JP2002030017A - Process for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel optical activity 1 having excellent herbicidal activity.
Provided is a method for producing a compound useful as a synthetic intermediate for 2-disubstituted-2,3-epoxypropanes. SOLUTION: The following general formula: (Wherein A is a 2-substituted indane-1,3-dione-2-
Represents an yl group or a haloalkyl group. 1, 2)
-Disubstituted-2,3-epoxypropanes (a) hydrolyzing in the presence of an inorganic acid, or (b) ring-opening in the presence of a carboxylic acid, followed by solvolysis, Formula 2 (Wherein, A and B have the same meanings as described above.) A process for producing an optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula:

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes, which is useful as a synthetic intermediate for agricultural chemicals and the like.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 2-304043 discloses 1,2-disubstituted-2,3- as a compound having herbicidal activity.
1,2 which is a dihydroxypropane or a derivative thereof
-Disubstituted-2,3-epoxypropanes are described. Further, as a method for producing 1,2-disubstituted-2,3-dihydroxypropanes, a method of oxidizing a corresponding olefin derivative is disclosed. However, any of the 1,2-disubstituted-2,3-dihydroxypropanes and derivatives thereof described in the above publications are racemic compounds, and optical isomers are not specifically disclosed. There is no description about.

[0003]

SUMMARY OF THE INVENTION The present inventors have reported that the optical isomers of 1,2-disubstituted-2,3-epoxypropanes having certain substituents described in the above publication are excellent. It has been found that the herbicide has a herbicidal activity, is a low dose and has a high activity. An object of the present invention is to provide a method for producing an optically active 1,2-disubstituted-2,3-dihydroxypropane useful as a synthetic intermediate for industrially producing such an excellent herbicide. It is in.

[0004]

The present inventors have made intensive studies and as a result, have found that optically active 1,2-disubstituted-2,3-epoxypropanes, which are enantiomers of the desired optical isomer, are obtained. Was hydrolyzed with an acid or by ring opening and solvolysis to produce optically active 1,2-disubstituted-2,3-dihydroxypropanes. That is, the present invention provides the following general formula (1)

[0005]

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In the formula, A is the following general formula (2)

[0007]

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(Wherein R ¹ represents a hydrogen atom or a lower alkyl group or an alkenyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms,
It represents an alkoxyl group, a nitro group or a cyano group having 1 to 2 carbon atoms. n shows the integer of 0-4. ) Or the following general formula (3)

[0009]

Embedded image ^{_{CX 1 3 (CX 2 2)}} p - (3)

(Wherein, X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, and p represents 0 to 2), and B represents optionally substituted benzene. Shows a ring. Optically active 1,2-disubstituted-2 represented by｝
The following general formula (4) characterized in that 3-epoxypropanes are hydrolyzed in the presence of (a) an inorganic acid or (b) ring-opened in the presence of a carboxylic acid and then solvolyzed.

[0011]

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(Wherein A and B have the same meanings as defined in the above formula (1).) A process for producing an optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula: Exists.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The optically active 1,2-disubstituted-2,3-dihydroxypropanes of the general formula (4) which is the object of the present invention, or the optically active 1,2-dithiol of the general formula (1) which is the starting material of the present invention In the substituted-2,3-epoxypropanes, A is a group represented by the general formula (2) or (3). In the general formula (2), R ¹ is a hydrogen atom, a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group; a lower alkenyl group such as a vinyl group or an allyl group; And a lower alkynyl group such as an ethynyl group and a propargyl group. In this case, “lower” means having 4 or less carbon atoms. Q represents a halogen atom such as a chlorine atom, a bromine atom or a fluorine atom, an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, an n-propyl group or an i-propyl group; a chloromethyl group; a dichloromethyl group; A haloalkyl group having 1 to 3 carbon atoms such as a fluoromethyl group, a fluoroethyl group, a methoxy group, an ethoxy group, a nitro group or a cyano group;
Represents an integer of 0 to 4. In the general formula (3), X ¹ ,
X ² represents a hydrogen atom or a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom, and p represents an integer of 0 to 2. B in the general formula (1) is an aryl group such as a phenyl group and a pyridyl group which may have a substituent, and examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom; Haloalkyl having 1 to 3 carbon atoms such as an alkyl group having 1 to 3 carbon atoms such as group, ethyl group, n-propyl group, i-propyl group, chloromethyl group, dichloromethyl group, trifluoromethyl group, and fluoroethyl group Group, methoxy group, ethoxy group, chloromethoxy group, fluoroethoxy group and the like, haloalkoxyl group, nitro group, cyano group and the like. .

In the general formula (2), R ¹ is preferably a lower alkyl group, particularly preferably an ethyl group. Also, n is preferably 0. In the general formula (3), X ¹ ,
X ² is preferably a chlorine atom or a fluorine atom,
Among them, a chlorine atom is preferred, and p is preferably 0. B is preferably a benzene ring which may be substituted by an electron-withdrawing group, and the electron-withdrawing group is preferably a chlorine atom.
A dichlorophenyl group is preferred. The reaction (a) of the present invention is carried out by adding water and an inorganic acid to the optically active 1,2-disubstituted-2,3-epoxypropane (1) and hydrolyzing the epoxy group. After completion of the reaction, a high-purity optically active 1,2-disubstituted-2,3-dihydroxypropane having a tertiary structure inverted by crystallization, distillation, column chromatography or the like after extraction with an organic solvent as appropriate. (4) is obtained. When the optically active 1,2-disubstituted-2,3-dihydroxypropanes (4) are purified by crystallization, aliphatic hydrocarbon solvents such as hexane and heptane or benzene, toluene, xylene, chlorobenzene and the like can be used. When a single or mixed aromatic hydrocarbon solvent is used, the resulting optically active 1,2
-Disubstituted-2,3-dihydroxypropanes are preferred because of their high optical purity.

The inorganic acids used for the hydrolysis include sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid,
Examples include perchloric acid, chloric acid, chlorous acid, hypochlorous acid, boric acid, and the like. Above all, when sulfuric acid is used, both the optical purity and the yield of the optically active 1,2-disubstituted-2,3-dihydroxypropanes (4) which are inexpensive and obtained are both high and are preferred.
The amount of the acid used is, for example, optically active 1,2-disubstituted-2,3.
-0.01 to 100 relative to epoxy propane (1)
The equivalent is used, preferably 0.1 to 10 equivalents. The amount of water used is at least the equivalent (equimolar) of the optically active 1,2-disubstituted-2,3-epoxypropanes (1), preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents. And the optical purity and yield of the optically active 1,2-disubstituted-2,3-dihydroxypropanes (4) are both high and are preferred. In particular, when sulfuric acid is used, it is preferable to use 3 to 6 equivalents of water with respect to the compound of the general formula (1). If the amount of water is out of the above range, the optical purity of the product will decrease. Further, it is preferable to add a sulfuric acid aqueous solution in which water and sulfuric acid are previously mixed, since the optical purity of the product is higher than when water and sulfuric acid are separately added.

This reaction is preferably carried out in the presence of an organic solvent as appropriate. The solvent used in this reaction is not particularly limited, but includes, for example, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, tetrahydropyran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl Ether, ether solvents such as diethylene glycol dibutyl ether, hexane, heptane and other aliphatic hydrocarbon solvents, benzene, toluene, xylene,
Aromatic hydrocarbon solvents such as chlorobenzene, acetone,
Ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; halogenated hydrocarbon solvents such as dichloromethane and chloroform; nitrile solvents such as acetonitrile, propionitrile and butyronitrile; amide solvents such as dimethylformamide and N-methylpyrrolidone; acetic acid Examples include ester solvents such as methyl, ethyl acetate and methyl propionate, alcohol solvents such as t-butyl alcohol and t-amyl alcohol, and dimethyl sulfoxide. These may be used alone or as a mixed solvent. Among them, ether solvents, ester solvents and ketone solvents are preferable, and ethylene glycol ethers or 6-membered ring ethers are particularly preferable.

The optically active 1,2-disubstituted-2,3 obtained
It is preferable to use an ether-based solvent, a ketone-based solvent, an ester-based solvent, or an amide-based solvent because the optical purity or the yield of the dihydroxypropanes (4) is high.
More preferred are ether-based solvents, ketone-based solvents, and ester-based solvents. Use of these solvents increases both the optical purity and the yield of the optically active 1,2-disubstituted-2,3-dihydroxypropanes. Among them, ethylene glycol ethers or 6-membered ring ethers are preferable, and diethylene glycol diethyl ether is particularly preferable. The solvent is used in an amount of 0 to 100 times, preferably 1 to 100 times the weight of the optically active 1,2-disubstituted-2,3-epoxypropane.
Used in 20 times the amount. The reaction temperature is in the range of −50 to 100 ° C., preferably −20 to 70 ° C., and the reaction time is usually within 48 hours. This method has the advantage that the target compound can be obtained in one step and the optical yield is good.

The reaction (b) of the present invention is carried out using an optically active 1,2-
Disubstituted-2,3-epoxypropanes are obtained by ring opening in the presence of a carboxylic acid and then solvolysis. The carboxylic acid used in the reaction is not particularly limited, but includes formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid, and the like. is there. The use of formic acid is preferable because the optical purity and yield of the optically active 1,2-disubstituted-2,3-dihydroxypropanes (4) obtained at low cost are both high. The acid is used in an amount of at least the equivalent of the optically active 1,2-disubstituted-2,3-epoxypropane (1). −
The optical purity and the yield of the 2,3-dihydroxypropanes (4) are both high and are preferable. This reaction can also be suitably carried out in the presence of an acid other than a carboxylic acid. As the acid used in combination, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, inorganic acids such as boric acid, Organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, boron trifluoride, titanium tetrachloride, tin tetrachloride, aluminum chloride, iron chloride, antimony pentafluoride,
Lewis acids such as ytterbium triflate are exemplified. The amount of the acid used may be an optically active 1,2-disubstituted
0 to 100 with respect to 2,3-epoxypropane (1)
The equivalent is used, preferably 0 to 10 equivalents.

This reaction can be carried out in the presence of an organic solvent as appropriate. The solvent used in this reaction is not particularly limited. For example, the solvents exemplified in the above-mentioned reaction (a) can be used, and these may be a single solvent or a mixed solvent. The reaction may be appropriately performed in the presence of water. Preferred are aromatic hydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene. Particularly, when chlorobenzene is used, the optical purity or yield of the optically active 1,2-disubstituted-2,3-dihydroxypropanes (4) is obtained. The reaction rate is high, and the post-treatment of the reaction is simple and preferable. The solvent is used in an amount of 0 to 100 times, preferably 1 to 20 times the weight of the optically active 1,2-disubstituted-2,3-epoxypropane (1).

The reaction is carried out using an optically active 1,2-disubstituted-2,3
The ring-opening of the epoxypropanes (1) in the presence of a carboxylic acid, followed by solvolysis of the resulting carboxylate, wherein the solvent for the solvolysis is water or methanol, ethanol, propanol , Butanol and other protic solvents are used. The reaction may be either acidic or basic, but it is preferable to carry out the reaction in a basic manner since the reaction rate and the reaction yield are high. When carried out in an acidic manner, there is no particular limitation,
Inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, boric acid, methanesulfonic acid, p-toluene Organic acids such as sulfonic acid and formic acid are used, and preferably inexpensive sulfuric acid is used. The amount of the acid used is 0.01 to 10 of the optically active 1,2-disubstituted-2,3-epoxypropane (1).
Used in equivalent. The reaction temperature is in the range of −50 to 100 ° C., preferably −20 to 70 ° C., and the reaction time is usually 48 to 100 ° C.
Within hours.

When the reaction is carried out in a basic condition, there is no particular limitation, but amines such as triethylamine and N, N-dimethylaniline; pyridines such as pyridine, picoline and lutidine; and metals such as sodium methoxide and sodium ethoxide. Inorganic bases such as alkoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate are used, and preferably, inexpensive metal alkoxides or inorganic bases are used. The amount of the base used is at least the equivalent of the optically active 1,2-disubstituted-2,3-epoxypropane (1) used in the reaction after neutralizing the excess carboxylic acid, and preferably 1 to 5 Used in equivalent. The reaction temperature is in the range of -50 to 150C, preferably -20 to 100C, and the reaction time is usually within 48 hours. The method of the reaction (b) is a two-step reaction, and the optical yield tends to be lower than that of the method of the reaction (a). However, when a solvent is used for the reaction, it is not always necessary to use a hydrophilic solvent. Therefore, even when a hydrophobic solvent is used for the production of the compound of the general formula (1), there is an advantage that the reaction can be continued in the same solvent system.

The starting material of the method of the present invention is the general formula (1)
Are optically active 1,2-disubstituted-2,3-epoxypropanes, which can be synthesized, for example, according to the following route.

[0023]

Embedded image

(In the above formula, A and B have the same meanings as defined in formula (1). R ² represents an alkyl group, alkenyl group, aryl group or aralkyl group having 20 or less carbon atoms. ⁴ represents an alkyl group or an aryl group having 10 or less carbon atoms which may have a substituent.) Each reaction will be described below. 1,2-disubstituted-2,3- represented by the general formula (5)
Dihydroxypropanes are reacted with a compound represented by the following general formula (10) in the presence of an enzyme having a stereoselective transesterification ability.

[0025]

Embedded image (R ² CO ₂ ) _m R ³ _m (10)

(Where R^Two And R^Three Are independent
And an alkyl having 20 or less carbon atoms which may have a substituent
Represents an alkyl group, an alkenyl group, an aralkyl group or an aryl group.
Then R ^Two And R^Three May be bonded to each other to form a ring
No. m shows 1-3. Carboxylic acid ester represented by)
Reaction in the presence of
Optically active 1,2-disubstituted-2,3- represented by the formula (6)
Possesses the stereostructure of dihydroxypropanes and their enantiomers
Optically active 1,2-disubstituted-2-hydrido of the general formula (7)
Roxy-3-acyloxypropanes are obtained. This anti
Of the racemic form represented by the general formula (5)
1,2-disubstituted-2,3-dihydroxypropanes are
As shown in Japanese Patent Application Laid-Open No. 2-304043,
Oxidation of olefin derivatives, or racemic
Optically active 1,2-disubstituted-2,3-epoxypropanes
Same as 1,2-disubstituted-2,3-epoxypropanes
It can be produced by ring opening under the following conditions.

As the enzyme used in this reaction, any enzyme can be used as long as it has a stereoselective transesterification ability for the compound of the general formula (5).
Preferably, genus Penicillium, genus Pseudomonas, Alcalige
lipases derived from microorganisms belonging to the genus nes, Rhizopus or Aspergilus, and more preferably Ps
Lipases derived from microorganisms belonging to the genus eudomonas are exemplified. In addition, these enzymes may be raw enzymes, or may be treated with acetone, freeze-dried, or the like.
These enzymes can be immobilized on a carrier and used.
In addition, these enzymes may be those obtained by an appropriate expression system by gene recombination. Pseudomonas
Specific examples of lipases derived from microorganisms belonging to the genus
Lipase AK (genus Pseudomonas, manufactured by Amano Pharmaceutical Co., Ltd.), Li
pase AKG (genus Pseudomonas, manufactured by Amano Pharmaceutical Co., Ltd.), Toyo
zyme LIP (genus Pseudomonas, manufactured by Toyobo Co., Ltd.) and the like.

In the carboxylic acid ester of the general formula (10), the alkyl group having 20 or less carbon atoms in R ² and R ³ includes a methyl group, an ethyl group, an n-propyl group and an n-propyl group.
Butyl, n-pentyl, n-hexyl, n-heptyl, n-undecyl, n-tridecyl, n-pentadecyl, n-heptadecyl, t-butyl,
-Ethylpentyl group and the like, and as the alkenyl group, a vinyl group, an isopropenyl group, a 2-pentenyl group,
8-heptadecenyl group and the like, and the aryl group include a phenyl group, a naphthyl group and the like, and these further include a chlorine atom, a bromine atom, a halogen atom such as a fluorine atom,
It may have a substituent such as a hydroxy group. m is 1
3, that is, any of a monocarboxylic acid ester, a dicarboxylic acid ester, and glyceride. Instead of carboxylic esters, carboxylic anhydrides which form these esters can also be used. Specifically, vinyl acetate, vinyl chloroacetate, vinyl propionate, vinyl butyrate, vinyl caproate, vinyl caprylate, vinyl caprate, vinyl laurate, vinyl myristate,
Vinyl palmitate, vinyl stearate, vinyl pivalate, vinyl 2-ethylhexanoate, vinyl methacrylate, methyl acetate, methyl propionate, methyl butyrate,
Methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate, methyl palmitate, methyl stearate, methyl pivalate,
Examples thereof include methyl 2-ethylhexanoate, methyl methacrylate, and isopropenyl acetate. As the acid anhydride,
Acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride,
Examples include caproic anhydride, capric anhydride, caprylic anhydride, lauric anhydride, succinic anhydride, maleic anhydride, and benzoic anhydride. Among them, vinyl ester is preferred because it is inexpensive, has high stereoselectivity, and has a high reaction rate. The amount of these used is 1,2-disubstituted-2,3-
It is used in an amount of 0.5 equivalent or more based on the dihydroxypropane (5).

This reaction is carried out, for example, by 1,2-disubstituted-2,
This is carried out by suspending the enzyme in an organic solvent in which 3-dihydroxypropanes (5) and a carboxylic acid ester or a carboxylic anhydride are dissolved, and stirring or shaking the enzyme. After completion of the reaction, the enzyme can be produced by removing the enzyme by filtration or centrifugation and collecting the filtrate.
The solvent used in this reaction is not particularly limited, but ether solvents such as diethyl ether, diisopropyl ether, and tetrahydrofuran; hydrocarbon solvents such as hexane, heptane, toluene, and xylene; and ester solvents such as methyl acetate and ethyl acetate. Solvents, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, halogen solvents such as chloroform and chlorobenzene, nitriles such as acetonitrile, propionitrile and butyronitrile, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like are used. Above all, it is preferable to carry out the reaction using the carboxylic acid ester used in the enzymatic reaction as a solvent because the reaction rate is high. The solvent is used in an amount of 0 to 20 times the weight of the 1,2-disubstituted-2,3-dihydroxypropane. This reaction is carried out by reacting at 0 to 100 ° C, preferably 10 to 50 ° C, for 5 hours to several days.

From the mixture of the compound of the general formula (6) and the compound of the formula (7) thus obtained, the compound (6) is isolated or reacted without isolation with a sulfonic acid derivative in the presence of a base. To synthesize the compound of the general formula (8). As the sulfonic acid derivative, the following general formula (11) or general formula (12)

[0031]

Embedded image R ⁴ SO ₂ Y (11) (R ⁴ SO ₂ ) ₂ O (12)

(Wherein, R ⁴ represents an alkyl group or an aryl group having 10 or less carbon atoms which may have a substituent;
Represents a halogen atom. )). The sulfonic acid derivative of the general formula (11) or (12) is not particularly limited, but methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, or p-toluenesulfonic anhydride is preferably used. More preferably, inexpensive methanesulfonyl chloride or p-toluenesulfonyl chloride is used. The sulfonic acid derivative is used in an amount of at least the equivalent of the optically active 1,2-disubstituted-2,3-dihydroxypropane, preferably 1.0 to 1.5 equivalent. Any base can be used as the base to be used, for example, triethylamine, amines such as N, N-dimethylaniline, pyridines such as pyridine, picoline and lutidine, metal alkoxides such as sodium methoxide and sodium ethoxide, Examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. Preferably, amines or pyridines are used. The amount of base used is optically active 1,2-disubstituted-
Used in an equivalent amount of 2,3-dihydroxypropanes,
Preferably, 1 to 2 equivalents are used.

The reaction can be carried out by appropriately diluting with a solvent. The solvent used is not particularly limited, but hydrocarbons such as toluene, xylene, hexane, and heptane; ethers such as diethyl ether, diisopropyl ether, and tetrahydrofuran; esters such as methyl acetate and ethyl acetate; and halogens such as chloroform and chlorobenzene. System solvents, acetone, methyl ethyl ketone, ketones such as methyl isobutyl ketone, acetonitrile, propionitrile, nitriles such as butyronitrile, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, polar solvents such as water, and the like. A single solvent or a mixed solvent may be used. When amines or pyridines are used as the base, the reaction can be carried out using these as a solvent. The amount of the solvent used is 0 by weight based on the optically active 1,2-disubstituted-2,3-dihydroxypropane.
It is used in an amount of 10 to 10 times. The reaction temperature is -50 to 100C,
It is preferably in the range of -20 to 50 ° C, and the reaction time is usually within 30 hours. In the above reaction, even when the compound of the general formula (7) coexists, the compound of the general formula (4) is hydrolyzed as it is, or in some cases hydrolyzed substantially without reacting with the sulfonic acid derivative. And coexist in the reaction product.

Then, the desired compound of the general formula (1) can be obtained by isolating the sulfonic acid ester of the general formula (8) from the reaction product or by subjecting it to a base without isolation. As the base used,
Although not particularly limited, amines such as triethylamine and N, N-dimethylaniline, pyridines such as pyridine, picoline and lutidine, metal alkoxides such as sodium methoxide and sodium ethoxide, sodium hydroxide,
Inorganic bases such as potassium hydroxide, potassium carbonate and sodium carbonate are used, and preferably, metal alkoxides or inorganic bases are used. The base is used in an amount equal to or more than the equivalent of the optically active sulfonic acid ester, and preferably in an amount of 1.0 to 1.5 equivalent. Reaction temperature is -50 to 1
The temperature is in the range of 00 ° C, preferably 0 to 70 ° C, and the reaction time is usually within 30 hours.

In this reaction, when a compound of the general formula (7) is present, it is hydrolyzed by the action of a base,
It becomes a compound of the general formula (4) or a part thereof coexists in a reaction product without being reacted. These coexistent compounds may be prepared by subjecting the compound of the general formula (1) to hydrolysis or solvolysis when (a) hydrolyzing or (b) ring opening / solvolysis using an acid according to the method of the present invention. They are all decomposed to convert to the compound of the general formula (4). Therefore, in a series of steps for producing a target compound of the general formula (4) using the compound of the general formula (5) as a starting material, all the steps are carried out without separating and purifying the product in each step. It is possible to carry out in the same reactor. The compound of the general formula (1) can also be produced by the following route (II).

[0036]

Embedded image

(Wherein A and B have the same meanings as defined in the above formula (1). R is an optionally substituted alkyl group, alkenyl group having 20 or less carbon atoms, aralkyl R ⁵ represents a hydrogen atom or an optionally substituted alkyl or alkenyl group having 20 or less carbon atoms.) 1,2-Disubstituted-2-hydroxy-3-acyloxypropanes (9) in the presence of an enzyme having a stereoselective solvolysis ability in the presence of the following general formula (13)

[0038]

Embedded image R ⁵ OH (13)

(Wherein R ⁵ represents a hydrogen atom or an optionally substituted almol group or alkenyl group having 20 or less carbon atoms) by reacting with water or an alcohol represented by the general formula (6): And the compound of the general formula (7) are obtained. Thereafter, the compound of the general formula (1) can be produced according to the reaction of the reaction route-(I). The racemic 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the general formula (9) used in the reaction are prepared from the racemic 1,2-disubstituted-2,3- It can be obtained by reacting dihydroxypropanes (5) with a carboxylic acid halide or carboxylic acid anhydride according to a conventional method.

In the 1,2-disubstituted-2-hydroxy-3-acyloxypropanes of the general formula (9), R may be the same group as R ² of the general formula (10).
Represents an n-propyl group, an i-propyl group, or n
-A pentyl group is preferred because of its high reaction rate and stereoselectivity. As the enzyme used in the reaction, any enzyme can be used as long as it has a stereoselective solvolysis ability to 1,2-disubstituted-2-hydroxy-3-acyloxypropanes (9). Is Penicillium
And lipases derived from microorganisms belonging to the genus, Pseudomonas, Alcaligenes, Rhizopus or Aspergilus, and more preferably lipases derived from the microorganism belonging to the genus Penicillium. In addition, these enzymes may be raw enzymes or may be treated with acetone, freeze-dried, or the like, and these enzymes may be immobilized on a carrier before use. In addition, these enzymes may be those obtained by an appropriate expression system by gene recombination. Genus Penicillium, genus Pseudomonas, Alc
Specific examples of lipases derived from microorganisms belonging to the genus aligenes, Rhizopus, or Aspergilus include Lipase.
R (Penicillium genus, Amano Pharmaceutical Co., Ltd.), Lipase AK
(Pseudomonas genus, Amano Pharmaceutical Co., Ltd.), Lipase AKG
(Genus Pseud omonas, manufactured by Amano Pharmaceutical Co., Ltd.), Toyozyme LIP
(Genus Pseudomonas, manufactured by Toyobo Co., Ltd.), Lipase QL (Al
genus caligenes, manufactured by Meito Sangyo Co., Ltd., Lipase PL (Alka
ligenes genus, Meito Sangyo Co., Ltd.) Lipase D (Rhizopus
Genus, Amano Pharmaceutical Co., Ltd.), Lipase AP6 (Aspergillus
Genus, manufactured by Fluka).

In the general formula (13), examples of the alkyl group having 20 or less carbon atoms in R ⁵ include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group,
n-hexyl group, n-heptyl group, n-undecyl group,
n-tridecyl group, n-pentadecyl group, n-heptadecyl group, t-butyl group, 2-ethylpentyl group and the like. R ⁵ preferably includes a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, and an n-butyl group. More preferably, when R ⁵ is a hydrogen atom, that is, water is used as the compound of the general formula (13), the reaction is inexpensive, and the reaction rate and the stereoselectivity are high. These usages are
It is used in an amount of 0.5 equivalent or more based on the racemic 1,2-disubstituted-2-hydroxy-3-acyloxypropane (9).

This reaction is carried out, for example, by dissolving or suspending a racemic 1,2-disubstituted-2-hydroxy-3-acyloxypropane (9) and water or an alcohol of the formula (13) or a mixture thereof. The reaction is carried out by adding an enzyme therein and stirring or shaking. After completion of the reaction, the enzyme can be produced by filtering, centrifuging, or removing the enzyme by adding water to separate the filtrate, and collecting the filtrate or the organic layer. This reaction can also be carried out appropriately in the presence of an organic solvent. In particular, when water is used as the compound of the general formula (13), 1,2-disubstituted-2-hydroxy-3-acyloxypropanes (9) can be effectively treated in the presence of an organic solvent. It is preferable because it can be dispersed in a reaction system and operability and reactivity can be improved. The solvent used in this reaction is not particularly limited, but ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether and tetrahydrofuran; aliphatic hydrocarbon solvents such as hexane and heptane; and aromatic hydrocarbons such as toluene and xylene. Hydrogen solvents, ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone,
Halogen solvents such as chloroform and chlorobenzene, nitriles such as acetonitrile, propionitrile and butyronitrile, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like are used. Among them, a water-insoluble organic solvent is preferable because 1,2-disubstituted-2-hydroxy-3-acyloxypropanes can be effectively dispersed in the reaction system. It is preferable to use a group hydrocarbon solvent, a ketone solvent, or a halogen solvent because the reaction rate is high. The amount of solvent used is 1, 2
-It is used in an amount of 0 to 10 times, preferably 0 to 5 times the weight of the disubstituted-2,3-dihydroxypropane.
This reaction is carried out by reacting at 0 to 100 ° C, preferably 10 to 50 ° C, for 5 hours to several days.

When water is used as the compound of the general formula (13), it is preferable to carry out the reaction while maintaining an optimum pH depending on the type of the enzyme.
It is good to keep in the range of 0, preferably in the range of 7-8. As a method for maintaining the pH, 1,2-disubstituted-2
Performing the reaction while adding a base to neutralize the carboxylic acid generated from -hydroxy-3-acyloxypropanes,
An appropriate buffer solution should be used. Any base can be used as the base to be used, for example, triethylamine, amines such as N, N-dimethylaniline, pyridines such as pyridine, picoline and lutidine, metal alkoxides such as sodium methoxide and sodium ethoxide, Examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. Preferably, inexpensive inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate are used.

In the above description, in the compounds of the general formulas (4), (5), (6), (7), (8) and (9), A is the indandione structure of the general formula (2) In the case of a group having a, depending on the solvent used in the reaction, in the solvent, a hydroxyl group bonded to an asymmetric carbon atom and a carbonyl group of indandione are bonded, and a ring structure compound that becomes a hemiketal shown below. May be an equilibrium mixture of The general formulas (4), (5), (6), (7),
(8) and (9) include the presence of such a ring structure compound.

[0045]

Embedded image

The optically active 1,2 obtained by the method of the present invention
-Disubstituted-2,3-dihydroxypropanes (4) are novel compounds and are useful as intermediates for synthesizing biologically active substances having optical activity. For example, as shown below from compound No. (-)-1 in Table 2 below, which is a compound of general formula (4), a novel herbicide described in Japanese Patent Application No. 10-285042 (-) 2- [ -(3-chlorophenyl)
-2,3-epoxypropyl] -2-ethylindane-
1,3-dione can be synthesized.

[0047]

Embedded image

[0048]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist of the present invention. Tables 1 to 3 show the structures of the compounds represented by the compound No. in the examples. The reactions described in the following examples were analyzed by high performance liquid chromatography (column: InertsilODS 2, elution solvent: methanol: water (70:30), flow rate: 0.6 ml / min, detection: 220 nm). The optical purity of the compounds described in Examples was determined by high performance liquid chromatography (column: Chiralcel-OJ, manufactured by Daicel Chemical Industries, Ltd., elution solvent: n-hexane: isopropanol (85:15 to 90:10) or n-hexane). Hexane: ethanol: methanol (91:
3: 6), flow rate 1.0 ml / min, detection 220 nm).

[0049]

[Table 1]

[0050]

[Table 2]

[0051]

[Table 3]

Example 1 <Synthesis of Compound No. (+)-6> Compound No. (±) -1 was added to 5.00 g of Lipase R (Penicill).
5.00 g of ium roqueforti (manufactured by Amano Pharmaceutical Co., Ltd.) and 50 ml of vinyl acetate were charged and stirred at room temperature for 5 days. After completion of the reaction, the enzyme was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to give Compound No.
(-)-1 (2.55 g, yield 51%, optical purity 78% ee, white solid) and compound No. (+)-2 (2.73 g, yield 49%, optical purity 81% ee, yellow liquid) I got Compound No. (+)-obtained
2 A solution consisting of 90 mg of sodium hydroxide and 10 ml of methanol was added dropwise to 840 mg of (81% ee optical purity) at room temperature. After stirring for 1 hour to complete the reaction, methanol was distilled off under reduced pressure. Demineralized water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give Compound No. (+)-1 (690 mg, yield 92%
, An optical purity of 81% ee and a white solid) were obtained. To 670 mg of the obtained compound No. (+)-1 (optical purity 81% ee), Li was added.
670 mg of pase R (Penicillium roqueforti, manufactured by Amano Pharmaceutical Co., Ltd.) and 7.0 ml of vinyl acetate were charged and stirred at room temperature for 2 days. After completion of the reaction, the enzyme was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to give compound No. (+)-2 (324 mg, yield 43%, optical purity> 99% ee , Yellow liquid) and Compound No. (+)-1 (382 m
g, yield 57%, optical purity 68% ee, white solid). The analytical values of this compound were as follows.

[0053] Compounds No. (+) - 2: [ α] D 25; +55.2 (C 0.502, CHCl 3) IR (KBr); 3450, 1720, 1710, 1700 cm -1 1 H NMR (CDCl 3); d = 0.58 (0.9H, t, J = 7.5 Hz),
0.81 (0.9H, t, J = 7.5 Hz), 0.83 (1.2H, t, J = 7.5
Hz), 1.59-1.98 (4H, m), 1.78 (0.9H, s), 2.02 (0.9H,
s), 2.12 (1.2H, s), 2.36 (0.3H, d, J = 13.5 Hz),
2.38 (0.4H, d, J = 13.5 Hz), 2.56 (0.3H, d, J = 13.
5 Hz), 2.59 (0.3H, d, J = 13.5 Hz), 2.88 (0.4H, d, J
= 13.5 Hz), 2.93 (0.6H, s), 3.13 (0.4H, br), 3.14
(0.3H, d, J = 13.5 Hz), 3.74 (0.3H, d, J = 12.0 H
z), 3.91 (0.3H, d, J = 12.0 Hz), 3.98 (0.3H, d, J =
11.4 Hz), 4.06 (0.4H, d, J = 11.8 Hz), 4.19 (0.3H,
d, J = 11.4 Hz), 4.29 (0.4H, d, J = 11.8 Hz), 6.83
-7.33 (4H, m), 7.45-7.95 (4H, m)

To 252 mg of the compound No. (+)-2 (optical purity> 99% ee) thus obtained was added sodium hydroxide 9 at room temperature.
A solution consisting of 0 mg and 10 ml of methanol was added dropwise.
After stirring for 1 hour to complete the reaction, methanol was distilled off under reduced pressure. Demineralized water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain Compound No. (+)-1 (219 mg, yield 97%, optical purity> 99% ee, white solid). The analysis values of the compound No. (+)-1 were as follows. mp; 97.3-98.9 ° C [α] _D ²⁵ ; +62.2 (C 0.460, CHCl ₃ ) Compound No. (+)-1 thus obtained (optical purity> 99% ee)
168 mg was dissolved in 80 ml of pyridine, and 81 mg of methanesulfonyl chloride was added dropwise under ice cooling. After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour, and ethyl acetate was added thereto,
The extract was washed with a 10% aqueous hydrochloric acid solution, water, and saturated saline in this order, and concentrated to give Compound No. (+)-5 (211 mg, yield 100%, optical purity> 9).
9% ee, yellow liquid).

The thus obtained compound No. (+)-5 of 21
1 mg was dissolved in 5.0 ml of methanol, 95 mg of potassium carbonate was added at room temperature, and the mixture was allowed to react for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added for extraction, and the organic layer was washed with water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the compound
No. (+)-6 (152 mg, yield 95%, optical purity> 99% ee, yellow liquid) was obtained. The analysis values of the compound No. (+)-6 were as follows. [Α] _D ²⁵ ; +58.8 (C 0.464, CHCl ₃ )

Example 2 <Synthesis of Compound No. (-)-1> To a solution of 50 mg of Compound No. (+)-6 (optical purity> 99% ee) in 1.0 ml of methanol was added 1.0 ml of 1N hydrochloric acid. Plus 5
Stirred at 0 ° C. for 2 hours. The reaction mixture was analyzed by high performance liquid chromatography to find that the conversion of compound No. (+)-6 was 100% and that of compound No. (-)-1 (yield 56%, optical purity
45% ee). Compound No. The analysis value of (-)-1 was as follows. mp; 98.2-99.0 ° C, [α] _D ²⁵ -58.8 (C 0.507, CHC
_{l 3) IR (KBr) 3470,3320,1720,1700} cm -1 1 H NMR (CDCl 3); d = 0.60 (0.6H, tJ = 7.5Hz), 0.84 (2.4H, t, J
= 7.5Hz), 1.69-1.82 (1H, m), 1.93-2.05 (1H, m), 2.55 (0.2H,
d, J = 14.4Hz), 2.62 (0.2H, d, J = 14.4Hz), 2.65 (0.8H, d, J = 1
3.2Hz), 2.82 (0.8H, d, J = 13.2Hz), 3.12 (1H, br), 3.60 (2H,
s), 5.10 (1H, s), 6.83-7.70 (4H, m), 7.44-7.92 (4H, m).

Example 3 <Synthesis of Compound No. (-)-1> To a solution of 50 mg of Compound No. (+)-6 (optical purity> 99% ee) in 1.0 ml of acetone was added 1.0 ml of 1N hydrochloric acid. 50 ℃
For 2 hours. When the reaction solution was analyzed by high performance liquid chromatography, the conversion of Compound No. (+)-6 was 1
Compound No. (-)-1 (yield 82%, optical purity 70% e
e) had been generated.

Example 4 <Synthesis of Compound No. (-)-1> In a solution of 50 mg of Compound No. (+)-6 (optical purity> 99% ee) in acetone (1.0 ml), 10% aqueous sulfuric acid was added. Add 0 ml and 5
Stirred at 0 ° C. for 2 hours. When the reaction solution was analyzed by high performance liquid chromatography, the conversion of Compound No. (+)-6 was 100%, and the conversion of Compound No. (-)-1 (94% yield, optical purity
75% ee).

Example 5 <Synthesis of Compound No. (-)-1> A 10% sulfuric acid solution was added to a solution of 50 mg of Compound No. (+)-6 (optical purity> 99% ee) in 1.0 ml of diisopropyl ether.
0 ml was added and the mixture was stirred at 50 ° C. for 5 hours. When the reaction solution was analyzed by high performance liquid chromatography, compound N
The conversion of o. (+)-6 was 6% and Compound No. (-)-1 (yield 4
%, Optical purity 47% ee).

Example 6 <Synthesis of Compound No. (-)-1> To a solution of 50 mg of compound No. (+)-6 (optical purity> 99% ee) in 1.0 ml of toluene was added 1.0 ml of 10% aqueous sulfuric acid. And add
Stirred at 50 ° C. for 5 hours. The reaction mixture was analyzed by high performance liquid chromatography to find that the conversion of compound No. (+)-6 was 4%, and that the compound No. (-)-1 (yield 3%, optical purity 79%
e) had been generated. Table 4 shows the results of Examples 2 to 6.

[0061]

[Table 4]

Example 7 Compound <Synthesis of No. (-)-1> To a solution of 10.1 g of compound No. (+)-6 (70% ee in optical purity) in 20 ml of acetone, 20 ml of 10% aqueous sulfuric acid was added. 5
Stirred at 0 ° C. for 5 hours. After completion of the reaction, the reaction solution was neutralized by adding sodium carbonate. Ethyl acetate was added and the layers were separated, and the organic layer was washed with water and saturated saline. After the solvent was distilled off under reduced pressure, 5 ml of toluene and 25 ml of n-hexane were added to the concentrate, and the mixture was ice-cooled. The precipitated crystals were collected by filtration and dried to give Compound No. (-)-1 (9.1 g, yield 86%, optical purity
36% ee, white solid) was obtained.

Example 8 <Synthesis of Compound No. (-)-1> To a solution of 4.67 g of compound No. (+)-6 (optical purity 70% ee) in 10 ml of acetone, 10 ml of 10% aqueous sulfuric acid was added. 5
Stirred at 0 ° C. for 5 hours. After completion of the reaction, the reaction solution was neutralized by adding sodium carbonate. Ethyl acetate was added and the layers were separated, and the organic layer was washed with water and saturated saline. After the solvent was distilled off under reduced pressure, 2.5 ml of toluene and n-hexane were added to the concentrate.
5 ml was added and the mixture was ice-cooled. The precipitated crystals were filtered and then dried to give compound No. (-)-1 (4.13 g, yield 84%
, Optical purity 33% ee, white solid).

Example 9 <Synthesis of Compound No. (-)-1> 0.50 g of Compound No. (+)-6 (optical purity> 99% ee) was dissolved in 5.0 ml of acetonitrile, and 65% aqueous sulfuric acid was added. .15m
was added and stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was neutralized by adding sodium carbonate. Ethyl acetate was added and the layers were separated, and the organic layer was washed with water and saturated saline. When the organic layer was analyzed by high performance liquid chromatography, the conversion of Compound No. (+)-6 was 76%, and that of Compound No. (-)-1
(Yield 60%, optical purity 38% ee).

Examples 10 to 23 <Synthesis of Compound No. (-)-1> Reaction was carried out in the same manner as in Example 9 using the solvents shown in Table 5 and the obtained results were combined with those of Example 9. The results are shown in Table-5.

[0066]

[Table 5]

Example 24 <Synthesis of Compound No. (-)-1> Compound No. (+)-6 (6.82 g, optical purity> 99% ee) was dissolved in chlorobenzene (40.0 g), and formic acid (13.8 g) was dissolved. g) and water (5.4 g) were added, and the mixture was stirred at 50 ° C for 3 hours. After completion of the reaction, a 25% aqueous sodium hydroxide solution (60 g) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 0.5 hour. The layers were separated and the organic layer was washed with water and brine. When the organic layer was analyzed by high performance liquid chromatography, the conversion of Compound No. (+)-6 was 1
Compound No. (-)-1 (yield 85%, optical purity 55% e
e) had been generated.

Example 25 <Synthesis of Compound No. (-)-1> 0.50 g of Compound No. (+)-6 (optical purity> 99% ee) was dissolved in 10 ml of chlorobenzene, and 0.5 ml of formic acid was added. Stirred at room temperature for 30 hours. After completion of the reaction, 10 ml of a 25% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The layers were separated and the organic layer was washed with water and brine. When the organic layer was analyzed by high performance liquid chromatography, the conversion of Compound No. (+)-6 was 100%, and the conversion of Compound No. (-)-
1 (79% yield, 64% ee optical purity) was produced.

Example 26 <Synthesis of Compound No. (-)-1> 160 g of Compound No. (±) -3 was added to Lipase R (Penicilliu).
mroqueforti, 85 g of Amano Pharmaceutical Co., Ltd., 350 ml of diisopropyl ether and a phosphate buffer solution (pH 7.
2) 1050 ml of the mixture was stirred at 25 ° C for 24 hours. After completion of the reaction, the reaction mixture was extracted with chlorobenzene, and the organic layer was filtered through celite.The organic layer was washed with aqueous sodium carbonate, water and brine in that order, and the organic layer was analyzed by high performance liquid chromatography. Conversion rate of ±) -3 is 5
At 0%, compound No. (-)-3 (optical purity 82% ee) and compound No. (+)-1 (optical purity 82% ee) were formed. 30 g of pyridine was added to this chlorobenzene solution, and the mixture was cooled with ice.
30 g of methanesulfonyl chloride was added dropwise. After the completion of the dropwise addition, the mixture was reacted at room temperature for 24 hours, washed with water and aqueous hydrochloric acid, and the organic layer was analyzed by high performance liquid chromatography. Compound No. (-)-3 (optical purity 82% ee) and compound No. N
o. (+)-5 (optical purity 82% ee) was produced.

The chlorobenzene solution was added at room temperature to 25%
320 g of an aqueous sodium hydroxide solution was added, and the reaction was allowed to proceed for 5 hours. After completion of the reaction, the organic layer was washed with water and brine, and the solvent was distilled off under reduced pressure. The residue was analyzed by high performance liquid chromatography. Compound No. (-)-1 (optical purity 82% ee) and compound No. (+)-6 (optical purity 82% ee)
) Was generated. This residue was dissolved in a mixed solvent of 350 ml of diethylene glycol diethyl ether and 9.0 ml of water, and 9.0 ml of concentrated sulfuric acid was slowly added dropwise under ice-cooling. After completion of the addition, the mixture was stirred at room temperature for 5 hours. After the reaction,
The reaction solution was neutralized by adding an aqueous solution of sodium hydroxide, and the organic layer was washed with brine. After evaporating the solvent under reduced pressure, the residue was crystallized from a toluene-n-hexane mixed solvent to give compound No. (-)-1 (98 g, yield 73% from compound No.
(±) -3, optical purity 81% ee, white solid).

Example 27 <Compound No. Synthesis of (−)-1> Compound No. 102 g of (±) -6 (0.300 mo
l), 600 g of chlorobenzene and 81.1 g of water (4.
207 g of formic acid (4.5 mol) at 50 ° C.
0 mol) was added dropwise. After completion of the dropwise addition, the mixture was reacted at 50 ° C. for 2 hours, and then 768 g of a 25% aqueous sodium hydroxide solution
(4.80 mol) was added and reacted at 50 ° C. for 1 hour.
After the reaction, the organic layer was separated and washed with saturated saline. About 1 /
3 chlorobezen is distilled off under reduced pressure, and chlorobenzene 20
0 g and pyridine 29.7 g (0.37 mol) were added, followed by caproic chloride 48.5 g (0.360 mol).
mol) was added dropwise. After completion of the dropwise addition, the mixture was reacted at 50 ° C. for 1 hour. The organic layer was separated, washed with a saline solution containing hydrochloric acid and a saturated saline solution, and concentrated under reduced pressure. (±) −
161 g of Compound No. 4 was obtained.

The crude compound No. (±) -4 (161 g)
Was dissolved in 250 ml of diisopropyl ether, and washed with 1N aqueous hydrochloric acid, aqueous sodium carbonate, and saturated saline. Add this solution to Lipase R Penicilliumuro
queforti (manufactured by Amano Pharmaceutical Co., Ltd.) (55 g) and a phosphate buffer solution (pH 7.2) (750 ml) were added, followed by stirring at 25 ° C. for 16 hours. After completion of the reaction, 150 g of sodium chloride was added, and the mixture was extracted with 375 ml of chlorobezen. The organic layer was filtered through celite, washed with a saline solution containing sodium carbonate and brine, and the organic layer was analyzed by high performance liquid chromatography.
Compound No. The conversion of (±) -4 was 50% and the compound N
o. (-)-4 (85% ee optical purity) and Compound N
o. (+)-1 (85% ee optical purity) was produced.

About 1/3 of chlorobenzene was distilled off under reduced pressure, 19.0 g (0.188 mol) of triethylamine was added, and 20.6 g of methanesulfonyl chloride was added under ice cooling.
(0.180 mol) was added dropwise. After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour, washed with water and hydrochloric acid, and the organic layer was analyzed by high performance liquid chromatography.
o. (-)-4 (optical purity 79% ee) and compound N
o. (+)-5 (85% ee optical purity) was produced.

To this chlorobezen solution, 236 g (1.48 mol) of a 25% aqueous sodium hydroxide solution was added, and
The reaction was carried out at 2 ° C. for 2 hours. After completion of the reaction, brine was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and the solvent was distilled off under reduced pressure. The residue was analyzed by high performance liquid chromatography. (-)-1 (optical purity 85
% Ee) and Compound No. (+)-6 (optical purity 85%
ee) had been produced. This residue was dissolved in 500 ml of diethylene glycol diethyl ether, and water
2.2 mol (0.675 mol) and concentrated sulfuric acid 12.2
ml of the mixed solution was slowly added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was neutralized by adding an aqueous sodium hydroxide solution, the organic layer was separated and concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of toluene / n-heptane. (-)-1 (81 g, yield 75% from compound No. (±) -4, optical purity 8)
1% ee, white solid) was obtained.

Example 28 <Compound No. Synthesis of (−)-1> Compound No. (+)-6 (optical purity> 99% ee)
40 g (4.11 mol) was dissolved in diethylene glycol diethyl ether (14 ml), and concentrated sulfuric acid (0.1 ml) was added under ice-cooling.
ml and water 0.1ml (5.56mmol, H ₂ O-
A mixed solution of 1.35 eq / (+)-6) was added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was neutralized by adding sodium carbonate. Ethyl acetate was added and the layers were separated, and the organic layer was washed with water and saturated saline. When the organic layer was analyzed by high performance liquid chromatography, Compound No. The optical purity of (−)-1 was 76% ee.

Example 29 <Compound No. Synthesis of (−)-1> 0.35 ml of concentrated sulfuric acid and 0.35 ml of water (19.4 mm
_{ol, H 2 O-4.7eq /} (+) - mixture except using 6) is performed in the same manner as in Example 28, was analyzed organic layer by high-performance liquid chromatography, the compound N
o. The optical purity of (−)-1 was 83% ee.

Example 30 <Compound No. Synthesis of (−)-1> 0.75 ml of concentrated sulfuric acid and 0.75 ml of water (41.6 mm
ol and H ₂ O-10 eq / (+)-6), except that a mixed solution was used. The organic layer was analyzed by high performance liquid chromatography to find that the compound N
o. The optical purity of (−)-1 was 78% ee.

Example 31 <Compound No. Synthesis of (−)-1> Compound No. (+)-6 (optical purity> 99% ee)
40 g (4.11 mol) and water 0.1 ml (5.56)
_{mmol, H 2 O-1.35eq /} (+) - 6) was dissolved in diethylene glycol diethyl ether 14ml and
0.1 ml of concentrated sulfuric acid was added dropwise at room temperature, and after completion of the addition, the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was neutralized by adding sodium carbonate. Ethyl acetate was added and the layers were separated, and the organic layer was washed with water and saturated saline. When the organic layer was analyzed by high performance liquid chromatography, Compound No. (−) −
The optical purity of No.1 was 70% ee.

Example 32 <Compound No. Synthesis of (−)-1> Compound No. (+)-6 (optical purity> 99% ee)
40 g (4.11 mol) and 0.35 ml of water (19.
_{4mmol, H 2 O-4.7eq /} (+) - 6) was dissolved in diethylene glycol diethyl ether 14ml and
0.35 ml of concentrated sulfuric acid was added dropwise at room temperature, and after completion of the addition, the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was neutralized by adding sodium carbonate. Ethyl acetate was added and the layers were separated, and the organic layer was washed with water and saturated saline. When the organic layer was analyzed by high performance liquid chromatography, Compound No. (-)
The optical purity of -1 was 75% ee.

Reference Example 1 <Synthesis of (-) 2- [2- (3-chlorophenyl) -2,3-epoxypropyl] -2-ethylindane-1,3-dione> Compound No. (-)-1 (Optical purity 80% ee) 17.9g, p-
2.7 g of toluenesulfonyl chloride and 10 g of toluene
To 0 ml of the mixture, 40 g of a 20% aqueous sodium hydroxide solution was added dropwise at 40 ° C. After completion of the dropwise addition, the mixture was reacted at 50 ° C. for 3 hours. The organic layer was separated, washed with water and concentrated to obtain 16.9 g of the title compound ((−)-6) (yield> 99). %, Optical purity 80% ee). This was added with n-hexane and cooled with ice to give Compound No. A white solid (-)-6 was obtained. The analytical values of this compound were as follows. mp 41-42 ℃ [α] _D ²⁵ -47.6 (C 0.556, CHCl ₃ )

REFERENCE EXAMPLE 2 <Field Soil Treatment Test> A field-made volcanic ash soil was filled in a resin vat having an area of 200 cm ² , and after fertilization, a soil uniformly mixed with Brassica napus, Enokorogosa, Poa annua and Poa annua was put on the soil surface. A wettable powder containing the compound synthesized in Reference Example 1 as an active ingredient was diluted and adjusted with water, and a predetermined amount was uniformly treated with a small power pressurized sprayer. A survey was performed on the 28th day after the drug treatment, and a ratio (%) to the no-treatment ratio was calculated for each of the treated plots and weed species, and the 90% inhibitory amount of the compound of the present invention was calculated. The results are shown in Table-4. In addition, the test was performed in the same manner as described above using a racemate (comparative agent A) corresponding to the active ingredient compound as a comparative agent, and the same evaluation was performed. The results are shown in Table-6.

[0082]

[Table 6]

[0083]

According to the method of the present invention, an optically active compound useful as a synthetic intermediate of a physiologically active substance such as an agricultural chemical can be produced in a high yield and a high optical purity by using a racemic compound as a starting material. Further, it is possible to carry out the reaction continuously in one reaction vessel without separating and purifying the product for each reaction step, which is an industrially advantageous method.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 29/10 C07C 29/10 33/26 33/26 49/443 49/443 // C07B 61/00 300 C07B 61/00 300

Claims (18)

[Claims] [Claim 1] The following general formula (1) Ａ In the formula, A is the following general formula (2): (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group or an alkenyl group; Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms,
Represents an alkoxyl group, a nitro group or a cyano group.
n shows 0-4. ), A group represented by following general formula (3) ## STR3 ## _{^{CX 1 3 (CX 2 2)}} p - (3) ( wherein, the X ^1, X ² are each independently a halogen atom or a hydrogen atom And p represents 0 to 2), and B represents an optionally substituted benzene ring. ｝
The optically active 1,2-disubstituted-2,3-epoxypropanes represented by the formula (a) is hydrolyzed in the presence of an inorganic acid, or (b) is ring-opened in the presence of a carboxylic acid; The following general formula (4) characterized by decomposition: (Wherein, A and B have the same meaning as defined in the general formula (1)).
-A process for producing dihydroxypropanes. 2. An optically active 1,2-disubstituted-2,3-epoxypropane represented by the general formula (1) is hydrolyzed in the presence of an inorganic acid. A process for producing the optically active 1,2-disubstituted-2,3-dihydroxypropanes described in the above. 3. The method for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 2, wherein the inorganic acid is sulfuric acid. 4. The optically active 1,2-disubstituted-2,2 according to claim 1, wherein an ether solvent, a ketone solvent or an ester solvent is used as a reaction solvent. A method for producing 3-dihydroxypropanes. 5. The optically active 1,2-disubstituted compound according to claim 4, wherein ethylene ether or 6-membered ring ether is used as the ether solvent.
A method for producing 2,3-dihydroxypropanes. 6. An optically active 1,2-disubstituted-2,3-epoxypropane represented by the general formula (1) is subjected to ring opening in the presence of a carboxylic acid, followed by solvolysis. The optically active 1,2-disubstituted compound according to claim 1,
A method for producing 2,3-dihydroxypropanes. 7. The method for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 6, wherein the carboxylic acid is formic acid. 8. The process for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 6, wherein an aromatic hydrocarbon solvent is used as a reaction solvent. 9. The method according to claim 1, wherein in the general formula (1), A is a 2-ethylindan-1,3-dione-2-yl group, and B is a 3-chlorophenyl group. A process for producing the optically active 1,2-disubstituted-2,3-dihydroxypropanes described in the above. 10. An optically active 1,2-disubstituted-2,3-epoxypropane represented by the general formula (1):
The following general formula (8) (Wherein, A and B have the same meanings as defined in the general formula (1). R ⁴ has 10 carbon atoms which may have a substituent.
The following alkyl groups or aryl groups are shown. The optical activity according to any one of claims 1 to 9, wherein a reaction product of the optically active sulfonic acid ester represented by the formula) and a base is used, if necessary, by separating and purifying by-products. 1,2
-A process for producing disubstituted-2,3-epoxypropanes. 11. The optically active sulfonic acid ester represented by the general formula (8) is represented by the following general formula (6): (Wherein, A and B have the same meaning as defined in the general formula (1)).
-Dihydroxypropanes and the following general formula (11) or (12): R ⁴ SO ₂ Y (11) (R ⁴ SO ₂ ) ₂ O (12) (wherein R ⁴ has a substituent Represents an alkyl group or an aryl group having 10 or less carbon atoms, wherein Y represents a halogen atom.) A reaction product with a sulfonic acid derivative represented by The method for producing optically active 1,2-disubstituted-2,3-epoxypropanes according to claim 10, which is used. The manufacturing method. 12. The optically active 1,2- compound represented by the general formula (6).
As the disubstituted-2,3-dihydroxypropanes, the following general formula (5): (Wherein, A and B have the same meanings as defined in the general formula (1)), and the 1,2-disubstituted-2,3-dihydroxypropane represented by the formula is stereoselectively transesterified. (R ² CO ₂ ) _m R ³ _m (10) (wherein R ² and R ³ each independently represent a substituent Represents an alkyl group, an alkenyl group, an aralkyl group or an aryl group having 20 or less carbon atoms which may be contained, and R ^{2 and} R ³ may be bonded to each other to form a ring; The product obtained by reacting with the carboxylic acid ester represented by the formula (1) is used, if necessary, by separating and purifying by-products, and then using the product. -A process for producing disubstituted-2,3-epoxypropanes. 13. The method for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 12, wherein the enzyme is a lipase derived from a microorganism belonging to the genus Pseudomonas. 14. The carboxylic acid ester of the general formula (10), wherein R ³ is a vinyl group.
Or the optically active 1,2-disubstituted-2,3-2,
A method for producing 3-dihydroxypropanes. 15. The optically active 1,2-disubstituted-2,3-dihydroxypropane of the general formula (6) is converted to the following general formula (9): (Wherein, A and B have the same meanings as defined in the general formula (1). R ² has 20 carbon atoms which may have a substituent.
The following alkyl group, alkenyl group, aralkyl group, or aryl group is shown. 1,2) -disubstituted-2-
In the presence of an enzyme having a stereoselective solvolysis ability, hydroxy-3-acyloxypropanes are converted to a compound represented by the following general formula (13): R ⁵ OH (13) (where R ⁵ is a hydrogen atom or substituted Represents an alkyl or alkenyl group having 20 or less carbon atoms which may be used), and if necessary, separating and purifying by-products before use. Item 15. The optically active 1,2-disubstituted-2,3 according to any one of Items 12 to 14,
-A process for producing epoxypropanes. 16. The method for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 15, wherein the enzyme is a lipase derived from a microorganism belonging to the genus Penicillium. 17. The method for producing an optically active 1,2-disubstituted-2,3-dihydroxypropane according to claim 15, wherein the compound of the general formula (13) is water. 18. The optical activity 1 according to claim 15, wherein R ^{2 in the} general formula (9) is an n-propyl group, an i-propyl group, or an n-pentyl group. For producing 2,2-disubstituted-2,3-dihydroxypropanes.