JPH01242555A - Optically active benzenecarboxylic acid esters and production thereof - Google Patents

Abstract

NEW MATERIAL:Compounds expressed by formula I (R is 1-20C alkyl which may contain halogen; R' is H, lower alkyl, lower alkoxyl or halogen; n is 1 or 2, provided that R is not methyl; * indicates asymmetric carbon). EXAMPLE:Benzyl (+)-4-(1-hexanoyloxyethyl)benzoate. USE:A synthetic intermediate for organic electronic materials, especially liquid crystal compounds and also for medicines, agricultural chemicals, etc. PREPARATION:Optically active alcohols expressed by formula II and an aliphatic carboxylic acid expressed by the formula R-COOH or a derivative thereof are subjected to condensation reaction in the presence or absence of a solvent (e.g., THF) using a catalyst (e.g., dimethylaminopyridine) at -30-100 deg.C to afford the aimed compounds expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Application Fields The present invention relates to -soft formula (wherein R is an alkyl group having 1 to 20 carbon atoms and may contain a halogen atom, and R' is a hydrogen atom). atom, lower alkyl group, lower alkoxyl group or halogen atom, n
is 1 or 2. However, R is never a methyl group. The eastern part indicates an asymmetric carbon. ) and a method for producing the same.

<Prior art> The optically active benzenecarboxylic acid ester represented by the soft formula (1) above is a new compound that has not been described in any literature, and there have been no studies regarding its production method or usefulness as a compound. Not known at all.

<Problems to be Solved by the Invention> Optically active benzene carboxylic acid esters represented by the general formula I\H (1) are used as intermediates for medicines, agricultural chemicals, etc. Very useful as an intermediate for compounds.

For example, the optically active benzenecarboxylic acid esters can be typically converted into a liquid crystal compound by the method shown in the following formula, and this compound is excellent as a strongly conductive liquid crystal.

Means for Solving the Problems> The present invention provides such novel and useful optically active benzenecarboxylic esters represented by the general formula -Soft formula (n) (in the formula, R/, n and eastern have the same meanings as above).
It can be produced by reacting with an aliphatic carboxylic acid represented by COOH(III) (wherein R has the same meaning as above) or a derivative thereof.

Here, the aliphatic carboxylic acids represented by the soft formula (m) include 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, isolafic acid, 2-methylbutanoic acid, 4-methylpentanoic acid, 2
-Methylhexanoic acid, 2-methylhebutanoic acid, 2-methyloctanoic acid, 2.8-dimethylhebutanoic acid, 2゜3.
8-trimethylbutanoic acid, 8-methylpentanoic acid, 2.
8-dimethylpentanoic acid, 2.4-dimethylpentanoic acid, 2.8.8.4-tetramethylpentanoic acid, 8-methylhexanoic acid, 4-methylhexanoic acid, 2.5-dimethylhexanoic acid, haloacetic acid, 2-) Lihalomethylpentanoic acid, 2-trihalomethylhexanoic acid, 2-trihalomethylhebutanoic acid, 2-halopropanoic acid, 8-halo 2-methylpropanoic acid, 2.8-dihalobutanoic acid, 2゜8- Dihalobutanoic acid, 2.4-dihalobutanoic acid, 8.4-dihalobutanoic acid, 2-halo 8-methylbutanoic acid, 2-halo 3.3-dimethylbutanoic acid, 2-halopentanoic acid, 8
-halopentane &, 4-halopentane a, 2,4-dihalopentanoic acid, 2゜5-dihalopentanoic acid, 2-halo 8-methylpentanoic acid, 2-halo 4-methylpentanoic acid, 2-balor 8-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 aliphatic carboxylic acids, their acid anhydrides, or their acid halides (for example, acid bromide, acid chloride) (hereinafter, these are collectively referred to as Some of these optically active aliphatic carboxylic acids can be obtained by oxidation of the corresponding alcohol, reductive deamination of the amino acid, and some are naturally occurring. Alternatively, it can be derived from the following optically active amino acids and optically active oxyacids obtained by resolution.

Alanine, valine, leucine, isoleucine, phenylalanine, serine, threonine, allothreonine, homoserine, alloisoleucine, tert-leucine, 2-
Aminoacetic acid, norvaline, norleucine, ornithine,
Lysine, hydroxylysine, phenylglycine, trifluoroalanine, aspartic acid, glutamic acid, lactic acid, man7'7L/acid, tropic acid, 8-hydroxybutyric acid, malic acid, tartaric acid, isopropylmalic acid, etc.

The reaction between the optically active alcohol Q (n) and the aliphatic carboxylic acid is usually carried out in the presence or absence of a solvent, and generally in the presence of a catalyst.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane,
Examples include solvents that are inert to the reaction of aliphatic or aromatic hydrocarbons such as pyridine, ethers, halogenated hydrocarbons, organic amines, etc., alone or as a mixture, and there are particular restrictions on the amount used.

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 must be at least 1 equivalent relative to the optically active alcohol, and there is no particular upper limit on the upper limit, but
Preferably it is 4 times the equivalent.

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

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

The amount of the catalyst to be used varies depending on the type of aliphatic carboxylic acid and the combination of the catalyst used, and is not necessarily specified, but for example, when using an acid halide, it is at least 1 equivalent to the amount of the acid halide.

In addition, when using an aliphatic carboxylic acid as the aliphatic carboxylic acid, it is usually used in an amount of 1 to 2 times the optically active alcohol 01), and the reaction is carried out by dehydration condensation in the presence of a condensing agent. This is done by

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

In this case, the paper used as the condensing agent is usually 1 to 162 equivalents to the aliphatic carboxylic acid, and when a base is used together, the base toilet wax is 0.01 to 02 equivalents to the condensing agent. It is.

The reaction temperature is usually -30°C-IQ0°C, preferably -25°C to 80°C.

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

After completion of the reaction, the desired general formula (1
) The optically active benzenecarboxylic acid esters shown in ) can be obtained in good yield, and can be produced by tR using column chromatography, ancient crystallization, etc., if necessary.

Optically active alcohols, which are the raw materials for this reaction (
(2) is the ability to hydrolyze only one of the enantiomers of the dj-ester represented by -soft formula (iv) (wherein R' and n have the same meanings as above). It can be produced by hydrolyzing one of the optically active forms of the esters (asymmetric hydrolysis) using an esterase having the following.

Here, the above-mentioned esterase means a broad capsule esterase containing lipase.

The microorganism that produces the esterase used in this reaction may be any microorganism that produces an esterase that has the ability to asymmetrically hydrolyze dj-esters (IV), and is not particularly limited. Specific examples of such microorganisms include Enterobacter genus, Arthrobacter genus, Brevibacterium genus, Pseudomonas genus, alkaline earth metals, Micrococcus genus, Chromobacterium 5@, Microbacterium genus, and Corynebacterium genus. , Parsis sp., Lactobacillus Ji
I4, Trichoderma sp., Candida sp., Satucharomyces sp., Rhodotorula sp., Cryptococcus sp., Torrolobusima spp., Hihia sp., Penicillium, @, Aspergillus sp., Rhizopus sp., Mucor sp., Aureobasidium sp.
Examples include microorganisms belonging to the genus Actinomyces, Nocardia, Streptomyces, Hansenula, and Achromobacter.

The above-mentioned microorganisms are usually cultured according to conventional methods, and culture samples can be obtained by, for example, liquid culture. Liquid culture is, for example, sterilized limb culture [molds,
For yeast, malt extract/yeast extract medium (dissolve peptone 5 in 11 water, glucose 107, malt extract 3z1, yeast extract 39, adjust to pH 6.5), and for bacteria, sweetened bouillon medium (water 1j to 1j). Dissolve peptone 5), glucose 10, meat extract 59, NaC/85',
The pH is set to 7.2)] and microorganisms are injected into the solution, usually at a pH of 30 to 4.
This is carried out by columnar (12i1d) culture at 0° C. for 1 to 3 days, and solid culture may be carried out if necessary.

In addition, some of these microbial Z and K esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following.

Pseudomonas lipase [Lipase P (Ohno fi
)), Aspergillus lipase [Lipase AP (
Ohno Pharmaceutical)], Mucor lipase [Lipase MA
P (manufactured by Ohno Pharmaceutical Co., Ltd.)], Candida cylindrasse lipase MY (manufactured by Nag Sangyo Co., Ltd.)], lipase between alkaline earths [Lipase PL (manufactured by Octosuga Sangyo Co., Ltd.)], Achromobacter lipase [Lipase AL (Made by Name & F Sangyo)],
] Arthrobacter lipase [Lipase Joint BSL (
Joint Sake Refining)], lipase of the genus Chromobacterium (Toyo Jozo!I!li, lipase of the genus Rhizopus deremer)
Talipase (manufactured by Tanabe Seiyaku)], Rhizopus lipase [
Riverze Saloken (Osaka Bacteria Research Institute)].

Further, animal/plant esterases can also be used, and specific examples of these esterases include the following.

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

As the esterase used in this reaction, enzymes obtained from animals, plants, and microorganisms are used, and their usage forms include purified enzymes, crude enzymes, enzyme-containing substances, wI lost culture samples, cultures, bacterial cells, and culture samples. They can be used in various forms as needed, including processed products, and enzymes and microorganisms can also be used in combination. Alternatively, it can also be used as an immobilized enzyme immobilized on a resin or the like, or as a stabilized bacterial cell.

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

As the buffer, commonly used buffers of inorganic acid salts such as sodium phosphate and potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc. The pH is preferably 8 to 11 for a culture solution of a microorganism that is not alkaliphilic or an alkaline esterase, and the pH is preferably 5 to 8 for a culture solution of a microorganism that is not alkalophilic or an esterase that does not have alkali resistance. Concentration is usually 0.05-2
M.

Preferably it is in the range of 0.05 to 0.5M.

The reaction temperature is usually 10 to 60°C, and the reaction time is generally 8 to 70 hours, but is not limited thereto.

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

In addition to the buffer, an inert organic solvent such as toluene, chloroform, methyl isobutyl ketone, or dichloromethane can also be used during this asymmetric hydrolysis reaction. Decomposition can also be advantageously carried out.

Through such asymmetric hydrolysis reaction, only one of the optically active forms of the raw material dl-esters (IV) is hydrolyzed to produce an optically active alcohol represented by -soft formula (II), and on the other hand, Among the raw material d/-esters (rV), the other optically active ester remains as a hydrolysis residue. - After completion of such hydrolysis reaction, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, or ethyl ether, and after distilling off the solvent from the organic layer, the concentrated residue is treated with column chromatography. The optically active alcohols (It), which are the hydrolysis products, and the optically active esters, which are the hydrolysis residue [among the optically active substances in the raw material dl-esters (IV), which are not hydrolyzed, can be separated.

The optically active esters obtained here can be further hydrolyzed as necessary to produce optically active alcohols that are enantiomers of the optically active alcohols obtained previously.

The dl-esters (IV), which are the raw materials for such asymmetric hydrolysis reaction, are generally dl-alco-esters (IV) represented by It can be produced by reacting -ols with acetic acids to acetylate them.

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

This reaction is usually carried out using a catalyst in the presence or absence of a solvent.

In this reaction, the amount of acetic acid used is required to be 1 equivalent or more relative to the dl-alcohol (2), and although the upper limit is not particularly limited, it is preferably 4 equivalent.

When a solvent is used in this reaction, it may be a fatty acid such as tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, hexane, pyridine, etc. or aromatic hydrocarbons, needles,
Solvents inert to the reaction of halogenated hydrocarbons, organic amines, etc. may be used alone or as a mixture, and the amount used is not particularly limited.

Examples of the catalyst include organic or inorganic basic substances such as dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine, picoline, imidazole, sodium carbonate, sodium megylate, and potassium bicarbonate, and the amount used is particularly determined. Although not limited,
It is usually 1 to 5 times as much as the raw material alcohol (7).

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

Furthermore, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as catalysts.

The reaction temperature is usually -80°C to 100°C, preferably -20°C to 90°C.

The reaction time is not particularly limited, and the end point of the reaction can be set as the time when the dl-alcohol intercondylar material as a raw material disappears from the reaction system.

After the reaction is complete, standard separation methods such as extraction, separation, etc.
dl-esters (I) by recrystallization etc.
V) can be obtained in good yield, which can be further purified by column chromatography or the like if necessary, but can be used as a reaction mixture in the next step of asymmetric hydrolysis reaction.

In addition, d4-alcohols (V), which are raw materials for this reaction,
can be easily produced by reducing a ketone represented by -soft formula (Vl) (wherein R' and n have the same meanings as above) using a reducing agent.

The reducing agent at this time is preferably sodium borohydride, borohydride, lithium aluminum hydride-silica gel, aluminum isopropoxide, lithium tri-t-butoxyaluminum hydride, lithium tri-S-butyl boron. Hydride, borane, alkali metal-ammonia, Raney nickel-hydrogen, etc. are used, and the amount used is at least 1 equivalent or more, and usually in the range of 1 to 10 equivalents, relative to the raw material ketones (VI).

The reduction reaction is usually carried out in a solvent, such as tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, toluene, benzene, chloroform, dichloromethane ether, carbonized halides, etc. Solvents inert to the reaction, such as hydrogen, aromatic hydrocarbons, and alcohol, may be used alone or in mixtures as appropriate.

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

From the reaction mixture thus obtained, liquid separation, concentration,
dl-alcohols (1) by distillation, crystallization, etc.
can be obtained in good yield, but dl-esters (I
In order to produce T), it is not necessary to use dl-alcohols (
It is not necessary to isolate 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, optically active benzenecarboxylic acid ester M, which is a novel compound, can be produced with high optical purity and in good yield, and the compound of the present invention can be used in medicine,
It is not only useful as an intermediate for agricultural chemicals, but also very useful as an intermediate for liquid crystal materials.

Example 1 4-Acetylbenzoic acid benzyl ester 60.989 (0,24
mol), ethanol 100 rnl and chloroform 8
00- is charged, and sodium borohydride 4.6F (0.12 mol) is added thereto at 15-26°C over 10 minutes.

After incubating at the same temperature for 2 hours, the reaction mixture was poured into ice water.
Extract twice with 200% ethyl acetate. After washing the organic j- with water, it was concentrated under reduced pressure to give 4-(1-hydroxyethyl)benzoic acid benzyl ester (V-1) 58.87
y (yield: 95 cm) was obtained.

(n251.5682) 55.902 (0.22 mol) of (V-1) obtained here was dissolved in a mixed solution consisting of 300 d of toluene and 100 ml of pyridine, and acetyl chloride 18.849<0.
24 mol) at 15-20°C over a period of 2 hours. Incubate at the same temperature for 1 hour and at 30-35°C for 2 hours.

After the reaction is completed, cool to below 10°C and add 60% of 8N4 acid water.
After adding 0- and separating the organic layer, the organic layer was washed successively with water and 5% deuterated water. The organic layer was concentrated under reduced pressure and further purified by column chromatography to obtain benzyl 4-(1-acetoxyethyl)benzoic acid ester (IV-1) 82.15
9 (yield 98%) was obtained.

(n” 1.5804) Obtained here (IV -1) 29.817 (0,1
mol) in 0.1M phosphate buffer (pH 7) soo, y
, 15 m/chloroform and lipase P6P and stir vigorously at 40-45°C for 20 hours.

After the reaction is complete, the reaction mixture is diluted with 90% methyl isobutyl ketone.
Extraction processing is performed at 0-. 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 give (+)-4-(1
-hydroxyethyl)benzoic acid hensyl ester (n-
1) 11.21ri((t)D+85.6°(C=
1. CHCl5), "Dl, 5694) and H-4-(1-acetoxyethyl)benzoic acid benzyl ester 15.96y((α)25-52°(C■1°C
HCzs),nDL-52983 was obtained.

1.022 (4 mmol) of (n-1) obtained here was mixed with 5 rnl of pyridine and 10-l of toluene, and 0.66 F (4.4 mmol) of hexanoyl chloride was added to this for 15 rnl.
Add dropwise at ~20°C. After that, at 20℃ for 2 hours, 4
Continue the reaction at 0-50°C for 2 hours. After the reaction is completed, the reaction solution is poured into ice water and extracted with 80ml of toluene. The toluene layer is sequentially washed with IN-hydrochloric acid water, 2-diluted sodium chloride water, and water.

The toluene layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (distillation solvent: toluene) to obtain (+)-4.
-(1-hexanoyloxyethyl)benzoic acid benzyl ester 1.899 (yield 98%) was obtained.

(d) +49.2° (C-1, CHC/Rn26
1.5221 Example 2 10LI of H-4-(1-acetoxyethyl)benzoic acid benzyl ester obtained in Example 1 was combined with 200ml of 0.2 M phosphorus buffer, chloroform 5- and pig liver esterase 1y. , react at 30-35°C for 300 hours. Thereafter, post-treatment and purification were carried out in the same manner as in Example 1, and H-4
-(1-Hydroxyethyl)benzoic acid benzyl ester (II-2) 7.79% was obtained.

(11-2) 1.02 mmol (4 mmol) obtained here, (
2S, as)-2-chloro-3-methylpentanoic acid 0.
72F (4,8 mmol) and dichloromethane 20-
Dicyclocarbodiimide 0.91P in a solution consisting of
(4.4 mmol) and 0.4-pyrrolidinopyridine.
Add 029 and react at room temperature for 12 hours. After the reaction is completed, the precipitated crystals are separated and the seven-house solution is concentrated. The concentrated residue was purified in the same manner as in Example 1 to obtain H-4-(1-((2S,
8S)-2-chloro-3-methylpentanoyloxy]
ethyl)benzoic acid benzyl ester 1.607 (yield 9)
Section 6.5) was obtained.

[αzo'-59.5°nD 1.5858 Example 3 cm-1)1.02y (4 mmol) obtained in Example 1 was added to 10 ml of pyridine. mixed with 10rnl dichloroethane and butanoic anhydride 0176F (4.4 mmol),
React at 20-25°C for 15 hours. After the reaction is completed, the reaction solution is poured into ice water, and 20 m/dichloroethane is added for extraction. Thereafter, the product was post-treated and purified according to Example 1 to obtain (10)-4-[1-(butanoyloxy)ethyl]benzoic acid benzyl ester 1,272 (yield 97%).

[a] o + 51°5° (C-1, CHC/engine) nDl. 5243 Example 4 In a flask similar to that used in Example 1, 32.17% of 4-methylbenzyl ester of 4-acetylbenzoic acid (0,
12 mol), ethanol 50, dichloromethane 100
Prepare rnl and 50rnl of tetrahydrofuran,
Add 21y of sodium borohydride to this at 15-25℃.
(0.06 mol) was added over a period of 10 minutes. After incubating at the same temperature for 2 hours, the reaction solution was poured into ice water and subjected to the same post-treatment as in Example 1 to obtain 4-methylbenzyl ester (vs)ai of 4-(1-hydroxyethyl)benzoic acid. 437
(yield 97%).

The (V-8) 29.71 F (0.11 mol) obtained here was mixed with dichloromethane 20Off+/ and pyridine 5
Dissolve in a mixture consisting of 〇- and add acetyl chloride 9.
Dichloromethane solution 5 containing 42' (0.12 mol) (
Add L+7 dropwise at room temperature. Pour for about 2 hours, add 3N reaction solution
Hydrochloric acid 800. Pour into nl and perform extraction operation. The organic layer was first washed with water, 7% heavy backwater, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give a light yellow oily 4-methylbenzyl ester of 4-(1-acetoxyethyl)benzoic acid (■-1)BB, 8? (Yield 97cm)
I got it.

(IV-8) 15.69 (50 mmol) to 0.
8M phosphate buffer (pH 7) 200. nl, mixed with chloroform 104 and lipase P8, 38-4
Stir vigorously for 24 hours at 0°C.

After the reaction was completed, the reaction mixture was mixed with 600% ethyl acetate. Extract with nl. The organic 1- was purified under reduced pressure, and the residue was separated and purified by column chromatography using a 12:1 mixture of hexane and ethyl acetate as an eluent to obtain (10)-4-(1).
-hydroxyethyl) 4-methylbenzyl ester of amino acid (...-8) 5.95F[((t) +86.
8° (C-1, CHC/3), nDl, 5688
) was obtained.

(n-f3) 0.91P (4.8 mmol) of decanoyl chloride was added to a mixed solution consisting of 1.085' (4 mmol), 5-pyridine, and 10 m/l of toluene at 20°C.
Add at. Thereafter, the mixture was stirred for 10 hours, and stirring was continued for 2 hours at 40-45°C. Thereafter, 4-methylbenzyl ester of (i)-4-[1-(decanoyloxy)ethyl]benzoic acid 1.60P(
A yield of 94.5% was obtained.

(1) 25 +44.5° (C-1, CHCz3)
nD 1.5172 Example 5 Example 4 except that 84.099 (0.12 mol) of 4-methoxybenzyl ester of 4-acetylbenzoic acid is used in place of the 4-methylbenzyl ester of 4-acetylbenzoic acid. Perform the reaction and post-treatment ft in the same manner as (+l-4
-(1-hydroxyethyl)benzoic acid 4-methoxybenzyl ester (n-4) 2.84P was obtained.

Cd) D+ 87.0° (C-1, CHC/3)nD
1.5724 The intermediates obtained during this period and their yields are as follows.

4-Methoxybenzyl ester of 4-(1-hydroxyethyl)benzoic acid (V4) Yield 96.5% 4-
4-Methoxybenzyl ester of (1-acetoxyethyl)benzoic acid (IT-4) Yield: 96. a% above (
II-4) 1.14y (4 mmol), pyridine 1
1.82 S' (4.8 mmol) of balmitic acid chloride is added to a mixed bath solution consisting of 0- and 5 rnl of toluene and reacted at 25-80°C for 10 hours. Thereafter, the product was post-treated and purified according to Example 1 to obtain 4-methoxybenzyl ester of (+)-4-[1-(palmitoyloxy)ethyl]benzoic acid 1.91F (yield: 90%).

[α], +16° (C-1, CHCl,) Example 7 4′-acetyl-4-biphenylcarboxylic acid benzyl ester 8 was placed in a 4-ton flask equipped with a stirrer and a thermometer.
8. (1 (0.1 mol), tetrahydrofuran 200-
and 50 rnl of ethanol, and 8.87 (0.1 mol) of sodium borohydride was added at 15 to 25°C.
It takes 0 minutes to add. After incubating at the same temperature for 2 hours, the reaction solution was poured into ice water and extracted twice with 800% chloroform. After washing the organic layer with water, it was concentrated under reduced pressure to give 4-(1
-hydroxyethyl)-4'-biphenylcarboxylic acid benzyl ester (V-5) 82.9 Li (yield 99
h) was obtained.

(V-5) 29.9 P (0.09 mol) is dissolved in toluene 150- and pyridine 50-, and acetyl chloride 9.42y (0.12 mol) is added thereto.

Thereafter, it is kept at the same temperature for 2 hours and at 40-45°C for 2 hours. After the reaction is completed, cool to below 10°C and add 3N hydrochloric acid 8.
00ml was added, and the organic no. was separated and washed sequentially with water, 5% sodium bicarbonate, and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to obtain 4-
(1-acetoxyethyl)-4-biphenylcarboxylic acid benzyl ester (ff-5) 8 B, OLi (yield: 98 cm) was obtained.

(■-5) 29.9 F (0.08 mol) to 0.1
M phosphate buffer (pH 7,5) 800rnl,
Chloroform 30- and Lipase P 6. Mix with OF and stir vigorously at 30-85°C for 20 hours. After the reaction is completed, the reaction mixture is added with 600 rn of methyl isobutyl ketone.
Extraction processing is carried out at l.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a chloroform:ethyl acetate (12:1) mixture as a dissolution solvent to obtain (+)-4'-(1-hydroxyethyl).
-4-biphenylcarboxylic acid benzyl ester (II-
5) 10.6 P (m, p, 108-110.5
'C) and (c)-4'-(1-acetoxyethyl)
-4-biphenylcarboxylic acid benzyl ester 17.5
I got no.

(II-6) 1.00F (8 mmol), pyridine 10m7. ) Luen 10. Mix rLl and 0.77' (8.6 mmol) of hexanoic anhydride,
React at 5°C for 15 hours. After the reaction is completed, the reaction solution is poured into 50ml of ice water, and 30ml of toluene is added for extraction. The organic layer was washed sequentially with IN hydrochloric acid, 2% aqueous sodium bicarbonate, and water, concentrated under reduced pressure, and the residue was further purified by chromatography (
)-4-(1-hexanoyloxyethyl)-4-biphenylcarboxylic acid benzyl ester 1.24F (yield 96%) was obtained.

[α), +46.5 (C-1,CHC/3)nD
1.5480 Example 8 (-1-4-(1-acetoxyethyl) obtained in Example 7
4-biphenylcarboxylic acid benzyl ester 15y was dissolved in chloroform 10m/0.2M phosphate buffer 400ml.
and Pig liver esterase 3y, mixed with 80
React for 80 hours at ~85°C. After the reaction is completed, the reaction solution is extracted with chloroform. The chloroform layer was concentrated, and the residue was purified by chromatography to obtain 11.8y of H-4'-(1-hydroxyethyl)-4-biphenylcarboxylic acid benzyl ester (II-6).

(V-6) 1.009 (8'E rimole) dichloromethane 15-, (2S,8S)-2-chloro-8-methylpentanoic acid 0.54P (8.6 mmol), dicyclohexylcarbodiimide 0.68P (fll, 8 mmol) and 0.02 F of 4-pyrrolidinopyridine are mixed and reacted at 20-25°C for 12 hours.

After removing insoluble materials, the P solution was concentrated, and the concentrated residue was purified by column chromatography to obtain H-4'-(1-[(23).

8S)-2-chloro-3-methylpentanoyloxy]
Ethyl)-4-biphenylcarboxylic acid benzyl ester was obtained.

[α) −84,8° (C-1, CHCl3)n
Dl, 5800 Example 9 In a flask similar to that used in Example 7, 4'-acetyl-
86.59 (0.1 mol) of 4-chlorobenzyl ester of 4-biphenylcarboxylic acid, 150 - of chloroform and 50 - of ethanol were charged, and 3.87 (0.1 mol) of sodium borohydride was added at 15-25°C. Add over a period of 10 minutes.

After incubating at the same temperature for 2 hours, the reaction solution was poured into ice water, and 200% of ethyl acetate was added. Extract twice at nt. After washing the organic layer with water, it was concentrated under reduced pressure to obtain 4-(1-hydroxythi).

(V-7) obtained here 88.09 (0.09 mol)
is dissolved in 150° of toluene and 50° of pyridine,
Add 9.0% acetyl chloride to this. ．． 12Z (0.12 mol)
is added over a period of 2 hours at 15-20°C.

Thereafter, the mixture is kept at the same temperature for 1 hour and at 40 to 50°C for 2 hours. After the reaction is completed, the mixture is cooled to below 10°C, 800°C of 8N hydrochloric acid is added, and the organic liquid is separated and washed sequentially with water, 5% sodium bicarbonate, and water. Organic J- was concentrated under reduced pressure, and the residue was further purified by column chromatography to obtain 4
'-(1-acetoxyethyl)-4-biphenylcarboxylic acid 4-chlorobenzyl ester (iy-7) 86
．． 49 (yield 99.0%) was obtained.

(IV-7) 82.79 (0.08 mol) obtained here was added to 0. IM phosphate buffer y (+) l (7,5) 80
0rn! .

Mix with 30 rnl of chloroform and 6.09 ml of lipase and stir vigorously for 20 hours at 40-45°C.

After the reaction is complete, the reaction mixture is diluted with 60% methyl isobutyl ketone.
Extraction processing is performed at 0-.

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).
18.8y of 4-chlorobenzyl ester of -4-biphenylcarboxylic acid (II-7) was obtained.

[α), +21.7°(C-0,544,CH(J,
)m, p 108~llO,5°C Next, 8 mmol of (n-7) obtained here was added to 10 ml of pyridine.
- and dichloromethane10. nl and add thereto 0.819 (8.8 mmol) of propionic acid chloride. The reaction is carried out at 20-25°C for 8 hours and at 40-45°C for 3 hours. The following work-up and purification were carried out as in Example 7 to obtain 1.11 y (yield: 97 y) of 4-chlorobenzyl ester of (+1-4'-(1-propionyloxyethyl)-4-biphenylcarboxylic acid). Obtained.

(d) D +28° (c-1, chcm) Example 10
~12 In the esterification of Example 2, (2S,8S)-2-
Esterification and post-treatment were carried out in the same manner as in Example 2, except that the carboxylic acids shown in Table 1 (4.8 mmol each) were used in place of chloro-3-methylpentanoic acid, and the results shown in Table 1 were obtained. .

Example 18 In Example 2, (n-2) was replaced with (II-1)1.
Example 2 except that 2s-2-methylbutanoic acid (4,8 mmol) was used in place of (2S,8S)-2-chloro-3-methylpentanoic acid for 02F (4 mmol).
The reaction, work-up and purification were carried out according to the esterification reaction of (10)-4-1-28-methylbutanoylexy)ethyl]benzoic acid benzyl ester (yield 95.5).
.

('')D+67.6° (C-1, CMCl5)n, 1
．． 5802

Claims (5)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. Indicates an alkoxyl group or a halogen atom, n
is 1 or 2. However, R is never a methyl group. * indicates an asymmetric carbon. ) Optically active benzenecarboxylic acid esters. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R' represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom, and n is 1 or 2. The optically active alcohols represented by the general formula R-CO
OH (In the formula, R represents an alkyl group having 1 to 20 carbon atoms and may contain a halogen atom. However, R is not a methyl group.) 2. The method for producing optically active benzenecarboxylic acid esters according to claim 1, which comprises reacting. (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. n is 1 or 2.) 3. The optically active alcohol according to claim 2, wherein the optically active alcohol is produced by asymmetrically hydrolyzing the dl-ester using an esterase that has the ability to hydrolyze only one of the enantiomers of the ester. A method for producing benzenecarboxylic acid esters. (4) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. n is 1 or 2.) dl-Alcohols are reacted with acetic acids to produce d
4. The method for producing optically active benzenecarboxylic acid esters according to claim 3, wherein l-esters are produced. (5) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. n is 1 or 2.) Ketones are reduced using a reducing agent to form dl-
5. The method for producing optically active benzenecarboxylic acid esters according to claim 4, wherein alcohols are produced.