solvent include tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, hexane and other aliphatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons. Solvents such as hydrocarbons inert to the reaction are used alone or as a mixture, and the amount thereof is not particularly limited.

Further, a polar solvent such as dimethyl sulfoxide, hexamethylphosphorylamide, N-methylpyrrolidone or the like can be used.

The reaction temperature is generally -50 ° C to 120 ° C, preferably -30 ° C.
The range is up to 100 ° C.

After completion of the reaction, usual separation means such as extraction, liquid separation,
Optically active ethers (I) can be obtained in good yield by an operation such as concentration, and this can be purified by column chromatography, recrystallization or the like, if necessary.

The optically active alcohols (III) have the general formula (V) (In the formula, R ′ and l have the same meanings as described above, and R ″ represents a lower alkyl group.) The ester represented by the formula (1) is hydrolyzed with one of the optically active forms of the ester. It can be produced by asymmetric hydrolysis using an esterase having the ability to

The esterase-producing microorganism used in this reaction is not particularly limited as long as it is an esterase-producing microorganism having the ability to asymmetrically hydrolyze esters (VI).

The esterase in the present invention means an esterase in a broad sense including lipase.

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Previbacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus,
Examples include microorganisms belonging to the genera Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter.

The cultivation of the microorganism is generally performed according to a conventional method. For example, a culture solution can be obtained by performing liquid culture.

For example, a sterilized liquid medium [for molds and yeasts, malt extract / yeast extract medium (dissolve 5 g of peptone, 10 g of glucose, 3 g of malt extract, 8 g of yeast extract in 1 water, p
H6.5), and for bacteria, a broth containing sweetened broth (dissolving 5 g of peptone, 10 g of glucose, 5 g of meat extract, and 3 g of NaCl in water 1 to adjust pH to 7.2)] with a microorganism, usually 30 to 40
The culture may be performed by reciprocal shaking culture at ℃ for 1 to 3 days, and if necessary, solid culture may be performed.

Some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the followings.

Pseudomonas lipase [Lipase P (Amano Pharmaceutical)], Aspergillus lipase [Lipase AP (Amano Pharmaceutical)], Mucor lipase [Lipase MAP]
(Manufactured by Amano Pharmaceuticals)], lipase of Candida cylindrasse [lipase MY (manufactured by Meito Sangyo)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL] Industrial)],
Lipase of the genus Arthrobacter [lipase-combined BSL (combined liquor refinement)], lipase of the genus Chromobacterium (manufactured by Toyo Brewing Co.), lipase of the genus Rhizopus derema [talipase (manufactured by Tanabe Seiyaku)], lipase of the genus Rhizopus [lipase] Saiken (Osaka Bacteria Research Institute)].

Also, animal / plant esterase can be used,
Specific examples of these esterases include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Germ esterase.

As the esterase used in this reaction, enzymes obtained from animals, plants and microorganisms are used, and the usage forms thereof include purified enzymes, crude enzymes, oxygen-containing substances, microbial culture liquids, cultures, fungus bodies, culture liquids. Further, they can be used in various forms such as those obtained by treating them as necessary, and an enzyme and a microorganism can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

The asymmetric hydrolysis reaction is usually carried out by vigorously stirring a mixture of the starting ester (V) and the enzyme or microorganism in a buffer solution.

As the buffer solution, sodium phosphate which is usually used,
A buffer solution of an inorganic acid salt such as potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate and sodium citrate, etc. is used, and the pH thereof is 8 to 11 in a culture solution of an alkaliphilic bacterium or alkaline esterase, A pH of 5 to 8 is preferable for a culture solution of a non-alkaline microorganism or an esterase having no alkali resistance. The concentration is usually 0.05 to 2M, preferably 0.05 to 0.5M.

The reaction temperature is usually 10 to 60 ° C., and the reaction time is generally 10 to 70 hours, but is not limited thereto.

After completion of such asymmetric hydrolysis reaction, the asymmetric hydrolysis reaction solution is treated with, for example, methyl isobutyl ketone, ethyl acetate,
Extraction treatment with a solvent such as ethyl ether, evaporation of the solvent from the organic layer, and treatment of the concentrated residue with column chromatography will yield asymmetric hydrolysis products that do not react with optically active alcohols (III). It is possible to separate optically active esters which are residues of asymmetric hydrolysis [optically active substances in the starting ester (IV) which have not been asymmetrically hydrolyzed].

The optically active ester obtained here is further hydrolyzed if necessary to obtain the optically active alcohol (II
I) may be enantiomeric optically active alcohols.

When a lipase belonging to the genus Pseudomonas or the genus Arthrobacter is used as the lipase in this asymmetric hydrolysis reaction, optically active alcohols can be obtained with a relatively high optical purity.

In addition, in the case of this asymmetric hydrolysis, in addition to the buffer solution, it is also possible to use an organic solvent inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, dichloromethane, etc. Can be advantageously performed.

Esters (V) have the general formula (VI) (In the formula, R'is an alkyl group having 1 to 15 carbon atoms or Indicates a group. Here, A is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2. ) Is reacted with a lower alkylcarboxylic acid to acylate.

In this acylation, the lower alkyl carboxylic acids are lower alkyl carboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, their acid anhydrides or acid halides (eg acid chloride, acid bromide).
Can be given.

In this reaction, the amount of the lower alkylcarboxylic acid used is required to be 1 equivalent or more times the amount of the alcohol (VI), and the upper limit is not particularly limited, but preferably 1.
It is 1 to 4 equivalent times.

This reaction is carried out by reacting with a catalyst in the presence or absence of a solvent. When a lower alkylcarboxylic acid is used as the acylating agent, a suitable dehydrating agent is used in combination.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether,
Acetone, methyl ethyl ketone, toluene, benzene,
An aliphatic or aromatic hydrocarbon such as chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, or hexane, an ether, or a solvent inert to a reaction such as a halogenated hydrocarbon is used alone or in combination. The amount used is not particularly limited.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine,
Examples thereof include organic or inorganic basic substances such as picoline, imidazole, sodium carbonate, and potassium hydrogen carbonate, and organic or inorganic acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as a catalyst.

The amount of catalyst used depends on the type of lower alkyl carboxylic acids used, the combination of catalysts used, etc.
Although not necessarily specified, for example, when an acid halide is used as a lower alkyl carboxylic acid, it is 1 equivalent or more times the acid halide.

When a lower alkyl carboxylic acid is used as the lower fatty acid carboxylic acid, a carbodiimide derivative such as dicyclohexylcarbodiimide is particularly preferably used as a dehydrating agent used in combination. The amount of the carbodiimide derivative is generally 1 equivalent to the lower alkyl carboxylic acid. Used over. At this time, the use of the basic catalyst is effective in improving the reaction rate and yield, and the amount used is 0.01 equivalent times or more with respect to the lower alkylcarboxylic acid, and particularly preferably 0.
01 to 1 equivalent times.

The reaction temperature is usually -30C to 100C, preferably -20C to 90C.

The reaction time is not particularly limited, and the starting alcohols (V
The time when I) disappears from the reaction system can be used as the end point of the reaction.

After completion of the reaction, usual separation means such as extraction, liquid separation,
The ester (V) can be obtained in good yield by concentration, recrystallization, etc., which can be further purified by column chromatography or the like, if necessary, but can be used as is in the reaction mixture in the next step.

Alcohols (VI) have the general formula (VII) (In the formula, R'and l have the same meaning as described above.) The ketones can be produced by reducing with a reducing agent capable of reducing the ketone to give an alcohol.

As such a reducing agent, preferably, sodium borohydride, zinc borohydride, aluminum isopropoxide, lithium tri-tert-butoxyaluminum hydride, lithium tri-s-butylborohydride, borane, lithium aluminum hydrogen Compound-silica gel, alkali metal-ammonia, Raney nickel-hydrogen and the like are used in an amount of at least 1 to the starting ketones.
It is required to be equivalent times or more, and usually in the range of 1 to 10 equivalent times.

This reaction is usually performed in a solvent. Examples of such a solvent include tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, ethers such as toluene, benzene, chloroform, dichloromethane, halogenated hydrocarbons, and the like. Or a mixture of solvents inert to the reaction, such as alcohols and the like.

The reaction temperature is usually in the range of -30C to 100C, preferably in the range of -20C to 90C.

From the reaction mixture thus obtained, alcohols (VI) are obtained by operations such as liquid separation, concentration, distillation and crystallization.
The alcohol (VI) does not necessarily have to be isolated in order to obtain the ester (V) in the next step, but the reaction mixture may be directly used in the next step.

<Effect of the Invention> Thus, according to the method of the present invention, the optically active ethers represented by the general formula (I), which are novel compounds, can be industrially advantageously produced, and the compound of the present invention is used for liquid crystals. Not only is it useful as a material, but it can also be used as an intermediate for agricultural chemicals, pharmaceuticals, and the like.

<Example> Hereinafter, the present invention will be described with reference to Examples.

Example 1 A 4-necked flask equipped with a stirrer and a thermometer was charged with 71.2 g (0.4 mol) of methyl 4-acetylbenzoate, 300 ml of tetrahydrofuran and 100 ml of ethanol, and the temperature was 15 to 25 ° C.
Sodium borohydride (7.6 g, 0.2 mol) is added over 3 hours. After keeping at the same temperature for 5 hours, the reaction solution is poured into ice water and extracted twice with 400 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give 71.0 g (yield 98.6%) of methyl 4- (1-hydroxyethyl) benzoate (III-1).

70.0 g (0.388 mol) of (III-1) obtained here was added to toluene 3
It is dissolved in 00 ml and 100 ml of pyridine and to this is added 36.6 g (0.466 mol) of acetyl chloride over 2 hours at 15-20 ° C. Thereafter, it is kept at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After the reaction is complete, cool to 10 ° C or below and then water 60
After adding 0 ml and separating the organic layer, 2N hydrochloric acid water, water, 5%
Wash sequentially with sodium carbonate and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to 4
Methyl (IV-1) 8- (1-acetoxyethyl) benzoate
5.2 g (yield 99%) was obtained.

72.0 g (0.324 mol) of (IV-1) obtained here was added to 400 ml of 0.3 M phosphate buffer (pH 7.5) and amanolipase "P" 4.
Mix with 8g and stir vigorously at 40-45 ° C for 40 hours. After completion of the reaction, the reaction mixture is extracted with 600 ml of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixed solution of hexane: ethyl acetate (12: 1) as a developing solvent to methyl (+)-4- (1-hydroxyethyl) benzoate (V-1 ) 25.52g [▲ [α] ²⁰ _D ▼ + 42.3 ° (c = 1, CH
Cl ₃ ), 99.4% ee, melting point 52-53 ° C.], and 39.6 g of unreacted ester.

3.6 g (0.02 mol) of [V-1] obtained here is dissolved in 30 ml of dimethylformamide and cooled to 10 ° C. Sodium hydride (0.62 g, 0.026 mol) is added to this, and the mixture is kept at 30 to 35 ° C for 1 hour. Next, 6.0 g of n-propyl tosylate (0.028
Mol) is added at 20 to 25 ° C, and the mixture is reacted at 40 ° C for 5 hours. After the reaction is completed, the reaction mixture is poured on ice, and ethyl acetate is added.
Extract with 50 ml. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain methyl (+)-4- (1-propoxyethyl) benzoate (I-1) 4.0 g (yield 90%). [▲ [α] ²⁰ _D ▼
+ 63.4 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.4928] Example 2 A solution of 3.6 g (0.02 mol) of [V-1] obtained in Example 1 and 30 ml of N-methylpyrrolidone was added. Cool to 5 ° C. and add 0.95 g (0.04 mol) of sodium hydride. Later, 30
Incubate at ~ 35 ° C for 1 hour. Then 7.1 g of methyl iodide (0.
05 mol) at 15-20 ° C. Thereafter, the reaction is carried out at 20 to 30 ° C. for 2 hours and further at 40 to 50 ° C. for 2 hours. After completion of the reaction, the reaction mixture is poured on ice and extracted with 60 ml of ethyl acetate. Then, post-treatment is performed according to Example 1 to obtain (+)-4-
Methyl (1-methoxyethyl) benzoate (I-2) 3.59 g
(Yield 92.5%) was obtained.

[▲ [α] ²⁰ _D ▼ + 75.9 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼
1.4996] Example 3 A solution of 3.6 g (0.02 mol) of [V-1] obtained in Example 1 and 30 ml of dimethylformamide was cooled to 10 ° C., and 0.62 g (0.026 mol) of sodium hydride was added thereto. 30 ~ 35 ℃
Keep it warm for 1 hour. Then n-hexyl silate 7.69
g (0.03 mol) is added at 20 to 25 ° C, and the mixture is reacted at 40 to 50 ° C for 5 hours. After completion of the reaction, post-treatment was carried out according to Example 1 to obtain 4.60 g (yield 92%) of methyl (+3) -4- (1-hexyloxyethyl) benzoate (I-3).

[▲ [α] ²⁰ _D ▼ + 60.6 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼
1.4922 Example 4 3.6 g (0.02 mol) of [V-1] obtained in Example 1 is dissolved in a solution consisting of 20 ml of dimethylformamide and 10 ml of tetrahydrofuran and cooled to 10 ° C. Sodium hydride (0.62 g, 0.026 mol) is added to this, and the mixture is kept at 30 to 35 ° C for 1 hour.

Next, 8.26 g (0.032 mol) of ω-ethoxypropyl tosylate is added at 20 to 25 ° C., and the mixture is reacted at 50 to 60 ° C. for 5 hours. After completion of the reaction, post-treatment was carried out according to Example 1 to give (+)-
Thus, 4.79 g (yield 90%) of methyl 4- (1-ethoxypropoxyethyl) benzoate (I-4) was obtained.

[▲ [α] ²⁰ _D ▼ + 46.5 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼
1.4933] Example 5 4′-in a 4-necked flask equipped with a stirrer and a thermometer.
Ethyl acetyl-4-biphenylcarboxylate 32.2 g (0.1
(2 mol), 150 ml of chloroform and 50 ml of ethanol were charged, and sodium borohydride, 2.3 g (0.
06 mol) is added over 10 minutes. After incubating at the same temperature for 2 hours, the reaction solution was poured into ice water, and added with 200 ml of ethyl acetate.
Extract twice. The organic layer was washed with water and then concentrated under reduced pressure to 4'-
Ethyl (1-hydroxyethyl) -4-biphenylcarboxylate (III-5) (30.8 g, yield 95%) was obtained.

29.7 g (0.11 mol) of (III-5) obtained here was added to toluene 15
Dissolve in 0 ml and 50 ml of pyridine and add 9.42 g (0.12 mol) of acetyl chloride over 2 hours at 15-20 ° C. Thereafter, it is kept at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After completion of the reaction, cool to 10 ° C or below, then
After adding 300 ml, the organic layer is separated and then washed successively with water, 5% sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to obtain 4'-
33.7 g (yield 98%) of ethyl (1-acetoxyethyl) -4-biphenylcarboxylate (IV-5) was obtained.

20.0 g (64 mmol) of (IV-5) obtained here was added to 400 ml of 0.1 M phosphate buffer (pH 7.5) and amanolipase "P".
Mix with 4g and stir vigorously at 40-45 ° C for 20 hours. After completion of the reaction, the reaction mixture is extracted with 600 ml of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixed solution of hexane: ethyl acetate (12: 1) as a developing solvent to obtain (+)-4 '-(1-hydroxyethyl) -4-biphenylcarboxylic acid. Ethyl (V-5) 7.0 g [▲ [α] ²⁰ _D ▼
+ 35.5 ° (c = 0.544, CHCl ₃ ), 98.1% ee, melting point 74.6
C.] and 10.8 g of unreacted ester were obtained.

1.0 g (3.7 mmol) of [V-5] obtained here is dissolved in 30 ml of dimethylformamide and cooled to 10 ° C. Sodium hydride (0.19 g, 4.8 mmol) was added to this, and the mixture was kept at 30 to 35 ° C for 1 hour. Next, 1.0 g of n-propyl tosylate (4.
(8 mmol) is added at 20 to 25 ° C, and the mixture is reacted at 40 ° C for 5 hours. After completion of the reaction, the reaction mixture is poured on ice and extracted with 50 ml of ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue is purified by column chromatography, (+)-4 '-(1-propoxyethyl) -4
-Ethyl biphenylcarboxylate (I-5) 0.87 g (yield 75
%) Was obtained. [▲ [α] ²⁰ _D ▼ + 78.1 ° (c = 0.98, CHCl
₃ ), ▲ n ²⁰ _D ▼ = 1.5542] Example 6 A solution of 1.0 g (3.7 mmol) of [V-5] obtained in Example 5 and 30 ml of N-methylpyrrolidone was cooled to 5 ° C. and hydrogen was added thereto. 0.19 g (4.8 mmol) of sodium iodide is added.
Then, incubate at 30-35 ° C for 1 hour. Then 1.23 g (4.8 mmol) of hexyl tosylate are added at 15-20 ° C. rear,
The reaction is carried out at 20 to 30 ° C for 2 hours, and further at 40 to 50 ° C for 2 hours. After the reaction is completed, the reaction mixture is poured on ice, and ethyl acetate is added.
Extract with 60 ml. Then, post-treatment was carried out according to Example 5 to obtain 1.09 g (yield: 83%) of ethyl (+6) -4 '-(1-hexyloxyethyl) -4-biphenylcarboxylate (I-6).

[▲ [α] ²⁰ _D ▼ + 64.5 ° (c = 1.01, CHCl ₃ ), ▲ n ²⁰ _D
▼ 1.5462] Example 7 A solution of 1.0 g (3.7 mmol) of [V-5] obtained in Example 5 in 30 ml of dimethylformamide was cooled to 10 ° C., and 0.19 g (4.8 mmol) of sodium hydride was added thereto. , 30 ~
Incubate at 35 ° C for 1 hour. Then n-dodecyl tosylate
1.63 g (4.8 mmol) is added at 20 to 25 ° C, and the mixture is reacted at 40 to 50 ° C for 5 hours. After completion of the reaction, post-treatment was carried out according to Example 6 to obtain (+)-4 '-(1-dodecyloxyethyl).
Ethyl-4-biphenylcarboxylate (I-7) 1.31 g (yield
81%).

[▲ [α] ²⁰ _D ▼ + 46.0 ° (c = 0.99, CHCl ₃ ), ▲ n ²⁰ _D
(1.5291) Example 8 1.0 g (3.7 mmol) of [V-5] obtained in Example 5 is dissolved in a solution consisting of 20 ml of dimethylformamide and 10 ml of tetrahydrofuran, and cooled to 10 ° C. Sodium hydride (0.19 g, 4.8 mmol) is added to this, and the mixture is kept at 30 to 35 ° C for 1 hour.

Next, 1.24 g (4.8 mmol) of ω-ethoxypropyl tosylate is added at 20 to 25 ° C, and the mixture is reacted at 50 to 60 ° C for 5 hours. After completion of the reaction, post-treatment was carried out according to Example 5 (+).
0.95 g (yield 72%) of ethyl 4 '-(1-ethoxypropoxyethyl) -4-biphenylcarboxylate (I-8) was obtained.

[▲ [α] ²⁰ _D ▼ + 65.5 ° (c = 0.978, CHCl ₃ )] Example 9 Except that 66.4 g (0.2 mol) of dodecyl 4-acetylbenzoate was used in place of methyl 4-acetylbenzoate. Reaction, post-treatment, etc. were carried out in accordance with Example 1 to give (+)-4-
Dodecyl (1-hydroxyethyl) benzoate (V-9) 26.
3 g [▲ [α] ²⁰ _D ▼ = + 21.7 ° (c = 1, CHCl ₃ )] were obtained.

3.34 g (10 mmol) of [V-9] obtained here is dissolved in 30 ml of dimethylformamide and cooled to 10 ° C. To this, 0.48 g (12 mmol) of sodium hydride was added, and the mixture was kept warm at 30-40 ° C for 1 hour. Next, 3.1 g of n-hexyl tosylate (12
(Mmol) and added at 20 to 25 ° C, and reacted at 40 ° C for 5 hours. After completion of the reaction, the reaction mixture is poured into ice water and extracted with 100 ml of toluene. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain 3.47 g (yield 83%) of dodecyl (I-9) (+)-4- (1-hexyloxyethyl) benzoate. [▲
[Α] ²⁰ _D ▼ + 32.6 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ = 1.4
970] Example 10 Reaction and post-treatment according to Example 5 except that 17.6 g (0.05 mol) of octyl 4'-acetyl-4-biphenylcarboxylate was used instead of ethyl 4'-acetyl-4-biphenylcarboxylate. Etc., and octyl (V-10) (+)-4 '-(1-hydroxyethyl) -4-biphenylcarboxylate (V-10) 7.6 g (yield 43%) [▲ [α] ²⁰ _D ▼ + 17.8 °
(C = 1, CHCl ₃ ), melting point 70-71 ° C.] was obtained.

3.54 g (10 mmol) of [V-10] obtained here is dissolved in 30 ml of dimethylformamide and cooled to 10 ° C. To this, 0.48 g (12 mmol) of sodium hydride was added, and 30-40 ° C
Keep it warm for 1 hour. Next, 3.1 g of n-hexyl tosylate
(12 mmol) is added at 20 to 25 ° C, and the mixture is reacted at 40 ° C for 5 hours. After completion of the reaction, the reaction mixture is poured into ice water and extracted with 100 ml of toluene. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to give 3.55 g of octyl (+)-4 '-(1-hexyloxyethyl) -4-biphenylcarboxylate (81% yield) [▲ [α] ²⁰ _D ▼ + 44 .6 ° (c = 1, CHCl ₃ ), ▲
n ²⁰ _D ▼ = 1.5021] was obtained.

Example 11 A 4-necked flask equipped with a stirrer and a thermometer was charged with 30.49 g (0.12 mol) of benzyl 4-acetylbenzoate, 150 ml of chloroform and 50 ml of ethanol, and 2.3 g of sodium borohydride at 15 to 25 ° C ( 0.06 mol) over 10 minutes. After keeping the temperature at the same temperature for 2 hours, the reaction solution is poured into ice water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure, and 29.2 g of benzyl (III-11) 4- (1-hydroxyethyl) benzoate (yield 95
%) Was obtained.

27.95 g (0.11 mol) of (III-11) obtained here was added to toluene.
Dissolve in 150 ml and 50 ml of pyridine, to which 9.42 g (0.12 mol) of acetyl chloride are added over 2 hours at 15-20 ° C. Then, it is kept at the same temperature for 1 hour and at 30 to 35 ° C. for 2 hours. After completion of the reaction, the mixture is cooled to 10 ° C or lower, 300 ml of 3N hydrochloric acid is added, the organic layer is separated, and then washed successively with water, 5% sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to give 4-
Benzyl (1-acetoxyethyl) benzoate (IV-11) 3
2.14 g (98% yield) was obtained.

19.08 g (0.064 mol) of (IV-11) obtained here was mixed with 400 ml of 0.1 M phosphate buffer (pH 7.0), 10 ml of chloroform and 4 g of amanolipase "P" and stirred vigorously at 40 to 45 ° C for 20 hours. To do. After completion of the reaction, the reaction mixture is extracted with 600 ml of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixed solution of hexane: ethyl acetate (12: 1) as a developing solvent and subjected to benzyl (+)-4- (1-hydroxyethyl) benzoate (V-11 ) 7.21 g [▲ [α] ²⁰ _D ▼ ＋ 35.4 ° (c = 1,
CHCl ₃ ), ▲ n ²⁵ _D ▼ = 1.5691], and unreacted ester
9.8 g was obtained.

1.28 g (5 mmol) of [V-11] obtained here is dissolved in 15 ml of N-methylpyrrolidone and cooled to 10 ° C. 0.15 g (6 mmol) of sodium hydride was added to this, and the temperature was 30-35 ° C.
Keep it warm for 1 hour. Next, 2.1 g of n-dodecyl tosylate
(6 mmol) at 20-25 ° C. and react at 40 ° C. for 5 hours. After completion of the reaction, the reaction mixture is poured on ice and extracted with 50 ml of ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue is purified by column chromatography, (+)-4- (1-dodecyloxyethyl)
1.74 g (yield 82%) of benzyl benzoate was obtained.

▲ n ²⁵ _D ▼ ＝ 1.5016 ▲ [α] ²⁵ _D ▼ ＋ 32.4 ° (c = 1, CH
Cl ₃ ) Example 12 32.17 g (0.12 mol) of 4-acetyl benzoic acid methylbenzyl ester, 4 ml of a 4-neck flask equipped with a stirrer and a thermometer, 50 ml of ethanol, 100 ml of dichloromethane and THF.
Charge 50 ml and add thereto 2.3 g (0.06 mol) of sodium borohydride over 10 minutes at 15-25 ° C. After incubating at the same temperature for 2 hours, the reaction mixture was poured into ice water,
Post-treatment was conducted in the same manner as in 11, 4- (1-hydroxyethyl) benzoic acid methylbenzyl ester (III-12) 31.43 g
(Yield 97%) was obtained.

Next, 29.71 g (0.11 mol) of (III-12) obtained here was dissolved in a mixed liquid consisting of 200 ml of dichloromethane and 50 ml of pyridine, and 50 ml of a dichloromethane solution containing 9.42 g (0.12 mol) of acetyl chloride was added thereto at room temperature. Drop it. After about 2 hours, the reaction solution is poured into 300 ml of 3N hydrochloric acid, and an extraction operation is performed. The organic layer is washed successively with water, 7% aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 33.3 g (yield 97%) of pale yellow oily 4- (1-acetoxyethyl) benzoic acid methylbenzyl ester (IV-12).

15.6 g (50 mmol) of (IV-12) obtained above was mixed with 200 ml of 0.3 M phosphate buffer (pH 7.0), 10 ml of chloroform and 3 g of amanolipase "P" and stirred vigorously at 38-40 ° C for 24 hours. To do.

After completion of the reaction, the reaction mixture is extracted with 600 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was subjected to column chromatography separation and purification using a mixed solution of hexane: ethyl acetate = 12: 1 as a developing solvent, and methylbenzyl (+)-4- (1-hydroxyethyl) benzoate. Ester (V-12) 5.95
g [▲ [α] ²⁰ _D ▼ + 36.3 ° (c = 1, CHCl ₃ ), ▲ n ²⁵ _D ▼
1.5688] was obtained.

1.35 g (5 mmol) of [V-12] obtained above is dissolved in 15 ml of dimethylformamide and cooled to 10 ° C. To this, 0.15 g (6 mmol) of sodium hydride was added, and the mixture was kept at 30 to 35 ° C for 1 hour. Then ω-ethoxypropyl tosylate
1.55 g (6 mmol) is added at 20 to 25 ° C, and the mixture is reacted at 35 to 40 ° C for 5 hours. After completion of the reaction, post-treatment and purification were carried out according to Example 11, and (+)-4- (1-ω-ethoxypropoxyethyl) benzoic acid methylbenzyl ester (I-12)
1.37 g (77% yield) was obtained.

[▲ [α] ²⁰ _D ▼ + 52.1 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼
= 1.5180] Example 13 Instead of 4-acetylbenzoic acid methylbenzyl ester, 4-acetylbenzoic acid methoxybenzyl ester 3
The reaction and post-treatment were carried out in the same manner as in Example 11 except that 4.09 g (0.12 mol) was used, and (+)-4- (1-hydroxyethyl) benzoic acid methoxybenzyl ester (V-13) was obtained.
Obtained 2.34 g.

▲ [α] ²⁵ _D ▼ + 37.2 ° (c = 1, CHCl ₃ ) n ²⁵ _D ▼ 1.5721 The yield of each intermediate is as follows. 4- (1
-Hydroxyethyl) benzoic acid methoxybenzyl ester (III-13) yield 95.5% 4- (1-acetoxyethyl) benzoic acid methoxybenzyl ester (IV-13) yield 98.5% Obtained above (V-13) 1.43 g (5 mmol) is dissolved in 15 ml of dimethylformamide and cooled to 10 ° C. To this, 0.15 g (6 mmol) of sodium hydride was added, and the mixture was kept at 30 to 35 ° C for 1 hour. Next, 2.1 g (15 mmol) of methyl iodide was added at 20 to 25 ° C., and the mixture was added at the same temperature for 3 hours and 40
React for 3 hours at ℃. After completion of the reaction, post-treatment and purification are carried out according to Example 1.

1.36 g (yield 91%) of (+)-4- (1-methoxyethyl) benzoic acid methoxybenzyl ester (I-13) was obtained.

[▲ [α] ²⁰ _D ▼ ＝ ＋ 53.2 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D
▼ = 1.5043] Example 14 4′-in a 4-necked flask equipped with a stirrer and a thermometer.
Charge 36.5 g (0.1 mol) of p-chlorobenzyl acetyl-4-biphenylcarboxylate, 150 ml of chloroform and 50 ml of ethanol and add 3.8 g (0.1 mol) of sodium borohydride at 15 to 25 ° C over 10 minutes. . After keeping at the same temperature for 2 hours, the reaction solution was poured into ice water, and ethyl acetate 20
Extract twice with 0 ml. The organic layer was washed with water and then concentrated under reduced pressure, and p-chlorobenzyl 4- (1-hydroxyethyl) -4-biphenylcarboxylate (III-14) 36.5 g (yield 99.
5%).

33.0 g (0.09 mol) of (III-14) obtained here was added to toluene 1
Dissolve in 50 ml and 50 ml of pyridine, to which 9.42 g (0.12 mol) of acetyl chloride are added over 2 hours at 15-20 ° C. Thereafter, it is kept at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After completion of the reaction, cool to 10 ° C or below, then
After adding 300 ml, the organic layer is separated and then washed successively with water, 5% sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to obtain 4'-
36.4 g (yield 99.0%) of p-chlorobenzyl (IV-14) (1-acetoxyethyl) -4-biphenylcarboxylate was obtained.

32.7 g (0.08 mol) of (IV-14) obtained here was mixed with 800 ml of 0.1 M phosphate buffer (pH 7.5), 30 ml of chloroform and 6.0 g of amanolipase "P", and the mixture was vigorously heated at 40 to 45 ° C for 20 hours. Stir. After completion of the reaction, the reaction mixture is extracted with 600 ml of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixed solution of hexane: ethyl acetate (12: 1) as a developing solvent to obtain (+)-4 '-(1-hydroxyethyl) -4-biphenylcarboxylic acid. p-chlorobenzyl (V-14) 13.8g
[▲ [α] ²⁰ _D ▼ + 21.7 ° (c = 0.544, CHCl ₃ ), melting point 10
8-110.5 ° C.] and 16.5 g of unreacted ester were obtained.

3.65 g (10 mmol) of [V-14] obtained here is dissolved in 30 ml of dimethylformamide and cooled to 10 ° C. 0.48 g (12 mmol) of sodium hydride was added to this, and the temperature was 30-35 ° C.
Keep it warm for 1 hour. Then n-octadecyl tosylate 5.
1 g (12 mmol) is added at 20 to 25 ° C, and the mixture is reacted at 40 ° C for 5 hours.

After the reaction was completed, the reaction mixture was poured into ice and washed with ethyl acetate 50
Extract with ml. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue is purified by column chromatography, (+)-4 '-(1-octadecyloxyethyl)
-4-biphenylcarboxylic acid p-chlorobenzyl 5.07 g
(Yield 82%) was obtained. [▲ [α] ²⁰ _D ▼ + 21.1 ° (c =
0.98, CHCl ₃ ), ▲ n ²⁰ _D ▼ = 1.5314] Example 15 1.8 g (10 mmol) of [V-1] obtained in Example 1 is dissolved in 30 ml of dimethylformamide and cooled to 10 ° C. Sodium hydride (0.3 g, 13 mmol) was added to this, and the temperature was 30-35 ° C.
Keep it warm for 1 hour. Next, 4.2 g of n-nonyl tosylate (14
(Mmol) and added at 20 to 25 ° C, and reacted at 40 ° C for 3 hours. After the reaction was completed, the reaction mixture was poured into ice and washed with ether 10.
Extract with 0 ml. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain 2.54 g (yield 83%) of methyl (+15) -4- (1-nonyloxyethyl) benzoate (I-15). [▲ [α]
²⁰ _D ▼ + 35.1 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.4856] Examples 16-18 In Example 15 except that n-nonyl tosylate was replaced with the alkylating agent shown in Table 1. The reaction and post-treatment were carried out in the same manner, and the results shown in Table 1 were obtained.

Example 19 In a four-necked flask equipped with a stirrer and a thermometer, 4'-
Acetyl-4-biphenylcarboxylic acid benzyl ester
33.0 g (0.1 mol), 200 ml of tetrahydrofuran and 50 ml of ethanol are charged, and 3.8 g (0.1 mol) of sodium borohydride is added over 10 minutes at 15 to 25 ° C. After keeping at the same temperature for 2 hours, the reaction solution is poured into ice water and extracted twice with 300 ml of chloroform. The organic layer was washed with water and then concentrated under reduced pressure to obtain 42.9 g of 4- (1-hydroxyethyl) -4-biphenylcarboxylic acid benzyl ester (III-19) (yield 99%).

29.9 g (0.09 mol) of (III-19) obtained here was added to toluene 1
Dissolve in 50 ml and 50 ml of pyridine, to which 9.42 g (0.12 mol) of acetyl chloride are added over 2 hours at 15-20 ° C. Then, it is kept at the same temperature for 2 hours and at 40 to 45 ° C. for 2 hours. After completion of the reaction, cool to 10 ° C or below and then add 3N hydrochloric acid.
After adding 300 ml, the organic layer is separated and then washed successively with water, 5% sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to obtain 4'-
33.0 g (yield 98%) of (1-acetoxyethyl) -4-biphenylcarboxylic acid benzyl ester (IV-19) was obtained.

29.9 g (0.08 mol) of (IV-19) obtained here was added to 800 ml of 0.1 M phosphate buffer (pH 7.5) and amanolipase "P" 6.
Mix with 0 g and stir vigorously at 30-35 ° C for 20 hours. After completion of the reaction, the reaction mixture is extracted with 600 ml of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixed solution of chloroform: ethyl acetate = (12: 1) as a developing solvent (+)-4 '-(1-hydroxyethyl) -4-.
Bifelcarboxylic acid benzyl ester (V-19) 10.6g
[▲ [α] ²⁰ _D ▼ + 23.7 ° (c = 1.0, CHCl ₃ ), melting point 104
~ 106 ° C] was obtained.

1.66 g (5 mmol) of (V-19) obtained here is dissolved in 20 ml of dimethylformamide and cooled to 10 ° C. 0.15 g (6 mmol) of sodium hydride was added to this, and the temperature was 30-35 ° C.
Keep it warm for 1 hour. Next, 1.7 g of n-octyl silate
(6 mmol) at 20-25 ° C. and react at 40 ° C. for 5 hours. After completion of the reaction, the reaction mixture is poured into ice and extracted with 50 ml of chloroform. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to give (+)-4 '-(1-octyloxyethyl) -4-biphenylcarboxylic acid benzyl ester (I-
19) 1.49 g (yield 81%) was obtained.

[▲ [α] ²⁰ _D ▼ + 26.2 ° (c = 1.0, CHCl ₃ ), ▲ n ²⁰ _D
▼ = 1.5534] Example 20 2.56 g (0.01 mol) of (V-11) obtained in Example 11 is dissolved in 20 ml of N-methylpyrrolidone and cooled to 10 ° C. Sodium hydride 0.31g (0.013mol) was added to this, 30-35 ℃
Keep it warm for 1 hour.

Next, 3.6 g (0.014 mol) of n-hexyltosylate was added to 20
Add at ~ 25 ° C and react at 40 ° C for 5 hours. After completion of the reaction, the reaction mixture is poured into ice and extracted with 50 ml of ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue is purified by column chromatography, (+)
3.11 g (yield 92%) of benzyl (I-20) -4- (1-hexyloxyethyl) benzoate was obtained.

▲ [α] ²⁰ _D ▼ = + 60.8 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼
= 1.5210 Example 21 1.28 g (5 mmol) of [V-11] obtained in Example 11 is dissolved in 15 ml of dimethylformamide and cooled to 10 ° C. Next, add 0.15 g (6 mmol) of sodium hydride, and add 30-35
Incubate at ℃ for 1 hour. Next, 1.46 g (6 mmol) of s-2-methylbutyl tosylate was added at 20 to 25 ° C, and 40 ° to 5 ° C.
React at 0 ° C for 5 hours. Hereinafter, the post-treatment and purification are performed according to Example 11.

(+)-4- (1-s-2'-methylbutoxyethyl) benzoic acid benzyl ester (I-21) 1.40 g (yield 86
%) Was obtained.

▲ [α] ²⁰ _D ▼ = 59.3 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ =
1.5190 Example 22 1.66 g (5 mmol) of [V-19] obtained in Example 19 is dissolved in 20 ml of dimethylformamide and cooled to 10 ° C. Next, add 0.15 g (6 mmol) of sodium hydride, and add 30-35
Incubate at ℃ for 2 hours. Next, 1.22 g of propyl bromide (10
(Mmol) and added at 20 to 25 ° C, and reacted at the same temperature for 2 hours and at 40 to 50 ° C for 5 hours. After completion of the reaction, post-treatment and purification were conducted according to Example 19, and (+)-4 '-(1-propoxyethyl) -4-biphenylcarboxylic acid benzyl ester (I-22) 1.50 g (yield 80%). Got

▲ [α] ²⁰ _D ▼ + 56.8 ° (c = 1.0, CHCl ₃ )

Claims (5)

[Claims] 1. A general formula (In the formula, R is an alkyl group having 1 to 20 carbon atoms or an alkoxyalkyl group, and R'is an alkyl group having 1 to 15 carbon atoms or Indicates a group. Here, A is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2, and * is an asymmetric carbon atom. ) An optically active ether represented by. 2. General formula (In the formula, R'is an alkyl group having 1 to 15 carbon atoms or Indicates a group. Here, A is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2, and * is an asymmetric carbon. ) Is represented by the general formula R—X (wherein R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms, X is a halogen atom or —OSO ₂ R
Indicates. Wherein R represents a lower alkyl group or an optionally substituted phenyl group) and a general formula characterized by reacting with an alkylating agent represented by (Wherein R, R ', l and * have the same meanings as described above). 3. General formula (In the formula, R ″ represents a lower alkyl group, and R ′ has 1 carbon atom.
~ 15 alkyl groups or Indicates a group. Here, A is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2. ) Is asymmetrically hydrolyzed with an esterase having the ability to hydrolyze any one of the optically active forms of the esters. (In the formula, R ′ and l have the same meanings as described above. * Indicates an asymmetric carbon atom.) An optically active alcohol represented by the formula: R—X (wherein R is Represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms, X is a halogen atom or -OSO ₂ R
Indicates. Wherein R represents a lower alkyl group or an optionally substituted phenyl group) and a general formula characterized by reacting with an alkylating agent represented by (Wherein R, R ', l and * have the same meanings as described above). 4. A general formula (In the formula, R'is an alkyl group having 1 to 15 carbon atoms or Indicates a group. Here, A is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2. ) Is reacted with a lower alkylcarboxylic acid to give a compound of the general formula (In the formula, R ′ and l have the same meanings as described above, and R ″ represents a lower alkyl group.), An ester represented by any one of the optically active isomers of the ester is obtained. Asymmetrically hydrolyzed with an esterase having the ability to hydrolyze (In the formula, R ′ and l have the same meanings as described above. * Indicates an asymmetric carbon atom.) An optically active alcohol represented by the formula: R—X (wherein R is Represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms, X is a halogen atom or -OSO ₂ R
Indicates. Wherein R represents a lower alkyl group or an optionally substituted phenyl group) and a general formula characterized by reacting with an alkylating agent represented by (Wherein R, R ', l and * have the same meanings as described above). 5. A general formula (In the formula, R'is an alkyl group having 1 to 15 carbon atoms or Indicates a group. Here, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. l is 1 or 2. ) Is reduced with a reducing agent to give a compound of the general formula (Wherein R ′ and l have the same meaning as described above), and the alcohol is reacted with a lower alkylcarboxylic acid to give a compound of the general formula (In the formula, R ′ and l have the same meanings as described above, and R ″ represents a lower alkyl group.), And then one of the optically active isomers of the ester is hydrolyzed. Asymmetrically hydrolyzed with an esterase that has the ability to decompose (Wherein R ′ and l have the same meanings as described above, * is an asymmetric carbon atom), and an optically active alcohol represented by the formula: R—X (wherein R is a carbon atom) is obtained. Represents an alkyl group or an alkoxyalkyl group of the number 1 to 20, X is a halogen atom or -OSO ₂ R
Indicates. Wherein R represents a lower alkyl group or an optionally substituted phenyl group) and a general formula characterized by reacting with an alkylating agent represented by (Wherein R, R ', l and * have the same meanings as described above).