JP2551089B2 - Optically active 4 '-(1-hydroxyethyl) -4-biphenol and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to formula (I) (In the formula, * indicates that it is an asymmetric carbon.) It relates to a process for producing an optically active 4 ′-(1-hydroxyethyl) -4-biphenol.

<Prior Art> The optically active 4 ′-(1-hydroxyethyl) -4-biphenol shown here is a compound first discovered by the present inventors, and not only the production method thereof,
There is no known use.

<Problems to be Solved by the Invention> The compound represented by the formula (I) is not only useful as an intermediate for pesticides, pharmaceuticals and veterinary drugs, but is also particularly useful as an optically active site of a ferroelectric liquid crystal compound. Is.

For example, the biphenol can be typically led to a liquid crystal compound as shown below, and the compound is very excellent as a ferroelectric liquid crystal.

(Wherein R ₁ and R ₂ represent an alkyl group or an acyl group,
Ar represents an aromatic group or a cyclic saturated group. <Means for Solving the Problems> The present invention provides such a novel and useful optically active 4 ′-(1-hydroxyethyl) -4-biphenol represented by the above formula (I). It is a thing.

The optically active 4 '-(1-hydroxyethyl) -4-biphenol represented by the formula (I) is represented by the general formula (II) (In the formula, A represents a hydrogen atom, a methyl group, a methoxy group, or a halogen atom. The * mark represents an asymmetric carbon.) The compound is produced by debenzylation of an optically active ether. be able to.

This reaction usually produces optically active ethers (II)
It is carried out by dehydrogenating the catalyst by hydrogenating the catalyst with hydrogen in the presence of a hydrogenation catalyst.

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 such catalyst used is such that the optically active ethers (II)
Usually 0.001 to 0.5 times by weight, preferably 0.005 to 0.3
It is in the range of weight times. The reaction is usually carried out in a solvent, and examples of the solvent include water, dioxane, tetrahydrofuran, methanol, ethanol, n-propyl alcohol, acetone, dimethylformamide, toluene, dichloromethane, ethyl acetate and other aliphatic hydrocarbons and aromatic hydrocarbons. Solvents such as alcohols, ethers, ketones, esters, halogenated hydrocarbons and the like which are inert to the reaction are used alone or as a mixture.

This reaction is carried out under normal or elevated pressure of hydrogen, and the reaction end point is reached when the amount of absorbed hydrogen is 1 to 1.2 equivalent times that of the optically active ether (II) as a raw material. Is preferred.

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

After completion of the reaction, the desired optically active 4 ′-(1-hydroxyethyl) -4-biphenol (I) can be obtained by a method such as removing the catalyst from the reaction mixture by filtration and then concentrating it. .

Next, the optically active ethers (II) are represented by the general formula (III) (In the formula, R ″ is a lower alkyl group, A is a hydrogen atom, a methyl group, a methoxy group or a halogen atom.) An esterase having the ability to hydrolyze only one of the enantiomers It can be produced by using asymmetric hydrolysis.

The microorganism that produces the esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze the esters (III).
It 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, Previbacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus genus, Lactobacillus genus, Trichoderma genus, Candida genus, Saccharomyces genus, Rhodotorula genus, Cryptococcus genus, Tollovsis genus, Pichia genus, Penicillium genus, Aspergillus genus,
Examples are microorganisms belonging to the genus Rhizobus, the genus Mucor, the genus Aureobasidium, the genus Actinomucor, the genus Nocardia, the genus Streptomyces, the genus Hansenula, and the genus Achromobacter.

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, sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts (dissolve 5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in 1 of water, p
Inoculated with microorganisms in a sweetened bouillon medium (dissolve 10 g of glucose, 5 g of peptone, 5 g of meat extract, and 3 g of NaCl in water 1 to pH 7.2) for bacteria, usually 20 to 40
It may be carried out by reciprocal shaking culture for 1 to 3 days at 0 ° C., and if necessary, solid culture may be carried out.

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 Pharmaceutical Co., Ltd.)], lipase of Candida cylindrasse [lipase MY (manufactured by Meito Sangyo)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (name) Made by Sugar Industry)],
Lipase of Arthrobacter (manufactured by Shin Nippon Chemical Co., Ltd.)],
Chromobacterium lipase (manufactured by Toyo Brewery Co., Ltd.), lipase of Rhizohus delemer [Taripase (manufactured by Tanabe Seiyaku)], lipase of Rhizobus [Lipase Saiken (Osaka Bacterial Research Institute)].

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

Steapsin, buncreatin, 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 S (III) 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 10 to 70 hours, but is not limited thereto.

After completion of such asymmetric hydrolysis reaction, the asymmetric hydrolysis reaction solution is treated with, for example, methyl isobutyl ketone, ethyl acetate,
Extraction is performed with a solvent such as ethyl ether, the solvent is distilled off from the organic layer, and the concentrated residue is treated with column chromatography. For example, the hydrolysis product is optically active ethers (II) and the hydrolysis residue. It is possible to separate the optically active ester (the optically active substance in the raw material ester (III) which has not been hydrolyzed).

When a lipase belonging to the genus Pseudomonas or the genus Arthrobacter is used as the lipase in this asymmetric hydrolysis reaction, optically active ethers (II) 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 ester represented by the general formula (III) used as a raw material here can be obtained, for example, by acylating an alcohol (IV) shown below with a lower alkylcarboxylic acid.

(In the formula, A is the same as above.) Further, the optically active 4 ′-(1-hydroxyethyl) -4-biphenol represented by the formula (I) is represented by the general formula (V). (In the formula, R represents a COR ″ group, where R ″ is a lower alkyl group, and * represents an asymmetric carbon.) The optically active biphenol represented by It can be produced by hydrolysis with.

Examples of the alkali used in this hydrolysis reaction include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate,
Examples thereof include alkali metal hydroxides such as potassium carbonate and calcium hydroxide, alkali metal carbonates (hydrogen), and alkaline earth metal carbonates, and these are preferably used as an aqueous solution. The amount of the alkali used is usually 1 equivalent or more with respect to the optically active biphenol (V), and usually 1
Used in the range of up to 10 equivalents.

This reaction requires 1 equivalent or more of water with respect to the optically active biphenol (V), and the reaction is usually performed in the presence of an excess amount of water, but if necessary, an organic solvent (for example, methanol, A water-soluble organic solvent such as ethanol or tetrahydrofuran may coexist.

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

After completion of the reaction, an organic solvent is optionally removed from the reaction mixture, and the reaction solution is acid-precipitated with an acid, and subjected to treatments such as extraction and concentration to give the desired optically active compound represented by the formula (I). 4 '-(1-Hydroxyethyl) -4-biphenol can be obtained, which can be purified by recrystallization, column chromatography or the like, if necessary.

Next, the optically active biphenols (V) which are the raw materials for this hydrolysis reaction are represented by the general formula (VI) (In the formula, *, A and R are the same as above.) The optically active ester, which is the asymmetric hydrolysis residue, can be obtained by debenzylation.

This reaction can be carried out under exactly the same conditions as the reaction for obtaining optically active 4 '-(1-hydroxyethyl) -4-biphenol (I) from optically active ethers (II).

Further, the optically active ester (VI), which is a raw material for the debenzylation reaction, can be produced from the ester represented by the general formula (III) by an asymmetric hydrolysis reaction. As explained in.

<Effects of the Invention> Thus, according to the method of the present invention, it is possible to industrially advantageously produce an optically active 4 '-(1-hydroxyethyl) -4-biphenol represented by the formula (I) which is a novel compound. In addition, the compound of the present invention is not only useful as an intermediate for liquid crystal compounds, but can also be used as an intermediate for agricultural chemicals, pharmaceuticals and the like.

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

Reference Example 1 120.9 g of 4-benzyloxy-4'-acetyl-biphenyl (0.
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 pendyloxy-4 '-(1-hydroxyethyl) -biphenyl was obtained.

Next, 91.25 g (0.3 mol) of the biphenyl derivative 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 to
Add over 2 hours at 20 ° C. Thereafter, it is kept at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After the reaction is completed, the temperature is cooled to 10 ° C or lower, and 300 ml of water is added. The separated organic layer was washed successively with 2N-hydrochloric acid water, water, 5% sodium carbonate, and water, concentrated under reduced pressure, and purified by column chromatography.
101.57 g (yield 97.8%) of benzyloxy-4 '-(1-acetoxyethyl) -biphenyl (II-1) was obtained.

Example 1 86.55 g (0.25 mol) of (II-1) obtained above was added with 2,000 ml of 0.3 M phosphate buffer (pH 7.5) and amanolipase "P".
Stir vigorously with 50 g at 40-45 ° C for 120 hours. After the reaction was completed, 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 mixed solvent of toluene: ethyl acetate (5: 2) as a developing solvent, (+)-4-benzyloxy-4 '-(1-hydroxyethyl). -Biphenyl (III-1) 28.9 g (yield
38%) [▲ [α] ²⁰ _D ▼ + 34.8 ° (c = 1, CHCl ₃ ), m.
p.158-159 ° C] and 50.17 g of unreacted ester were obtained.

Next, 3.0 g (0.01 mol) of (III-1) obtained above was dissolved in 50 ml of methanol, 0.3 g of 5% Pd / c powder was added, and hydrogenated in an autoclave at 80 ° C and 5-10 atm for 3 hours. To do.
After the reaction was completed, Pd / c was separated, the organic layer was concentrated under reduced pressure, and the obtained white solid was purified by silica gel column chromatography to obtain (+)-4 ′-(1-hydroxyethyl) -4. -1.9 g (90% yield) of biphenol was obtained.

Melting point 192 to 193 ° C. [α] ²⁵ _D ▼ + 48 ° (c = 1, dimethylformamide) NMR (60 MHz, DMSO-d ₆ ) δ (ppm) 1.3 (d, 3H, -C
_{H 3), 4.7 (m,} 1H, CH), 5.1 (d, 1H, CH-O H, 6.8-7.5
(M, 8H, Ar H ), 9.4 (s, 1H, H 2 O) Example 2 3.46 g (0.01 mol) of the unreacted ester obtained in Example 1 is reacted under the same hydrogenation conditions as in Example 1. . Obtained (-)-4 '-(1-acetoxyethyl) -4-
To a methanol solution of biphenol, 10 ml of 20% sodium hydroxide aqueous solution is added, and the mixture is reacted at 40 to 45 ° C for 2 hours. After completion of the reaction, the mixture is poured into 200 ml of water and adjusted to pH 3 with 4N hydrochloric acid to obtain a white precipitate, which is separated. After washing well with water and drying, (-)-4 '-(1-hydroxyethyl)-
1.8 g (yield 85%) of 4-biphenol was obtained.

Melting point 187 to 191 ° C ▲ [α] ²⁵ _D ▼ -39 ° (c = 1, dimethylformamide) Reference Example 2 4-acetyl-4 ′-(p-chloro) in a four-necked flask equipped with a stirrer and a thermometer. 134.6 g (0.4 mol) of benzyl) oxybiphenyl, 100 ml of methanol and 400 ml of tetrahydrofuran are charged, and 15.1 g (0.4 mol) of sodium borohydride is added over 2 hours at 15 to 25 ° C.

After keeping the temperature at the same temperature for 5 hours, the reaction mixture is poured into ice water and extracted twice with 500 ml of chloroform. The organic layer was washed with water and then concentrated under reduced pressure to give 4- (1-hydroxyethyl) -4 '-(p-chlorobenzyl) oxybiphenyl.
135.1 g (yield 100%) was obtained.

Melting point 170.5-172 ° C Next, 101.5 g (0.3 mol) obtained here is added to 400 ml of toluene.
It is dissolved in a mixture of 100 ml of pyridine and pyridine, and 25.9 g (0.33 mol) of acetyl chloride is added thereto at 15 to 20 ° C over 2 hours. Thereafter, it is kept at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After the reaction is completed, the temperature is cooled to 10 ° C or lower, and 300 ml of water is added. The separated organic layer was washed successively with 2N-hydrochloric acid water, water, 5% sodium carbonate and water and then concentrated under reduced pressure.
(1-acetoxyethyl) -4 '-(p-chlorobenzyl) oxybiphenyl (II-3) 101.6 g (yield 97.8%)
I got

Example 3 (II-3) 15.1 g (0.04 mol) obtained in Reference Example 2 was added to 0.3M.
Stir vigorously for 5 days at 40-50 ° C with 0.5 g phosphate buffer (pH 7.5) and 5 g lipase (Amano "P"). After completion of the reaction, the reaction mixture was extracted with chloroform 0.5, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by column chromatography with toluene and ethyl acetate ((+)).
5.8 g of -4- (1-hydroxyethyl) -4 '-(p-chlorobenzyl) oxybiphenyl (III-3) (yield 85
%) [▲ [α] ²⁰ _D ▼ + 30.2 ° (c = 1, chloroform), melting point 165-167 ° C.].

Next, 1.0 g (2.9 mmol) of (II-3) obtained above was dissolved in 50 ml of toluene, 0.3 g (wet) of Raney nickel was added, and hydrogenation was carried out in an autoclave at 60 ° C. and 5 to 10 atm for 3 hours. After the reaction was completed, Raney nickel was separated, the organic layer was concentrated under reduced pressure, and the obtained white solid was purified by silica gel column chromatography to obtain (+)-4-
(1-hydroxyethyl) -4'-biphenol 0.56g
(90% yield).

Example 4 A reaction, a post-treatment, etc. were carried out according to Example 1 except that 4- (p-methoxybenzyl) oxy-4 ′-(1-acetoxyethyl) -biphenyl was used instead of the compound (II-3). (+)-4 '-(1-hydroxyethyl)
-4-Biphenol was obtained.

Example 5 Instead of the compound (II-1), 4- (p-methylbenzyl) oxy-4 ′-(1-propanoyloxyethyl)
-Reaction according to Example 1, but using biphenyl,
After post-treatment, etc., (+)-4- (p-methylbenzyl) oxy-4 '-(1-hydroxyethyl) biphenyl and (-)-4- (p-methylbenzyl) oxy-4'
-(1-Propanoyloxyethyl) biphenyl was obtained.

Next, the (-)-form ester residue was reacted and post-treated according to Example 2 to obtain (-)-4 '-(1-hydroxyethyl) -4-biphenol.

Claims (4)

(57) [Claims] 1. A general formula (In the formula, A represents a hydrogen atom, a methyl group, a methoxy group, or a halogen atom. The * mark represents an asymmetric carbon.) Debenzylation of the optically active ethers represented by Expression (In the formula, * indicates an asymmetric carbon.) Optically active 4 '-(1-hydroxyethyl)
-4-Preparation of biphenol. 2. General formula (In the formula, R ″ is a lower alkyl group, A is a hydrogen atom, a methyl group, a methoxy group or a halogen atom.) An esterase having the ability to hydrolyze only one of the enantiomers is used. Asymmetrically hydrolyzed to give a general formula (In the formula, A has the same meaning as described above. The * mark indicates an asymmetric carbon.) An optically active ether represented by (In the formula, * indicates an asymmetric carbon.) Optically active 4 '-(1-hydroxyethyl)
-4-Preparation of biphenol. 3. General formula (In the formula, R represents a COR ″ group, where R ″ is a lower alkyl group. The * mark indicates an asymmetric carbon.) Characterized expression (In the formula, * indicates an asymmetric carbon.) Optically active 4 '-(1-hydroxyethyl)
-4-Preparation of biphenol. 4. A general formula (In the formula, R ″ is a lower alkyl group, A is a hydrogen atom, a methyl group, a methoxy group or a halogen atom) An enzyme or microorganism having the ability to hydrolyze only one of the enantiomers Asymmetrically hydrolyzed using (In the formula, R represents a COR ″ group, wherein R ″ is a lower alkyl group. A has the same meaning as described above, and the * mark represents an asymmetric carbon.) Optically active esters, which are residues of simultaneous hydrolysis, were obtained and debenzylated to give the compound of the general formula (In the formula, R and * have the same meaning as described above.) An optically active biphenol represented by the following formula is obtained, and the compound is hydrolyzed. (In the formula, * indicates an asymmetric carbon.) Optically active 4 '-(1-hydroxyethyl)
-4-Preparation of biphenol.