JPH09289897A - Production of optically active 2-halo-1-(substituted phenyl)ethanol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply obtain the subject compound for medicines and agrochemicals or shythetic intermediate thereof by bringing a specific 2- halo-1-(substituted phenyl)ethanol into contact with an enzyme having stereoselective ester exchange ability in the presence of carboxylic acid anhydride. SOLUTION: A 2-halo-1-(substituted phenyl)ethanol represented by formula I (X is Cl or Br; R1 to R3 are each H, a halogen, a 1-5C alkyl, a 1-5C haloalkyl, a 1-5C alkoxy, cyano, nitro or two groups of R1 to R3 together may form a ring, with the proviso that R1 to R3 are simultaneously not H) is brought into contact with an enzyme (e.g. a lipase derived from a microorganisms of the genus Pseudomonas) having stereoselective ester exchange ability to simply provide the objective optically active 2-halo-1-(substituted phenyl)ethanol represented by formula II useful as an optically active medicine or an agrochemical or a synthetic intermediate thereof.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active 2-halo-1- (substituted phenyl) ethanol. Specifically, the present invention efficiently produces optically active 2-halo-1- (substituted phenyl) ethanol (II) from 2-halo-1- (substituted phenyl) ethanol (I) using a specific enzyme. , A method for easily producing an optically active substituted styrene oxide (IV) by treating the compound with a base, and treating the compound with a base to obtain an optically active substituted styrene oxide (IV), Then, by reacting with an amine compound, an optically active 2-amino-
It relates to a method for producing 1- (substituted phenyl) ethanol (V). These compounds are useful as optically active medicines and agricultural chemicals or their synthetic intermediates.

[0002]

2. Description of the Related Art Conventionally, as a method for producing optically active 2-halo-1- (substituted phenyl) ethanol and optically active substituted styrene oxide, 3-chlorophenacyl chloride is asymmetrically borane-reduced to give optically active compounds. 2-chloro- (3-
(Chlorophenyl) ethanol is produced, and then the ring is closed to produce an optically active 3-chlorostyrene oxide (J. Med. Chem., 35, 3081).
(1992)) and an asymmetric reduction of a substituted phenacyl halide with a microorganism to produce an optically active 2-halo-1- (substituted phenyl) ethanol, which is then ring-closed to give an optically active substituted styrene oxide. A manufacturing method (Japanese Patent Laid-Open No. 4-218384) and the like are known.

[0003]

However, since the above-mentioned production method uses a substituted phenacyl halide having strong tearing property and high toxicity, there are problems in operability and waste disposal, and in the former case, ) Use borane which is expensive, unstable and difficult to handle as a reaction reagent 2)
There are drawbacks such as the use of an expensive optically active ligand, and 3) the optical purity of the product is not sufficient at 85% ee. In the latter case, the optical purity of the product is 95% ee or more, which is satisfactory. However, it is not satisfactory as an industrial production method because it has a drawback that it can be performed only at a low concentration of 1% or less. An object of the present invention is to provide an optically active 2 which is useful as a medicine, a pesticide or an intermediate thereof.
A method for industrially producing -halo-1- (substituted phenyl) ethanol is provided, and in addition, optically active substituted styrene oxide or optically active 2-amino-1- (substituted phenyl) ethanol is easily prepared. It is to provide a manufacturing method.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that 2-halo-1- (substituted phenyl) ethanol (I) is enzymatically stereoselectively esterified with 2-halo-1- (substituted phenyl) ethanol (I). Optically resolved into optically active 2-halo-1- (substituted phenyl) ethanol ester (VI) and enantiomer optically active 2-halo-1- (substituted phenyl) ethanol (II). The optically active 2-halo-1- (substituted phenyl) ethanol compound is obtained by separating and collecting the body, and the optically active 2-halo-1- (substituted phenyl) ethanol (II) obtained by the above method. Is treated with a base to undergo ring closure to form an optically active substituted styrene oxide (IV), and then reacted with an amine compound to give an optically active 2-amino-1- Substituted phenyl) ethanol (V)
The present invention has been completed by finding that the compound can be easily produced. That is, the gist of the present invention is the general formula (I)

[0005]

[Chemical 6]

(In the formula, X represents a chlorine atom or a bromine atom. R ₁ , R ₂ and R ₃ are hydrogen atoms, halogen atoms, alkyl groups having 1 to 5 carbon atoms, and haloalkyl having 1 to 5 carbon atoms. Group, an alkoxy group having 1 to 5 carbon atoms, a cyano group or a nitro group, which may be the same or different, and when two of the above substituents are an alkyl group or an alkoxy, they are integrally To form a ring, provided that 2-halo-1- (substituted phenyl) ethanol represented by R ₁ , R ₂ and R ₃ are not hydrogen atoms at the same time. General formula (II) characterized by contacting with an enzyme having stereoselective transesterification in the presence of a substance

[0007]

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(Wherein X, R ₁ , R ₂ and R ₃ have the same meanings as in formula (I)), a method for producing an optically active 2-halo-1- (substituted phenyl) ethanol, An optically active substituted styrene oxide (I) characterized in that the optically active 2-halo-1- (substituted phenyl) ethanol (II) obtained by the production method is further treated with a base.
V) and a method for producing an optically active 2-amino-1- (substituted phenyl) ethanol (V), which comprises reacting the optically active substituted styrene oxide (IV) with an amine. Exist in. Hereinafter, the present invention will be described in detail.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Method for producing optically active 2-halo-1- (substituted phenyl) ethanol (II) The production method of the present invention is a 2-halo-1- (substituted phenyl) ethanol represented by the general formula (I). And an acyl donor carboxylic acid anhydride with an enzyme having a stereoselective transesterification ability. In this reaction, as shown in the following reaction formula-1, only the (S) form of 2-halo-1- (substituted phenyl) ethanol is esterified, and the (R) form is obtained as an alcohol form as it is.
If necessary, each of these reaction mixtures can be separated to obtain highly pure optically active isomers.

[0010]

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Further, the compound of the general formula (VI) can be used in various reactions as an optically active alcohol in the (S) form, if deprotected while retaining its steric structure.
It can also be recycled as a starting material (I) for this reaction by racemization in a protic solvent using an acid catalyst. As a raw material for the method of the present invention, a compound represented by the general formula (I)

[0012]

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The compound represented by In the above general formula (I), X is a chlorine atom or a bromine atom, and R ₁ , R
₂ and R ₃ are hydrogen atoms; halogen atoms such as chlorine atom, bromine atom, iodine atom; methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, n
An alkyl group having 1 to 5 carbon atoms such as a pentyl group; a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group,
C1-C5 haloalkyl group such as trichloromethyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group, 2,2-dimethylpropoxy group, butoxy group, 2-methylbutoxy group, pentoxy group, etc. 1
An alkoxy group of 5; a cyano group; or a nitro group. Of these, a halogen atom and a carbon number of 1 to 5 are preferable.
Is an alkyl group, a haloalkyl group having 1 to 2 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, and particularly preferably a halogen atom. In addition, R ₁ , R ₂ and R ₃ may be the same or different. When two of the above substituents are an alkyl group or an alkoxy, they may be combined together to form an alkylene group, an alkyleneoxy group or an alkylenedioxy group. However,
R ₁ , R ₂ and R ₃ are not hydrogen atoms at the same time.

Specific examples of 2-halo-1- (substituted phenyl) ethanol used in the present invention include 2-bromo-1- (3-chlorophenyl) ethanol and 2-bromo-1- (3-bromophenyl). ) Ethanol, 2-bromo-1- (4-bromophenyl) ethanol, 2-bromo-1- (4-fluorophenyl) ethanol, 2-bromo-1- (3-iodophenyl) ethanol, 2-bromo-1 -(3,5-dichlorophenyl) ethanol, 2
-Bromo-1- (3-trifluoromethylphenyl) ethanol, 2-bromo-1- (3-methoxyphenyl)
Ethanol, 2-bromo-1- (4-methoxyphenyl) ethanol, 2-bromo-1- (3,4-methylenedioxyphenyl) ethanol, 2-bromo-1- (4
-Cyanophenyl) ethanol, 2-bromo-1- (4
-Nitrophenyl) ethanol, 2-chloro-1- (3
-Chlorophenyl) ethanol, 2-chloro-1- (3
-Bromophenyl) ethanol, 2-chloro-1- (4
-Bromophenyl) ethanol, 2-chloro-1- (4
-Fluorophenyl) ethanol, 2-chloro-1-
(3-Iodophenyl) ethanol, 2-chloro-1-
(3,5-Dichlorophenyl) ethanol, 2-chloro-1- (3-trifluoromethylphenyl) ethanol, 2-chloro-1- (3-methoxyphenyl) ethanol, 2-chloro-1- (4-methoxyphenyl) ) Ethanol, 2-chloro-1- (3,4-methylenedioxyphenyl) ethanol, 2-chloro-1- (4-cyanophenyl) ethanol, 2-chloro-1- (4-nitrophenyl) ethanol, etc. And preferably 2
-Bromo-1- (3-chlorophenyl) ethanol, 2
-Bromo-1- (3-bromophenyl) ethanol, 2
-Bromo-1- (4-bromophenyl) ethanol, 2
-Bromo-1- (4-fluorophenyl) ethanol,
2-bromo-1- (3-iodophenyl) ethanol,
2-Bromo-1- (3,5-dichlorophenyl) ethanol, 2-bromo-1- (3-trifluoromethylphenyl) ethanol, 2-bromo-1- (3-methoxyphenyl) ethanol, 2-bromo-1 -(4-methoxyphenyl) ethanol, 2-bromo-1- (3,4-methylenedioxyphenyl) ethanol, 2-chloro-1
-(3-chlorophenyl) ethanol, 2-chloro-1
-(3-Bromophenyl) ethanol, 2-chloro-1
-(4-Bromophenyl) ethanol, 2-chloro-1
-(4-Fluorophenyl) ethanol, 2-chloro-
1- (3-iodophenyl) ethanol, 2-chloro-
1- (3,5-dichlorophenyl) ethanol, 2-chloro-1- (3-trifluoromethylphenyl) ethanol, 2-chloro-1- (3-methoxyphenyl) ethanol, 2-chloro-1- (4- Methoxyphenyl) ethanol and 2-chloro-1- (3,4-methylenedioxyphenyl) ethanol, and more preferably 2
-Bromo-1- (3-chlorophenyl) ethanol, 2
-Bromo-1- (3-bromophenyl) ethanol, 2
-Bromo-1- (4-bromophenyl) ethanol, 2
-Bromo-1- (4-fluorophenyl) ethanol,
2-bromo-1- (3-iodophenyl) ethanol,
2-chloro-1- (3-chlorophenyl) ethanol,
2-chloro-1- (3-bromophenyl) ethanol,
2-chloro-1- (4-bromophenyl) ethanol,
2-chloro-1- (4-fluorophenyl) ethanol and 2-chloro-1- (3-iodophenyl) ethanol are exemplified.

The compound represented by the general formula (I) used in the present invention is hydrolyzed, for example, by using 1,2-dihalo-1-substituted phenylethane in an aqueous solution and optionally using iodide as a catalyst. It can be easily synthesized by a method of decomposing, a method of reducing an acetophenone compound with sodium borohydride or the like. The carboxylic acid anhydride used in the method of the present invention has the general formula (III)

[0016]

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What is represented by is used. The above general formula (II
In I), R ₄ and R ₅ are each independently a halogen atom, an alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 5 carbon atoms and 6 to 10 carbon atoms, of which 1 to 3 are N,
A linear or branched alkyl group having 1 to 20 carbon atoms or 1 to carbon atoms, which may be substituted with a substituent selected from any of aromatic groups which may be replaced by either O or S. 20 straight or branched alkenyl groups, or a carbon which may be substituted with a substituent selected from a halogen atom, an alkoxy group having 1 to 5 carbon atoms and an acyl group having 1 to 5 carbon atoms. The number is 6 to 10, and 1 to 3 of them are aromatic groups which may be replaced by any of N, O, and S. R ₄ and R ₅ may together form a ring, in which case R ₄ and R 5
_It is preferable that ₅ are combined to form a carbon ring having 2 to 3 carbon atoms. Of these, preferably halogen and 1 to 1 carbon atoms.
5 alkoxy group, 1 to 5 carbon acyl group and 1 to 20 carbon linear or branched alkyl group which may be substituted with a substituent selected from any of phenyl groups, 1 to 10 carbon atoms Is a linear or branched alkenyl group, or a phenyl group or a pyridyl group which may be substituted with a halogen atom, and particularly preferably a linear alkyl group having 1 to 12 carbon atoms.

Examples of the halogen atom include a chlorine atom and a bromine atom; examples of the alkoxy group having 1 to 5 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a 2,2-dimethylpropoxy group, Examples thereof include butoxy group, 2-methylbutoxy group, pentoxy group, etc .; as the acyl group, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, acryloyl group, methacryloyl group, crotonoyl group, isocrotonoyl group. And the like; carbon number 6 to 10
Examples of the aromatic group in which 1 to 3 of them may be replaced by any of N, O and S include a phenyl group and a pyridyl group.

As the linear or branched alkyl group having 1 to 20 carbon atoms, methyl group, ethyl group, n-propyl group, n
-Butyl group, t-butyl group, n-pentyl group, 2-ethylpentyl group, n-hexyl group, n-heptyl group, n-
Undecyl group, n-tridecyl group, n-pentadecyl group, n-heptadecyl group, etc. are mentioned; C1-C20
Examples of the linear or branched alkenyl group include vinyl group, 1
-Propenyl group, isopropenyl group, 1-butenyl group,
2- (1-butenyl) group, 2- (2-butenyl) group, 1
-Pentenyl group, 2- (1-pentenyl) group, 2- (2
-Pentenyl) group, 1-hexenyl group, 2- (1- (4
-Methylpentenyl) group, 2- (2- (4-methylpentenyl) group and the like; and further having 6 to 10 carbon atoms, 1 to 3 of which may be replaced by N, O or S. Examples of the good aromatic group include a phenyl group and a pyridyl group.

Among these, specific examples of the carboxylic acid anhydride include acetic anhydride, chloroacetic anhydride, bromoacetic anhydride, methoxyacetic anhydride, ethoxyacetic anhydride, phenylacetic anhydride, chlorophenylacetic anhydride, propionic anhydride, and chloropropion anhydrous. Acid, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, caproic anhydride, caprylic anhydride, capric anhydride, lauric acid anhydride, acrylic acid anhydride, methacrylic acid anhydride, crotonic acid anhydride, benzoic acid anhydride, Examples thereof include chlorobenzoic anhydride, picolinic anhydride, chloropicolinic anhydride and the like, and those in which R ₄ and R ₅ are integrated include succinic anhydride, maleic anhydride, glutaric anhydride, phthalic anhydride and the like. Can be mentioned. Preferably, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, caproic anhydride,
Examples thereof include caprylic anhydride, capric anhydride, and lauric anhydride. From the viewpoint of reaction rate, ease of repeated use of enzyme, and ease of post-treatment, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, caproic anhydride, caprylic anhydride, capric anhydride are more preferable. An acid is mentioned.

The amount of these carboxylic acid anhydrides used is 0.5 to 100 equivalents relative to the racemic 2-halo-1- (substituted phenyl) ethanol (I). As the enzyme used in the present invention, any enzyme having stereoselective transesterification ability with respect to 2-halo-1- (substituted phenyl) ethanol can be used. Examples of the enzyme include lipase and esterase.
The lipase and esterase are preferably those derived from microorganisms, particularly preferably Pseudomonas (Ps).
eudomonas genus, Alcaligenes (Alcal
igenes), Achromobacter
It is a lipase derived from a microorganism belonging to the genus Bacter, the genus Candida or the genus Rhizopusu. Of these, lipases derived from microorganisms belonging to the genus Pseudomonas or the genus Alcaligenes are more preferable in terms of reactivity or selectivity of optical isomers.

Pseudomona
s) As a lipase derived from a microorganism belonging to the genus, specifically, Toyozyme. LIP (Toyobo Co., Ltd. immobilized lipase), Lipase PS (Amano Pharmaceutical Co., Ltd.), Lipase A
K (manufactured by Amano Pharmaceutical Co., Ltd.) and the like, and as the lipase derived from a microorganism belonging to the genus Alcaligenes, specifically, lipase PL (manufactured by Meito Sangyo Co., Ltd.), lipase QL (Meito Sangyo Co., Ltd.) Manufactured). In addition, as these enzymes, bacterial cells, processed bacterial cells,
A culture supernatant, a culture solution, a crude enzyme solution, a purified enzyme solution, etc. dried by acetone treatment or freeze-drying treatment may be directly used, or may be further immobilized on a carrier before use. Good.

Further, these enzymes may be produced by a recombinant bacterium into which the gene of the enzyme has been introduced by a gene recombination technique. The enzyme used in the present invention is used in an amount of 0.01 to 200% by weight, preferably 1 to 50% by weight, based on racemic 2-halo-1- (substituted phenyl) ethanol (I). It should be noted that, when the enzyme is immobilized or the enzyme reaction is performed, 0.01 to 1 is added to the enzyme.
Coexistence of sucrose fatty acid ester in an amount of 00% by weight is preferable because the reactivity and stereoselectivity in the enzymatic reaction are improved, the productivity and the optical purity of the product are increased. Examples of the sucrose fatty acid ester generally include partial esters of sucrose with higher fatty acids having 10 to 24 carbon atoms such as stearic acid, lauric acid, palmitic acid, behenic acid, and mistyric acid.

The addition amount is 0.01 to 1 with respect to the enzyme.
Used between 00% by weight. The method for immobilizing the enzyme may be any of binding, adsorption, deposition and entrapment, for example,
0.01 to 0.01 in a buffer having a concentration of 0.001 to 0.1 molar
Dissolve sucrose fatty acid ester to a concentration of 1 wt%, dissolve 0.1 to 20 times equivalent amount of enzyme with respect to sucrose fatty acid ester, stir for 1 hour to 2 days, and allow sufficient contact. Immobilized carrier is 1-100 for enzyme
Add 0 times the equivalent amount and allow to fully adsorb for 1 to 7 days.
This is freeze-dried or air-dried to produce an immobilized enzyme. Any buffer may be used as long as it is suitable for expressing the activity of the enzyme, but Tris buffer, phosphate buffer, Good's buffer and the like are preferable. The immobilization carrier may be any carrier as long as it can immobilize the enzyme, and examples thereof include diatomaceous earth, activated carbon, silica gel, porous glass, ion exchange resin and the like. The shape of the immobilization carrier may be any of fine particles, beads, films, fibers, and the like, but is preferably fine particles or beads.

The pH of the buffer solution is 4-10, preferably 6-.
9 The temperature for immobilization is 1 to 50 ° C, preferably 4 to 20 ° C. When one or more hydrophobic porous substances, disaccharides and surfactants are added to the reaction system during the reaction of the enzyme, the reactivity and stereoselectivity in the enzyme reaction are improved and the productivity and the optical purity of the product are increased. Therefore, it is preferable. Examples of the hydrophobic porous substance include molecular sieves, activated carbon, and Celite. The amount of addition is 0.1 to 100 times the amount of the enzyme. Examples of the disaccharide include lactose, sucrose, maltose and trehalose. The amount added was 0.
It is used in an amount of 1 to 100 times by weight. As the surfactant, in addition to sugar ester, CHAPS (manufactured by Nacalai Tesque, Inc.), Nonidet P-40, Brij58 (manufactured by Sigma), n-octyl-b-thioglucosi.
de, n-Heptyl-b-thioglucosi
de (manufactured by Doujin Kagaku Co., Ltd.), Tween 20, Tween 4
0, Tween80 (manufactured by Kao Corporation), TritonX-1
00, Triton N-101 (manufactured by Aldrich) and the like.

In this reaction, the reaction is carried out without a solvent or in the presence of an organic solvent, but it is preferable to use a solvent in order to suppress the activity decrease of the enzyme. The solvent used in the reaction is not particularly limited, but is an ether solvent such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran; hexane, heptane, isooctane, toluene, xylene, etc. Hydrocarbon solvents; ester solvents such as methyl acetate and ethyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvents such as chloroform and dichloromethane; dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like. However, an ether solvent or a hydrocarbon solvent is preferably used.

The amount of the solvent used is usually 0 to 100 times the weight of 2-halo-1- (substituted phenyl) ethanol represented by the general formula (I), which is a productivity factor. Therefore, the amount is preferably 0.01 to 20 times, and particularly preferably 0.05 to 10 times. In the method of the present invention,
Good reaction can be performed even at a relatively high concentration. As the reaction mode of this reaction, an enzyme having stereoselective transesterification ability is suspended in a mixture of 2-halo-1- (substituted phenyl) ethanol (I) and carboxylic acid anhydride (III) which is an acyl donor. Alternatively, the enzyme may be packed in a column, and a mixture of 2-halo-1- (substituted phenyl) ethanol (I) and carboxylic acid anhydride (III) is passed through the column. It can also be done by After completion of the reaction, the enzyme is removed by filtration or centrifugation, the filtrate is concentrated, and then purified by extraction, distillation, column chromatography or the like to obtain highly pure optically active 2-halo-1- (substituted phenyl) ethanol. The compound (II) and the optically active 2-halo-1- (substituted phenyl) ethanol ester (VI) are obtained. The enzyme separated by filtration can be reused as it is in the next enzymatic reaction.

The reaction can be carried out in an aerobic atmosphere or an anaerobic atmosphere, and the reaction temperature is usually 0-100.
C., preferably in the range of 20 to 50.degree. C., and the reaction time is usually in the range of 1 hour to several days. The optical purity of the optically active 2-halo-1- (substituted phenyl) ethanol (II) obtained by this reaction was determined by high performance liquid chromatography (column: manufactured by Daicel Chemical Industries Ltd., Chiral).
cel-OJ, elution solvent: hexane-isopropanol (10: 1 to 50: 1), flow rate 1.0 ml / min, detection 2
20 nm).

The optically active 2-halo-1- (substituted phenyl) ethanol ester (VI) produced as a by-product of the above-mentioned enzymatic reaction is usually separated after completion of the enzymatic reaction or after the ring-closing reaction described below, and this is isolated. Can be deprotected to give an optically active alcohol, which is then converted into a compound represented by the general formula (I) by racemization in a protic solvent using an acid catalyst for recycling. The protic solvent used in the deprotection reaction is not particularly limited, but water or an alcohol solvent such as methanol, ethanol, propanol or butanol is preferable. The protic solvent is preferably used in an equimolar amount or more with respect to the optically active 2-halo-1- (substituted phenyl) ethanol ester.

The acid catalyst is not particularly limited, but sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, acetic acid,
Bronsted acids such as trifluoroacetic acid, phosphoric acid, methanesulfonic acid, and p-toluenesulfonic acid; Lewis acids such as zinc chloride, aluminum chloride, titanium tetrachloride, tin chloride, and boron trifluoride, and preferably brene. Steadic acid, particularly preferably sulfuric acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, which can be used in common with the below-described racemization reaction, and more preferably inexpensive and industrially Sulfuric acid which is easy to use is mentioned. The amount of the acid catalyst used is preferably 0.001 mol or more based on the raw material ester.

The reaction can be carried out at normal pressure or under pressure, and the reaction temperature is -20 to 200 ° C, preferably 0 to 15
It is carried out at 0 ° C., particularly preferably in the range of 20 to 120 ° C. for about 5 minutes to 100 hours. Further, the racemization reaction is carried out in an aqueous solvent, but alcoholic solvents such as methanol, ethanol, propanol, butanol; hydrocarbon solvents such as hexane, heptane, isooctane, benzene, toluene; diethyl ether, diisopropyl ether, diether. Ether solvents such as butyl ether and t-butyl methyl ether; dichloromethane, chloroform,
A halogen-based solvent such as dichloroethane; an organic solvent selected from ester solvents such as methyl acetate, ethyl acetate, methyl propionate, methyl butyrate, methyl valerate, and methyl caproate may coexist. Of these, hydrocarbon-based solvents, halogen-based solvents and mixed solvents thereof are preferable. The amount of the solvent used is about 0.01 to 100 times by weight of the optically active 2-halo-1- (substituted phenyl) ethanol.

As the acid catalyst, a Bronsted acid is usually used, and sulfuric acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid is particularly preferable.
In this case, if the catalyst concentration with respect to water is low, the racemization rate is slow, and at a high concentration, the optically active 2-halo-1- (substituted phenyl) ethanol is decomposed. For this reason,
When sulfuric acid water is used, it is usually 20-80 with respect to water.
It is carried out at a concentration of wt%, preferably 30-70 wt%, more preferably 40-60 wt%.

In each of the above deprotection reaction and racemization reaction, the product can be isolated by an operation such as salting out or extraction after completion of the reaction, and purified by distillation, column chromatography or the like. In the above reaction, by selecting a solvent and a catalyst, after the deprotection reaction is completed, the obtained (S) -2-halo-1- (substituted phenyl) ethanol is directly subjected to the racemization reaction without isolation. You can also do it. (2) Method for producing optically active substituted styrene oxide Optically active 2-halo-1 obtained by the above microbial reaction
-(Substituted phenyl) ethanol (II) is treated with a base to cause ring closure to give a compound of the general formula (IV)

[0034]

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(Wherein R ₁ , R ₂ and R ₃ have the same meanings as in formula (I)) and can be converted into an optically active substituted styrene oxide. In the microbial reaction, an optically active 2-halo-1- (substituted phenyl) ethanol ester (VI) is produced as a by-product, but in this reaction, the optically active 2-halo-1- (substituted phenyl) ethanol ester (VI) is not separated and the optically active 2-halo-1 The mixture with-(substituted phenyl) ethanol (II) can be directly used for the reaction. In this case, the number of isolation and purification steps can be reduced, which is industrially preferable.

The base used in the ring-closing reaction includes alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; or sodium methoxy. Alkali metal alkoxides such as sodium ethoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide; butylamine, dibutylamine, triethylamine, 1,4-diazabicyclo [2.2.
2] Octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5
-Diazabicyclo [4.3.0] non-5-ene (DB
Examples thereof include organic bases such as amine compounds such as N); however, inorganic bases are preferable from the viewpoint of reaction yield and the ease of post-treatment, and among them, alkali metal hydroxides or alkali metal carbonates are preferable. Used for. The amount of the base used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to the optically active 2-halo-1- (substituted phenyl) ethanol (II).

The above ring closure reaction is carried out without solvent or in the presence of a solvent. The solvent used in the reaction is not particularly limited, but is an ether solvent such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran; hexane, heptane, isooctane, toluene, xylene, etc. Hydrocarbon solvents; ester solvents such as methyl acetate and ethyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvents such as chloroform and dichloromethane; dimethylformamide,
Dimethyl sulfoxide, N-methylpyrrolidone and the like are used, and preferably ether solvents and hydrocarbon solvents are used. The solvent used in the ring-closing reaction may be the same as or different from the solvent used in the enzyme reaction. The amount of the solvent used is 0 to 100 times the weight ratio of the optically active 2-halo-1- (substituted phenyl) ethanol (II), and preferably 0 to 20 times the amount in terms of productivity.

The ring-closing reaction is carried out under normal pressure or under pressure,
In addition, although it depends on the type of base used, it is usually -50.
To 150 ° C, preferably 0 to 50 ° C for 5 minutes to 2
It is carried out by reacting for 4 hours. After completion of the reaction, the obtained optically active substituted styrene oxide (IV) can be isolated by a simple means such as distillation. The optical purity of the optically active substituted styrene oxide obtained by this reaction was measured by high performance liquid chromatography (column: Daicel Chemical Industries Ltd., Chiralpack AD, elution solvent: hexane-isopropanol (1000: 0.
4), flow rate 1.0 ml / min, detection 220 nm).

When the reaction is carried out in the presence of the optically active 2-halo-1- (substituted phenyl) ethanol ester (VI), which is a by-product in the above-mentioned enzymatic reaction, the ethanol ester is distilled. Since it is separated as a high-boiling substance in the above, the above-mentioned deprotection reaction and racemization reaction are carried out, and it can be recycled and used as a starting material 2-halo-1- (substituted phenyl) ethanol (I) in the enzymatic reaction. .

(3) Method for producing optically active 2-amino-1- (substituted phenyl) ethanol Further, the optically active substituted styrene oxide (IV) obtained by the above reaction is reacted with an amine compound to give It can be converted into an optically active 2-amino-1- (substituted phenyl) ethanol represented by the following general formula (V).

[0041]

[Chemical 12]

(In the formula, R ₆ and R ₇ are each independently a straight-chain or branched alkyl group having 1 to 10 carbon atoms which may be substituted with a hydrogen atom or an aromatic group. Group group is halogen atom, hydroxyl group, carbon number 1-10
May be substituted with an alkyl group, an alkoxy group having 1 to 10 carbon atoms or an alkoxycarbonyl group having 1 to 10 carbon atoms. )

The amine compound is not particularly limited as long as it is ammonia or a primary or secondary amine which can react with styrene oxide, but is preferably ammonia or a linear or branched chain having 1 to 10 carbon atoms. Alkyl amines of As the alkylamine,
It may be substituted with an aromatic group such as a phenyl group or a pyridyl group, and examples of the aromatic group further include a halogen atom, a hydroxyl group, an alkyl group having 1 to 10 carbon atoms, and 1 carbon atom.
It may be substituted with an alkoxy group having 10 to 10 or an alkoxycarbonyl group having 1 to 10 carbon atoms.

The reaction between the amine compound and the styrene oxide is carried out by heating in a polar solvent such as dimethyl sulfoxide (Eur. J. Med. Chem., 29, 25).
9-267 (1994), J. Med. Chem. , 3
5,3081-3084 (1992)) and the like. The 2-amino-1- (substituted phenyl) ethanol (V) is useful as a drug such as a diabetes drug and an antiobesity drug represented by the following general formula (VII) and the like, and according to the method of the present invention, The above compounds can be efficiently synthesized from inexpensive and safe raw materials by a simple operation.

[0045]

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[0046]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples as long as the gist thereof is not exceeded. In addition, in this example, the optical purity of the optically active 2-halo-1- (substituted phenyl) ethanol was determined by high performance liquid chromatography (column: manufactured by Daicel Chemical Industries Ltd., Chiralce).
l-OJ, elution solvent: hexane-isopropanol (1
0: 1 to 50: 1), flow rate 1.0 ml / min, detection 220
nm), and the optical purity of the optically active substituted styrene oxide was determined by high performance liquid chromatography (column:
ChiralpackA, manufactured by Daicel Chemical Industries, Ltd.
D, elution solvent: hexane-isopropanol (100
0: 0.4), flow rate 1.0 ml / min, detection 220 nm)
Determined by

Production Example 1 Synthesis of 2-bromo-1- (3-chlorophenyl) ethanol 3-chloro-α, β-dibromoethylbenzene 996 g
Potassium iodide (10.8 g) and water (3.5 L) were added to the mixture and heated under reflux for 49 hours while removing free iodine.
After completion of the reaction, the reaction solution was cooled to room temperature, and the separated oil layer was separated and washed with water to be neutral, and 2-bromo-1- (3
714 g of -chlorophenyl) ethanol were obtained.

Example 1 (R) -2-Bromo-1- (3
Synthesis of -chlorophenyl) ethanol 2-bromo-1- (3-chlorophenyl) ethanol 1
Lipase QL (manufactured by Meito Sangyo Co., Ltd.) 30 mg, acetic anhydride 40 mg (0.4 mm) to 00 mg (0.4 mmol)
ol) to which diisopropyl ether was added to bring the total amount to 1 ml, and the reaction was carried out at 35 ° C. for 72 hours. After the reaction was completed, the enzyme was filtered off and the filtrate was concentrated under reduced pressure. When the concentrated liquid was analyzed by ¹ HNMR, (R) -2-bromo-1- (3-chlorophenyl) ethanol and (S) -2-bromo-1
Almost 2 :-( 3-chlorophenyl) ethyl acetate:
It was produced at a rate of 3. The concentrated solution was separated by thin layer silica gel chromatography to obtain (R) -2-bromo-1-
(3-Chlorophenyl) ethanol [α] _D ²⁰ = -2
5.6 °, C = 1.05) and (S) -2-bromo-1
-(3-Chlorophenyl) ethyl acetate ([α] _D
²⁰ = + 40.4 °, C = 0.60) was obtained.
When the optical purity of (R) -2-bromo-1- (3-chlorophenyl) ethanol was analyzed by chiral HPLC, it was 100% ee.

Examples 2 and 3 The amount of lipase QL was 10 mg, and the acid anhydride was 39 mg (0.3 mmol) of propionic anhydride or 47 m of butyric anhydride.
The reaction was performed in the same manner as above except that the amount was changed to g (0.3 mmol). The results of each reaction are shown in Table 1.

[0050]

Table 1 Table 1 Examples Acylating agent Optical purity Conversion 2 Propionic anhydride 99.7 51.2 3 Butyric anhydride 99.4 54.4 (ee%) (%)

Examples 4-8 (R) -2-Bromo-1-
Synthesis of (3-chlorophenyl) ethanol Using 0.3 mmol of various acid anhydrides, the reaction time was 122
The reaction was performed in the same manner as in Example 2 except that the time was set. Table 2 shows the results.

[0052]

Table 2 Examples Acylating agents Optical purity Conversion 4 Isobutyric anhydride 99.8 55.8 5 Valeric anhydride 90.1 50.1 6 Isovaleric anhydride 73.2 43.6 7 Caproic anhydride 83.7 50.9 8 Caprylic anhydride 89.4 50.1 (ee%) (%)

Examples 9 to 16 (R) -2-Bromo-1
Synthesis of-(3-chlorophenyl) ethanol 2-Bromo-1- (3-chlorophenyl) ethanol 1
00 mg (0.4 mmol), Toyozyme LIP (manufactured by Toyobo Co., Ltd.) 20 mg, various acid anhydrides 0.3 mmo
1 ml, diisopropyl ether was added, and the total amount was 1 ml.
And each was reacted at a reaction temperature of 27 ° C. for 98 hours. The results are shown in Table 3.

[0054]

Table 3 Table 3 Examples Acylating agents Optical purity Conversion 9 Acetic anhydride 79.3 45.4 10 Propionic anhydride 99.0 54.4 11 Butyric anhydride 99.8 53.1 12 Isobutyric anhydride 95.3 52.8 13 Valeric anhydride 99.0 53.7 14 Isovaleric anhydride 98.8 50.7 15 Caproic anhydride 100 55.0 16 Caprylic anhydride 100 60.3 (ee%) (%)

Example 17 and Comparative Example 1 Synthesis of (R) -2-Bromo-1- (3-chlorophenyl) ethanol 2-Bromo-1- (3-chlorophenyl) ethanol 1
00 mg (0.4 mmol), lipase QL (manufactured by Meito Sangyo Co., Ltd.) 10 mg, propionic anhydride 39 mg (0.3 mmol) or vinyl propionate 30 mg (0.36 mmol) as an acylating agent, and t- Butyl methyl ether was added to bring the total amount to 1 ml, and the reaction was performed at a reaction temperature of 35 ° C. for 22 hours. The results are shown in Table 4.

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Table 4 Acylating agent Optical purity Conversion rate Example 17 Propionic anhydride 96.0 50.8 Comparative example 1 Vinyl propionate 69.1 42.6 (ee%) (%)

Example 18 and Comparative Example 2 Synthesis of (R) -2-Bromo-1- (3-chlorophenyl) ethanol 2-Bromo-1- (3-chlorophenyl) ethanol 1
00 mg (0.4 mmol), Toyozyme LIP (manufactured by Toyobo Co., Ltd.) 10 mg, n-capric anhydride 100 mg (0.31 mmol) or vinyl laurate 61 mg (0.27 mmol) as an acylating agent,
Diisopropyl ether was added to bring the total volume to 1 ml, and the reaction was carried out at a reaction temperature of 27 ° C. for 30 hours. After completion of the reaction, the reaction supernatant was removed by centrifugal filtration, and fresh 2-bromo-1- (3-chlorophenyl) ethanol,
Add an acylating agent and diisopropyl ether to a total volume of 1 m
The same reaction was repeated twice. Table 5 shows the initial velocity and total activity value of each time. The initial speed is 1
It is shown as a relative value (%) when the initial speed in the second reaction is 100%.

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[Table 5] Activity = total amount of acylated 2-bromo-1- (3-chlorophenyl) ethanol (g) / total amount of enzyme used (g)

Examples 19 to 24 (R) -2-Bromo-
Synthesis of 1- (3-chlorophenylethanol) Toyozyme LIP (manufactured by Toyobo Co., Ltd.) 5 mg, caproic anhydride 0.052 ml, 2-bromo-1- (3-chlorophenyl) ethanol 50 mg, and each additive 5 mg were mixed, and diisopropyl ether was added. The total volume was 0.5 ml and the reaction was carried out for 68 hours at 27 ° C. The results are shown in Table 6.

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Table 6 Additives Optical purity (ee%) Example 19 None 95.2 Example 20 Sucrose (manufactured by Wako Pure Chemical Industries) 95.2 Example 21 Maltose (manufactured by Wako Pure Chemical Industries) 96.5 Examples 22 Sugar ester S370 (manufactured by Mitsubishi Chemical Co., Ltd.) 97.1 Example 23 Sugar ester S570 (manufactured by Mitsubishi Chemical Co., Ltd.) 97.1 Example 24 CHAPS (surfactant manufactured by Nacalai Tesque, Inc.) 97.1

Examples 25, 26 (R) -2-Bromo-
Synthesis of 1- (3-chlorophenyl) ethanol Lipoprotein lipase (Toyobo Lipase) 20m
g, Sugar Ester S570 (manufactured by Mitsubishi Chemical Foods) 5m
g was dissolved in 5 ml of 20 mM TES-Na buffer and stirred at 4 ° C. for 20 hours. Further Hyflo Su
2 g of per-Cel (manufactured by Wako Pure Chemical Industries, Ltd.) was added and 2
After contacting for 0 hours, it was lyophilized to obtain immobilized lipase (S570 product). 20m of the obtained immobilized enzyme
g, molecular sieves 4A 10 mg, butyric anhydride 0.
049 ml or caproic anhydride 0.060 ml,
2-Bromo-1- (3-chlorophenyl) ethanol 1
00 mg were mixed, and diisopropyl ether was added to a total amount of 1.
The reaction was carried out at 27 ° C as 0 ml. Further, instead of the immobilized enzyme, Toyozyme LIP (Lot.
0) The reaction was performed in the same manner except that 20 mg was used.

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[Table 7]

Example 27 Synthesis of (R) -3-chlorostyrene oxide 2-bromo-1- (3-chlorophenyl) ethanol 5
10 g of lipase QL (manufactured by Meito Sangyo Co., Ltd.) was charged to 0 g, and 330 ml of t-butyl methyl ether was charged to 19.5 g of propionic anhydride, and the reaction was carried out at 35 ° C. for 22 hours.
After completion of the reaction, lipase was filtered off, 260 g of 1M aqueous sodium hydroxide solution was added to the filtrate, and the mixture was stirred for 1 hour at room temperature. After the reaction was completed, the organic layer was separated and washed with water and saturated saline to be neutral. Analysis of the reaction liquid by gas chromatography confirmed that (R) -3-chlorostyrene oxide and (S) -2-bromo-1- (3-chlorophenyl) ethyl propionate were produced. It was The conversion rate of (R) -2-bromo-1- (3-chlorophenyl) ethanol at this time was 100%,
The yield of (R) -3-chlorostyrene oxide was 98%. The organic layer was concentrated under reduced pressure and then distilled to obtain (R) -3-
Chlorostyrene oxide 13.2g (boiling point 77 ° C / 3m
mHg, [α] ₂₀ ^D = -11.6 °, C = 0.40) was obtained. The yield of this compound from 2-bromo-1- (3-chlorophenyl) ethanol was 40.6%. When the optical purity of (R) -3-rostyrene oxide was analyzed by high performance liquid chromatography using an optically active column, it was 98.6% ee.

Example 28 Synthesis of (R) -3-chlorostyrene oxide (R) -2-Bromo-1- (3-chlorophenyl) ethanol and (S) -2-bromo-1- (3-chlorophenyl) ethyl 50 mg of a mixture of acetates (1: 1) is dissolved in 2 ml of dichloromethane and (R) -2-bromo-1
Equivalent amount of 1,8-diazabicyclo [5,4,0] undec-7- with respect to-(3-chlorophenyl) ethanol
15 mg of ene (DBU) was allowed to act. After reacting for 30 minutes at room temperature, the reaction mixture was analyzed by gas chromatography to find that (R) -3-chlorostyrene oxide contained 88% of (R) -2-bromo-1- (3-chlorophenyl) ethanol. It was produced in a yield. This time,
The conversion rate of (R) -2-bromo-1- (3-chlorophenyl) ethanol was 92%.

Example 29 Synthesis of (R) -3-chlorostyrene oxide (R) -2-Bromo-1- (3-chlorophenyl) ethanol and (S) -2-bromo-1- (3-chlorophenyl) ethyl 50 mg of a mixture with acetate (1: 1) is dissolved in 2 ml of dichloromethane and (R) -2-bromo-
Equivalent amount of 1,4-diazabicyclo [2.2.2] octane (DA with respect to 1- (3-chlorophenyl) ethanol)
(BCO) 11 mg. After reacting for 1 hour under reflux, the reaction liquid was analyzed by gas chromatography to find that (R) -3-chlorostyrene oxide was (R) -2.
It was produced in a yield of 6% based on -bromo-1- (3-chlorophenyl) ethanol. At this time, the conversion rate of (R) -2-bromo-1- (3-chlorophenyl) ethanol was 7%.

Example 30 Synthesis of (R) -3-chlorostyrene oxide (R) -2-Bromo-1- (3-chlorophenyl) ethanol and (S) -2-bromo-1- (3-chlorophenyl) ethyl 50 mg of a mixture with acetate (1: 1) is dissolved in 2 ml of dichloromethane and (R) -2-bromo-
An equivalent amount of triethylamine (10 mg) was allowed to act on 1- (3-chlorophenyl) ethanol. After reacting for 10 hours under reflux, the reaction liquid was analyzed by gas chromatography to find that (R) -3-chlorostyrene oxide contained 32% of (R) -2-bromo-1- (3-chlorophenyl) ethanol. It was produced in a yield. This time,
The conversion rate of (R) -2-bromo-1- (3-chlorophenyl) ethanol was 58%.

Example 31 Synthesis of (R) -3-chlorostyrene oxide (R) -2-bromo-1- (3-chlorophenyl) ethanol and (S) -2-bromo-1- (3-chlorophenyl) ethyl 50 mg of a mixture with acetate (1: 1) was dissolved in 2 ml of dimethylformamide, and (R) -2-bromo-1- (3-chlorophenyl) ethanol was reacted with 14 mg of an equivalent amount of K ₂ CO ₃ . After reacting at 50 ° C. for 2 hours, the reaction liquid was analyzed by gas chromatography to find that (R) -3-chlorostyrene oxide was 58% relative to (R) -2-bromo-1- (3-chlorophenyl) ethanol. Was produced in a yield of. This time,
The conversion rate of (R) -2-bromo-1- (3-chlorophenyl) ethanol was 92%. The results of Examples 28 to 31 are summarized in Table 8.

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[Table 8]

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INDUSTRIAL APPLICABILITY According to the present invention, optically active 2-halo-1- (substituted phenyl) ethanol can be easily obtained by splitting 2-halo-1- (substituted phenyl) ethanol with a specific enzyme. . Further, it is possible to obtain an optically active 2-amino-1- (substituted phenyl) ethanol by reacting an optically active substituted styrene oxide with an amine compound by treating it with a base without separating it, These are compounds useful as medicines, agricultural chemicals or intermediates between them.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area C12R 1:38) C07M 7:00

Claims (9)

[Claims] 1. A compound of the general formula (I) (In the formula, X represents a chlorine atom or a bromine atom.
R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms,
It represents an alkoxy group having 1 to 5 carbon atoms, a cyano group or a nitro group, which may be the same or different. When two of the above substituents are an alkyl group or an alkoxy group, they may be integrated together to form a ring. However, R ₁ , R ₂ and R ₃ are not hydrogen atoms at the same time. ) 2-halo-1- (substituted phenyl)
Ethanol is brought into contact with an enzyme having a stereoselective transesterification ability in the presence of a carboxylic acid anhydride, and the compound represented by the general formula (II): (In the formula, X, R ₁ , R ₂ and R ₃ have the same meanings as in formula (I).) A process for producing an optically active 2-halo-1- (substituted phenyl) ethanol. 2. The substituents R ₁ , R ₂ and R ₃ are each independently a halogen atom, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group having 1 to 2 carbon atoms or 1 to 5 carbon atoms.
2. The production method according to claim 1, wherein the alkoxy group is 3. The carboxylic acid anhydride is represented by the general formula (III): (In the formula, R ₄ and R ₅ are each independently a halogen atom, an alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 5 carbon atoms, and 6 to 10 carbon atoms; N,
A linear or branched alkyl group having 1 to 20 carbon atoms or 1 to carbon atoms, which may be substituted with a substituent selected from any of aromatic groups which may be replaced by either O or S. 20 straight or branched alkenyl groups, or a carbon which may be substituted with a substituent selected from a halogen atom, an alkoxy group having 1 to 5 carbon atoms and an acyl group having 1 to 5 carbon atoms. The production method according to claim 1, wherein the formula 6 to 10 are represented by 1 to 3 of which is an aromatic group which may be replaced by any of N, O and S). 4. The substituents R ₄ and R ₅ are each independently selected from halogen, an alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 5 carbon atoms, and a phenyl group. A linear or branched alkyl group having 1 to 20 carbon atoms which may be substituted with a group, a linear or branched alkenyl group having 1 to 10 carbon atoms, or a phenyl group which may be substituted with a halogen atom, or It is a pyridyl group, The manufacturing method of Claim 3 characterized by the above-mentioned. 5. The method according to claim 1, wherein the enzyme is a lipase derived from a microorganism. 6. The enzyme is Pseudomonas.
onas) or Alcalige (Alcalige)
The method according to claim 1, which is a lipase derived from a microorganism belonging to the genus (nes). 7. The optically active 2-halo-1- (substituted phenyl) ethanol (II) obtained by the production method according to claim 1 is further treated with a base, and the compound of the general formula (IV): Chemical 4] (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as in formula (I).) A method for producing an optically active substituted styrene oxide. 8. The method according to claim 5, wherein an alkali metal hydroxide or an alkali metal carbonate is used as the base. 9. An optically active substituted styrene oxide (IV) produced by further treating the optically active 2-halo-1- (substituted phenyl) ethanol (II) obtained by the production method according to claim 1 with a base. Of the general formula (V), characterized in that the compound is then reacted with an amine compound. (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as in formula (I),
R ₆ and R ₇ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 10 carbon atoms which may be substituted with an aromatic group, and the aromatic group is a halogen atom or a hydroxyl group. Group, alkyl group having 1 to 10 carbon atoms, carbon number 1
It may be substituted with an alkoxy group having 10 to 10 or an alkoxycarbonyl group having 1 to 10 carbon atoms. ) The method for producing optically active 2-amino-1- (substituted phenyl) ethanol represented by