JPH01199934A - Optically active substituted biphenylcarboxylic acids and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is 1-20C alkyl or alkoxyalkyl which may be substituted with halogen; * represents asymmetric carbon atom.). EXAMPLE:(+)-4'-(1-Propoxyethyl)-4-biphenylcarboxylic acid. USE:Useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., especially for liquid crystal compounds. PREPARATION:The objective compound of formula I can be produced by condensing optically active alcohols of formula II (R' is lower alkyl) with a alkylation agent of formula R-X [X is a halogen or OSO2R''' (R''' is lower alkyl or (substituted)phenyl)] and hydrolyzing the resultant optically active ether derivative of formula III under alkaline condition. The starting compound of formula II is produced by reacting alcohols of formula IV with lower alkylcarboxylic acids and subjecting the resultant esters of formula V to asymmetric hydrolysis with an esterase capable of hydrolyzing either one of the optically active isomers of said esters.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention is directed to the general formula (I) c, where R is an alkyl group or an alkoxyalkyl group having 1 to 2 carbon atoms and optionally substituted with a halogen atom. shows. The present invention relates to optically active substituted biphenylcarboxylic acids represented by (tea garden is an asymmetric carbon atom) and a method for producing the same, and the optically active substituted biphenylcarboxylic acids are used as intermediates for pharmaceuticals, agricultural chemicals, etc., especially for organic electronics. It is very useful as an intermediate for materials, especially liquid crystal compounds.

<Prior Art> The optically active substituted biphenylcarboxylic acids represented by the above general formula (I) are new compounds that have not been described in any literature, and there have been no studies regarding their production methods or their usefulness as compounds. Not known at all.

<Problems to be Solved by the Invention> In order to use the optically active substituted biphenylcarboxylic acids represented by the general formula (I) as a liquid crystal material, particularly a ferroelectric liquid crystal material, for example, the optically active substituted biphenylcarboxylic acid There is a method of reacting acids with phenols to derive corresponding ester compounds.

The present invention provides an optically active substituted biphenylcarboxylic acid represented by the general formula (I) that is useful as an intermediate for such liquid crystal materials, and a method for producing the same.

Means for Solving the Problems> The present inventors have studied the novel and useful method for producing optically active substituted biphenylcarboxylic acids represented by general formula (I), and as a result, have arrived at the present invention.

[First Step] The ketones represented by the general formula (2) (in the formula, R' represents a lower alkyl group) are reduced using a reducing agent to obtain the ketones represented by the general formula (ITI) c in the formula (ITI). , R' has the same meaning as above).Second Step 1 The alcohols having the general formula value obtained in the first step are reacted with lower alkylcarboxylic acids to obtain the alcohols having the general formula (5) Step 8 of obtaining esters represented by the formula %00 (in which R' and R11 represent lower alkyl groups) Ether represented by the general formula (5) obtained in the second step is asymmetrically hydrolyzed using an esterase that has the ability to hydrolyze either one of the optically active forms of the esters to obtain the general formula ff) OCHs (wherein, R' has the same meaning as above) (*marks are asymmetric carbon atoms) Process for obtaining optically active alcohols represented by [4th step] Optically active alcohols represented by general formula (v) obtained in 8th step , the general formula (to) it-x (9
) In formula 1, R represents an alkyl group or alkoxyalkyl group having 1 to 2 carbon atoms which may be substituted with a halogen atom, and X represents a halogen atom or 105O2R"'. Here, R"' is a lower represents an alkyl group or a phenyl group that may be substituted) to form an optically active ether represented by the general formula (2) obtained in the fourth step. In the step of hydrolyzing the derivative under alkaline conditions to obtain the optically active substituted biphenylcarboxylic acids represented by the general formula (I), the first to fifth steps and the second step are performed, respectively.
The present invention provides a method for producing optically active substituted biphenylcarboxylic acids represented by general formula (I), which comprises steps 1 to 5, steps 8 to 5, steps 4 to 5, and step 5.

The present invention will be explained in detail below.

Ketones (1), which are the raw materials in the first step, can be easily produced from 4-acetyl-4'-biphenylcarboxylic acid and a lower alcohol, for example, as shown below.

Reduction of the ketone dish is carried out using a reducing agent that can reduce ketones to alcohols.

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

This reaction is usually carried out in a solvent, such as
For example, a solvent inert to the reaction such as tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, toluene, benzene, chloroform, dichloromethane, etc., a halogenated hydrocarbon, alcohol, etc. alone or A mixture is used.

The reaction temperature is usually in the range of -a o "c to 150"C, preferably in the range of -20"C to 100"C.

There is no particular restriction on the reaction time.

From the reaction mixture thus obtained, liquid separation, concentration,
Alcohol saliva can be obtained in good yield by cleaning such as distillation and crystallization, but in order to obtain esters qv) in the next step, it is not necessarily necessary to isolate alcohol saliva; You may proceed to the next step.

Reaction to obtain esters from the alcohol side (second reaction)
Step) is carried out by reacting the alcohol (g) with a lower alkylcarboxylic acid to acylate it.

In this acylation, acid anhydrides or acid halides of lower alkylcarboxylic acids are used as the lower alkylcarboxylic acids, specifically acetic anhydride, acetic chloride or bromide, propionic anhydride, propionic acid chloride or bromide, and butyryl. Examples include chloride or bromide, valeroyl chloride or bromide.

In this reaction, the amount of lower alkyl carboxylic acids used is 1 equivalent or more relative to alcohol (2),
The upper limit is not particularly limited, but is preferably 4 equivalents.

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

When a solvent is used in this reaction, examples of the solvent include aliphatic or Solvents inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, etc. may be used alone or in mixtures, 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, potassium bicarbonate, and toluenesulfonic acid, methanesulfonic acid, Organic or inorganic acids such as sulfuric acid can also be used as catalysts.

The amount of catalyst used varies depending on the type of lower alkyl carboxylic acids used, the combination of catalysts used, etc., and is not necessarily specified, but for example, when using an acid halide as the lower alkyl carboxylic acids, the amount of the acid halide 1 equivalent or more.

The reaction temperature is usually -30"CN300"C,
Preferably the temperature is -20°C to 90″C.

The reaction time is not particularly limited, and the raw material alcohol (2)
The end point of the reaction can be defined as the point in time when it disappears from the reaction system.

After completion of the reaction, esters (I) can be obtained in good yield by conventional separation means such as extraction, separation, concentration, recrystallization, etc., which can be further purified by column chromatography etc. if necessary. The reaction mixture can be used as is for the next step.

The reaction (third step) to obtain an optically active alcohol (V) from esters (3) involves the use of an esterase capable of hydrolyzing one of the optically active forms of the esters. This is carried out by hydrolyzing one of the optically active substances (asymmetric hydrolysis).

The esterase-producing microorganism used in this reaction is not particularly limited, and may be any microorganism that produces an esterase capable of asymmetrically hydrolyzing the ester (5).

In addition, esterase in the present invention means esterase in a broad sense including lipase.

Specific examples of such microorganisms include Enterobacter, Arthrobacter, Brevibacterium, Sheetmonas, alkaline earth metals, Micrococcus, Chromobacterium, Microbacterium, and Corynebacterium. Bacillus, Lactobacillus, Trichoderma, Candida, Satucharomyces, Rhodotorula, Cryptococcus, Torsibsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium Examples include microorganisms belonging to the genus Actinomyces, genus Nocardia, genus Streptomyces, genus Hansenula, and genus Achromobacter.

For culturing the above-mentioned microorganisms, a culture solution is usually obtained by carrying out liquid culture according to a conventional method.

For example, a sterilized liquid medium [malt extract/yeast extract medium for frequent use of mold and yeast (dissolve 5y of peptone, 10f of glucose, 8f of malt extract, and 8f of yeast extract in 11 parts of water, and adjust the pH to 6.5); for bacteria, use Sweetened bouillon medium (dissolve peptone 5F, gelcol 10Ii1 meat extract 5I/, NaCl3f in 1 water!!, I) H7,2
microorganisms are inoculated into the microorganisms (
This is carried out by repeating shaking culture for 8 days, and solid culture may be carried out if necessary.

Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following.

Pseudomonas lipase [Lipase PC Ohno fil
i[)], Aspergillus lipase [Lipase AP (manufactured by Ohno Pharmaceutical Co., Ltd.)], lipase of Mucor genus [Lipase M-AP (manufactured by Ohno Pharmaceutical Co., Ltd.)], lipase of Candida cylindracea [Lipase MY (manufactured by Hexasaccharide Sangyo Co., Ltd.)] ], Alkaline earth-like lipase Lipase PL (manufactured by Hexasaccharide Sangyo)], ] Achromobacter lipase C lipase AL (
6 sugar industry)], a2. Yu. Bacterium lipase [Lipase Joint BSL (Joint Sake Refining Co., Ltd.)], Chromobacterium lipase (Toyo Jojo!Iri, Rhizopus).

Lipase of the genus Delemer [Talipase (manufactured by Tanabe Seiyaku)],
Rhizopus lipase [Lipase Saiken (Osaka Bacteria Research Institute)].

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

Steapsin, pancreatin, pig liver esterase, Wheat Germ x x -r 5-ase.

As the esterase used in this reaction, enzymes obtained from animals, plants, and microorganisms are used, and the usage forms include purified enzyme, crude enzyme, enzyme-containing material, microorganism culture solution,
It can be used in various forms as needed, such as cultures, bacterial cells, culture zero liquid, and processed products thereof, and enzymes and microorganisms can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterial cells immobilized on a resin or the like.

The asymmetric hydrolysis reaction is usually carried out by vigorously stirring a mixture of the raw material ester (g) and the 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 3 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 in the range of 0.05-0.5M.

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

After completion of such hydrolysis reaction, the hydrolysis reaction solution is extracted 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 subjected to column chromatography. By the method of can be separated.

The optically active esters obtained here are further hydrolyzed as necessary, and the optically active alcohols ('V
) can also be an enantiomerically active alcohol.

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

Furthermore, during this asymmetric hydrolysis, in addition to the buffer, it is also possible to use organic solvents that are inert to the reaction, such as toluene, chloroform, methyl isobutyl ketone, and dichloromethane. can be done advantageously.

The reaction (fourth step) for obtaining an optically active ether derivative (III) from an optically active alcohol (FF) is carried out by reacting the optically active alcohol (FF) with an alkylating agent (I).

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

Such basic substances have a ratio of 1 to optically active alcohols.
An equivalent or more is required, and the upper limit is not particularly limited, but is preferably in the range of 1 to 5 equivalents.

The alkylating agent used in this reaction is a halogen such as chloride, bromide, or iodine having an alkyl group or alkoxyalkyl group which may be substituted with a halogen atom having 1 to 20 carbon atoms as exemplified below. compounds or sulfuric esters (methanesulfonic acid ester, ethanesulfonic acid ester, benzenesulfonic acid ester,
toluenesulfonic acid ester, etc.).

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methoxymethyl, methoxyethyl,
Methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, methoxyheptyl, methoxyoctyl, methoxynonyl, methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyheptyl, ethoxyoctyl, ethoxynonyl , ethoxydecyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, propoxyoctyl, propoxydecyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, butoxyheptyl, butoxy Nonyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyoctyl, pentyloxydecyl, hexyloxymethyl, hexyloxyethyl,
Hexyloxypropyl, hexyloxybutyl, hexylhexypentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, heptyloxymethyl, heptyloxyethyl, heptyloxypropyl, heptyloxypentyl, octyloxymethyl, octyloxy Ethyl, decyloxymethyl, decyloxyethyl, decyloxyprovir.

1-methylethyl, 2-methylbutyl, 2゜8-dimethylbutyl, 2,8.8-trimethylbutyl, 2-methylpentyl, 8-methylpentyl, 2.8-dimethylpentyl, 2,4-dimethylpentyl, 2 .8.8.4-Tetramethylpentyl, 2-methylhexyl, 8-methylhexyl, 4-methylhexyl, 2.5-dimethylhexyl, 2-methylhebutyl, 2-methyloctyl, 2-
Trihalomethylpentyl, 2-trihalomethylhexyl, 2-trihalomethylhebutyl, 2-halopropyl, 3
-halo 2-methylpropyl, 2,3-dihalopropyl, 2-halobutyl, 3-halobutyl, 2,8-dihalobutyl, 2,4-dihalobutyl, 8,4-dihalobutyl,
2-halo-8-methylbutyl, 2-halo 8,8-dimethylbutyl, 2-halopentyl, 8-halopentyl, 4
-halopentyl, 2,4-dihalopentyl, 2,5-dihalopentyl, 2-lohexyl, 4-halohexyl, 5
- Halohexyl, 2-haloheptyl, 2-halooctyl (however, halo in the above alkyl group represents fluorine, chlorine, bromine or iodine, but fluorine or chlorine is preferred in practice).

Note that the alkyl group or alkoxyalkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom may be an optically active group.

These halides or sulfuric esters having optically active groups are derived from the corresponding alcohols, and some of the optically active alcohols can be asymmetrically reduced by asymmetric metal catalysts, microorganisms, or enzymes.
easily obtained. Also, does something exist naturally?
Alternatively, it can be derived from the following optically active amino acids and optically active oxyacids obtained by resolution.

Valine, leucine, isoleucine, phenylalanine,
Threonine, allothreonine, homoserine, alloisoleucine, tert-leucine, 2-aminobutyric acid, /luvaline, norleucine, ornithine, lysine, hydroxylysine, phenylglycine, aspartic acid, glutamic acid, mandelic acid, tropic acid, 8-hydroxyacetic acid, Malic acid, tartaric acid, isopropylmalic acid, etc.

The amount of such an alkylating agent to be used is arbitrary at least 1 equivalent to the optically active alcohol (V), but is usually in the range of 1 to 5 equivalents.

As the reaction solvent, in addition to the solvents exemplified in the second step, polar solvents such as dimethyl sulfoxide, hexamethylphosphorylamide, and N-methylpyrrolidone can be used.

The reaction temperature is usually -50°C to 120°C, preferably -80°C.
It is in the range of 0°C to 100°C.

After the reaction is complete, optically active ether derivatives can be obtained in good yield by conventional separation methods such as extraction, splitting, and concentration, and if necessary, purified by column chromatography, recrystallization, etc. However, the reaction mixture can also be used as is for the next step.

The reaction (fifth step) to obtain the desired optically active substituted biphenylcarboxylic acids from the optically active ether derivative (1) is as follows:
This is usually carried out by hydrolyzing an optically active ether derivative under alkaline conditions.

Examples of the alkali used in this reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and calcium hydroxide;
Examples include alkali metal hydrogen and alkaline earth metal carbonate, and it is preferable to use these as an aqueous solution. The amount of such alkali used is usually determined by the optically active ether derivative (■
), and is usually used in an amount of 1 to 10 equivalents.

In this reaction, 1 for the optically active ether derivative (■)
An equivalent or more amount of water is required, and the reaction is usually carried out in the presence of an excess amount of water, but a neutral organic solvent (natural organic solvent) may also be present.

The reaction temperature is usually in the range of -20°C to 100°C, and the reaction time is not particularly limited.

After the reaction is completed, the organic solvent is removed from the reaction mixture as necessary, the reaction solution is precipitated with an acid, and the desired optical activity represented by general formula (I) is obtained by performing treatments such as extraction and concentration. Substituted biphenylcarboxylic acids can be obtained,
This can be purified by recrystallization or column chromatography, if necessary.

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

<Example> The present invention will be explained below with reference to Examples.

Example 1 82.2 f of ethyl 4'-acetyl-4-biphenylcarboxylate was added to a 4-tubular flask equipped with a stirrer and a thermometer.
(0,12 mol), chloroform 150- and ethanol 50ffi7! and 2.81 (0.06 mol) of sodium borohydride at 15-25°C.
Add it in a few minutes. After keeping at the same temperature for 2 hours, the reaction solution was poured into ice water and extracted twice with 200 mt of ethyl acetate. After washing the organic layer with water, it was concentrated under reduced pressure to give ethyl 4-(1-hydroxyethyl)-4-biphenylcarboxylate (I
II-1) 80.8y (yield 95%) was obtained.

The (DI-1) 29.7F (0.11 mol) obtained here was dissolved in 150 - of toluene and 50 - of pyridine, and 9.42 f (0.12 mol) of acetyl chloride was added thereto.
Addition takes 2 hours at 5-20°C. Thereafter, it is kept at the same temperature for 1 hour and at 40 to 50°C for 2 hours. After the reaction is completed, cool to below 10"C, add 800 g of 8N hydrochloric acid, separate the organic layer, and wash sequentially with water, 5% sodium bicarbonate, and water. Concentrate the organic layer under reduced pressure, The residue was further purified by column chromatography to obtain ethyl 4'-(1-acetoxyethyl)-4-biphenylcarboxylate (17-
1) 88.7 g (yield 98%) was obtained.

The (W-1'J20.of (64 mmol) obtained here is mixed with 0.1 M phosphate buffer (pH 7,5) 400- and Amanolipase I-PJ4f and stirred vigorously at 40-45 °C for 20 hours. After the reaction is completed, the reaction mixture is extracted with methyl isobutyl ketone 600-.

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 a developing solvent to obtain ethyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate ( V-1)7. Of[[α]D
185.5° (c=0.544, CHCl5), 9
8.1%ee, melting point 74.degree. 6.degree. C.] and unreacted ester 10.8F.

[V-1]1. obtained here. (1' (8.7 mmol) is dissolved in 80 ml of dimethylformamide and cooled to 10"C. Add 0.19f (4.8 mmol) of sodium hydride to this and keep warm at 80-85"C for 1 hour. Next, 1.0j' (4.8 mmol) of n-propyl tosylate is added at 20-25°C, and the mixture is reacted at 40°C for 5 hours.

After the reaction was completed, the reaction mixture was poured into water and 50% of ethyl acetate was added.
Extract with tnt. After washing the organic layer with water, it is concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain (t)-4'-(1-propoxyethyl)-4-
Ethyl biphenylcarboxylate (■-1) O, 87f (l
[5175%) was obtained. [[α]D+78.1° (c
=0,98 CHCIg ) ] The (■-1)O, 80f (8.2 mmol) obtained here is stirred with 10 f of methanol and 10 f of 10% caustic soda water at room temperature for 8 hours. After the reaction is complete, methanol is distilled off, the mixture is made weakly acidic with 5% hydrochloric acid, and extracted with 30% ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography using an acetic acid-toluene (1:10) mixture as a developing solvent to obtain (-1-) -4'-(1-propoxyethyl)-4-biphenylcarboxylic acid. (I-1)0
．． 70f (yield 96%) was obtained.

[[α] parable +84.2° (C = 0.82, CHC
Ig), m, p; 191.2°C] Example 2 [V-111,0f (8.7 mmol) obtained in Example 1
and 80tR1 of N-methylpyrrolidone.
0.19y of sodium hydride (4,
8 mmol).

After that, keep warm at 80-85"C for 1 hour. Next, add hexyl tosylate 1.28 F (4.8 mmol) at 15-85"C.
Add at 20"C. Then, react at 20-80°C for 2 hours and then at 40-50°C for 2 hours. After the reaction is complete,
The reaction mixture was poured into water and extracted with 60% of ethyl acetate. Hereinafter, after treatment according to Example 1, (g)-4'-
Ethyl (1-hexyloxyethyl)-4-biphenylcarboxylate (■-2) 1,09y (yield: 8B%) was obtained.

([α]D+64.5° (c=1.01, CHC
Ls), ] obtained here (■-2)l,0Of(2,8
mmol) in 10 ml of tetrahydrofuran and 10%
Mix with caustic potash lot and stir at room temperature for 8 hours. After the reaction is completed, tetrahydrofuran is distilled off.

After making the mixture weakly acidic with IN-sulfuric acid, extraction treatment was performed with 80 m of ethyl acetate, and the organic layer was concentrated under reduced pressure.

Hereinafter, (+)-4'-(1
0.90 g (yield: 98%) of -hexyloxyethyl)-4-biphenylcarboxylic acid (I-2) was obtained.

[[α]” + 71.8° (C=0.809,
CHCla), m, p, 154.1"C) Example 8 A solution consisting of [mer 1] 1.(1' (8.7 mmol) obtained in Example 1 and 80 wj of dimethylformamide was
”C, and add sodium hydride 0.19F (4
, 8 mmol) and kept at 30-35°C for 1 hour. Next, n-dodecyl tosylate 1.68 f (4,
8 mmol) at 20-25"C, 40-50"
React at C for 5 hours. After completion of the reaction, post-treatment was performed according to Example 1 to obtain ethyl (-1-)-4'-41-dodecyloxyethyl)-4-biphenylcarboxylate (■-3).
1.81F (yield 81%) was obtained.

[[α], +46.0' (c=0.99.CHCl
5)] 1.0f (2.28 mmol) of (■-3) obtained here was mixed with 10 m of methanol and 1 ml of 10% caustic soda water.
2y and stirred at room temperature for 8 hours. After the reaction is complete,
Methanol was distilled off, the mixture was made weakly acidic with 5% HC1 water, and extracted with 40% ethyl acetate. The organic layer was concentrated under reduced pressure, and the remaining liquid was purified by column chromatography in the same manner as in Example 1 to obtain (t)-4'-(1-dodecyloxyethyl)-4.
-Biphenylcarboxylic acid ()-8) 0.92F (yield 9
8%).

[[α]D+51.7° (C1=0.78, CH
Cl; js ), m, p, 70.5°C] Example 4 [V-111,0f (8.7 mmol) obtained in Example 1
is dissolved in a solution consisting of 20-dimethylformamide and 10-tetrahydrofuran and cooled to 10°C.

Add to this 0.19y (4.8 mmol) of sodium hydride.
and keep warm at 30-35"C for 1 hour.

Next, ω-ethoxypropyl tosylate 1.24F (4,
8 mmol) was added at 20-25°C and reacted at 50-60°C for 5 hours. After the reaction, post-treatment was carried out according to Example 1 to obtain ethyl (-F-)-4'-(1-ethoxypropoxyethyl)-4-biphenylcarboxylate (■-
4) O,95y (yield 72%) was obtained.

[[α]” +65.5° (C=0.978, CH
Cla)] [■-4]0.71F (2 mmol) obtained here was mixed with 24 f of 5% caustic soda water and stirred at room temperature for 15 hours. After the reaction is completed, the mixture is made weakly acidic with 10% HC1 water and extracted twice with 40% of ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography in the same manner as in Example 1 to obtain (t)-4'-(1-ethoxypropoxyethyl)-4-biphenylcarboxylic acid (1-4
) 0.68f (yield 96%) was obtained.

[[α]D +72.8° (C=0.97, CH
Clg)] To Example 5-9 Ethyl 4'-acetyl-4-biphenylcarboxylate 82
．． Reduction, acylation, asymmetric hydrolysis reaction, and post-treatment were carried out in the same manner as in Example 1, except that 87.2 y (0.12 mol) of pentyl 4'-acetyl-4-biphenylcarboxylate was used in place of 29. Pentyl [)-4'-(1-hydroxyethyl)-4-biphenylcarboxylate (V-5) was obtained.

[V-5] obtained here was subjected to alkylation and hydrolysis reactions and post-treatments in the same manner as in Example 1, and the results shown in Table 1 were obtained.

(Margin below)

Claims (6)

[Claims] (1) General formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is a halogen group having 1 to 20 carbon atoms. an optionally substituted alkyl group or represents an alkoxyalkyl group. *Not marked carbon atom) Optically active substituted biphenylcarboxylic acids represented by (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is an alkyl group or alkoxyalkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, and R' is a lower alkyl group. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, (R and *marks have the same meanings as above) A method for producing an optically active substituted biphenylcarboxylic acid represented by: (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' represents a lower alkyl group. The * mark is an asymmetric carbon atom) R -
'' indicates a lower alkyl group or an optionally substituted phenyl group) is condensed with an alkylating agent represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R, R' and * (marks have the same meanings as above) General formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R and *marks have the same meanings as above) A method for producing an optically active substituted biphenylcarboxylic acid. (4) Esters represented by the general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R' and R'' represent lower alkyl groups). A general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' has the same meaning as above. ※ mark is an asymmetric carbon An optically active alcohol represented by the general formula and X represents a halogen atom or -OSO_2R'''. Here, R'
'' indicates a lower alkyl group or an optionally substituted phenyl group) is condensed with an alkylating agent represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R, R' and * (marks have the same meanings as above) General formulas ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formulas, R and *marks have the same meanings as above) A method for producing optically active substituted biphenylcarboxylic acids. (5) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' represents a lower alkyl group) By reacting alcohols represented by lower alkyl carboxylic acids with general formula ▲ Numerical formulas, chemical formulas, etc. There are tables, etc. ▼ Esterase that has the ability to obtain esters represented by (wherein R' and R'' represent lower alkyl groups) and to hydrolyze either one of the optically active forms of the esters. Asymmetric hydrolysis using alcohols of the general formula R-X (wherein R represents an alkyl group or alkoxyalkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, and X represents a halogen atom or -OSO_2R ′”, where R′
'' indicates a lower alkyl group or an optionally substituted phenyl group) is condensed with an alkylating agent represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R, R' and * (marks have the same meanings as above) General formulas ▲Mathematical formulas, chemical formulas, tables, etc. are available that are characterized by obtaining optically active ether derivatives shown by and further hydrolyzing under alkaline conditions▼ (In the formulas, R and *marks have the same meanings as above) A method for producing optically active substituted biphenylcarboxylic acids. (6) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R' represents a lower alkyl group)By reducing the ketones represented by the following using a reducing agent, the general formula▲mathematical formula, chemical formula, etc. There are tables, etc. ▼ (In the formula, R' has the same meaning as above) Alcohols shown by are obtained, and this is reacted with lower alkyl carboxylic acids to form the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ ( In the formula, R' and R'' represent lower alkyl groups) are obtained, and subjected to asymmetric hydrolysis using an esterase capable of hydrolyzing either one of the optically active forms of the esters. By decomposition, we obtain optically active alcohols represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Then, the general formula R-X (wherein R represents an alkyl group or alkoxyalkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, and X represents a halogen atom or -OSO_2R'''. R'
'' indicates a lower alkyl group or an optionally substituted phenyl group) is condensed with an alkylating agent represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R, R' and * (marks have the same meanings as above) General formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formulas, (R and *marks have the same meanings as above) A method for producing an optically active substituted biphenylcarboxylic acid represented by: