JP2526629B2 - Optically active benzenecarboxylic acid esters 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, R represents an alkyl group having 1 to 20 carbon atoms and optionally containing a halogen atom, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2. However, R is not a methyl group, and when n is 2, R is not an alkyl group having 1 to 5 carbon atoms. * Indicates an asymmetric carbon atom.) Relates to an optically active benzenecarboxylic acid ester represented by and a method for producing the same.

<Prior Art> The optically active benzenecarboxylic acid esters represented by the above-mentioned general formula (I) are novel compounds which have not been described in the literature, and their production methods as well as their usefulness as compounds have hitherto been known. Not known at all.

<Problems to be Solved by the Invention> The optically active benzenecarboxylic acid esters represented by the general formula (I) are used as intermediates for medicines, agricultural chemicals, etc. Very useful as a body.

For example, the optically active benzenecarboxylic acid esters can be typically introduced into a liquid crystal compound by a method represented by the following formula, and the compound is extremely excellent as a ferroelectric liquid crystal.

<Means for Solving the Problems> The present invention provides such a novel and useful optically active benzenecarboxylic acid ester represented by the general formula (I), wherein the optically active benzenecarboxylic acid is provided. Esters have the general formula (II) (In the formula, R ′, n and * have the same meanings as described above.) The optically active alcohols represented by the general formula (III) R—COOH (III) (wherein R is the same as above) It has a meaning.) It can be produced by reacting with an aliphatic carboxylic acid or a derivative thereof.

Here, as the aliphatic carboxylic acid represented by the general formula (III), propionic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid,
Undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, isolac acid, 2-methylbutanoic acid, 4-methylpentanoic acid, 2-methylhexanoic acid, 2-methylheptanoic acid, 2
-Methyloctanoic acid, 2,3-dimethylheptanoic acid, 2,3,3
-Trimethylbutanoic acid, 3-methylpentanoic acid, 2,3-
Dimethylpentanoic acid, 2,4-dimethylpentanoic acid, 2,3,
3,4-tetramethylpentanoic acid, 3-methylhexanoic acid, 4-methylhexanoic acid, 2,5-dimethylhexanoic acid, haloacetic acid, 2-trihalomethylpentanoic acid, 2-trihalomethylhexanoic acid, 2-trihalomethyl Heptanoic acid, 2-halopropanoic acid, 3-halo-2-methylpropanoic acid, 2,3-dihalobutanoic acid, 2,3-dihalobutanoic acid, 2,
4-dihalobutanoic acid, 3,4-dihalobutanoic acid, 2-halo-
3-methylbutanoic acid, 2-halo-3,3-dimethylbutanoic acid, 2-halopentanoic acid, 3-halopentanoic acid, 4-halopentanoic acid, 2,4-dihalopentanoic acid, 2,5-dihalopentanoic acid, 2-halo- 3-methylpentanoic acid, 2-halo-4-methylpentanoic acid, 2-halo-3-monohalomethyl-4-methylpentanoic acid, 2-halohexanoic acid, 4-
Halohexanoic acid, 5-halohexanoic acid, 2-haloheptanoic acid, 2-halooctanoic acid, etc. are exemplified, and in the above reaction, these fatty acid carboxylic acids or their acid anhydrides or their acid halides (eg acid bromide, acid chloride).
(Hereinafter, these are collectively referred to as aliphatic carboxylic acids)
Is used.

(In the above, halo represents chloro, bromo, etc.) Incidentally, these aliphatic carboxylic acids may have an optically active group, and some of such optically active aliphatic carboxylic acids are the corresponding alcohols. Is obtained by reductive deamination of amino acids. Some are naturally occurring or can be derived from the following optically active amino acids and optically active oxyacids obtained by resolution.

Alanine, valine, leucine, isoleucine, phenylalanine, serine, steonine, alosreonine, homoserine, alloisoleucine, tert-leucine, 2-aminobutyric acid, norvaline, norleucine, ornithine, lysine, hydroxylysine, phenylglycine, trifluoroalanine, asparagine Acid, glutamic acid, lactic acid,
Mandelic acid, tropic acid, 3-hydroxybutyric acid, malic acid, tartaric acid, isopropylmalic acid, etc.

The reaction between the above-mentioned optically active alcohols (II) and aliphatic carboxylic acids is usually carried out in the presence or absence of a solvent, generally in the presence of a catalyst.

When a solvent is used in this reaction, as the solvent, for example, tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane, pyridine or the like or Examples thereof include aromatic hydrocarbons, ethers, halogenated hydrocarbons, organic amines, and other solvents inert to the reaction, and mixtures thereof, and the amount thereof is not particularly limited.

In this reaction, when an acid anhydride or an acid halide of an aliphatic carboxylic acid is used as the aliphatic carboxylic acid, the amount used is required to be 1 equivalent or more times the amount of the optically active alcohol, and the upper limit is particularly limited. However, it is preferably 4 equivalents.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine,
Examples thereof include organic or inorganic basic substances such as picoline, lysine, imidazole, sodium carbonate, sodium methylate and potassium hydrogen carbonate. Further, an organic acid such as toluene sulfonic acid, methane sulfonic acid or sulfuric acid or an inorganic acid can be dissolved as a catalyst.

In using such a catalyst, pyridine is particularly preferably used when, for example, an acid halide of an aliphatic carboxylic acid is used as a raw material.

The amount of the catalyst used varies depending on the combination of the type of the aliphatic carboxylic acids and the catalyst used, and is not necessarily specified. For example, when an acid halide is used, it is 1 equivalent or more times the acid halide.

When an aliphatic carboxylic acid is used as the aliphatic carboxylic acid, usually an optically active alcohol (II) is used.
1 to 2 equivalent times, and the reaction is carried out by dehydration condensation in the presence of a condensing agent.

As the condensing agent, carbodiimides such as N, N'-cyclohexylcarbodiimide and N-cyclohexyl-N '-(4-diethylamino) cyclohexylcarbodiimide are preferably used, and if necessary organic compounds such as 4-pyrrolidinopyrroline, pyridine and triethylamine are used. A base is used in combination.

In this case, the amount of the condensing agent used is usually 1 to 1.2 equivalent times relative to the aliphatic carboxylic acid, and when a base is used in combination, the amount of the base used is 0.01 to 0.2 equivalent times relative to the condensing agent.

The reaction temperature is usually -30 ° C to 100 ° C, preferably -25 ° C to 80 ° C.

The reaction time is not particularly limited, and the time point at which the optically active alcohol (II) as the raw material disappears can be the end point of the reaction.

After completion of the reaction, usual separation means such as extraction, liquid separation,
The desired optically active benzenecarboxylic acid ester represented by the general formula (I) can be obtained from the reaction mixture in a good yield by an operation such as concentration, and if necessary, it can be purified by column chromatography, recrystallization or the like. it can.

The optically active alcohol (II), which is a material in this reaction, has the general formula (IV) (Wherein R ′ and n have the same meanings as described above), an esterase having the ability to hydrolyze only one of the enantiomers of the ester is used to form the ester. Can be produced by hydrolyzing one of the optically active substances (asymmetric hydrolysis).

Here, the above esterase means esterase in a broad sense including lipase.

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

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Previbacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Parsis, Lactopalsis, 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. Liquid culture can be carried out, for example, by using a sterilized liquid medium [malt extract, yeast extract medium (mold 1)
Dissolve 5 g of peptone, 10 g of glucose, 3 g of malt extract and 3 g of yeast extract to pH 6.5, and for bacteria, dissolve broth containing sugar (5 g of peptone, 10 g of glucose, 5 g of meat extract, 3 g of NaCl in 1 water). , PH 7.2)] with a microorganism, and is generally cultivated at 30 to 40 ° C. for 1 to 3 days under reciprocal shaking culture, 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 Pharmaceutical Co., Ltd.)], lipase MY of Candida cylindrasse (manufactured by Meito Sangyo)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (Meito Sangyo) )), Arthrobacter genus lipase [Lipase Joint BSL (manufactured by Godo Sake)], Chromobacterium genus lipase (Toyo brewing), Rhizopus derema lipase [Talipase (manufactured by Tanabe Seiyaku)], Rhizopus genus Lipase [Lipase Saloken (Osaka Institute for Bacteria)].

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, an enzyme obtained from an animal, a plant, or a microorganism is used, and the form of use is a purified enzyme, a crude enzyme, an enzyme-containing substance, a microorganism culture solution, a culture, a cell, a culture solution. In addition, they can be used in various forms, such as those obtained by treating them, as needed, and enzymes and microorganisms can 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 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 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 3 to 70 hours, but is not limited thereto.

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

In addition, in the case of this asymmetric hydrolysis reaction, an organic solvent inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, and dichloromethane may be used in addition to the buffer solution. The decomposition can also be carried out advantageously.

By such asymmetric hydrolysis reaction, only one of the optically active dl-esters (IV) is hydrolyzed to generate optically active alcohols represented by the general formula (II), while The optically active ester which is the other optically active substance of the raw material dl-esters (IV) remains as a hydrolysis residue as it is.

After the completion of the hydrolysis reaction, the hydrolysis reaction solution is subjected to extraction treatment with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc., the solvent is distilled off from the organic layer, and the concentrated residue is treated with column chromatography. Etc., the optically active alcohols (II) which are hydrolysis products and the optically active esters which are the hydrolysis residue [of the optically active substances in the starting dl-esters (IV) were not hydrolyzed Can be separated.

The optically active ester obtained here may be further hydrolyzed as necessary to form an optically active alcohol of an antipode with the previously obtained optically active alcohol.

The raw material dl-esters (IV), which is a raw material for such an asymmetric hydrolysis reaction, has the general formula (V) (In the formula, R ′ and n have the same meanings as described above) and can be produced by reacting dl-alcohols with acetic acid to acetylate.

In this acetylation, acetic acid, acetic anhydride, or acid halide is used as acetic acid, and acetic anhydride or acid halide (eg, acetic acid chloride, acetic acid bromide) is preferably used.

This reaction is usually performed by reacting with a catalyst in the presence or absence of a solvent.

In this reaction, the amount of acetic acid to be used needs to be 1 equivalent or more with respect to dl-alcohol (V), and the upper limit is not particularly limited, but it is preferably 4 equivalents.

When a solvent is used in this reaction,
For example, tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, hexane,
A single or mixture of solvents inert to the reaction of aliphatic or aromatic hydrocarbons such as pyridine, ethers, halogenated hydrocarbons, organic amines and the like is used, and the amount of the solvent 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, and the amount thereof is not particularly limited, but is usually 1 to 5 equivalent times with respect to the raw material alcohol (V). Is.

When an organic amine is used as a solvent, the amine may act as a catalyst.

Further, acids such as toluene sulfonic acid, methane sulfonic acid and sulfuric acid can also be used as a catalyst.

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

The reaction time is not particularly limited, and the time when the starting dl-alcohol (V) 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., which can be further purified by column chromatography or the like, if necessary. It can be used as a mixture.

In addition, dl-alcohols (V) which are the raw materials of this reaction
Is the general formula (VI) (In the formula, R ′ and n have the same meaning as described above) The ketones can be easily produced by reducing with a reducing agent.

As the reducing agent at this time, sodium borohydride, zinc borohydride, lithium aluminum hydride-silica gel, aluminum isopropoxide, lithium-tri-t-butoxyaluminum hydride, lithium-tri-S-butyl is preferable. Boron hydride, borane, alkali metal-ammonia, Raney nickel-hydrogen and the like are used, and the amount thereof is at least 1 equivalent or more, usually 1 to 1 equivalent, with respect to the starting ketones (VI).

The reduction reaction is usually performed in a solvent, and examples of the solvent include tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, toluene, benzene, chloroform, dichloromethane, and other ethers, halogenated hydrocarbons. Solvents such as aromatic hydrocarbons, alcohols and the like which are inert to the reaction may be used alone or as a mixture.

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

From the reaction mixture thus obtained, dl-alcohols (V) can be obtained in good yield by operations such as liquid separation, concentration, distillation and crystallization, but dl-esters (IV) are produced. In order to do so, it is not always necessary to isolate the dl-alcohol (V), and the reaction mixture may proceed to the next step as it is.

<Effects of the Invention> Thus, according to the method of the present invention, it is possible to produce optically active benzenecarboxylic acid esters which are novel compounds with high optical purity in a high yield, and moreover, the compound of the present invention can be used for medicines, agricultural chemicals, etc. Not only is it useful as an intermediate, but it is also very useful as an intermediate for liquid crystal materials.

Example 1 60.98 g (0.24 mol) of 4-acetylbenzoic acid benzyl ester was added to a four-necked flask equipped with a stirrer and a thermometer.
100 ml of ethanol and 300 ml of chloroform are charged, and 4.6 g (0.12 mol) of sodium borohydride is added thereto at 15 to 25 ° C over 10 minutes.

After keeping at the same temperature for 2 hours, the reaction mixture is poured into ice water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and then contracted under reduced pressure to obtain 58.37 g (yield 95%) of 4- (1-hydroxyethyl) benzoic acid benzyl ester (V-1).

(▲ n ²⁵ _D ▼ 1.5682) 55.90 g (0.22 mol) of (V-1) obtained here was added to toluene.
Dissolve it in a mixture consisting of 300 ml and 100 ml of pyridine, and add 18.84 g (0.24 mol) of acetyl chloride to the mixture at 15-20 ° C for 2 hours.
Add it over time. Incubate at the same temperature for 1 hour and at 30-35 ° C for 2 hours.

After completion of the reaction, cool to 10 ° C or below, then 600 ml of 3N hydrochloric acid water
Is added, and the organic layer is separated, and washed successively with water, 5% aqueous sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure and further purified by column chromatography to give 4- (1-acetoxyethyl) benzoic acid benzyl ester (IV-1) 32.15 g (yield 98%).
I got

(▲ n ²⁵ _D ▼ 1.5304) 29.81 g (0.1 mol) of (IV-1) obtained here was mixed with 600 ml of 0.1M phosphate buffer (pH 7), 15 ml of chloroform and 6 g of lipase P and mixed at 40 to 45 ° C. for 20 hours. Stir vigorously.

After the reaction was completed, the reaction mixture was mixed with methyl isobutyl ketone 90
Extract with 0 ml. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a hexane / ethyl acetate (12/1) mixture as an eluent to obtain (+)-4- (1-hydroxyethyl) benzoic acid benzyl ester (II -1) 1
1.21 g [▲ [α] ²⁵ _D ▼ + 35.6 ° (C = 1, CHCl ₃ ), ▲ n
²⁵ _D ▼ 1.5694] and (−)-4- (1-acetoxyethyl) benzoic acid benzyl ester 15.96 g [▲ [α] ²⁵ _D
▼ -52 ° (C = 1, CHCl ₃ ), ▲ n ²⁵ _D ▼ 1.5293] was obtained.

1.02 g (4 mmol) of (II-1) obtained here is mixed with 5 ml of pyridine and 10 ml of toluene, to which 0.66 g (4.4 mmol) of hexanoic acid chloride is added dropwise at 15 to 20 ° C. Thereafter, the reaction is continued at 20 ° C for 2 hours and at 40 to 50 ° C for 2 hours. After completion of the reaction, the reaction solution is poured into ice water and extracted with 30 ml of toluene. Toluene layer is 1N-hydrochloric acid water, 2
Sequentially wash with% heavy soda water and water. The toluene layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was further purified by chromatography on a silica gel column (distillation solvent: toluene) (+)-4- (1-hexanoyloxyethyl). Benzoic acid benzyl ester 1.39 g
(Yield 98%) was obtained.

▲ [α] ²⁵ _D ▼ + 49.2 ° (C = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5221 Example 2 (−)-4- (1-acetoxyethyl) benzoic acid benzyl ester obtained in Example 1. 10 g is mixed with 200 ml of 0.2 M phosphate buffer, 5 ml of chloroform and 1 g of pig liver esterase, and reacted at 30 to 35 ° C. for 30 hours. Thereafter, post-treatment and purification were carried out in the same manner as in Example 1, and (-)-4- (1-hydroxyethyl) benzoic acid benzyl ester (II-2) 7.
I got 7g.

1.02 g (4 mmol) of (II-2) obtained here, (2S, 3
S) -2-Chloro-3-methylpentanoic acid 0.72 g (4.8 mmol) and dichloromethane 20 ml in a solution consisting of
0.91 g (4.4 mmol) of dicyclocarbodiimide and 4
-Add 0.02 g of pyrrolidinopyridine and react at room temperature for 12 hours. After the reaction is completed, the precipitated crystals are separated and the liquid is contracted. The concentrated residue was purified in the same manner as in Example 1 to obtain (-)-
4- {1-[(2S, 3S) -2-chloro-3-methylpentanoyloxy] ethyl} benzoic acid benzyl ester 1.
60 g (yield 96.5%) was obtained.

▲ [α] ²⁵ _D ▼ -59.5 ° ▲ n ²⁵ _D ▼ 1.5353 Example 3 1.02 g (4 mmol) of (II-1) obtained in Example 1 was added to 10 ml of pyridine, 10 ml of dichloroethane and butanoic anhydride.
Mix with 0.76 g (4.4 mmol) and react at 20-25 ° C for 15 hours. After completion of the reaction, the reaction solution is poured into ice water, 20 ml of dichloroethane is added, and extraction treatment is carried out. Then, post-treatment and purification were carried out according to Example 1 to obtain 1.27 g (yield 97%) of (+)-4- [1- (butanoyloxy) ethyl] benzoic acid benzyl ester.

▲ [α] ²⁵ _D ▼ + 51.5 ° (C = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5243 Example 4 In a flask similar to that used in Example 1, 4-methylbenzyl ester of 4-acetylbenzoic acid 32.17. g (0.12 mol), ethanol (50 ml), dichloromethane (100 ml) and tetrahydrofuran (50 ml) are charged, and sodium borohydride (2.3 g, 0.06 mol) is added thereto at 15 to 25 ° C over 10 minutes. After incubating at the same temperature for 2 hours, the reaction solution was poured into ice water and the same post-treatment as in Example 1 was performed to carry out 31.43 g of 4-methylbenzyl ester of 4- (1-hydroxyethyl) benzoic acid (V-3) ( Yield 97%) was obtained.

29.71 g (0.11 mol) of (V-3) obtained here was dissolved in a mixed solution 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 dropwise thereto at room temperature. . After about 2 hours,
The reaction solution is poured into 300 ml of 3N hydrochloric acid and extracted.
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 4- (1-acetoxyethyl) benzoic acid 4-methylbenzyl ester (IV-1) as a pale yellow oil.

(IV-3) 15.6 g (50 mmol) was added with 0.3 M phosphate buffer (pH 7) 200 ml, chloroform 10 ml and lipase P3 g
And stir vigorously at 38-40 ° C for 24 hours.

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 / purification using a mixed solution of hexane: ethyl acetate = 12: 1 as an eluting solvent to obtain (+)-4- (1-hydroxyethyl) benzoic acid (4). -Methylbenzyl ester (II-
3) 5.95 g [▲ [α] ²⁵ _D ▼ + 36.3 ° (C = 1, CHC
l ₃ ), ▲ n ²⁵ _D ▼ 1.5688] was obtained.

(II-3) 1.08 g (4 mmol), pyridine 5 ml and toluene 10 ml were added to a mixed solution of decanoic acid chloride 0.91.
g (4.8 mmol) is added at 20 ° C. Then, the mixture is stirred for 10 hours, and further stirred at 40 to 45 ° C for 2 hours. Thereafter, post-treatment was carried out in the same manner as in Example 1 to obtain 1.60 g (yield 94.5%) of 4-methylbenzyl ester of (+)-4- [1- (decanoyloxy) ethyl] benzoic acid.

▲ [α] ²⁵ _D ▼ + 44.5 ° (C = 1, CHCl ₃ ) n ²⁵ _D ▼ 1.5172 Example 5 4-Acetylbenzoic acid 4-substituted in place of 4-methylbenzyl ester of 4-acetylbenzoic acid Example 4 except 84.09 g (0.12 mol) of methoxybenzyl ester was used.
The reaction and post-treatment were carried out in the same manner as in (4) to obtain 2.34 g of (+)-4- (1-hydroxyethyl) benzoic acid 4-methoxybenzyl ester (II-4).

▲ [α] ²⁵ _D ▼ + 37.0 ° (C = 1, CHCl ₃ ) n ²⁵ _D ▼ 1.5724 The intermediates obtained during this period and the yields thereof are as follows.

4- (1-Hydroxyethyl) benzoic acid 4-methoxybenzyl ester (V-4) yield 96.5% 4- (1-acetoxyethyl) benzoic acid 4-methoxybenzyl ester (IV-4) yield 96.3% 1.14 g (4 mmol) of (II-4) above, 10 ml of pyridine
To a mixed solution consisting of and 5 ml of toluene, 1.32 g (4.8 mmol) of palmitic acid chloride is added, and the mixture is reacted at 25-30 ° C for 10 hours. Then, after post-treatment and purification according to Example 1, 1.91 g of 4-methoxybenzyl ester of (+)-4- [1- (palmitoyloxy) ethyl] benzoic acid (yield 90
%) Was obtained.

[Α] ²⁵ _D ▼ + 36 ° (C = 1, CHCl ₃ ) Example 7 4′-in a 4-necked flask equipped with a stirrer and a thermometer.
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 the temperature at the same temperature for 2 hours, the reaction solution is poured into ice water and extracted twice with 800 ml of chloroform. The organic layer is washed with water and then concentrated under reduced pressure to give 4- (1-hydroxyethyl) -4'-.
Biphenylcarboxylic acid benzyl ester (V-5) 32.9
g (yield 99%) was obtained.

29.9 g (0.09 mol) of (V-5) was dissolved in 150 ml of toluene and 50 ml of pyridine, to which acetyl chloride 9.42 was added.
Add g (0.12 mol). Then, at the same temperature for 2 hours, 40
Incubate at ~ 45 ° C for 2 hours. After completion of the reaction, after cooling to 10 ° C or lower, 300 ml of 3N hydrochloric acid was added, the organic layer was separated, and then water,
Wash sequentially with 5% sodium hydrogen carbonate and water. The organic layer was condensed under reduced pressure, and the residue was further purified by column chromatography to obtain 33.0 g of 4 '-(1-acetoxyethyl) -4-biphenylcarboxylic acid benzyl ester (IV-5) (yield 98
%) Was obtained.

(IV-5) 29.90 (0.08 mol) was added with 800 ml of 0.1 M phosphate buffer (pH 7.5), chloroform 30 ml and lipase P6.0.
Mix with 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 is concentrated under reduced pressure, and the residue is purified by column chromatography using a chloroform: ethyl acetate (12: 1) mixture as an eluting solvent to give (+)-4 '-(1-hydroxyethyl) -4.
-Biphenylcarboxylic acid benzyl ester (II-5) 1
0.6 g (mp108-110.5 ° C) and (-)-4 '-(1-
Acetoxyethyl) -4-biphenylcarboxylic acid benzyl ester (17.5 g) was obtained.

(II-5) 1.00 g (3 mmol), pyridine 10 ml, toluene 10 ml and hexanoic anhydride 0.77 g (3.6 mmol) are mixed and reacted at 20 to 25 ° C. for 15 hours. After completion of the reaction, the reaction solution is poured into 50 ml of ice water and 30 ml of toluene is added for extraction treatment. The organic layer was washed successively with 1N hydrochloric acid, 2% aqueous sodium hydrogen carbonate and water, concentrated under reduced pressure, and the residue was further purified by chromatography to obtain (+)-4- (1-hexanoyloxyethyl) -4'-biphenyl. Carboxylic acid benzyl ester 1.
24 g (96% yield) was obtained.

▲ [α] ²⁵ _D ▼ + 46.5 ° (C = 1, CHCl ₃ ) n ²⁵ _D ▼ 1.5480 Example 8 (−)-4 ′-(1-acetoxyethyl) 4-biphenyl obtained in Example 7. 15 g of carboxylic acid benzyl ester is mixed with 10 ml of chloroform, 400 ml of 0.2M phosphate buffer and 3 g of Amanobuta liver esterase, and the mixture is mixed at 30 to 35 ° C for 30 minutes.
React for hours. After completion of the reaction, the reaction solution is extracted with chloroform. The chloroform layer was concentrated and the residue was purified by chromatography to obtain (-) 4 '-(1-hydroxyethyl) -4-biphenylcarboxylic acid benzyl ester (II
-6) Obtain 11.8 g.

(V-6) 1.00 g (3 mmol) dichloromethane 15 ml,
(2S, 3S) -2-Chloro-3-methylpentanoic acid 0.54g
(3.6 mmol), dicyclohexylcarbodiimide 0.6
8 g (3.3 mmol) and 4-pyrrolidinopyridine 0.02 g
Are mixed and reacted at 20 to 25 ° C for 12 hours. After the insoluble matter was removed, the liquid was concentrated, and the concentrated residue was purified by column chromatography (-)-4 '-{1-[(2S, 3S) -2-chloro-3-methylpentanoyloxy] ethyl}. -4-Biphenylcarboxylic acid benzyl ester was obtained.

▲ [α] ²⁵ _D ▼ -34.8 ° (C = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5800 Example 9 In a flask similar to that used in Example 7, 4'-acetyl-4-biphenylcarboxylic acid of 4- was added. Chlorobenzyl ester (36.5 g, 0.1 mol), chloroform (150 ml) and ethanol (50 ml) are charged, and sodium pour hydride (3.8 g, 0.1 mol) is added over 10 minutes at 15 to 25 ° C.

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 4- (1-hydroxyethyl) -4-biphenylcarboxylic acid 4-chlorobenzyl ester (V
-7) 36.5 g (yield 99.5%) was obtained.

33.0 g (0.09 mol) of (V-7) obtained here was dissolved in 150 ml of toluene and 50 ml of pyridine, and 9.42 g (0.12 mol) of acetyl chloride was added thereto at 15 to 20 ° C. for 2 hours. Add. Then, at the same temperature for 1 hour, at 40-50 ° C for 2 hours
Add it over time. Then, at the same temperature for 1 hour, 40-50
Incubate at ℃ for 2 hours. After completion of the reaction, cool to 10 ° C or below, add 300 ml of 3N hydrochloric acid, separate the organic layer, and then add 5% water.
Wash sequentially with sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure, the residue was further purified by crow chromatography, and 46.4 g of 4-chlorobenzyl ester of 4 '(1-acetoxyethyl) -4-biphenylcarboxylic acid (IV-7) was obtained.
(Yield 99.0%) was obtained.

32.7 g (0.08 mol) of (IV-7) obtained here is mixed with 800 ml of 0.1 M phosphate buffer (pH 7.5), 30 ml of chloroform and 6.0 g of lipase P and stirred vigorously at 40 to 45 ° C. for 20 hours. After the reaction was completed, the reaction mixture was mixed with ityl isobutyl ketone.
Extract with 600 ml.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a hexane: ethyl acetate (12: 1) mixture as an eluent, and (+)-4 '-(1-hydroxyethyl) -4-biphenylcarboxylic acid. 4-chlorobenzyl ester of acid (II
-7) Obtained 13.8 g.

▲ [α] ²⁰ _D ▼ + 21.7 ° (C = 0.544, CHCl ₃ ) mp 108-110.5 ° C. Next, 3 mmol of (II-7) obtained here was added to pyridine 10
ml and 10 ml dichloromethane, to which 0.31 g (3.3 mmol) propionyl chloride is added. afterwards,
The reaction is carried out at 20 to 25 ° C for 3 hours and at 40 to 45 ° C for 3 hours. Then, post-treatment and purification were carried out according to Example 7, and (+)-4 '-(1
-Propionyloxyethyl) -4-biphenylcarboxylic acid 4-chlorobenzyl ester 1,11 g (yield 97%)
I got

▲ [α] ²⁵ _D ▼ + 28 ° (C = 1, CHCl ₃ ) Examples 10 to 12 In the esterification of Example 2, (2S, 3S) -2-chloro-3-methylpentanoic acid was used instead of Table- Esterification and post-treatment were carried out in the same manner as in Example 2 except that the carboxylic acid shown in Example 1 (4.8 mmol each) was used, and the results shown in Table 1 were obtained.

Example 13 (II-1) 1.02 in place of (II-2) in Example 2
According to the esterification reaction of Example 2, except that g (4 mmol) was replaced with (2S, 3S) -2-chloro-3-methylpentanoic acid and 2S-2-methylbutanoic acid (4.8 mmol) was used. The reaction, post-treatment, and purification were carried out to obtain (+)-4-1-2S-methylbutanoylex) ethyl] benzoic acid benzyl ester (yield 95.5%).

▲ [α] ²⁵ _D ▼ + 67.6 ° (C = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5302

Claims (5)

(57) [Claims] 1. A general formula (In the formula, R represents an alkyl group having 1 to 12 carbon atoms and optionally containing a halogen atom, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2. However, R is not a methyl group, and when n is 2, R is not an alkyl group having 1 to 5 carbon atoms. * Indicates an asymmetric carbon atom.) An optically active benzenecarboxylic acid ester represented by. 2. General formula (In the formula, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2. The * mark indicates an asymmetric carbon atom.) Alcohols represented by the general formula R-COOH (wherein R is an alkyl group having 1 to 12 carbon atoms and optionally containing a halogen atom, R'is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom). And n is 1 or 2. provided that R is not a methyl group, and when n is 2, R is not an alkyl group having 1 to 5 carbon atoms. The method for producing an optically active benzenecarboxylic acid ester according to claim 1, which comprises reacting with a fatty acid carboxylic acid or a derivative thereof. 3. General formula (In the formula, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2.) The dl-ester represented by any one of the enantiomers of the ester is represented by Asymmetric hydrolysis using an esterase that has the ability to hydrolyze only one of the general formulas (In the formula, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2. The * mark indicates an asymmetric carbon atom.) Of the general formula R-COOH (wherein R is an alkyl group having 1 to 12 carbon atoms and optionally containing a halogen atom, R'is a hydrogen atom, a lower alkyl group, a lower alkoxy group or It represents a halogen atom, and n is 1 or 2. However, R is not a methyl group, and when n is 2, R is not an alkyl group having 1 to 5 carbon atoms. The method for producing an optically active benzenecarboxylic acid ester according to claim 1, which comprises reacting with a fatty acid carboxylic acid or a derivative thereof. 4. A general formula (In the formula, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2.) The dl-alcohol represented by the formula is reacted with acetic acid to give a compound of the general formula (In the formula, R ′ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a dl-ester represented by a halogen atom, and an esterase having the ability to hydrolyze only either one of the enantiomers of the ester. Asymmetric hydrolysis using general formula (In the formula, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2. The * mark indicates an asymmetric carbon atom.) Of the general formula R-COOH (wherein R is an alkyl group having 1 to 12 carbon atoms and optionally containing a halogen atom, R'is a hydrogen atom, a lower alkyl group, a lower alkoxy group or It represents a halogen atom, and n is 1 or 2. However, R is not a methyl group, and when n is 2, R is not an alkyl group having 1 to 5 carbon atoms. The method for producing an optically active benzenecarboxylic acid ester according to claim 1, which comprises reacting with a fatty acid carboxylic acid or a derivative thereof. 5. A general formula (In the formula, R ′ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2.) A ketone represented by the general formula (In the formula, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2.) Then, a dl-alcohol represented by the formula: A dl-ester represented by the following formula and asymmetrically hydrolyzed with an esterase having the ability to hydrolyze only one of the enantiomers of the ester (In the formula, R'represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n is 1 or 2. The * mark indicates an asymmetric carbon atom.) Of the general formula R-COOH (wherein R is an alkyl group having 1 to 12 carbon atoms and optionally containing a halogen atom, R'is a hydrogen atom, a lower alkyl group, a lower alkoxy group or It represents a halogen atom, and n is 1 or 2. However, R is not a methyl group, and when n is 2, R is not an alkyl group having 1 to 5 carbon atoms. The method for producing an optically active benzenecarboxylic acid ester according to claim 1, which comprises reacting with a fatty acid carboxylic acid or a derivative thereof.