JP2689474B2 - Optically active ethanol derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. Z represents a hydrogen atom or a halogen atom, and l is 0 or 1. The * mark represents an asymmetric carbon atom. The present invention relates to an optically active ethanol derivative represented by and a method for producing the same.

<Prior Art> The optically active ethanol derivative represented by the general formula (I) is useful as an intermediate for a liquid crystal material, especially a ferroelectric liquid crystal material. It is not known, and of course nothing is known about its manufacturing method and its specific application.

<Problems to be Solved by the Invention> In order to use the optically active ethanol derivative represented by the general formula (I) as a liquid crystal material, particularly a ferroelectric liquid crystal material, for example, a hydroxyl group of the optically active ethanol derivative is used. There is a method of alkylating or acylating the corresponding ether or ester, and then debenzylating it to give an optically active phenol, and further converting the phenol into an ester or ether compound. The present invention provides such an optically active ethanol derivative.

<Means for Solving the Problems> The present inventors have proposed such a new and useful general formula (I)
As a result of examination on a method for producing an optically active ethanol derivative represented by, the present invention has been accomplished.

The present invention relates to the following: [First Step] General Formula (II) (In the formula, A, Z and l have the same meaning as described above) The ketones represented by the formula (III) are reduced by using a reducing agent. (In the formula, A, Z and l have the same meanings as described above.) A step of obtaining a dl-alcohol represented by the formula:

[Second Step] The dl-alcohol obtained in the first step is reacted with a lower alkylcarboxylic acid to give a compound represented by the general formula (IV): (In the formula, A, Z and l have the same meanings as described above, and R ′
Represents a lower alkyl group. ) The process of obtaining dl-ester shown by these.

[Third step] The dl-ester obtained in the second step is asymmetrically hydrolyzed using an esterase having the ability to hydrolyze only one of the enantiomers of the ester to give the above-mentioned general formula ( A step of obtaining an optically active ethanol derivative represented by I).

In the first to third steps, the second to third steps,
The compound represented by the above general formula (I) is obtained by hydrolyzing the optically active ester (asymmetric hydrolysis residue) having the opposite coordination to the optically active ethanol derivative obtained in the third step and the third step. A method for producing an optically active ethanol derivative represented by the general formula (I), which comprises the step of obtaining an optically active ethanol derivative.

 Hereinafter, the present invention will be described in detail.

The ketones (II) that are the raw materials in the first step can be easily obtained by reacting benzyl halides with phenols as shown below, for example.

The reduction of ketones (II) is performed using a reducing agent capable of reducing ketone to alcohol.

As such a reducing agent, preferably sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, aluminum isopropoxide, lithium-tri-t-butoxyaluminum hydride, lithium-tri-s- Examples thereof include butylboron hydride, borane, and alkali metal-ammonia, and the amount used is required to be at least 1 equivalent or more with respect to the starting ketones (II), and usually in the range of 1 to 10 equivalents.

This reaction is usually performed in a solvent, and as such a solvent,
For example, tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, toluene, benzene, chloroform, dichloromethane, and other ethers; halogenated hydrocarbons; A mixture is used.

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, dl-alcohols (III) can be obtained in good yield by operations such as liquid separation, concentration, distillation and crystallization.
In order to obtain the ester (IV), it is not always necessary to isolate the dl-alcohol (III), and the reaction mixture may be directly used in the next step.

From dl-alcohols (III) to dl-esters (IV)
(2nd step) for obtaining dl-alcohol (III)
Is reacted with a lower alkylcarboxylic acid to perform acylation.

In this acylation, lower alkylcarboxylic acids, lower alkylcarboxylic acids, acid anhydrides or acid halides of lower alkylcarboxylic acids are used, and specifically, acetic acid, propionic acid, butyric acid, acetic anhydride, acetic acid chloride or bromide, Propionic anhydride, propionyl chloride or bromide, butyryl chloride or bromide,
Examples include valeyl chloride or bromide.

In this reaction, when the above-exemplified acid anhydrides, acid chlorides and acid bromides are used as the lower alkylcarboxylic acids, the amount used is required to be 1 equivalent or more with respect to the dl-alcohol (III), and the upper limit is Although not particularly limited, it is preferably 4 equivalents.

This reaction is carried out by applying a usual esterification condition and reacting with a catalyst in the presence or absence of a solvent.

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, sodium methylate, potassium hydrogencarbonate, etc., and organic acids or inorganic acids such as toluenesulfonic acid, methanesulfonic acid and sulfuric acid can also be used as catalysts. it can.

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 alkylcarboxylic acid, the amount is at least 1 equivalent to the acid halide.

When a lower alkyl carboxylic acid is used as the lower alkyl carboxylic acid, the carboxylic acid is dehydrated and condensed in the presence of a condensing agent in an amount of 1 to 2 equivalents with respect to the dl-alcohol (III) to form a dl-ester. Class (IV) can be obtained. As the condensing agent, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-
A carbodiimide such as (4-diethylamino) cyclohexylcarbodiimide is preferably used, and if necessary, an organic base such as 4-pyrrolidinopyridine, pyridine or triethylamine is used in combination.

The amount of condensing agent used is 1 with respect to the lower alkylcarboxylic acid.
~ 1.2 equivalent times, and when an organic base is used, the amount used is 0.01 to 0.2 equivalent times with respect to the condensing agent.

As the reaction solvent, a solvent inert to the reaction exemplified above is used.

The reaction temperature is usually -30 ° C to 100 ° C regardless of the type of lower alkylcarboxylic acid, but preferably -20 ° C.
~ 90 ° C.

The reaction time is not particularly limited, and the time when the starting dl-alcohol (III) disappears from the reaction system can be the reaction end point.

After completion of the reaction, usual separation means such as extraction, liquid separation,
The dl-esters (IV) can be obtained in good yield by concentration, recrystallization, etc. This can be further purified by column chromatography etc. if necessary, but the reaction mixture can be used as it is for the next step. .

The reaction for obtaining the optically active ethanol derivative (I) from the dl-esters (IV) (third step) uses an esterase capable of hydrolyzing either one of the enantiomers of the dl-esters (IV). Then, one of the optically active substances of the esters is hydrolyzed (asymmetrical hydrolysis).

The microorganism that produces esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze dl-esters (IV), and is not particularly limited.

In addition, the esterase in the present invention means 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,
Microorganisms belonging to the genera Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula and Achromobacter are exemplified.

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

For example, sterilized liquid medium [for molds and yeasts, malt extract / yeast extract medium (5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in water 1;
H6.5), and for bacteria, a broth containing sugar (10 g of glucose, 5 g of peptone, 5 g of meat extract, and 3 g of Nacl are dissolved in 1 of water to have a pH of 7,2)] and the microorganisms are inoculated, usually 20-40
The culture is performed by reciprocating shaking culture at 1 ° C. for 1 to 3 days, and solid culture may be performed if necessary.

Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, the following.

Pseudomonas lipase [Lipase P (Amano Pharmaceutical)], Aspergillus lipase [Lipase AP (Amano Pharmaceutical)], Mucor lipase [Lipase MAP]
(Manufactured by Amano Pharmaceutical Co., Ltd.)), lipase of Candida syrindrasse [lipase MY (manufactured by Meito Sangyo)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (name Sugar industry)),
Lipase of the genus Arthrobacter [lipase joint BSL (joint liquor purification)], lipase of the genus Chromobacterium (manufactured by Toyo Brewery), lipase of Rhizopus delemar [talipase (manufactured by Tanabe Seiyaku)], lipase of the genus Rhizopus [lipase syrup] Ken (Osaka Bacteria Research Institute)].

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

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

As the esterase used in this reaction, an enzyme obtained from animals, plants, or microorganisms is used, and the usage forms thereof include purified enzyme, crude enzyme, enzyme-containing material, microbial culture solution, culture solution, microbial cells, and culture medium. It can be used in various forms such as a liquid and a product obtained by treating them as needed, and an enzyme and a microorganism can also be used in combination. Alternatively, it can also be used as an immobilized catalyst or immobilized cells immobilized on a resin or the like.

The asymmetric hydrolysis reaction is generally carried out by vigorously stirring a mixture of the raw material dl-esters (IV) and the above-mentioned enzyme or microorganism in a buffer solution.

As the buffer, 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 or sodium citrate, or the like is used, and its pH is 8 to 11 in a culture solution of an alkaliphilic bacterium or an alkaline esterase. PH 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 in the range of 0.05-2M, preferably 0.05-0.5M.

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

By such asymmetric hydrolysis reaction, one of the optically active dl-esters (IV) is hydrolyzed to produce an optically active ethanol derivative represented by the general formula (I). The other optically active substance of the raw material dl-esters (IV) remains as a hydrolysis residue as it is, and, in the end, in the asymmetric hydrolysis, the above two products are obtained as a hydrolysis product and a hydrolysis residue. The species of optically active compounds will be obtained simultaneously.

When a lipase belonging to the genus Cydudomonas or the genus Arthrobacter is used as the lipase in this asymmetric hydrolytic reaction, the optically active ethanol derivative (I) can be obtained with a relatively high optical purity.

During the hydrolysis, toluene,
Organic solvents that are inert to the reaction, such as chloroform, methyl isobutyl ketone, and dichloromethane, can also be used.
By using these, asymmetric hydrolysis can be advantageously performed.

After completion of such asymmetric hydrolysis reaction, the hydrolysis reaction solution is subjected to extraction treatment with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc., and the concentrated residue is further distilled after the solvent is distilled off from the organic layer. , An optically active ethanol derivative (I) which is a hydrolysis product and an optically active ester which is a hydrolysis residue [raw material ester (IV)
Which are not hydrolyzed among the optically active isomers of 1.) can be separated.

The optically active ester obtained here is further hydrolyzed, if necessary, and is the enantiomer of the optically active ethanol derivative (I).
It can be.

<Effects of the Invention> Thus, according to the method of the present invention, the optically active ethanol derivative represented by the general formula (I), which is a novel compound, can be industrially advantageously produced, and the compound of the present invention is stable. In addition to being useful as an intermediate for a ferroelectric liquid crystal material having excellent high-speed reactivity, 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 the present invention.

Example 1 In a four-necked flask equipped with a stirrer and a thermometer,
90.45 g (0.4 mol) of 4-benzyloxyacetophenone, 300 ml of tetrahydrofuran and 100 ml of methanol
, And sodium borohydride 15.14g at 15-25 ℃
(0.4 mol) is added over 2 hours. After keeping at the same temperature for 5 hours, the mixture is poured into ice water and extracted twice with 500 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give 4-benzyloxy-1-phenethyl alcohol (III-1) 88.5 g (yield
97%).

Next, 68.44 g (0.3 mol) of (III-1) obtained here was dissolved in a mixed liquid of 300 ml of toluene and 50 ml of pyridine, and 25.91 g (0.33 mol) of acetic acid chloride was added thereto at 15 to 20 ° C. for 2 hours. Need to add. Incubate at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After completion of the reaction, the mixture was cooled to 10 ° C or lower, 200 ml of water was added thereto, the organic layer was separated, and then 1N-hydrochloric acid water,
Wash sequentially with water, 5% sodium carbonate, and water. The organic layer was concentrated under reduced pressure and further purified by column chromatography to
79.8 g (yield 98.5%) of acetic acid ester (IV-1) of -benzyloxy-1-phenethyl alcohol was obtained.

67.5 g (0.25 mol) of (IV-1) obtained here was mixed with 700 ml of 0.3 M phosphate buffer (pH 7.5) and 6.75 g of Lipase P (manufactured by Amano Pharmaceutical Co., Ltd.), and the mixture was mixed at 40 to 45 ° C. for 40 minutes. Stir vigorously for hours. After completion of the reaction, the reaction mixture is extracted with 500 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, the residue was purified by column chromatography with a mixed solution of toluene: ethyl acetate 5: 2,
23.38 g (yield 41%) of (+)-4-benzyloxy-1-phenethyl alcohol (I-1) and 37.4 g of unreacted acetic ester of 4-benzyloxy-1-phenethyl alcohol were obtained.

The optical rotation and melting point of the obtained alcohol (I-1) and unreacted ester were as follows.

Alcohol (I-1): ▲ [α] ²⁰ _D ▼ + 35.9 ° (c = 1, CHCl ₃ ), melting point 66-68 ° C Unreacted ester: ▲ [α] ²⁰ _D ▼ -93 ° (c = 1 , CHCl ₃ ), melting point 52-55 ° C. Example 2 A mixture of 13.5 g (50 mmol) of unreacted ester obtained in Example 1, 50 ml of methanol, 30 ml of 20% sodium hydroxide and 30 ml of tetrahydrofuran at 30 ° C.-40 ° C. Stir for 2 hours.

After completion of the reaction, 200 ml of water was added to the reaction mixture, pH was adjusted to 6 with 4N hydrochloric acid, and the mixture was extracted with 500 ml of ether. The organic layer was washed with water and then concentrated under reduced pressure to give 11.2 g of white solid (-)-4-benzyloxy-1-phenethyl alcohol (yield 9
8%).

Example 3 2- (4-methylbenzyloxy) acetophenone (II-3) 24.0 g (0.1 mol), chloroform 100 ml and methanol 30 ml were charged in the same apparatus as in Example 1, and 4.5 g of sodium borohydride ( 0.12 mol) 15-20 ° C
Add in 2 hours. Then, the temperature is kept at the same temperature for 5 hours. After the reaction is completed, the temperature is cooled to 10 ° C or lower, and 200 ml of water is added. The organic layer separated by extraction with chloroform was concentrated under reduced pressure to obtain 23.1 g of 4- (4-methylbenzyloxy) -1-phenethyl alcohol (III-3) (yield 95.5%).

Then, 18.16 g (0.075 mol) of (III-3) obtained above, a mixture of 100 ml of dichloromethane and 0.5 g of 4-pyrrolidinopyridine were added to 16.7 g of N, N'-cyclohexylcarbodiimide.
(82.5 mmol) and 5.0 g of acetic acid (82.5 mmol) are added. After stirring at room temperature for 10 hours, the white precipitate was separated and the solution was washed successively with water, 5% acetic acid, water and 5% aqueous sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure, and the concentrated residue was purified by column chromatography to obtain 20.78 g of 4- (4-methylbenzyloxy) -1-phenethyl alcohol acetate (IV-3) (yield 97.5).
%).

Next, 19.2 g (70 mmol) of (IV-3) was added to 200 ml of 0.3 M phosphate buffer (pH 7.0) and amano lipase “P” 2.
Stir vigorously with 88 g for 20 hours at 35-40 ° C. After completion of the reaction, post-treatment and purification were carried out according to Example 1, and (+)-
4- (4-methylbenzyloxy) -1-phenethyl alcohol (V-3) 6.6 g (yield 39%) [▲ [α] ²⁰ _D ▼
+ 34.2 ° (c = 1, CHCl ₃ ), mp 52-53 ° C.) was obtained.

Example 4 Reduction was carried out in the same manner as in Example 3 except that 25.6 g (0.1 mol) of 4- (4-methoxybenzyloxy) acetophenone (II-4) was used instead of 4- (4-methylbenzyloxy) acetophenone. The reaction and post-treatment gave 4- (4-methoxybenzyloxy) -1-phenethyl alcohol (III-4) in a yield of 97%.

Then, the acylation reaction, post-treatment and purification were carried out in the same manner as in Example 3 except that 0.075 mol of (III-4) was used.
Acetic acid ester (IV-4) of (4-methoxybenzyloxy) -1-phenethyl alcohol was obtained with a yield of 96%.

Next, asymmetric hydrolytic reaction, post-treatment and purification were carried out in the same manner as in Example 3 except that (IV-4) was used to obtain (+)-4- (4-
Methoxybenzyloxy) -1-phenethyl alcohol (V-4) was obtained with a yield of 35%. ▲ [α] ²⁰ _D ▼ + 31.8 ° (c = 1, CHCl ₃ ) Example 5 120.9 g (0) of 4-benzyloxy-4′-acetyl-biphenyl in a 4-neck flask equipped with a stirrer and a thermometer. .
4 mol), tetrahydrofuran 400 ml and methanol 10
0 ml was charged, and 15.14 g (0.4 mol) of sodium borohydride was added thereto at 15 to 25 ° C. over 2 hours. After incubating at the same temperature for 5 hours, pour into ice water and add chloroform 50
Extract twice with 0 ml. The organic layer was concentrated under reduced pressure to 4-
117.4 g (yield 96.5%) of benzyloxy-4 '-(1-hydroxyethyl) biphenyl (III-5) was obtained.

Next, 91.25 g (0.3 mol) of (III-5) obtained here was dissolved in a mixed solution of 400 ml of toluene and 100 ml of pyridine, and 25.91 g (0.33 mol) of acetyl chloride was added thereto at 15 to 20 ° C.
Add it over time. Then, at the same temperature for 1 hour, 40-50
Incubate at ° C for 2 hours. After the reaction is completed, cool to 10 ° C or less,
Add 200 ml of water. The separated organic layer was washed with 2N aqueous hydrochloric acid, water,
After successively washing with 5% sodium carbonate and water, the mixture was concentrated under reduced pressure and further purified by column chromatography to obtain 101.57 g of 4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl acetate (IV-5) (IV-5). Yield 97.8%) was obtained.

Next, 86.55 g (0.25 mol) of (IV-5) obtained above was vigorously stirred with 2,000 ml of 0.3M phosphate buffer (pH 7.5), 200 ml of chloroform and 50 g of amanolipase “P” at 40 to 45 ° C. for 120 hours. To do. After the reaction was completed, the reaction mixture was extracted with 1,000 ml of chloroform, the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a toluene: ethyl acetate (5: 2) mixed solution as an eluent, (+). -4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl (V-5) 28.9 g (yield 38%) [▲ [α] ²⁰ _D ▼ + 34.8 ° (c = 1, CHCl ₃ ), mp158-159 ° C] and unreacted (−)-4-benzyloxy-4 ′-(1-hydroxyethyl) biphenyl acetate 50.17 g [▲ [α] ²⁰
_D ▼ -56.3 ° C (c = 1, CHCl ₃ ), mp 137-139 ° C] was obtained.

Example 6 A 4-necked flask equipped with a stirrer and a thermometer was charged with 134.6 g (0.4 mol) of 4-acetyl-4 '-(4-chlorobenzyl) oxybiphenyl, 400 ml of tetrahydrofuran and 100 ml of methanol, and the mixture was charged with 15 Add 15.14 g (0.4 mol) of sodium borohydride over 2 hours at -25 ° C. After incubating at the same temperature for 5 hours, pour into ice water and extract twice with 500 ml of chloroform. The organic layer was concentrated under reduced pressure to give 4 '-(4-chlorobenzyl) oxy-4-.
(1-Hydroxyethyl) biphenyl (III-6) 135.1
g (yield 99.9%) was obtained.

Melting point 170.5 to 172 ° C. Next, 101.5 g (0.3 mol) of (III-6) obtained here was dissolved in a mixed solution of 400 ml of toluene and 100 ml of pyridine, and 25.91 g (0.33 mol) of acetyl chloride was added to this solution in an amount of 15 to 20. 2 at ℃
Add it over time. Then, at the same temperature for 1 hour, 40-50
Incubate at ° C for 2 hours. After the reaction is completed, cool to 10 ° C or less,
Add 300 ml of water. The separated organic layer was washed with 2N aqueous hydrochloric acid, water,
It was washed with 5% sodium carbonate and water successively, concentrated under reduced pressure and further purified by column chromatography to obtain 4 '-(4-chlorobenzyl) oxy-4- (1-hydroxyethyl).
101.57 g of biphenyl acetate (IV-6) (yield 97.
8%).

15.1 g (0.04 mol) of (IV-6) obtained above is then vigorously stirred with 500 ml of 0.3 M phosphate buffer (pH 7.5), 20 ml of chloroform and 5 g of amanolipase "P" at 40-45 ° C for 5 days. . After the reaction was completed, the reaction mixture was mixed with chloroform 50
After extraction with 0 ml and concentration of the organic layer under reduced pressure, the residue was purified by column chromatography using a toluene: ethyl acetate mixed solution as an eluting solvent, and (+)-4 '-(4-chlorobenzyl) oxy-4-. 5.8 g (yield 85%) of (1-hydroxyethyl) biphenyl (V-6) [▲ [α] ²⁰ _D ▼ + 30.2 ° (c = 1, CHCl ₃ ), mp 165-167 ° C.] were obtained.

Example 7 Unreacted ester (-)-4-benzyloxy-4 '-(1-acetoxyethyl) biphenyl obtained in Example 5.
45 g (0.01 mol) are stirred for 2 hours at 30-40 ° C. in a mixture of 50 ml of methanol and 25 ml of 20% sodium hydroxide solution. After the reaction was completed, 200 ml of water was added to the reaction mixture, and then 4
Adjust to pH 4 with N hydrochloric acid and extract with 500 ml of ether.
After liquid separation, the organic layer was washed with water and concentrated under reduced pressure to obtain 3.0 g of white solid (-)-4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl (yield 99%).

Example 8 2-Fluoro-4-benzyloxyacetophenone (II-8) was placed in a 4-necked flask equipped with a stirrer and a thermometer.
24.4 g (0.1 mol) and 300 ml of ethanol were charged, and to this, sodium borohydride 3.8 g (0.1
Mol) over 10 minutes. After keeping at the same temperature for 5 hours, the mixture is poured into ice water and extracted twice with 500 ml of ethyl acetate. The organic layer is washed with water and then concentrated under reduced pressure to give 2-fluoro-
4-benzyloxy-1-phenethyl alcohol (III
-8) 24.0 g was obtained.

Next, 19.7 g (0.08 mol) of (III-8) obtained here was dissolved in 200 ml of pyridine, and 12.2 g of acetic anhydride was added thereto at 30-40 ° C.
Then, the mixture is kept warm at 40 to 50 ° C for 6 hours. After the reaction, 10
Cool to below ℃ and add 400 ml of water. The separated organic layer is 2
The extract was washed successively with N-hydrochloric acid water, water, 5% sodium hydrogen carbonate and water, and concentrated under reduced pressure to give 2-fluoro-4-benzyloxy-1-phenethyl alcohol acetate (IV
-8) 22.6 g (yield 98%) was obtained.

Then 20 g (0.07 mol) of (IV-8) obtained above is vigorously stirred with 500 ml of 0.3 M phosphate buffer (pH 7.0) and 3 g of Arthrobacter lipase at 38-40 ° C. for 24 hours.
After completion of the reaction, the reaction mixture was extracted with 500 ml of ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was toluene:
Purification by column chromatography using a mixed solution of ethyl acetate as an eluent, (+)-2-fluoro-4-benzyloxy-1-
8.32 g (yield 48%) of phenethyl alcohol (V-8) was obtained. [▲ [α] ²⁰ _D ▼ + 29.6 ° (c = 1, CHCl ₃ ), white oily substance] Example 9 Instead of 2-fluoro-4-benzyloxyacetophenone (II-8), 2-chloro- Reduction, acylation and asymmetric hydrolysis reaction, post-treatment and purification were carried out in the same manner as in Example 8 except that 26.1 g (0.1 mol) of 4-benzyloxyacetophenone (II-9) was used to obtain (+)-2-chloro-. 4-benzyloxy-1-phenethyl alcohol (V-9) 7.9 g
I got ▲ [α] ²⁰ _D ▼ + 33.2 ° (c = 1, CHCl ₃ ), ▲ n
²⁰ _D ▼ 1.5775

Claims (5)

(57) [Claims] (1) General formula (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. Z represents a hydrogen atom or a halogen atom, and l is 0 or 1. The * mark represents an asymmetric carbon atom. Shows an optically active ethanol derivative. 2. The general formula (In the formula, A, Z and l have the same meanings as described above,
R 'represents a lower alkyl group. ) The asymmetric hydrolysis of dl-esters represented by the following formula using a lipase of the genus Pseudomonas or the genus Arthrobacter (In the formula, A, Z, l and * have the same meanings as described above.) A method for producing a D-ethanol derivative represented by the formula: 3. The dl-esters have the general formula (In the formula, A, Z and l have the same meanings as described above.) D-ethanol according to claim 2, which is obtained by reacting a dl-alcohol represented by: with a lower alkylcarboxylic acid. Method for producing derivative. 4. The dl-esters have the general formula (In the formula, A, Z and l have the same meanings as described above.) A general formula obtained by reducing a ketone represented by (In the formula, A, Z and l have the same meanings as described above.) D-ethanol according to claim 2, which is obtained by reacting a dl-alcohol represented by: with a lower alkylcarboxylic acid. Method for producing derivative. 5. The general formula (In the formula, A, Z and l have the same meanings as described above,
R 'represents a lower alkyl group. ) Is asymmetrically hydrolyzed with a lipase of the genus Pseudomonas or Arthrobacter to the dl-ester represented by (In the formula, A, R ', Z, l and * have the same meanings as described above.) An L-ester represented by the following formula is obtained, and the ester is then hydrolyzed. formula (In the formula, A, Z, l and * have the same meanings as described above.) A method for producing an L-ethanol derivative represented by the formula: