JPH01104026A - Optically active alcohols and their production - Google Patents

Abstract

NEW MATERIAL:An optically active alcohol of formula I (A is 2-20C alkyl or alkoxy; X is COO, OCO, CH2O, OCH2, l, m are 1 or 2; * is asymmetric carbon). EXAMPLE:4'-(1-Hydroxyethyl)-4-biphenylil (t)-4-pentyloxybenzoate. USE:Intermediate of medicines, agrochemicals, organic electronic materials such as liquid crystal materials. PREPARATION:A ketone of formula II is reduced with a reducing agent which can reduce a ketone into an alcohol to give de-alcohol of formula III. The product is allowed to react with a lower alkyl carboxylic acid to give a de-ester of formula IV (R' is lower alkyl). Then, the de-ester is hydrolyzed with an esterase which is capable of hydrolyzing only one enantiomer to give the optically active compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (I) CH3 (wherein A is an alkyl group or alkoxyl group having 2 to 20 carbon atoms, and X is -COO-).

-0CO-, -CH20- or -0CR2-, respectively, and t and m are each 1 or 2. This invention relates to optically active alcohols indicated by a chestnut symbol (indicates an asymmetric carbon) and a method for producing the same.

The optically active alcohol represented by the general formula (I) is a novel compound discovered by the present inventors for the first time that has not been described in any literature. It is useful as

Such optically active alcohols have the general formula (wherein A
, X, t and m have the same meanings as above) is subjected to asymmetric hydrolysis using an esterase having the ability to hydrolyze only one of the enantiomers of the esters. It can be obtained by

The dt-esters (I[), which are the raw materials for this reaction, have the general formula (wherein A, X, L and m have the same meanings as above). In addition, dt-alcohols ■ are obtained by reacting with and acylating, and dt-alcohols ■ have the general formula ) Ketones represented by the following can be obtained by reducing ketones using a reducing agent.

Furthermore, the ketones (■), which are the raw materials for this reaction, have a substituent -X
- can be easily produced, for example, by the reactions shown below, depending on the type.

i) X: -Coo-, -0CO-ty) is produced by a generally widely used esterification reaction.

;;) In the case of x: -CH20-, -OCH2, it is produced by a generally widely used etherification reaction.

[Example D The reduction reaction for obtaining dt-alcohols (2) from ketones (1) is carried out using a reducing agent capable of reducing ketones to alcohols.

As the reducing agent at this time, when the substituent -butyl boron hydride, borane, etc., and substituent X is -CH20
- or -OCH2-, sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, aluminum isopropoxide, lithium tri-t-butoxyaluminum hydride, lithium tri-5-butyl Boron hydride, borane, alkali metal-ammonia, etc. are preferably used.

Such a reducing agent is required to be used in an amount of at least 1 equivalent to the raw material ketones (1), and is usually used in an amount of 1 to 10 times.

The reduction reaction is usually carried out in a solvent, such as ethers such as tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, toluene, benzene, chloroform, dichloromethane, and halogenated solvents. Solvents inert to the reaction, such as hydrocarbons, aromatic hydrocarbons, and alcohols, may be used alone or in combination.

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

From the reaction mixture thus obtained, liquid separation, concentration,
dt-alcohols used in operations such as distillation and crystallization [phase]
can be obtained in good yield, but dz-esters (I
In order to produce D, dt-alcohols, alcohols ■
There is no need to isolate the reaction mixture, and the reaction mixture may proceed to the next step as it is.

dt-7D-Jl/class ■dL-esters (l [
) is carried out by reacting dz-alcohols (1) with lower alkylcarboxylic acids to acylate them.

In such acylation, lower alkyl carboxylic acids as the acylating agent are usually acid anhydrides or acid halides of lower alkyl carboxylic acids, such as acetic anhydride, propionic anhydride, acetic chloride or bromide, propionic acid chloride or Examples include bromide, butyryl chloride or bromide, valeroyl chloride or bromide, and the like.

The reaction between the dt-alcohol (1) and the lower alkylcarboxylic acid is carried out under the usual esterification conditions using a catalyst in the presence or absence of a solvent.

In this reaction, when a solvent is used, examples of the solvent include aliphatic or Examples include solvents that are inert to the reaction, such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, and aprotic polar solvents, either singly or in mixtures. The amount used can be used without any particular restriction.

Lower alkyl carboxylic acids used in the reaction are raw materials d
One equivalent or more is required relative to the t-alcohol (1), and the upper limit is not particularly limited, but is preferably 4 equivalents.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine, picoline, and imidazole. The amount used is not particularly limited, but is usually 1 to 5 equivalents relative to 0 of the dt-alcohol.

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

Furthermore, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as catalysts.

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

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

The reaction time is not particularly limited, and the end point of the reaction can be set at the time when 0 of the raw material dt-alcohol disappears.

After completion of the reaction, dt-esters (ID) can be obtained in high yield by conventional separation methods such as extraction, separation, concentration, and recrystallization, which can be purified by column chromatography etc. if necessary. However, the reaction mixture can be used as is for the next step.

The reaction for obtaining the desired optically active alcohol (I) from such dt-esters (I[) is carried out using an esterase that has the ability to hydrolyze only one of the enantiomers of dL-esters (I[). This is carried out by hydrolyzing one of the optically active forms of the esters.

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

The esterase-producing microorganism used in this reaction is not particularly limited as long as it is a microorganism that produces an esterase capable of asymmetrically hydrolyzing dz-esters (1).

Specific examples of such microorganisms include Enterobacter sp., Arthrobacter sp., Brevibacterium sp., Pseudomonas sp., alkaline earth metals, Micrococcus sp., Chromobacterium sp., Microbacterium sp., Corynebacterium sp. , Bacillus, Lactobacillus metall, Trichoderma, Candida, Satucharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureopacidium, Actino Microorganisms belonging to the genus Mucor, Nocardia, Streptomyces, Hansenula, and Achromobacter, for example, in a sterilized liquid medium [For molds and yeasts, use malt extract/yeast extract medium (1 t of water, 5 y of peptone, 10 g of glucose, ``Malt extract 3f1 yeast extract 3d dissolved to pH 6.5'', for bacteria, sweetened bouillon medium (glucose 10f1 peptone 511 meat extract 59', NaCL 39 dissolved in 1 t of water, pH 7.2) microorganisms are in contact with the microorganisms (
This is carried out by performing reciprocating shaking culture for up to 3 days, and solid culture may be performed if necessary.

Furthermore, some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following.

Lipase of the genus Pseudomonas [Lipase P (manufactured by Ohno Pharmaceutical)], lipase of the genus Aspergillus [Lipase AP (manufactured by Ohno Pharmaceutical)], lipase of the genus Mucor [Lipase M-
AP (manufactured by Ohno Pharmaceutical Co., Ltd.)], Candida cylindrasse lipase [Lipase MY (manufactured by Octa Sangyo Sangyo)], alkaline earth metal lipase [Lipase PL (manufactured by Octa Sangyo Sangyo Co., Ltd.]),
Achromobacter lipase [Lipase AL (Octose Sangyo)], Arthrobacter lipase [Lipase Godo BSL (Godo Sake Refining)], Chromobacterium lipase (Toyo Jozo), Rhizopus delemer lipase [Talipase (manufactured by Tanabe Seiyaku)], Rhizopus lipase [Li.

Pase [Lipase Buiken (Osaka Bacteria Research Institute)].

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

Steagosine, pancreatin, porcine liver esterase, Wheat Germ x sterase.

The enzymes used in this reaction are enzymes obtained from animals, plants, and microorganisms, and their usage forms include purified enzymes, crude enzymes, enzyme-containing materials, microbial culture solutions, and cultured products. If necessary, it can be used in mild forms such as bacterial cells, cultured ear liquid, and processed products thereof, and enzymes and microorganisms can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterial cells immobilized on a resin or the like.

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

As the buffer, commonly used buffers of inorganic acid salts such as sodium phosphate and potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc. The pH is preferably 8 to 11 for a culture solution of a microorganism that is not alkaliphilic or an alkaline esterase, and the pH is preferably 5 to 8 for a culture solution of a microorganism that is not alkalophilic or an esterase that does not have alkali resistance. Concentration is usually 0.05-2
M, preferably in the range of 0.05-0.5M.

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

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

Additionally, during this hydrolysis, in addition to the buffer, organic solvents inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, dichloromethane, etc. can be used, and by using these, asymmetric ice thawing can be advantageously performed. It can be carried out.

Through such asymmetric hydrolysis reaction, only one of the optically active forms of the raw material dt-ester (D) is hydrolyzed to produce an optically active alcohol represented by the general formula (I), while the raw material dt - The optically active ester, which is the other optically active form of the esters (I), remains as it is as a hydrolysis residue.

After completion of such hydrolysis reaction, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc., the solvent is distilled off from the organic layer, and the concentrated residue is treated with column chromatography. Optically active alcohols (1), which are hydrolysis products, and optically active esters, which are hydrolysis residues [those that were not hydrolyzed among the optically active substances in the raw material esters CID] can be separated.

The optically active esters obtained here are further hydrolyzed as necessary, and the optically active alcohols (1) obtained above are
can be an optically active alcohol (I) as an enantiomer.

Thus, according to the method of the present invention, novel optically active alcohols represented by general formula (1) can be produced with high optical purity and good yield, and such optically active alcohols (I) can be used as pharmaceuticals. , as an intermediate for agricultural chemicals, organic electronic materials, etc.
It is particularly useful as an intermediate for liquid crystal materials.

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

To Example 1 4 4'-acetyl-4-biphenylyl ester of 4-pentyloxybenzoic acid was added to a four-piece flask equipped with a stirrer and a thermometer in an amount of 40.2! 7 (0.1 mol), ethanol 100- and chloroform 100-
Sodium borohydride 1.9 g (0,0
5 mol) was added over a period of 10 minutes.

After incubating at the same temperature for 3 hours, it was poured into ice water and extracted twice with 200% chloroform.

After washing the organic layer with water, it was concentrated under reduced pressure to obtain 40.1 g (yield: 99.1%) of 4'-(1-hydroxyethyl)-4-biphenylyl ester of 4-pentyloxybenzoic acid.

Next, 20.21 (0.05 mol) of the above-obtained 4-pentyloxybenzoic acid ester was added to 10 mol of pyridine.
0- and chloroform 200. d, and 5.51 (0.07 mol) of acetic acid chloride was added to this solution.
Add over 1 hour at ~15°C. After that 40-50
Incubate at °C for 2 hours.

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

8.9 g of this ester of 4-pentyloxybenzoic acid (
0.02 mol) in 063M phosphoric acid buffer (I)
H7) 300d, chloroform 20- and Amano Lipase rPJ 1. , 24 at 35-40”C with sy
After the reaction is completed, the reaction mixture is extracted with chloroform aOO-.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a 20:1 mixture of chloroform and ethyl acetate as a developing solvent (→-4-pentyloxybenzoic acid 4'-(1+ 24.2°) c=1.chloroform)) and unreacted ←)-4-pentyloxybenzoic acid 4'-(1-7cetoxyethyl)-4-biphenylyl ester 4,2 f (WA point 87.3-103.5 °
C1[α]D -70°C (C=1, chloroform)
) was obtained.

Similarly, the following compounds are synthesized.

(+)-4-hexadecyl oquine benzoic acid 4'-(1
-hydroquinethyl)-4-biphenylyl ester (
Compound N,,2) (+)-4-Denyloxybenzoic acid 4-(1-hydroxyethyl)phenyl ester (Compound N,,3) (+)-4'-(1-Hydroquinethyl)-4-
Biphenylcarboxylic acid 4-octyloquine phenyl ester (Compound N, 4) (+) -4' -(1- and droxyethyl)-4-
Biphenylcarboxylic acid 4-decyloxyphenyl ester (compound N0,5) (+) -4' -(1-hydroxyethyl)-4-
Biphenylcarboxylic acid 4-hexadecyloxyphenyl ester (compound m N 0.6)(+)-4-(1
-hydroxyethyl)benzoic acid 4' -hexyloxy-4-biphenylyl ester (compound N,, 7) (+)-4-(1-hydroxyethyl)benzoic acid 4'
-Octyloxy-4-biphenylyl ester (Compound N, 8) (+)-4-(1-hydroxyethyl)benzoic acid 4'
-decyloxy-4-biphenylyl ester (compound N0.9) (+)-4-(1-hydroxyethyl)benzoic acid 41-
Hephthyl-4-biphenylyl ester (compound No. 1
0) (+)-4-(1-hydroxyethyl)benzoic acid 4'
-f”y-4-biphenylyl ester (compound N
,,1l) (+)-4-(1-hydroxyethyl)benzoic acid 4'
-dodecyl-4-biphenylyl ester (compound N,
, 12) Examples 13 to 20 Reactions and post-treatments were carried out in accordance with the method of Example 1, except that the ketones (IV) shown in Table 1 were used as starting materials, and the results shown in Table 1 were obtained.

Example 21 After dissolving Pseudomonas lipase [Rino(-ze "P" (manufactured by Ohno Pharmaceutical Co., Ltd.)] 500 Misaki in distilled water, polypropylene glycol resin (ENTP-2000
(Kansai/Guindo)] 10y, photopolymerization initiator S (Kansai Paint) 0.2f and n-hexane 57! was added and mixed. This mixture was cast onto a propylene film soil to a thickness of 1 inch, and a propylene film was further adhered to the top surface. After discarding the mixture, the soil and lower sides of the two propylene films were irradiated with light for 3 minutes.
The polymerization reaction of NTP-2000 resin was successfully completed. The obtained sheet-like gel polymer was peeled off from two propylene films and cut into 5 square pieces to obtain an immobilized enzyme.

The immobilized enzyme 1.0i 7,4-octyloxybenzoic acid 1
1 of 4'-(L-acetoxyethyl)-4-biphenylyl ester 0.31, (13M sonoic acid buffer y (p
H7) Mix 10- and chloroform 1- and heat at 40°
The mixture was stirred at C for 24 hours. After the reaction was completed, the reaction mixture was extracted with 100% chloroform.

Thereafter, post-treatment was performed according to Example 1, and (+)-4-
4'-(Hydroxyethyl) of octyloxybenzoic acid
-4-biphenylyl ester 0.121 (melting point 135
．． 5~136°C1(12)D+22-1°(c
= 1', chloroform) was obtained.

Example 22 4'-acetyl-4- of 4-pentyloxybenzoic acid
0.1 mole of 4-(p-octyloxybenzyloxy)acetophenone in place of 0.1 mole of biphenylyl ester
Reduction, acetylation, and asymmetric ice-breaking reactions were carried out in the same manner as in Example 1 except that molar amounts were used to obtain (+)-4-(p-octyloxy)benzyloxy-α-phenethyl alcohol (melting point 95-97°C). I got it.

[α)+i'+23. I° (c=1.00, chloroform) Example 23 4'-acetyl-4- of 4-pentyloxybenzoic acid
Reduction, acetylation, and asymmetric deicing reaction in the same manner as in Example 1 except that 0.1 mole of 4'-dodenluoquine-4=biphenylyl ester of ethene-4-acetylbenzoic acid was used for 0.1 mole of biphenylyl ester. Do (+)−
4-(1-hydroxyethyl)benzoic acid 4'-dodecyloxy-4-biphenylyl ester (melting point 154~
155°C) was obtained.

[αla'+16.8° (c=1.00, ri o.

Examples 24 to 27 4′-acetyl-4- of 4-pentyloxybenzoic acid
Reduction, acetylation and asymmetric ice-breaking reaction in the same manner as in Example 1 except that 0.1 mol of 4-(4-acetylbenzyloxy)-4'-octyloxybiphenyl was used for 0.1 mol of biphenylyl ester. Do (+)−
4-C4-(1-hydroxyethyl)benzyloxy)
-4'-octyloxybiphenyl (compound N,
24) (melting point 143-144°C) was obtained.

[α]name'+16.8° (c=1-.00, chloroform) Similarly, the following compound is synthesized.

(+) -4'-(p-hexadecyloxybenzyl)oxy-4-(1-hydroxyethyl)biphenyl (Compound No. 25) (+) -4-(4-(p-decyloxyphenyl)benzyloxy Fu-1-hydroxyethylbenzene (Compound No. 26) (+) -4-(4-(p-decylphenyl)benzyloxyfu-1-hydroxyethylbenzene (Compound No.
, 27) (margin below)

Claims (4)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A is an alkyl group or alkoxyl group having 2 to 20 carbon atoms, and X is -COO-, -OCO
-, -CH_2O- or -OCH_2-, respectively, and l and m are each 1 or 2. Optically active alcohols indicated by *indicates an asymmetric carbon. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A is an alkyl group or alkoxyl group having 2 to 20 carbon atoms, and X is -COO-, -OCO
-, -CH_2O- or -OCH_2-, R' each represents a lower alkyl group, and l and m are each 1 or 2. ) General formula ▲Mathematical formula, chemical formula, table, characterized in that the dl-ester represented by the formula is asymmetrically hydrolyzed using an esterase that has the ability to hydrolyze only one of the enantiomers of the ester. ▼ (In the formula, A, X, l and m have the same meanings as above, and the * mark indicates an asymmetric carbon.) A method for producing optically active alcohols. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A is an alkyl group or alkoxyl group having 2 to 20 carbon atoms, and X is -COO-, -OCO
-, -CH_2O- or -OCH_2-, respectively, and l and m are each 1 or 2. ) is reacted with lower alkyl carboxylic acids to produce the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A, X, l and m have the same meanings as above, R ' represents a lower alkyl group) is obtained, and then asymmetric hydrolysis is carried out using an esterase capable of hydrolyzing only one of the enantiomers of the ester. and the general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A, X, l, and m have the same meanings as above, and the * mark indicates an asymmetric carbon.) A method for producing optically active alcohols. (4) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A is an alkyl group or alkoxyl group having 2 to 20 carbon atoms, and X is -COO-, -OCO
-, -CH_2O- or -OCH_2-, respectively, and l and m are each 1 or 2. ) by reducing the ketones using a reducing agent to obtain the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where A, X, l and m have the same meanings as above). The following dl-alcohols are obtained and reacted with lower alkyl carboxylic acids to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A, X, l and m have the same meanings as above. , R' represents a lower alkyl group), and then asymmetrically hydrolyzed using an esterase capable of hydrolyzing only one of the enantiomers of the esters. Characteristic general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A, X, l and m have the same meanings as above, and the * mark indicates an asymmetric carbon) A method for producing optically active alcohols.