JP3219531B2 - Method for producing optically active 1-aryl-3-chloro-1-propanol or carboxylic acid ester thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing optically active 1-aryl-3-chloro-1-propanol and its carboxylate useful as various bioactive substances such as pharmaceuticals and their synthetic intermediates. .

[0002]

BACKGROUND OF THE INVENTION Optically active 1-aryl-3-chloro-1
As a method for producing propanol or its carboxylic acid ester, a method for producing 3-chloropropiophenone by a chemical asymmetric reduction method [US Pat. No. 4,868,834, and
Tetrahedoron Lett., 30, 5207 (1989)], and a method of producing the same by a transesterification method using a lipase derived from Pseudomonas (Japanese Patent Laid-Open No. 1-2202296). However, the former method requires the use of an expensive asymmetric reducing agent. In the latter method, the reaction rate is low, and it is hard to say that it is an industrial production method. Thus, according to the conventional method, optically active 1-aryl-3 having high optical purity is used.
It is difficult to obtain -chloro-1-propanol and its carboxylic acid ester economically and efficiently.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for easily and efficiently producing an optically active 1-aryl-3-chloro-1-propanol or a carboxylic acid ester thereof having high optical purity. Is to provide.

[0004]

The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that an enantiomer mixture of 1-aryl-3-chloro-1-propanol and a carboxylic acid or a carboxylic acid ester are combined with Alcaligenes (Alcaligene).
s) When the reaction is carried out in the presence of an enzyme derived from a microorganism belonging to the genus, it has been found that a stereospecific esterification reaction rapidly proceeds, and the enantiomeric mixture is efficiently optically resolved, and the present invention has been completed. did.

That is, the present invention is represented by the general formula (I) RCH (OH) CH ₂ CH ₂ Cl (I) (wherein R represents an aryl group which may have a substituent). The enantiomer mixture of 1-aryl-3-chloro-1-propanol is reacted with a carboxylic acid or a carboxylic acid ester in the presence of a lipase derived from a microorganism belonging to the genus Alcaligenes, and the remaining optically active S form 1 -Aryl-3-chloro-1-propanol or optically active R-form carboxylic acid 1-aryl-3-chloropropyl ester to be produced is recovered. Optically active 1-aryl-3-chloro-1-propanol or a carboxylic acid ester thereof is recovered. Provide a manufacturing method.

The aryl group represented by R includes phenyl, naphthyl, phenanthryl, anthryl and the like.

The substituent of the aryl group includes halogen atoms of fluorine, chlorine, bromine and iodine; methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t.
-C such as butyl, pentyl, isopentyl, hexyl, etc.
Alkyl group of ₁ -C _6; vinyl, allyl, isopropenyl, 3-butenyl, alkenyl C ₂ -C ₆ such as 4-pentenyl; ethynyl, C ₂ ~ such as 2-propynyl
A C ₆ -alkynyl group; a C ₁ -C ₄ haloalkyl group such as chloromethyl and trifluoromethyl; a C ₁ -C ₄ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy; A nitro group; a cyano group; The aryl group may be substituted with a plurality of these substituents.

Specific examples of the compound represented by the general formula (I) include 3-chloro-1-phenyl-1-propanol and 3-chloro-1- (4-fluorophenyl) -1-
Propanol, 3-chloro-1- (2-chlorophenyl) -1-propanol, 3-chloro-1- (3-chlorophenyl) -1-propanol, 3-chloro-1-
(4-chlorophenyl) -1-propanol, 3-chloro-1- (2,4-dichlorophenyl) -1-propanol, 1- (4-bromophenyl) -3-chloro-1-
Propanol, 3-chloro-1- (4-methylphenyl) -1-propanol, 3-chloro-1- (4-isopropylphenyl) -1-propanol, 3-chloro-
1- (2,4-dimethylphenyl) -1-propanol, 1- (4-allylphenyl) -3-chloro-1-propanol, 3-chloro-1- (4-propargylphenyl) -1-propanol, -Chloro-1- (4-trifluoromethylphenyl) -1-propanol, 3-
Chloro-1- (2-methoxyphenyl) -1-propanol, 3-chloro-1- (3-methoxyphenyl) -1
-Propanol, 3-chloro-1- (4-ethoxyphenyl) -1-propanol, 3-chloro-1- (3-nitrophenyl) -1-propanol, 3-chloro-1-
(4-nitrophenyl) -1-propanol, 3-chloro-1- (4-cyanophenyl) -1-propanol,
3-chloro-1- (2-naphthyl) -1-propanol and the like.

The ratio of the R-form to the S-form in the enantiomeric mixture of 1-aryl-3-chloro-1-propanol is not particularly limited, but it is advantageous to use the racemic form from the viewpoint of economy.

The carboxylic acid may be a compound having a carboxyl group in the molecule, and may include a fatty acid, an alicyclic carboxylic acid, an aromatic carboxylic acid, and a heterocyclic carboxylic acid which may have a substituent. Can be

The optionally substituted fatty acids include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, hexanoic acid, decanoic acid, dodecanoic acid, hexadecanoic acid, octadecanoic acid, oxalic acid, malonic acid, succinic acid, saturated fatty acids C ₁ -C _18, such as adipic acid, acrylic acid, methacrylic acid, crotonic acid, oleic acid, maleic acid, C ₁ such as fumaric acid, acetylene dicarboxylic acid unsaturated fatty -C _18; chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, 3,3,
3-trichloro acid, 4-chloro-butyric acid, 6-chloro-hexanoic acid, C ₁ -C ₁₈ having 18-chloro octadecanoic acid, a halogen atom, such as 3-chloro-acrylic acid
Of fatty acids; methoxyacetic acid, ethoxy acetic acid, propoxy acetate, isopropoxy acetate, butoxy acetate, 3-methoxy propionic acid, C ₁ -C ₄ fatty acid having C ₁ -C ₄ alkoxy groups such as 4-ethoxy-butyric phenylacetate ,
3-phenylpropionic acid, fatty acid C ₁ -C ₄ or the like having an aryl group such as 4-phenylbutyric acid.

The alicyclic carboxylic acids which may have a substituent include cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, cycloheptanecarboxylic acid, cyclooctanecarboxylic acid, 2-octanecarboxylic acid, Chlorocyclopentanecarboxylic acid, 2
- it includes unsubstituted and halogen atoms, such as methyl cyclohexane carboxylic acid, alicyclic carboxylic acids such C ₄ -C ₁₁ having substituents such as C ₁ -C ₄ alkyl group.

The aromatic carboxylic acid which may have a substituent includes benzoic acid, phthalic acid, isophthalic acid, cinnamic acid, 2-naphthalene acid, 2-chlorobenzoic acid, toluic acid, 2-methoxybenzoic acid Acid, 3-cyanobenzoic acid, 4-
Unsubstituted and halogen atoms such as nitrobenzoic acid, C _1-
C ₄ alkyl group, C ₁ -C ₄ alkoxy group, cyano group,
An aromatic carboxylic acid having a substituent such as a nitro group is included.

The heterocyclic carboxylic acid which may have a substituent includes 5-membered heterocyclic carboxylic acids such as 2-furancarboxylic acid, 2-thiophenecarboxylic acid, 2-methyl-3-pyrrolecarboxylic acid; nicotine Acid, isonicotinic acid, 2-
6-membered heterocyclic carboxylic acids such as pyrazine carboxylic acid and 5-chloro-2-pyridimine carboxylic acid; condensed heterocyclic carboxylic acids such as 3-benzofuran carboxylic acid, 3-indole carboxylic acid and 2-quinoxaline carboxylic acid are included. It is.

The carboxylic acid ester may be any compound having an ester group in the molecule. Examples of the carboxylic acid esters described above, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl , Hexyl and the like C ₁ -C ₆ alkyl esters; vinyl, isopropenyl, 1-ethylvinyl, allyl, propargyl, 2-butenyl, 3-butenyl, 2
- C ₂ such as methyl-2-propenyl, 4-pentenyl
-C ₆ alkenyl or alkynyl ester; chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 4-C ₁ -C ₆ haloalkyl esters such as chlorobutyl; methoxymethyl, ethoxymethyl, methoxy cyclopropyl; benzyl, diphenylmethyl, trityl, phenethyl, 3-phenylpropyl C ₇ -C ₁₉ aralkyl esters such as Le; ethyl, isopropoxyethyl, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl esters, such as butoxybutyl , Cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl, C ₃ -C ₁₀ cycloalkyl esters, such as cyclooctyl group; phenyl, 1-naphthyl, 2-
Chlorophenyl, o- tolyl, m- tolyl, p- tolyl, 2,3-xylyl, unsubstituted or halogen atoms, such as 3-methoxyphenyl, C ₁ -C ₄ alkyl group, C ₁ ~
An aryl ester having a substituent such as a C ₄ alkoxy group is exemplified.

Of these carboxylic acids and carboxylic esters, carboxylic esters are preferred from the viewpoint of the reaction rate. Further, since the alcohol produced by the reaction isomerized immediately to acetaldehyde or ketone, the reverse reaction is almost completely suppressed, and therefore, carboxylic acid vinyl esters such as carboxylic acid vinyl esters and carboxylic acid isopropenyl esters are preferably used. Can be

[0017] Preferred carboxylic acid vinyl esters, vinyl formate, vinyl acetate, vinyl isopropenyl acetate, propionate, C ₁ isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl valerate, etc. valerate isopropenyl -C ₅ saturated fatty acid vinyl esters; vinyl chloroacetate, chloroacetic acid isopropenyl,
Vinyl trifluoroacetate, 4-C ₁ -C ₅ fatty acid vinyl esters having a halogen atom such as chloro vinyl butyrate; methoxyacetic acid vinyl, ethoxy isopropenyl acetate, vinyl isopropoxy acetate, vinyl butoxy acetate,
C having a C ₁ -C ₄ alkoxy group such as vinyl 3-methoxypropionate and isopropenyl 4-ethoxybutyrate
_{1 to} C ₄ fatty acid vinyl esters; vinyl benzoates, isopropenyl benzoate, vinyl o-toluate, vinyl 2-naphthalenecarboxylate, and other aromatic carboxylic acid vinyl esters. Among these, C ₁ to C _4, such as vinyl acetate, isopropenyl acetate and vinyl butyrate, are particularly preferred.
C ₅ saturated fatty acid vinyl esters are often used.

The enzyme used in the present invention may be an enzyme derived from a microorganism belonging to the genus Alcaligenes and has any asymmetric esterification ability.

The microorganism belonging to the genus Alcaligenes is a non-polar hairy flagella (peri- or subpolar hair).
Is a gram-negative rod-shaped bacterium having no 3-keto lactose, utilizing amino acids, nitrate, ammonium nitrogen and citric acid, growing aerobically without growing anaerobically, It has mycological properties such as not producing remarkable pigments. The microorganism may be any of a wild strain, a mutant strain, and a recombinant strain derived by cell fusion or genetic engineering.

The enzymes include lipase and the like.

The enzyme of the present invention can be obtained by culturing the microorganism by a conventional method. For example, a microorganism containing a carbon source such as starch, a nitrogen source such as soybean flour, an inorganic salt such as dipotassium phosphate is inoculated with the microorganism, and cultured at, for example, about 15 to 40 ° C., followed by extraction, filtration, The enzyme can be easily collected by separation and purification means such as centrifugation, concentration, and precipitation.

A method for producing a lipase derived from a microorganism belonging to the genus Alcaligenes is disclosed in
8-36953 and JP-B-60-15312 can be referred to. Examples of such microorganisms include, for example,
Meitosu PL-266 [Microtechnical Laboratory No. 3187 (FERM-P
No.3187)], Meito PL-679 [Microtechnical Laboratory No. 3
No. 783 (FERM-P No. 3783)]. Lipases derived from microorganisms belonging to the genus Alcaligenes include, for example, lipase PL [manufactured by Meito Sangyo Co., Ltd.]
It is commercially available as

The form of use of the enzyme is not particularly limited, and the cells of the microorganism producing the enzyme may be used as they are.
A crude enzyme or a purified enzyme obtained from cells may be used.
Further, the enzyme can be used by being immobilized on a carrier by a conventional method.

In the method of the present invention, the enantiomer mixture of 1-aryl-3-chloro-1-propanol represented by the general formula (I) and a carboxylic acid or a carboxylic acid ester are reacted in the presence of the enzyme. To react.

The reaction may be carried out without adding a solvent, or may be carried out in a solvent. The solvent is not particularly limited as long as the solvent does not adversely affect the reaction, for example, isobutane, isopentane, pentane, hexane, 2-methylpentane, heptane, octane, linear or branched aliphatic such as decane Hydrocarbons; alicyclic hydrocarbons such as cyclopentane and cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, cymene, mesitylene, diisopropylbenzene; methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane And the like; aliphatic ethers such as diethyl ether, diisopropyl ether and dibutyl ether; and alicyclic ethers such as tetrahydrofuran and tetrahydropyran. These solvents can be used alone or in combination of two or more. Among the above solvents, aliphatic hydrocarbons such as hexane, methylene chloride, halogenated hydrocarbons such as carbon tetrachloride, toluene,
Aromatic hydrocarbons such as diisopropylbenzene and aliphatic ethers such as diethyl ether, diisopropyl ether and dibutyl ether are particularly preferably used.

The concentration of the enantiomer mixture is not particularly limited, but may be, for example, 0.1 to 70% [w / v (g /
ml)], preferably 1 to 40% [w / v (g / m
l)].

The amount of the carboxylic acid or carboxylic acid ester to be used is appropriately determined in consideration of the reaction rate, economy and the like, but is usually 0.5 to 100 mol, preferably 0 to 100 mol, per 1 mol of the enantiomer mixture. It is about 6 to 30 mol.

The amount of the enzyme used can be selected within a range that does not reduce the amount of the target compound produced and the optical purity. For example, 1 to 1 part by weight based on 100 parts by weight of the enantiomeric mixture.
It is about 000 parts by weight.

The reaction temperature varies depending on the type of the enzyme used, but is usually 0 to 60 ° C, preferably 4 to 50 ° C, more preferably about 15 to 45 ° C. The reaction may be performed by any method with stirring or standing, but is preferably performed by efficiently contacting the reaction components and the enzyme with stirring.

The progress of the reaction was determined by gas chromatography,
It can be monitored by conventional analytical means such as thin layer chromatography and high performance liquid chromatography.

When the enantiomeric mixture of 1-aryl-3-chloro-1-propanol represented by the general formula (I) is reacted with the carboxylic acid or carboxylic acid ester in the presence of the enzyme, In the enantiomeric mixture, one of the enantiomers is stereospecifically and rapidly esterified to change to a corresponding carboxylic acid ester, and the other enantiomer selectively remains unreacted. Then, when a carboxylic acid is used as a reaction component, water is used, and when a carboxylic acid ester is used, a corresponding alcohol (however, in the case of vinyl esters,
Vinyl alcohols are isomerized to form acetaldehyde or ketone). The reaction rate is remarkably fast as compared with the case where a lipase derived from Pseudomonas is used.

The optically active 1-aryl-3-chloro-1-propanol remaining as a result of the reaction and the optically active carboxylic acid 1-aryl-3-chloropropyl ester formed by the reaction can be recovered by conventional separation and purification means. . For example, ordinary purification such as membrane separation, extraction, column chromatography, thin layer chromatography, concentration, distillation, and in some cases crystallization and recrystallization, after directly removing the enzyme from the reaction solution or by removing the enzyme by centrifugation or filtration. By subjecting to the means, the target compound can be easily obtained.

The optical purity of the target compound is, for example,
It can be measured by high performance liquid chromatography using an optical isomer separation column.

The recovered optically active carboxylic acid 1-aryl-3-chloropropyl ester is hydrolyzed by a conventional method to give the corresponding optically active 1-aryl-3-chloropropyl ester.
It can be easily converted to chloro-1-propanol. Therefore, according to the method of the present invention, an enantiomeric mixture of 1-aryl-3-chloro-1-propanol can be efficiently optically resolved, and two enantiomers having different configurations can be obtained with high optical purity and high yield. Can be. When only one enantiomer is useful,
Unwanted enantiomers can be prepared by conventional methods, for example, acid, base,
After racemization by an enzyme or heating, it can be converted into a useful enantiomer by using it as a reaction raw material of the present invention. Further, the separated enzyme can be reused in the reaction system.

The thus obtained optically active 1-aryl-
3-chloro-1-propanol and 1-aryl-3-chloropropyl ester of optically active carboxylic acid can be suitably used as various pharmaceuticals or synthetic intermediates thereof.

[0036]

According to the production method of the present invention, a stereospecific esterification reaction proceeds at a high reaction rate by the action of an enzyme, so that the optical activity of a high optical purity can be easily, efficiently and economically increased. -Aryl-3-chloro-1-propanol and optically active carboxylic acid 1-aryl-3-chloropropyl esters can be prepared.

[0037]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to only these Examples.

In the examples, the amounts of the reaction components and the reaction products were determined by gas chromatography [column: Silicone OV-1710 manufactured by Gaschrom Industry Co., Ltd.].
%, 2 m, temperature 180 ° C.], and the optical purity was measured by high performance liquid chromatography using an optical resolution column [Column: Chiral Cell O manufactured by Daicel Chemical Industries, Ltd.]
B, solvent: n-hexane / 2-propanol = 19/1
(V / v), flow rate: 1.0 ml / min, temperature: 40 ° C., wavelength: 220 nm].

Example 1 0.1 g of lipase PL [manufactured by Meito Sangyo Co., Ltd.] was placed in a 21 mm-diameter screw-mouth test tube, and 3-chloro-1 was added thereto.
0.2 g of racemic -phenyl-1-propanol, 0.1 ml of vinyl acetate and 5 ml of n-hexane were added, and 3
Shake at 0 ° C. for 48 hours. As a result of analyzing the reaction solution by gas chromatography, 3-chloro-1-phenyl-1-
The conversion of propanol to 3-chloro-1-phenylpropyl acetate was 20%.

The reaction solution was filtered to remove the enzyme, the solvent was distilled off, and the residue was purified by silica gel thin-layer chromatography (developing solution: n-hexane / ethyl acetate = 9/1).
Chloro-1-phenyl-1-propanol and acetic acid 3-
Chloro-1-phenylpropyl was isolated, and the optical purity was measured by high performance liquid chromatography. As a result, the obtained 3-chloro-1-phenyl-1-propanol was in the S form, and its optical purity was 22% ee. Further, the obtained 3-chloro-1-phenylpropyl acetate was an R-isomer and had an optical purity of 85% ee.

Example 2 A reaction was carried out in the same manner as in Example 1, except that 5 ml of toluene was used instead of n-hexane and the reaction time was 47 hours. Purification and analysis were performed in the same manner as in Example 1, and the conversion rate and the optical purity of the product were determined. As a result, the conversion was 26%, and the obtained 3-chloro-1-phenyl-1-propanol was in the S form, and had an optical purity of 32%.
ee, the obtained 3-chloro-1-phenylpropyl acetate was R-form, and the optical purity was 90% ee.

Example 3 In a 100 ml Erlenmeyer flask, 1.0 g of lipase PL [manufactured by Meito Sangyo Co., Ltd.], 3-chloro-1-phenyl-1
2.0 g of racemic propanol, 20 m of vinyl acetate
1 was shaken at 30 ° C. for 48 hours to carry out a reaction. Thereafter, purification and analysis were performed in the same manner as in Example 1, and the conversion rate and the optical purity of the product were determined. As a result, the conversion was 42%, the obtained 3-chloro-1-phenyl-1-propanol was in the S form, the optical purity was 68% ee, and the obtained acetic acid 3-
Chloro-1-phenylpropyl was an R-isomer and had an optical purity of 92% ee.

Example 4 0.2 g of lipase PL (manufactured by Meito Sangyo Co., Ltd.) and 3-chloro-1-phenyl-1 were placed in a 21 mm-diameter screw-mouth test tube.
0.2 g of racemic propanol, 0.4 of vinyl butyrate
Then, 5 ml of toluene and 5 ml of toluene were collected and shaken at 30 ° C. for 26 hours to carry out a reaction. Thereafter, purification and analysis were performed in the same manner as in Example 1. As a result, the conversion was 41%, and the obtained 3-chloro-1-phenyl-1-propanol was in the S form, and had an optical purity of 66% ee.

Example 5 A reaction, purification and analysis were carried out in the same manner as in Example 4 except that 0.4 ml of isopropenyl acetate was used instead of vinyl butyrate. As a result, the conversion was 18%, and the obtained 3-chloro-1-phenyl-1-propanol was in S form, and the optical purity was 85% ee.

Example 6 3-Chloro-1- (4-chlorophenyl) was used instead of the racemic 3-chloro-1-phenyl-1-propanol.
The reaction, purification and analysis were carried out in the same manner as in Example 1, except that 0.2 g of racemic -1-propanol was used. As a result, the conversion was 22%, the obtained 3-chloro-1- (4-chlorophenyl) -1-propanol was in the S form, the optical purity was 25% ee, and the obtained acetic acid 3-
Chloro-1- (4-chlorophenyl) propyl was in the R form and had an optical purity of 84% ee.

Claims (2)

(57) [Claims] 1. 1-aryl- represented by the general formula (I) RCH (OH) CH ₂ CH ₂ Cl (I) wherein R represents an aryl group which may have a substituent. The enantiomer mixture of 3-chloro-1-propanol is reacted with a carboxylic acid or a carboxylic acid ester in the presence of a lipase derived from a microorganism belonging to the genus Alcaligenes, and the remaining optically active S-form 1-aryl-3 is obtained. -A method for producing optically active 1-aryl-3-chloro-1-propanol or a carboxylic acid ester thereof by recovering chloro-1-propanol or the resulting optically active R-form carboxylic acid 1-aryl-3-chloropropyl ester. 2. The method for producing optically active 1-aryl-3-chloro-1-propanol or a carboxylic acid ester thereof according to claim 1, wherein a carboxylic acid vinyl ester is used as the carboxylic acid ester.