JP2560458B2 - Optically active biphenyl carbinol and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to an optically active biphenylcarbinol useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., or an intermediate for liquid crystal material additives.

<Prior Art> The optically active biphenylcarbinol of the present invention is a novel compound that has not been described in the literature, and was first discovered by the present inventors.

Therefore, not only the specific physical properties of the carbinol but also its usefulness have not been known at all.

<Problems to be Solved by the Invention> The present invention provides the above-mentioned optically active biphenylcarbinol, a method for producing the same, and cyanobiphenyl esters which are intermediates thereof.

<Means for Solving the Problems> That is, the present invention provides a compound of formula (I) (In the formula, * indicates an asymmetric carbon atom.) The optically active biphenylcarbinol represented by the formula and a method for producing the same.

Furthermore, the intermediate of the general formula (II) (In the formula, R represents a lower alkyl group.).

 Hereinafter, the present invention will be described in detail.

The above-mentioned optically active biphenylcarbinol (I) is
By subjecting the cyanobiphenyl ester represented by the general formula (II) to esterase to effect asymmetric hydrolysis, it can be easily produced at high optical purity at low cost.

Furthermore, in the above-mentioned asymmetric hydrolysis, the general formula (IV) obtained as an asymmetric hydrolysis residue is obtained. (In the formula, R represents a lower alkyl group, and the * mark represents an asymmetric carbon atom.) It can also be produced by hydrolyzing an optically active cyanobiphenyl ester.

Examples of the cyanobiphenyl esters (II) include the following compounds.

4- (1-acetoxyethyl) -4'-cyanobiphenyl, 4- (1-pyropionyloxyethyl) -4'-
Cyanobiphenyl, 4- (1-butyryloxyethyl)
-4'-cyanobiphenyl, 4- (1-pentylyloxyethyl) -4'-cyanobiphenyl, 4- (1-hexyloxyethyl) -4'-cyanobiphenyl, 4-
(1-Heptyryloxyethyl) -4'-cyanobiphenyl.

The asymmetric hydrolysis of cyanobiphenyl esters represented by the general formula (II) is caused by the action of an esterase produced by a microorganism or an esterase derived from animals and plants to produce a raw material (II
It is carried out by hydrolyzing either one of the optically active substances of I).

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

The esterase-producing microorganism used in this reaction may be any esterase-producing microorganism having the ability to asymmetrically hydrolyze the esters (II),
It is not particularly limited.

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

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

For example, sterilized liquid medium [for molds and yeasts, malt extract / yeast extract medium (dissolve 5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in 1 water, p
H6.5), and for bacteria, a broth containing sugar (broth 1 g, 5 g of peptone, 10 g of glucose, 5 g of meat extract, 3 g of NaCl dissolved in water 1 to have a pH of 7.2)] with a microorganism, usually 20 to 40
The culture is performed by performing reciprocal shaking culture at 1 ° C. for 1 to 3 days, and solid culture may be performed if necessary.

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

Pseudomonas lipase [Lipase P (Amano Pharmaceutical)], Aspergillus lipase [Lipase AP (Amano Pharmaceutical)], Mucor lipase [Lipase MAP]
(Manufactured by Amano Pharmaceuticals)], lipase of Candida cylindrasse [lipase MY (manufactured by each sugar industry)], lipase of genus Alcaligenes [lipase PL (manufactured by each sugar industry)], lipase of genus Achromobacter [lipase AL (each sugar) Industrial)],
Arthrobacter lipase (Nippon Kagaku), Chromobacterium lipase (Toyo Brewing), Rhizopus derema lipase (Taripase (Tanabe Seiyaku)),
Rhizopus 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, and the form of use is a purified enzyme, a crude enzyme, an enzyme-containing substance, a microorganism culture solution, a culture, a cell, a culture solution. In addition, they can be used in various forms, such as those obtained by treating them, as needed, and enzymes and microorganisms can be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

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

As the buffer solution, sodium phosphate which is usually used,
A buffer solution of an inorganic acid salt such as potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate and sodium citrate, etc. is used, and the pH thereof is 8 to 11 in a culture solution of an alkaliphilic bacterium or alkaline esterase, A pH of 5 to 8 is preferable for a culture solution of a non-alkaline microorganism or an esterase having no alkali resistance. The concentration is usually 0.05 to 2M, preferably 0.05 to 0.5M.

The reaction temperature is usually 10 to 60 ° C., and the reaction time is generally 3 to 70 hours, but is not limited thereto.

After completion of such hydrolysis reaction, the hydrolysis reaction solution is subjected to extraction treatment with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc., the solvent is distilled off from the organic layer, and the concentrated residue is treated with column chromatography. And the like, and an optically active biphenylcarbinol (I) which is a hydrolysis product and an optically active cyanobiphenyl ester (IV) which is a hydrolysis residue [of the optically active substance in the raw material cyanobiphenyl ester (II)] Which have not been hydrolyzed] can be separated.

Optically active cyanobiphenyl esters (IV) above
Can be hydrolyzed chemically to give an antipodal carbinol (I) with the optically active biphenylcarbinol obtained above.

This hydrolysis reaction is usually carried out in the presence of water in the presence of an acid or an alkali, but it is preferable to allow an alkali to coexist.

As the alkali used here, sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate,
Examples thereof include organic and inorganic bases such as 1,8-diazabicyclo [5,4,0] 7-undecene.

The amount of such alkali used is as described below.

It is at least 1-fold mol or more, preferably 10-fold mol or less, with respect to the raw material compound (IV). Of course, more than this amount can be used. These are usually used together with a solvent, and examples of such a solvent include the following.

Aliphatic or aromatic hydrocarbons such as water, methanol, ethanol, propanol, acetone, methyl ethyl ketone, chloroform, dichloromethane, toluene, xylene, hexane, heptane, ethyl ether, tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, ether, Solvents such as alcohols, ketones, amides and halogenated hydrocarbons which are inert to the reaction are used alone or as a mixture, and the amount thereof is not particularly limited.

The reaction temperature is usually -20 ° C to 100 ° C, preferably -10 ° C to 80 ° C.

The reaction time is not particularly limited. After completion of the reaction, the optically active biphenylcarbinol represented by the general formula (I) can be obtained in good yield by a usual separation means such as extraction, liquid separation, concentration, etc., which is further purified by column chromatography etc. if necessary. can do.

Cyanobiphenyl esters (II) can be produced by acylating biphenyl carbinol (dl-form corresponding to optically active biphenyl carbinol) with lower aliphatic carboxylic acids.

In this acylation reaction, examples of the lower aliphatic carboxylic acids include acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, and acid anhydrides of heptanoic acid, acid chlorides or acid bromides, and the like.

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

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether,
Acetone, methyl ethyl ketone, toluene, benzene,
Chlorbenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane and other aliphatic or aromatic hydrocarbons, ethers, ketones, halogenated hydrocarbons, aprotic polar solvents, etc. They may be used alone or in a mixture.
The amount used can be used without particular limitation.

The lower aliphatic carboxylic acid used in the reaction needs to be 1 equivalent or more with respect to the starting material, biphenylcarbinol (III), and the upper limit is not particularly limited, but it is preferably 4 equivalents.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine,
Examples thereof include organic or inorganic basic substances such as picoline, imidazole, sodium carbonate, sodium methylate, potassium hydrogen carbonate and the like.

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

When using such a catalyst, for example, when an acid halide is used as an acylating agent, pyridine and triethylamine are particularly preferably used.

The amount of the catalyst used varies depending on the combination of the type of acylating agent and the catalyst used, and cannot be specified.
For example, when an acid halide is used as the acylating agent, it is used in an amount of 1 equivalent or more based on the acid halide.

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

The reaction time is not particularly limited, and the time point at which the raw material biphenylcarbinol (III) disappears can be the end point of the reaction.

After completion of the reaction, usual separation means such as extraction, liquid separation,
Cyanobiphenyl esters (II) by operations such as concentration
Can be obtained in good yield, and can be purified by column chromatography or the like if necessary.

The starting material biphenylcarbinol (III) is
It can be easily produced by reducing 4-acetyl-4′-cyanobiphenyl with a reducing agent such as sodium borohydride as shown in the following formula.

<Effect of the Invention> Thus, according to the present invention, the optically active biphenylcarbinol represented by the formula (I) is industrially advantageously obtained, and the carbinol is etherified or esterified to add a liquid crystal material. It can be an agent.

<Example> Hereinafter, the present invention will be described with reference to Examples.

Reference Example 1 4-acetyl-4'-cyanobiphenyl 44.2 g (0.2 mol), tetrahydrofuran 200 ml and methanol 100 ml
Then, at room temperature, sodium borohydride (5.7 g, 0.15
Mol) over 2 hours.

Stir at the same temperature for 3 hours. After completion of the reaction, the reaction solution is poured into 500 ml of ice water and extracted twice with 300 ml of ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. If the solvent is distilled off under reduced pressure, 4- (1-hydroxyethyl) -4 '
42.9 g of cyanobiphenyl (96% yield) are obtained.

Melting point 151 ° C. Example 1 4- (1-hydroxyethyl) -4′-cyanobiphenyl 22.3 g (0.1 mol), pyridine 20 ml, toluene 60 ml were added, and acetyl chloride 9.4 g (0.12 mol) was added at 0 to 10 ° C. Add. Stirring is continued for 1 hour at the same temperature and for 3 hours at 25 to 30 ° C. After completion of the reaction, the reaction solution was treated with 5% hydrochloric acid water,
Wash sequentially with 5% sodium carbonate and water. The organic layer was concentrated under reduced pressure, and the concentrated residue was toluene-ethyl acetate (40:
Purify by chromatography in 1). 2-4.9 g of 4- (1-acetoxyethyl) -4'-cyanobiphenyl (II-1) (yield 9
4%).

▲ n ²⁰ _D ▼ 1.5914 Next, 23.9 g (0.09 mol) of (II-1) obtained here, 0.2
800 ml of M-phosphate buffer (pH 7.0) and 3.0 g of amanolipase “P” are vigorously disturbed at 25 to 30 ° C. for 25 hours. After completion of the reaction, the reaction solution is extracted with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and the concentrated residue was diluted with toluene: ethyl acetate (2
Purify by chromatography at 0: 1).

(+)-4- (1-hydroxyethyl) -4'-cyanobiphenyl 9.6 g (yield 48%) {▲ [α] ²⁰ _D ▼ + 44 ° (c = 1, CHCl ₃ ), mp165 ° C} and ( -)-4- (1-acetoxyethyl) -4 '
Cyanobiphenyl (IV-1) 12.05 g (yield 50.5%) was obtained. ▲ n ²⁰ _D ▼ 1.5909, ▲ [α] ²⁰ _D ▼ -106 ° (c =
1, CHCl ₃ ) 5.3 g (0.02 mol) methanol (IV-1) obtained above 20 ml
And 20% caustic soda 8g (0.04mol) at 20-30 ℃
Stir for hours. After completion of the reaction, methanol is distilled off and the residue is extracted with 50 ml of ethyl acetate. After washing the organic layer with water, ethyl acetate is distilled off under reduced pressure. The resulting residue is toluene:
Purify by chromatography with ethyl acetate (20: 1).

4.35 g (yield 97.5%) of (-)-4- (1-hydroxyethyl) -4'-cyanobiphenyl was obtained. ▲ [α] ²⁰ _D
▼ -40 ° (c = 1, CHCl ₃ ) mp. 162 ° C. Example 2 11.2 g (0.05 mol) of 4- (1-hydroxyethyl) -4′-cyanobiphenyl, 40 ml of pyridine and 11.9 g of butanoic acid anhydride ( 0.075 mol) is reacted at 10 to 15 ° C for 5 hours. After completion of the reaction, pour the reaction solution into ice water and add toluene 10
Extract with 0 ml. Then, it is washed successively with 5% hydrochloric acid water, water, 5% sodium carbonate and water. Hereinafter, post-treatment and purification are performed according to Example 1. 4- (1-butyryloxyethyl) -4'-cyanobiphenyl (II-2) 14.0 g (yield 9
5.5%).

▲ n ²⁰ _D ▼ 1.5855 Next, 13.2 g (0.045 mol) of (II-2) obtained here, 0.1.
450 ml of 2M-phosphate buffer (pH 6.5) and 3.5 g of Arthrobacter lipase (manufactured by Shin Nippon Kagaku Co., Ltd.) are vigorously stirred at 30 ° C. for 30 hours. After completion of the reaction, post-treatment according to Example 1,
Purify.

3.5 g of (+)-4- (1-hydroxyethyl) -4'-cyanobiphenyl (yield 35%) {▲ [α] ²⁰ _D ▼ + 42 ° (c = 1, CHCl ₃ ) and (-)-4. -(1-Butyryloxyethyl) -4'-cyanobiphenyl (IV-2) 8.
2 g (62% yield) are obtained. ▲ [α] ²⁰ _D ▼ -70 ° (c = 1, C
HCl ₃ ), ▲ n ²⁰ _D ▼ 1.5850 (IV-2) 5.9 g (0.02 mol), tetrahydrofuran 5 ml, methanol 10 ml and 10% caustic potash 33 g (0.
(06 mol) is reacted at 15 to 25 ° C for 4 hours. After completion of the reaction, post-treatment and purification are carried out according to Example 1.

4.3 g (yield 96.5%) of (-)-4- (1-hydroxyethyl) -4'-cyanobiphenyl was obtained.

Claims (5)

(57) [Claims] 1. A formula (In the formula, * indicates an asymmetric carbon atom.) An optically active biphenylcarbinol. 2. General formula (In the formula, R represents a lower alkyl group.) An asymmetric hydrolysis is carried out by acting an esterase on a cyanobiphenyl ester represented by the following formula: The production of the optically active biphenylcarbinol. Law. 3. General formula (In the formula, R represents a lower alkyl group.) Cyanobiphenyl esters represented by the formula: (In the formula, R represents a lower alkyl group, and the * mark represents an asymmetric carbon atom.) The optically active cyanobiphenyl esters represented by the formula (4) are obtained, and then the esters are hydrolyzed. The method for producing an optically active biphenylcarbinol according to claim 1. 4. A formula The method for producing an optically active biphenylcarbinol according to claim 2, wherein the biphenylcarbinol represented by the formula (3) is acylated with a lower aliphatic carboxylic acid to obtain a cyanobiphenyl ester. 5. A general formula (In formula, R shows a lower alkyl group.) The cyanobiphenyl ester shown by these.