JP2727568B2 - Optically active alcohols and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound represented by the general formula (I) (In the formula, A represents an alkyl group or an alkoxyl group having 2 to 20 carbon atoms, X is, -COO -, - OCO -, - CH 2 O-
Or -OCH ₂ - indicates, l and m are each 1 or 2. The asterisk indicates that it is an asymmetric carbon. Where l
But X is not -CH ₂ O- a time of 1. The asterisk indicates that it is an asymmetric carbon. ) And an optically active alcohol represented by the formula

The optically active alcohol represented by the general formula (I) is a novel compound discovered by the present inventors for the first time, which has not been described in any literature, and is an intermediate of a drug, an agricultural chemical, an organic electronic material such as a liquid crystal material. Useful as

Such optically active alcohols have the general formula (II) Wherein A, X, l and m have the same meanings as described above, using an esterase having the ability to hydrolyze only one of the enantiomers of the ester. Obtained by asymmetric hydrolysis.

The dl-esters (II) which are the raw materials for this reaction are represented by the general formula (III) (Wherein A, X, l and m have the same meaning as described above), which is obtained by reacting a dl-alcohol with a lower alcohol carboxylic acid to acylate the dl-alcohol. III) is the general formula (IV) (Wherein A, X, l and m have the same meaning as described above) can be obtained by reducing the ketone using a reducing agent.

Further, ketones (IV) as a raw material for this reaction can be easily produced, for example, by the following reaction, depending on the type of the substituent -X-.

i) In the case of X: -COO-, -OCO- It is produced by an esterification reaction generally used widely.

ii) X: —CH ₂ O—, —OCH ₂ It is produced by a generally widely used etherification reaction.

The reduction reaction for obtaining dl-alcohols (III) from ketones (IV) is performed using a reducing agent capable of reducing ketones to alcohols.

When the substituent X in the starting ketones (IV) is -COO- or -OCO-, sodium borohydride, lithium-tri-t-butoxyaluminum hydride, lithium-tri- S- butylboron hydride, borane are also substituents X is -CH ₂ O- or -OCH ₂ - sodium borohydride in the case of lithium borohydride, zinc borohydride, lithium aluminum hydride, Aluminum isopropoxide, lithium-tri-t-butoxyaluminum hydride, lithium-tri-S-butylboron hydride, borane, alkali metal-ammonia and the like are preferably used.

Such a reducing agent is required to be at least one equivalent or more times the amount of the starting ketone (IV), and is usually used in an amount of 1 to 10 equivalents.

The reduction reaction is usually performed in a solvent, and examples of the solvent include tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, ethers such as toluene, benzene, chloroform, and dichloromethane, and halogenated hydrocarbons. A single solvent or a mixture of solvents inert to the reaction, such as aromatic hydrocarbons and alcohols, is appropriately selected and used.

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

From the reaction mixture thus obtained, dl-alcohols (II
Although I) can be obtained in good yield, dl-esters (I
In order to produce I), dl-alcohols (II
It is not necessary to isolate I), and the reaction mixture may proceed to the next step.

dl-alcohols (III) to dl-esters (II)
Is carried out by reacting a dl-alcohol (III) with a lower alkyl carboxylic acid to effect acylation.

In such an acylation, as the lower alkylcarboxylic acid as an acylating agent, an acid anhydride or an acid halide of a lower alkylcarboxylic acid is usually used, for example, acetic anhydride, propionic anhydride, acetic chloride or bromide, propionic chloride or Bromide, butyryl chloride or bromide, valeroyl chloride or bromide, and the like.

The reaction between the dl-alcohols (III) and the lower alkylcarboxylic acids 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,
Solvents that are inert to the reaction such as aliphatic or aromatic hydrocarbons such as chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, and hexane, ethers, halogenated hydrocarbons, aprotic polar solvents alone or Mixtures. The amount can be used without any particular limitation.

Lower alkylcarboxylic acids used in the reaction are raw materials
1 equivalent or more is required for dl-alcohols (III), and the upper limit is not particularly limited.
Is equivalent.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine,
Organic or inorganic basic substances such as picoline, imidazole, sodium carbonate, sodium methylate, potassium hydrogen carbonate and the like can be mentioned. The amount used is not particularly limited, but is usually 1 to 5 equivalents to dl-alcohols (III).

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

Further, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can be used as the catalyst.

The amount of the catalyst used varies depending on the type of the lower alkyl carboxylic acid and the combination of the catalyst to be used, etc., and cannot always be specified. For example, when an acid halide is used as the lower alkyl carboxylic acid, 1 to the acid halide is used. Used more than equivalent.

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

The reaction time is not particularly limited, and the time when the dl-alcohols (III) as the raw material disappears can be regarded as the end point of the reaction.

After completion of the reaction, usual separation means such as extraction, liquid separation,
The dl-esters (II) can be obtained in good yield by operations such as concentration and recrystallization, which can be purified by column chromatography or the like, if necessary, but used as a reaction mixture for the next step. can do.

The reaction for obtaining the desired optically active alcohols (I) from the dl-esters (II) uses an esterase capable of hydrolyzing only one of the enantiomers of the dl-esters (II). The hydrolysis is performed by hydrolyzing one of the optically active forms of the esters.

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

The microorganism that produces an esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze dl-esters (II), and 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,
Microorganisms belonging to the genera Rhizopus, Mucor, Aureopacidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter are exemplified.

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

For example, sterilized liquid medium [for molds and yeasts, malt extract / yeast extract medium (5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in water 1;
H 6.5), for bacteria, a sweetened broth medium (1 water)
Dissolve 10 g of glucose, 5 g of peptone, 5 g of meat extract, and 3 g of NaCl to pH 7.2)] and inoculate the microorganism with
The culture is performed by reciprocal shaking culture at 40 ° C. for 1 to 3 days, and solid culture may be performed if necessary.

Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, the following.

Pseudomonas lipase [Lipase P (Amano Pharmaceutical)], Aspergillus lipase [Lipase AP (Amano Pharmaceutical)], Mucor lipase [Lipase M-AP]
(Manufactured by Amano Pharmaceutical Co., Ltd.)), lipase of Candida syrindrasse [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 Sugar industry)),
Lipase of the genus Arthrobacter [lipase joint BSL (joint sake refinement)], lipase of the genus Chromobacterium (manufactured by Toyo Brewery), lipase of Rhizopus delemar [talipase (manufactured by Tanabe Seiyaku)], lipase of the genus Rhizopus [lipase [ Lipase Saiken (Osaka Bacteria Research Institute)].

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

Stearpsin, pancreatin, porcine liver storage esterase, Wheat Germ esterase.

As the esterase used in this reaction, enzymes obtained from animals, plants, and microorganisms are used, and the forms of use include purified enzymes, crude enzymes, enzyme-containing substances, microbial cultures, cultures, cells, and cultures. In addition, they can be used as needed in various forms such as those obtained by treating them, and the enzymes and microorganisms can be used in combination. Alternatively,
It can also be used as an immobilized enzyme immobilized on a resin or the like, or immobilized cells.

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

As the buffer, 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 or sodium citrate, or the like is used, and its pH is adjusted to pH 8 to 11 in a culture solution of alkaliphilic bacteria or alkaline esterase. The pH is preferably 5 to 8 for a culture solution of a non-alkaliphilic microorganism or an esterase having no alkali resistance. The concentration is usually in the range of 0.05-2M, preferably 0.05-0.5M.

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

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

During the hydrolysis, toluene,
Organic solvents that are inert to the reaction, such as chloroform, methyl isobutyl ketone, and dichloromethane, can also be used.
By using these, asymmetric hydrolysis can be advantageously performed.

By such an asymmetric hydrolysis reaction, only one of the optically active isomers of the raw material dl-esters (II) is hydrolyzed to produce an optically active alcohol represented by the general formula (I). The optically active esters, which are the other optically active forms of the dl-esters (II), remain as hydrolysis residues.

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 (I) as hydrolysis products and optically active esters as hydrolysis residues [optically active compounds in raw material esters (II) which have not been hydrolyzed by the method described above. ] Can be separated.

The optically active esters obtained here may be further hydrolyzed, if necessary, to be enantiomerically optically active alcohols (I) from the previously obtained optically active alcohols (I). it can.

Thus, according to the method of the present invention, a novel optically active alcohol represented by the general formula (I) can be produced with high optical purity and high yield. It is useful as an intermediate for agricultural chemicals, organic electronic materials and the like, especially as an intermediate for liquid crystal materials.

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

Examples 1 to 12 A four-necked flask equipped with a stirrer and a thermometer was charged with 40.2 g (0.1 mol) of 4'-acetyl-4-biphenylyl ester of 4-pentyloxybenzoic acid, 100 ml of ethanol and 100 ml of chloroform, At 20-30 ° C., 1.9 g (0.05 mol) of sodium borohydride are added over 10 minutes.

After keeping at the same temperature for 3 hours, the mixture is poured into ice water and extracted twice with 200 ml of chloroform.

The organic layer was washed with water and concentrated under reduced pressure to obtain 40.1 g (yield 99.1%) of 4 '-(1-hydroxyethyl) -4-biphenylyl ester of 4-pentyloxybenzoic acid.

Next, 20.2 g (0.05 mol) of the above-obtained 4-pentyloxybenzoic acid ester was dissolved in a mixed solvent of 100 ml of pyridine and 200 ml of chloroform.
5.5 g (0.07 mol) are added over 1 hour at 10-15 ° C. Thereafter, it is kept at 40 to 50 ° C. for 2 hours.

After completion of the reaction, 200 ml of water is added at 10 ° C. or lower, and the organic layer is separated. The organic layer was washed successively with 3N hydrochloric acid, water, 7% sodium hydrogen carbonate and water, and then concentrated under reduced pressure to give 4 '-(1-acetoxyethyl) of 4-pentyloxybenzoic acid.
21.6 g of 4-biphenylyl ester (97% yield) was obtained.

8.9 g of this ester of 4-pentyloxybenzoic acid (0.
02 mol) together with 300 ml of 0.3 M phosphate buffer (pH 7), 20 ml of chloroform and 1.8 g of amano lipase "P"
Stir vigorously at 35-40 ° C for 24 hours.

After completion of the reaction, the reaction mixture is extracted with 300 ml of chloroform.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a chloroform: ethyl acetate = 20: 1 mixture as a developing solvent to give (+)-4-pentyloxybenzoic acid 4 ′-(1-hydroxyethyl). 3.6 g of 4-biphenylyl ester (Compound No. 1) ｛186-188 ° C., ▲
[Α] ²⁰ _D ▼ + 24.2 ° (c = 1, chloroform)} and 4′- of unreacted (−)-4-pentyloxybenzoic acid
(1-acetoxyethyl) -4-biphenylyl ester
4.2g ｛Melting point 87.3-103.5 ° C, ▲ [α] ²⁵ _D ▼ -70 ° C (c =
1, chloroform) was obtained.

 Similarly, the following compounds are synthesized.

(+)-4-Hexadecyloxybenzoic acid 4 '-(1
-Hydroxyethyl) -4-biphenylyl ester (Compound No. 2) (+)-4-decyloxybenzoic acid 4- (1-hydroxyethyl) phenyl ester (Compound No. 3) (+)-4 '-(1 -Hydroxyethyl) -4-biphenylcarboxylic acid 4-octyloxyphenyl ester (Compound No. 4) (+)-4 '-(1-hydroxyethyl) -4-biphenylcarboxylic acid 4-decyloxyphenyl ester (Compound No. .5) (+)-4 '-(1-Hydroxyethyl) -4-biphenylcarboxylic acid 4-hexadecyloxyphenyl ester (Compound No. 6) (+)-4- (1-hydroxyethyl) benzoic acid 4 ′
-Hexyloxy-4-biphenylyl ester (compound
No. 7) (+)-4- (1-hydroxyethyl) benzoic acid 4 '
-Octyloxy-4-biphenylyl ester (compound
No. 8) (+)-4- (1-hydroxyethyl) benzoic acid 4 '
-Decyloxy-4-biphenylyl ester (compound N
o.9) (+)-4- (1-hydroxyethyl) benzoic acid 4 '
-Heptyl-4-biphenylyl ester (Compound No. 1
0) (+)-4- (1-Hydroxyethyl) benzoic acid 4 '
-Decyl-4-biphenylyl ester (Compound No. 11) (+)-4- (1-hydroxyethyl) benzoic acid 4 '
-Dodecyl-4-biphenylyl ester (Compound No. 1
2) Examples 13 to 20 The reaction and post-treatment were carried out according to the method of Example 1 except that ketones (IV) shown in Table 1 were used as starting materials, and the results shown in Table 1 were obtained.

Example 21 After dissolving 500 mg of a lipase belonging to the genus Pseudomonas [Lipase "P" (manufactured by Amano Pharmaceutical)] in 1 ml of distilled water, 10 g of a polypropylene glycol-based resin [ENTP-2000 (manufactured by Kansai Paint)], and a photopolymerization initiator S (manufactured by Kansai Paint) 0.2g
And 5 ml of n-hexane were added and mixed. This mixture was cast on a propylene film to a thickness of 1 mm,
A propylene film was further adhered to the upper surface. The upper and lower surfaces of the two propylene films sandwiching the mixture were irradiated with light for 3 minutes to cause a polymerization reaction of the ENTP-2000 resin. The obtained sheet-like gel polymer was peeled off from the two propylene films, and cut into 5 mm squares to obtain immobilized enzymes.

1.0 g of the immobilized enzyme, 0.3 g of 4 '-(1-acetoxyethyl) -4-biphenylyl ester of 4-octyloxybenzoic acid, 10 ml of 0.3 M phosphate buffer (pH 7) and 1 ml of chloroform were mixed. Stirred at C for 24 hours. After the completion of the reaction, the reaction mixture was extracted with 100 ml of chloroform.

Thereafter, post-processing is performed according to the first embodiment, and (+)-4
0.12 g of 4 '-(hydroxyethyl) -4-biphenylyl ester of octyloxybenzoic acid (melting point: 135.5-13)
6 ° C., 〔[α] ²⁰ _D ▼ + 22.1 ° (c = 1, chloroform｝ was obtained.

Example 22 4'-Acetyl-4- of 4-pentyloxybenzoic acid
Reduction, acetylation and asymmetric hydrolysis were carried out in the same manner as in Example 1 except that 0.1 mol of 4- (p-octyloxybenzyloxy) acetophenone was used instead of 0.1 mol of biphenylyl ester, and (+)-4 was obtained. There was obtained-(p-octyloxy) benzyloxy-α-phenethyl alcohol (mp 95-97 ° C.).

▲ [α] ²⁵ _D ▼ + 23.1 ° (c = 1.00, chloroform) Example 23 4′-Acetyl-4- of 4-pentyloxybenzoic acid
Reduction in the same manner as in Example 1, except that 0.1 mol of 4-acetylbenzoic acid 4'-dodecyloxy-4-biphenylyl ester was used instead of 0.1 mol of biphenylyl ester;
Acetylation and asymmetric hydrolysis were carried out to give (+)-4-
(1-Hydroxyethyl) benzoic acid 4'-dodecyloxy-4-biphenylyl ester (mp 154-155 ° C) was obtained.

▲ [α] ²⁵ _D ▼ + 16.8 ° (c = 1.00, chloroform) Examples 24 to 27 4′-Acetyl-4- of 4-pentyloxybenzoic acid
Reduction, acetylation and asymmetric hydrolysis were carried out in the same manner as in Example 1 except that 0.1 mol of 4- (4-acetylbenzyloxy) -4'-octyloxybiphenyl was used instead of 0.1 mol of biphenylyl ester ( +)-4- [4
-(1-hydroxyethyl) benzyloxy] -4'-
Octyloxybiphenyl (Compound No. 24) [melting point 143-
144 ° C].

▲ [α] ²⁵ _D ▼ + 16.8 ° (c = 1.00, chloroform) Similarly, the following compounds are synthesized.

(+)-4 '-(p-hexadecyloxybenzyl) oxy-4- (1-hydroxyethyl) biphenyl (Compound No. 25) (+)-4- [4- (p-decyloxyphenyl) benzyloxy ] -1-hydroxyethylbenzene (compound
No. 26) (+)-4- [4- (p-decylphenyl) benzyloxy] -1-hydroxyethylbenzene (Compound No. 2
7)

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Shizuo Hattori 4-2-1 Takashi, Takarazuka-shi, Hyogo Sumitomo Chemical Industries Co., Ltd. (72) Inventor Ken Mitsuda 4-2-1 Takashi, Takarazuka-shi, Hyogo Sumitomo Chemical Industry Co., Ltd.

Claims (4)

(57) [Claims] 1. The compound of the general formula (I) (In the formula, A represents an alkyl group or an alkoxyl group having 2 to 20 carbon atoms, X is, -COO -, - OCO -, - CH 2 O-
Or -OCH ₂ - indicates, l and m are each 1 or 2. The asterisk indicates that it is an asymmetric carbon. Where l
But X is not -CH ₂ O- a time of 1. The asterisk indicates that it is an asymmetric carbon. ) Alcohols represented by. 2. A compound of the general formula (II) (Wherein A, X, l and m have the same meaning as described above, and R ′ represents a lower alkyl group.) In the dl-esters represented by A process for producing D-alcohols represented by the general formula (I), wherein asymmetric hydrolysis is carried out using a lipase having the ability to hydrolyze. 3. A compound of the general formula (III) Wherein A, X, l and m have the same meanings as described above. The dl-alcohols represented by the general formula (II) are reacted with a lower alkyl carboxylic acid to give a dl-ester represented by the general formula (II). And then asymmetric hydrolysis using a lipase having the ability to preferentially hydrolyze one of the enantiomers. 4. A compound of the general formula (IV) Wherein A, X, l and m have the same meanings as described above. The dl-alcohols represented by the general formula (III) are obtained by reducing the ketones by using a reducing agent. Which is reacted with a lower alkyl carboxylic acid to obtain a compound of the general formula (I
Dl-esters represented by the formula (I), and then asymmetric hydrolysis using a lipase having the ability to preferentially hydrolyze one of the enantiomers, wherein A method for producing D-alcohols as shown.