JP2522012B2 - Optically active biphenyl derivative and method for producing the same - Google Patents

Description

The present invention relates to an optically active biphenyl derivative useful as an intermediate for organic electronic materials, particularly liquid crystal materials.

In recent years, attention has been paid to organic electronic materials, particularly liquid crystal materials, and particularly ferroelectric liquid crystal materials.

However, the development of an intermediate of a strongly inductive liquid crystal material having excellent characteristics such as high-speed response and memory property is not yet sufficient, and the development of the intermediate has been desired.

The present invention provides a novel and useful optically active biphenyl derivative suitable for the above purpose and a method for producing the same.

That is, the present invention has the general formula (I) (In the formula, R is a carbon atom which may contain a halogen atom.
~ 20 alkyl groups or alkoxyalkyl groups.
* Indicates an asymmetric carbon atom. ) Is an optically active biphenyl derivative and a method for producing the same.

The optically active biphenyl derivative represented by the general formula (I) of the present invention can be produced according to the following steps.

[First step] General formula (II) (Wherein A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom), and the ketone represented by the general formula (III) (Wherein A has the same meaning as described above) [Step 2] Reaction of alcohols of general formula (III) obtained in Step 1 with lower alkylcarboxylic acids Let General Formula (IV) (In the formula, A has the same meaning as described above, and R'represents a lower alkyl group). [Step 3] Step represented by the general formula (IV) obtained in Step 2 The ester is hydrolyzed with an esterase having the ability to hydrolyze one of the optically active isomers of the ester to give a compound represented by the general formula (V): (In the formula, A has the same meaning as described above, and * indicates an asymmetric carbon atom.) Step of obtaining optically active alcohol [4th step] Obtained in 3rd step An optically active alcohol represented by the general formula (V) can be prepared by converting the optically active alcohol represented by the general formula (VI) RX (VI) Represents an alkoxyalkyl group, X represents a halogen atom or —OSO ₂ R ″, wherein R ″ represents a lower alkyl group or an optionally substituted phenyl group). General formula (VII) (Wherein A, R and * have the same meanings as described above) [Step 5] Optical step represented by general formula (VII) obtained in Step 4 The active ethers are debenzylated to give the above-mentioned general formula (I)
In the step of obtaining an optically active biphenyl derivative represented by, each of the first to fifth steps, the second to fifth steps,
A method for producing an optically active biphenyl derivative represented by the general formula (I), which comprises the third to fifth steps, the fourth to fifth steps and the fifth step.

Hereinafter, the present invention will be described in more detail according to each step.

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

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

As such a reducing agent, sodium borohydride, lithium aluminum hydride or borohydride is preferably used, and the amount used is at least 1 equivalent or more with respect to the starting ketones (II), and usually 1 to 10 It is in the equivalent range.

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

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

From the reaction mixture thus obtained, an alcohol (II) is obtained by operations such as liquid separation, concentration, distillation, and crystallization.
Although I) can be obtained in good yield, alcohols (III) are not necessarily required to obtain esters (IV) in the next step.
Is not required to be isolated, and the reaction mixture may be directly used in the next step.

The reaction to obtain the ester (IV) from the alcohol (III) (second step) is carried out by reacting the alcohol (III) with a lower alkylcarboxylic acid to acylate.

In this acylation, as the lower alkylcarboxylic acid, a lower alkylcarboxylic acid, an acid anhydride or acid halide of a lower alkylcarboxylic acid is used, and specifically, acetic acid, acetic anhydride, acetic acid chloride or bromide, propionic acid, propionic anhydride. Acid, propionyl chloride or bromide, butyric acid, butyryl chloride or bromide,
Examples include valeyl chloride or bromide.

In this reaction, the amount of the lower alkyl carboxylic acid to be used is at least 1 equivalent to the alcohol (III), and the upper limit is not particularly limited, but is preferably 4 or less.
It is equivalent.

This reaction is performed by using a catalyst in the presence or absence of a solvent.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether,
Acetone, methyl ethyl ketone, toluene, benzene,
Chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, hexane and other aliphatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like are used alone or as a mixture of solvents inert to the reaction. The amount used is not particularly limited.

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

The amount of the catalyst used varies depending on the type of the acid anhydride or acid halide of the lower alkylcarboxylic acid used, the combination of the catalysts used, and the like, and is not necessarily specified, but for example, when an acid halide is used, the acid It is 1 equivalent or more with respect to the halide.

When a lower alkylcarboxylic acid is used as the lower alkylcarboxylic acid, it can be acylated by dehydration condensation of the alcohol (III) and the carboxylic acid in the presence of a condensing agent.

As the condensing agent, a carbodiimide such as N, N'-dicyclohexylcarbodiimide or N-cyclohexyl-N '-(4-diethylamino) cyclohexylcarbodiimide is used, and if necessary, an organic base such as 4-pyrrolidinopyridine, pyridine or triethylamine is used. Used together.

The amount of condensing agent used is 1 with respect to the lower alkylcarboxylic acid.
~ 1.2 equivalent times, the amount of base used is 0.0 to the condensing agent
It is 1 to 0.2 equivalent times.

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

The reaction time is not particularly limited, and alcohols (II
The point at which I) disappears from the reaction system can be regarded as the reaction end point.

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

Esters (IV) to optically active alcohols (V)
In the reaction (third step) for obtaining the compound (1), one of the optically active esters is hydrolyzed using an esterase having the ability to hydrolyze one of the optically active esters (asymmetric hydrolysis). ) Is done by.

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

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

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

Cultivation of the above-mentioned microorganisms is usually carried out according to a conventional method, and for example, liquid culture can be carried out to obtain a culture solution.

For example, a sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts (5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract dissolved in 1 water, pH
6.5), and for bacteria, a broth containing sugar (10 g of glucose, 5 g of peptone, 5 g of meat extract, 3 g of Nacl are dissolved in 1 of water to have a pH of 7.2)] and inoculated with the microorganisms, and usually 20 to 40
The culture may be performed by reciprocal shaking culture at ℃ for 1 to 3 days, and if necessary, solid culture may be performed.

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

Pseudomonas lipase [Lipase P (manufactured by Amano Pharmaceuticals)] Aspergillus lipase [lipase AP (manufactured by Amano Pharmaceuticals)], Mucor lipase [lipase M-AP (manufactured by Amano Pharmaceuticals)], lipase of Candida syrindasse [ Lipase MY (manufactured by Meito Sangyo)], lipase of Alcaligenes genus [Lipase PL (manufactured by Meito Sangyo)], lipase of Achromobacter [lipase AL (manufactured by Meito Sangyo]], lipase of Arthrobacter (new Nihon Kagaku), Chromobacterium lipase (Toyo Brewing), Rhizopus derema lipase [Talipase (Tanabe Seiyaku)], Rhizobus lipase [Lipase Saiken (Osaka Bacterial Research Institute)].

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

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

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

The asymmetric hydrolysis reaction is usually carried out by vigorously stirring a mixture of the raw material 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 10 to 70 hours, but is not limited thereto.

After completion of the hydrolysis reaction, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, or the like, and the solvent is distilled off from the organic layer, and the concentrated residue is subjected to column chromatography. Optically active alcohols (V) as hydrolysis products and optically active esters as hydrolysis residues [optically active compounds in raw material esters (IV) which were not hydrolyzed] Can be separated.

The optically active esters obtained here may be further hydrolyzed, if necessary, to be enantiomers of the optically active alcohols (V) previously obtained.

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

Also, during this hydrolysis, in addition to the buffer solution, toluene,
It is also possible to use an organic solvent inert to the reaction such as chloroform, methyl isobutyl ketone, or dichloromethane.
By using these, asymmetric hydrolysis can be advantageously performed.

The reaction for obtaining the optically active ethers (VII) from the optically active alcohols (V) (4th step) is performed by reacting the optically active alcohols (V) with an alkylating agent (VI).

This reaction is usually carried out in the presence of a basic substance, and as the basic substance, alkali metal hydrides such as sodium hydride and potassium hydride, and alkali hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide. Metal or alkaline earth metal hydroxide, sodium carbonate,
Examples thereof include alkali metal carbonates such as potassium carbonate, butyllithium, and the like, and alkali metals such as lithium, sodium, potassium, and the like.

The basic substance needs to be 1 equivalent or more with respect to the optically active alcohol (V), and the upper limit is not particularly limited, but it is preferably in the range of 1 to 5 equivalents.

The alkylating agent (VI) used in this reaction is a chloride, bromide, iodo or the like having an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms which may include a halogen atom as exemplified below. And halides thereof (methanesulfonic acid ester, ethanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc.). The above alkylating agent can be easily produced from the corresponding alcohol, if necessary.

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxy. Butyl, methoxypentyl, methoxyhexyl, methoxyheptyl, methoxyoctyl, methoxynonyl, methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyheptyl, ethoxyoctyl, ethoxynonyl, ethoxydecyl, Propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhex Le, propoxy octyl, propoxy decyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, Butokishipenchiru, Butokishihekishiru, Butokishihepuchiru, Butokishinoniru,
Pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyoctyl, pentyloxydecyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl,
Hexylhexylpentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, heptyloxymethyl, heptyloxyethyl, heptyloxypropyl, heptyloxypentyl, octyloxymethyl, octyloxyethyl, decyloxymethyl, decyl Oxyethyl, decyloxypropyl, 2-trihalomethylpentyl, 2-trihalomethylhexyl, 2-trihalomethylheptyl,
2-halopropyl, 3-halo-2-methylpropyl, 2,
3-dihalopropyl, 2-halobutyl, 3-halobutyl, 2,3-dihalobutyl, 2,4-dihalobutyl, 3,4-dihalobutyl, 2-halo-3-methylbutyl, 2-halo-
3,3-dimethylbutyl, 2-halopentyl, 3-halopentyl, 4-halopentyl, 2,4-dihalopentyl, 2,5
-Dihalopentyl, 2-halo-3-methylpentyl, 2
-Halo-4-methylpentyl, 2-halo-3-monohalomethyl-4-methylpentyl, 2-halohexyl, 3-
Halohexyl, 4-halohexyl, 5-halohexyl,
2-haloheptyl and 2-halooctyl (however, halo in the above alkyl group represents fluorine, chlorine, bromine or iodine).

The alkyl group or alkoxyalkyl group exemplified above may be an optically active group.

The above-mentioned alkylating agent having an optically active group is easily produced from the corresponding optically active alcohol, and some of the optically active alcohols are obtained by asymmetric reduction of the corresponding ketone. Some can also be derived from optically active amino acids and optically active oxyacids that occur naturally or are obtained by resolution, such as:

Valine, leucine, isoleucine, phenylalanine, threonine, arosreonine, homoserine, alloisoleucine, tert-leucine, 2-aminobutyric acid, norvaline, norleucine, ornithine, lysine, hydroxylysine, phenylglycine, aspartic acid, glutamic acid, mandelic acid, tropa Acid, 3-hydroxybutyric acid, malic acid, tartaric acid, isopropylmalic acid and the like.

The alkylating agent (VI) may be used in an amount of 1 equivalent or more relative to the optically active alcohol (V), but is usually in the range of 1 to 5 equivalents.

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

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

After completion of the reaction, usual separation means such as extraction, liquid separation,
An optically active ether (VII) can be obtained in good yield by an operation such as concentration, which can be purified by column chromatography, recrystallization or the like, if necessary. It can be used as it is.

Reaction for obtaining desired optically active biphenyl derivative (I) from optically active ethers (VII) (step 5)
Usually, the optically active ethers (VII) are catalytically hydrogenated with hydrogen in the presence of a hydrogenation catalyst to debenzylate.

In this debenzylation reaction, a palladium-based metal catalyst is preferably used as the hydrogenation catalyst, and specific examples thereof include palladium-carbon, palladium oxide, palladium black, palladium chloride and the like.

The amount of the catalyst used is determined by the amount of the optically active ether (VI
I) Usually 0.001 to 0.5 times by weight, preferably 0.005 to
The range is 0.3 times by weight. The reaction is usually performed in a solvent,
Examples of the solvent include water, dioxane, tetrahydrofuran, methanol, ethanol, n-propyl alcohol, acetone, dimethylformamide, toluene, dichloromethane, aliphatic hydrocarbons such as ethyl acetate, aromatic hydrocarbons, alcohols, ethers, ketones, esters, and the like. A single or mixture of solvents inert to the reaction such as halogenated hydrocarbons is used.

This reaction is carried out under normal or elevated hydrogen pressure, and the amount of absorbed hydrogen is the optically active ether (VII) as a raw material.
It is preferable to set the reaction end point when the amount becomes 1 to 1.2 equivalent times with respect to.

The reaction temperature ranges from -10C to 100C, preferably from 10C to 60C.

After completion of the reaction, the desired optically active biphenyl derivative (I) can be obtained by a method such as removing the catalyst from the reaction mixture by filtration and then concentrating it. It can be purified by chromatography or the like.

Thus, according to the method of the present invention, an optically active biphenyl derivative represented by the general formula (I), which is a novel compound, can be industrially advantageously produced, and the derivative is an organic electronic material, particularly a material for liquid crystals. Above all, for example (In the formula, R ₁ represents an alkyl group or an alkoxyl group, Ar represents an aromatic group, R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms which may include a halogen atom, (Indicated by an asymmetric carbon atom) is useful as an intermediate for a ferroelectric liquid crystal material such as (1), and can also be used as an intermediate for agricultural chemicals, pharmaceuticals, and the like.

 Hereinafter, the present invention will be described with reference to examples.

Example 1 4-benzyloxy-4'-acetyl-biphenyl 120.9 g (0. 0) in a 4-necked flask equipped with a stirrer and a thermometer.
4 mol), tetrahydrofuran 400 ml and methanol 10
0 ml was charged, and 15.14 g (0.4 mol) of sodium borohydride was added thereto at 15 to 25 ° C. over 2 hours. After incubating at the same temperature for 5 hours, pour into ice water and add chloroform 50
Extract twice with 0 ml. The organic layer was concentrated under reduced pressure to 4-
117.4 g (yield 96.5%) of benzyloxy-4 '-(1-hydroxyethyl) -biphenyl (III-1) was obtained.

Next, 91.25 g (0.3 mol) of (III-1) obtained here was dissolved in a mixed solution of 400 ml of toluene and 100 ml of pyridine, and 25.91 g (0.33 mol) of acetyl chloride was added thereto at 15 to 20 ° C for 2 hours. Need to add. Thereafter, it is kept at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After the reaction is complete, cool to 10 ° C or below and add water 30
Add 0 ml. The separated organic layer is 2N-hydrochloric acid water, water, 5%
Wash sequentially with sodium carbonate and water, then concentrate under reduced pressure.
After further purification by column chromatography, 4-benzyloxy-4 '-(1-acetoxyethyl) -biphenyl (IV-
1) 101.57 g (yield 97.8%) was obtained.

Then 86.55 g (0.25 mol) of (IV-1) obtained above is vigorously stirred with 2,000 ml of 0.3M phosphate buffer (pH 7.5) and 50 g of amanolipase "P" at 40 to 45 ° C for 120 hours.
After completion of the reaction, the reaction mixture was extracted with 1,000 ml of chloroform, the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a toluene: ethyl acetate (5: 2) mixed solution as a developing solvent. -4-benzyloxy-4'-
(1-Hydroxyethyl) -biphenyl (V-1) 28.9
g (38% yield) [[α] ▲ ²⁰ _D ▼ + 34.8 ° (c = 1, CHCl
₃ ), melting point 158-159 ° C] and 50.17 g of unreacted ester.

Next, a solution of 4.56 g (0.015 mol) of [V-1] obtained here and 40 ml of dimethylformamide was cooled to 10 ° C, 0.47 g (0.0196 mol) of sodium hydride was added, and the mixture was stirred at 30 to 35 ° C for 1 hour.
Insulate for hours. Next, n-propyl tosylate 4.82 g (0.0
225 mol) is added at 20 to 25 ° C, and the mixture is reacted at 30 to 40 ° C for 5 hours. After completion of the reaction, the reaction mixture is poured into ice and extracted with 200 ml of chloroform. After washing the organic layer with water,
Concentrate under reduced pressure. The concentrated residue was purified by column chromatography, and (+)-4-benzyloxy-4'-
(1-propoxyethyl) -biphenyl (VII-1) 4.91 g
(Yield 94.5%) was obtained. [[Α] ▲ ²⁰ _D ▼ + 73.7 ° (c
= 1, CHCl ₃ ), melting point 106-108 ° C.] Next, 3.46 g of (VII-1) obtained here was mixed with 20 ml of methanol and 0.3 g of 5% Pd-carbon, and under a hydrogen atmosphere at atmospheric pressure. Contact hydrogenation. When the amount of absorbed hydrogen reaches 240 ml, stop the reaction and remove the catalyst separately. The liquid was concentrated, and the residue was purified by column chromatography using a toluene-ethyl acetate (5: 2) mixed liquid as a developing solvent to obtain (+)-4-.
2.43 g (yield 94.8%) of hydroxy-4 '-(1-propoxyethyl) -biphenyl was obtained. [[Α] ▲ ²⁰ _D ▼ +9
4.5 ° (c = 1, CHCl ₃ ), melting point 123 to 125 ° C.] Example 2 4.56 g (0.015 mol) of [V-1] obtained in Example 1 and N-
A solution of 80 ml of methylpyrrolidone is cooled to 5 ° C. and 0.72 g (0.03 mol) of sodium hydride are added thereto. After that, the temperature is kept at 30 to 35 ° C for 1 hour.

Next, 5.32 g (0.0375 mol) of methyl iodide is added at 15 to 20 ° C, and the mixture is reacted at 20 to 30 ° C for 2 hours and further at 40 to 50 ° C for 2 hours. After completion of the reaction, the reaction mixture is poured on ice and extracted with 50 ml of ethyl acetate. Then, purification treatment is carried out according to Example 1 to obtain (+)-4-benzyloxy-4 ′-(1-
Methoxyethyl) biphenyl (VII-2) 4.61 g (yield 96.5
%) Was obtained. [[Α] ▲ ²⁰ _D ▼ + 77.3 ° (c = 1, CHC
l ₃ ), melting point 97-98 ° C.] Next, 3.18 g (0.01 mol) of (VII-2) obtained here was mixed with 15 ml of tetrahydrofuran and 0.3 g of 5% Pd-carbon, and under a hydrogen atmosphere at normal pressure. Contact hydrogenation. Hydrogen absorption capacity is 240m
Stop the reaction at l and remove the catalyst separately. The liquid was concentrated, and the residue was further purified by column chromatography to obtain (+)-4-hydroxy-4 ′-(1-methoxyethyl) biphenyl (2.2 g, yield 96.7%).

[[Α] ▲ ²⁰ _D ▼ + 104.1 ° (c = 1, CHCl ₃ ), melting point 174
˜175 ° C.) Example 3 A solution of 4.56 g (0.015 mol) of [V-1] obtained in Example 1 and 40 ml of dimethylformamide was cooled to 10 ° C.
To this, 0.47 g (0.0196 mol) of sodium hydride was added, and 3
Incubate at 0-35 ° C for 1 hour. After that, 5.76 g (0.0225 mol) of n-hexyl tosylate is added, and the mixture is reacted at 40 to 45 ° C for 5 hours. After completion of the reaction, post-treatment was carried out according to Example 1 to obtain 5.5 g of (+)-4-benzyloxy-4 '-(1-n-hexyloxyethyl) biphenyl (VII-3) (yield 94.
4%). [[Α] ▲ ²⁰ _D ▼ + 37.8 ° (c = 1, CHCl
₃ ), melting point 61-63 ° C.] Next, 3.88 g (0.01 mol) of (VII-3) obtained here was added to 10 ml of tetrahydrofuran, 15 ml of methanol and 5% Pd-carbon.
Mix with 0.3 g and contact hydrogenate under hydrogen atmosphere at atmospheric pressure.
When the hydrogen absorption is 240 ml, stop the reaction and remove the catalyst separately. The liquid was concentrated, and the residue was purified by column chromatography to obtain (+)-4-hydroxy-4 '-(1-n-hexyloxyethyl) biphenyl 2.83 g (yield 94.8%).

[[Α] ▲ ²⁰ _D ▼ + 32.8 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼
1.5506] Examples 4 to 5 Reactions and post-treatments were conducted according to Example 3 except that n-hexyl tosylate was replaced with the alkylating agent shown in Table 1,
The results shown in the table were obtained.

Example 6 A 4-necked flask equipped with a stirrer and a thermometer was charged with 134.6 g (0.4 mol) of 4-acetyl-4 '-(4-chlorobenzyl) oxybiphenyl, 100 ml of methanol and 400 ml of tetrahydrofuran, and the temperature was 15 to 25 ° C. Sodium borohydride (15.1 g, 0.4 mol) is added over 2 hours.

After incubating at the same temperature for 25 hours, pour the reaction mixture into ice water,
Extract twice with 500 ml of chloroform. The organic layer is washed with water and then concentrated under reduced pressure to give 4- (1-hydroxyethyl).
-4 '-(4-chlorobenzyl) oxybiphenyl (II
I-6) 135.1 g (yield 100%) was obtained. Melting point 170.5 to 172 ° C. Next, 101.5 g (0.3 mol) of (III-6) obtained here was dissolved in a mixed solution of 400 ml of toluene and 100 ml of pyridine, and 25.9 g (0.33 mol) of acetyl chloride was added to this to 15 to 20 Add over 2 hours at ° C. Then, at the same temperature for 1 hour, 40-50 ℃
Keep it warm for 2 hours. After the reaction is complete, cool to 10 ° C or below and
Add 300 ml. The separated organic layer was mixed with 2N-hydrochloric acid water, water, 5
% Sodium carbonate and water successively and then concentrated under reduced pressure to give 4- (1-acetoxyethyl) -4 '-(4-chlorobenzyl) oxybiphenyl (IV-6) 101.6 g (yield 9
7.8%).

Next, 15.1 g (0.04 mol) of (IV-6) obtained above was vigorously mixed with 0.5 L of 0.3 M phosphate buffer (pH 7.5) and 5 g of lipase (Amano “P”) at 40 to 45 ° C. for 5 days. Stir. After the reaction was completed, the reaction mixture was extracted with 0.5 l of chloroform, the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography with a toluene: ethyl acetate system (+).
5.8 g of -4- (1-hydroxyethyl) -4 '-(4-chlorobenzyl) oxybiphenyl (V-6) (yield 42.5
%) [[Α] ^-20 _D ▼ + 30.2 ° (c = 1, chloroform), melting point 165-167 ° C].

Then, a solution of 1.35 g (4 mmol) of (V-6) obtained here and 20 ml of dimethylformamide was cooled to 10 to 15 ° C,
Add sodium hydride 0.2g (5mmol), 30-40 ℃
Keep it warm for 1 hour. Next, 2.0 g (5 mmol) of n-hexadecyl tosylate is added and the reaction is carried out for 3 hours. After completion of the reaction, the reaction mixture is poured into ice and extracted with 300 ml of toluene. The organic layer is washed with water and then concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (toluene; hexane system), and (+)-4- (1-hexadecyloxyethyl) -4 '-(p-chlorobenzyl) oxybiphenyl (VII-6) 2.07. g (yield 92%) was obtained. [[Α] ▲ ²⁰ _D ▼ + 19.8 ° (c = 1, chloroform), melting point 22-30 ° C.] Next, 1.0 g (0.0018 mol) of (VII-6) was added to 10 ml of tetrahydrofuran, 15 ml of methanol and 5% Pd. -Mix with 0.1 g of carbon and hydrogenate by contact under hydrogen atmosphere at atmospheric pressure. When the hydrogen absorption amount or the equivalent point is reached, the reaction is stopped, the catalyst is separated, the liquid is concentrated, and the concentrated residue is purified by column chromatography to obtain (+)-4-hydroxy-4 '-(1-n- Hexadecyloxyethyl) biphenyl (I-6) 0.68g
(87% yield).

[[Α] ▲ ²⁰ _D ▼ + 25.1 ° (c = 1, CHCl ₃ ) ▲ n ²⁰ _D ▼ 1.5398 Examples 7 to 8 Using (V-6) obtained in Example 6 as a starting material, n-hexadecyl The reaction and post-treatment were carried out according to Example 6 except that the tosylate was replaced with the alkylating agent shown in Table 2, and the results shown in Table 2 were obtained.

Example 9 A reaction was performed in the same manner as in Example 1 except that 4- (4-methylbenzyloxy) -4'-acetylbiphenyl was used instead of 4-benzyloxy-4'-acetylbiphenyl.
By carrying out post-treatment and purification, (+)-4-hydroxy-4 '-(1-propoxyethyl) biphenyl can be obtained.

Example 10 The reaction, post-treatment and purification were performed in the same manner as in Example 1 except that 4- (4-methoxybenzyloxy) -4'-acetylbiphenyl was used instead of 4-benzyloxy-4'-acetylbiphenyl. If carried out, (+)-4-hydroxy-4 '-(1-propoxyethyl) biphenyl can be obtained.

Example 11 Unreacted ester (-)-4-benzyloxy-4 '-(1-acetoxyethyl) biphenyl obtained in Example 1.
45 g (0.01 mol) are stirred in a mixed solution of 50 ml of methanol and 25 ml of 20% sodium hydroxide solution at 30-40 ° C. for 2 hours. After completion of the reaction, 200 ml of water is added to the reaction solution, 4N-hydrochloric acid is added to adjust the pH to 4, and extraction is performed with 500 ml of ether. The organic layer is washed with water and then concentrated under reduced pressure to give a white solid.
3.0 g (yield 99%) of (-)-4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl was obtained. this house
1.22 g (4 mmol) was reacted and worked up in the same manner as in Example 8 to give (−)-4-hydroxy-4 ′-{1- (2s
-Methylbutyloxy) ethyl} biphenyl (I-11) 0.
47 g (yield 91%) was obtained.

▲ n ²⁰ _D ▼ = 1.5479, [α] ▲ ²⁰ _D ▼ ＝ −60.0 ° (c =
1, CHCl ₃ ) Example 12 4-benzyloxy-4 ′ obtained in Example 1
-(1-Hydroxyethyl) biphenyl 9.1 g (0.03 mol) was dissolved in dichloromethane 100 ml, and acetic acid 2.4 g (0.04 mol).
Mol), 4-pyrrolidinopyridine (0.2 g) and N, N'-dicyclohexylcarbodiimide (7.1 g, 0.035 mol), and the mixture is stirred at 30 to 35 ° C for one day. After completion of the reaction, the white solid produced was separated, and the organic layer was separated from the mixture with water, 5% acetic acid water, water,
Wash with 5% aqueous sodium hydrogen carbonate and dry over anhydrous magnesium sulfate. After that, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-benzyloxy-4 ′-(1-atosexiethyl) biphenyl (IV-
1) 9.4 g (yield 91%) was obtained. After that, the reaction and the post-treatment were sequentially performed in the same manner as in Example 1 to obtain (+)-4-
Hydroxy-4 '-(1-propoxyethyl) biphenyl can be obtained.

Example 13 The reaction and post-treatment were carried out in the same manner as in Example 3 except that 6.5 g (0.0225 mol) of (s) -2-fluoroheptyl silate was used instead of n-hexyl tosylate, and (+)-4-benzyloxy- 5.6 g of 4 '-{1- (2 (s) -fluoroheptyloxy) ethyl} biphenyl (VII-13) was obtained.

4.2 g of this (VII-13) was debenzylated according to Example 3 and similarly post-treated to give (+)-4-hydroxy-4'-
{1- (2 (s) -fluoroheptyloxy) ethyl}
Biphenyl (3.0 g, yield 91%) was obtained.

▲ n ²⁰ _D ▼ 1.5883 [[α] ▲ ²⁰ _D ▼ + 33.8 ° (c = 1, CHCl ₃ )

Claims (6)

(57) [Claims] 1. A general formula (In the formula, R is a carbon atom which may contain a halogen atom.
~ 20 alkyl groups or alkoxyalkyl groups.
* Indicates an asymmetric carbon atom. ) An optically active biphenyl derivative represented by: 2. General formula (In the formula, R is a carbon atom which may contain a halogen atom.
To 20 alkyl groups or alkoxyalkyl groups, and A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. * Indicates an asymmetric carbon atom. ) Debenzylation of optically active ethers represented by (In the formula, R and * have the same meanings as described above.) A method for producing an optically active biphenyl derivative represented by 3. General formula (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. * Indicates an asymmetric carbon atom.) And an optically active alcohol represented by the general formula R- X (in the formula, R is a carbon atom which may include a halogen atom 1
To 20 alkyl groups or alkoxyalkyl groups, X represents a halogen atom or —OSO ₂ R ″, where R ″ represents a lower alkyl group or an optionally substituted phenyl group. ) Is condensed with an alkylating agent represented by (In the formula, R, A and * have the same meanings as described above.) The method for producing an optically active biphenyl derivative according to claim 2, wherein the optically active ethers represented by 4. A general formula (Wherein A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom, and R'represents a lower alkyl group), and any one of the optically active forms of the esters can be used. Asymmetric hydrolysis using an esterase that has the ability to hydrolyze one (In the formula, A has the same meaning as described above, and * indicates an asymmetric carbon atom.) The optically active biphenyl derivative according to claim 3, which is an optically active alcohol represented by the formula: Manufacturing method. 5. A general formula (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom.) An alcohol represented by the general formula is reacted with a lower alkylcarboxylic acid. (In the formula, A has the same meaning as described above, and R'represents a lower alkyl group.) The method for producing an optically active biphenyl derivative according to claim 4, wherein an ester is obtained. 6. A general formula (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom.) The method for producing an optically active biphenyl derivative according to claim 5, wherein the alcohols represented by the formula (A has the same meaning as described above) are obtained.