KR20010052811A - Mixtures of optical isomers of 1,2-disubstituted-2,3-epoxypropanes, process for producing the same, pesticides containing the same as the active ingredient and intermediates thereof - Google Patents

Abstract

Disclosed is an optically active 1,2-disubstituted-2,3-epoxypropane mixture represented by the following formula (1) and an optical isomer mixture of the optical isomer exhibiting excellent herbicidal activity and remarkably improved water solubility, And exhibits excellent herbicidal effect.

[Chemical Formula 1]

(Wherein A is a group represented by the following formula (2)

(2)

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3)

(3)

CX ¹ ₃ (CX ² ₂ ) _p -

(Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent.

Description

TECHNICAL FIELD [0001] The present invention relates to an optical isomer mixture of 1,2-disubstituted-2,3-epoxypropane, a method for producing the same, an agricultural chemical containing the same as an active ingredient, PRODUCING THE SAME, PESTICIDES CONTAINING THE SAME AS THE ACTIVE INGREDIENT AND INTERMEDIATES THEREOF}

Many agricultural chemicals such as herbicides are conventionally used for cultivation of important crops such as rice, barley and corn. Preferred properties for herbicides include low herbicidal activity, high herbicidal activity, broad herbicidal spectrum, suitable residual activity, and sufficient safety for crops. Most of existing herbicides do not satisfy these requirements, and especially herbicides which are effective at low dosage due to recent environmental problems are being demanded.

On the other hand, JP-A-2-304043 discloses that 1,2-dihydroxy-2,3-epoxypropane having a substituent of a certain kind has a herbicidal activity. However, since these compounds are low in water solubility (permeability to water), applications of them as herbicides are limited to medicines and the like. Further, the 1,2-disubstituted-2,3-epoxypropane described in the patent publication has an asymmetric carbon atom in its structure, so that the presence of an optical isomer is predicted. However, in the patent publication, There is no specific description.

The present invention has been made in view of the above circumstances, and it is an object of the present invention to provide an effective ingredient of an agricultural chemical which exhibits a high activity at a low dosage and a method for producing the same. Specifically, it is intended to provide an effective ingredient of an excellent herbicide having properties such as a high activity of actinicidal activity and a light soybean spectrum at a low dose, and a method for producing the effective ingredient which is inexpensive and suitable for an industrial production method.

DISCLOSURE OF INVENTION

As a result of intensive studies, the present inventors have found that, in optically active 1,2-disubstituted-2,3-epoxypropanes having a specific substituent group and an optical isomer mixture of the optical isomer, Can be used as a herbicide for field soil treatment which shows a much higher herbicidal activity than the corresponding racemate and is difficult to exert its effect due to its low permeability in the racemate. And completes the present invention.

The present invention has been accomplished on the basis of the production method of this optical isomer mixture and the production method which is inexpensive and industrially suitable for the production intermediate thereof.

That is, the present invention relates to an optically active 1,2-disubstituted-2,3-epoxypropane represented by the following formula (1) and an optical isomer mixture of the optical isomer, a process for producing the same, Manufacturing intermediates and processes for their preparation.

(Wherein A is a group represented by the following formula (2)

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3)

CX ¹ ₃ (CX ² ₂ ) _p -

(Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

(I) optical isomer mixture

The optically active 1,2-disubstituted-2,3-epoxypropane in the optical isomer mixture of the present invention is represented by the above formula (1).

In the above formula (1), A is a group represented by the formula (2) or (3). In the formula (2), R ¹ represents a hydrogen atom; Lower alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group and n-butyl group; Alkenyl groups such as a vinyl group and an allyl group; An alkynyl group such as an ethynyl group and a propargyl group.

Q is 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 methyl group, ethyl group, n-propyl group, and i-propyl group; A haloalkyl group having 1 to 3 carbon atoms such as a chloromethyl group, a dichloromethyl group, a trifluoromethyl group, and a fluoroethyl group; An alkoxy group having 1 to 5 carbon atoms such as methoxy group and ethoxy group; A nitro group; Or a cyano group, and n represents an integer of 0 to 4.

In the formula (3), X ¹ and X ² represent 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.

Examples of B in the formula (1) include a halogen atom such as a chlorine atom, a fluorine atom and a bromine atom; An alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, i-propyl group and n-butyl group; A haloalkyl group having 1 to 3 carbon atoms such as a chloromethyl group, a dichloromethyl group, a trifluoromethyl group, and a fluoroethyl group; An alkoxy group which may be substituted with a halogen atom such as a methoxy group, an ethoxy group, a chloromethoxy group, or a fluoroethoxy group; An aryl group such as a phenyl group or a pyridyl group which may be substituted with a nitro group or a cyano group.

As R ¹ in the formula (2), a lower alkyl group is preferable, and among these, a methyl group and an ethyl group are preferable, and an ethyl group is particularly preferable. Also, n is preferably 0. In the formula (3), X ¹ and X ² are preferably a halogen atom, more preferably a chlorine atom or a fluorine atom, particularly preferably a chlorine atom. And p is preferably 0 for p.

B is preferably a halogen atom, more preferably a phenyl group substituted by a chlorine atom, particularly preferably a 3-chlorophenyl group or a 3,5-dichlorophenyl group.

In the optically active 1,2-disubstituted-2,3-epoxypropane of the optical isomer mixture of the present invention, it is preferable that each of the above-described substituents is a combination of the preferable ones, 1), it is preferable that A is a group represented by the above-mentioned formula (2) and n is 0, and further, it is preferable that B is a phenyl group substituted with a chlorine atom, particularly 3-chlorophenyl group. Specific examples of the compound represented by the above-mentioned formula (1) include (-) - 2- [2- (3-chlorophenyl) -2,3-epoxypropyl] Particularly preferred is (-) - [2- (3-chlorophenyl) -1- (2-ethylindadione)] - 2,3-epoxypropane in a separate nomenclature.

The optical isomer mixture of the present invention comprises the optically active 1,2-disubstituted-2,3-epoxypropane represented by the above-mentioned formula (1) and the optical isomer thereof, wherein the optical isomer represented by the formula (1) Its enantiomer excess (% ee) is more than 40% ee. The content of the optical isomer mixture is 40% ee or more, and thus the herbicidal activity is much higher than that of the corresponding racemate, and the water solubility of the optical isomer mixture is 30 ppm or more, preferably 35 ppm or more, It can be used as a herbicide for field soil treatment which is difficult to exert its effect because it is low.

The content of the optical isomer mixture of the present invention is preferably 70% ee or more, more preferably 80% ee or more, particularly 90% ee or more. The content is preferably as close to 100% ee, but in general, a purification process is required for 100% ee, and the yield is likely to decrease. Therefore, it is industrially inexpensive and the effect of the agrochemical activity exhibited by the optical isomer mixture is in a sufficient range. In the present invention, the content is preferably 40 to 98% ee, more preferably 70 to 98% ee, 98% ee. The water solubility in the present invention means the solubility (ppm) in water at 25 캜.

Specific examples of the optically active 1,2-disubstituted-2,3-epoxypropane represented by the above-mentioned formula (1) are shown below. The optically active substance in the optical isomer mixture of the present invention is limited to these It is not.

(II) Pesticides

The pesticide of the present invention will be explained. The pesticide of the present invention contains the above-described optical isomer mixture of the present invention as an active ingredient, and exhibits excellent herbicidal activity and broadleaf spectrum particularly as a herbicide. Particularly, it is preferable to use it as a soil treatment agent because the effect becomes remarkable. When used as a herbicide, the content of the optically active substance represented by the formula (1) in the optical isomer mixture of the present invention is 40% ee or more, preferably 70% ee or more, more preferably 80% Or more.

The application amount of the pesticide of the present invention may be appropriately selected depending on the above-described content in the optical isomer mixture of the present invention used as the active ingredient, and the object to be used as the pesticide and the treatment conditions.

When the optical isomer mixture of the present invention is used as an active ingredient of a herbicide, the mixture may be used as it is to be used as a reagent. In general, it is preferable to use the active ingredient in the form of a composition by using a pesticide adjuvant commonly used in the art. The form of the preparation is not particularly limited, but is preferably in the form of, for example, an emulsion, a wetting agent, a powder, a blue blend, a fine granule, a granule, a jumbo formulation, a tablet, an emulsion, a spray, A mixture of two or more kinds of optical isomers may be used as an effective component.

In the production of the herbicide of the present invention, an agricultural chemical auxiliary agent may be used for the purpose of improving the herbicidal effect, stabilizing it, improving the dispersibility and the like. Examples of the agricultural chemical auxiliary agent include a carrier (diluent), an electrodeposition agent, an emulsifier, a wetting agent, a dispersant, and a disintegrating agent. More specifically, as the carrier, there are a liquid carrier and a solid carrier. Examples of the liquid carrier include aromatic hydrocarbons such as water, toluene and xylene; alcohols such as methanol, butanol and glucol; ketones such as acetone; amides such as dimethylformamide; sulfoxides such as dimethylsulfoxide; Cyclohexane, animal and plant oils, and fatty acids. Examples of the solid carrier include clay, kaolin, talc, diatomaceous earth, silica, calcium carbonate, montmorillonite, bentonite, feldspar, quartz, alumina, sawdust, nitrocellulose, starch and gum arabic.

Conventional surfactants can be used as emulsifiers and dispersants. For example, anionic surfactants such as higher alcohol sodium sulfate, stearyl trimethyl ammonium chloride, polyoxyethylene alkyl phenyl ether and lauryl betaine, cationic surfactants, nonionic surfactants and amphoteric surfactants can be used. Examples of the electrodeposition agent include polyoxyethylene nonylphenyl ether and polyoxyethylene lauryl ether. Examples of the wetting agent include polyoxyethylene nonylphenyl ether and dialkyl sulfosuccinate. Examples of the fixing agent include carboxymethyl cellulose and polyvinyl alcohol. , And as the disintegrating agent, sodium ligninsulfonate, sodium lauryl sulfate, and the like can be used. As other pesticide auxiliary agents, for example, those described in JP-A-60-25986 may be used.

When the pesticidal composition of the present invention is used to produce pesticides, the content of the active ingredient in the pesticide is usually 0.5 to 90% by weight and the content of the pesticide adjuvant is 10 to 99.5% by weight. As shown in FIG.

The herbicide of the present invention may contain an optional active ingredient such as an effective ingredient or the above-mentioned agricultural chemical auxiliary agent other than agricultural or horticultural fungicide, insecticide, herbicide, plant growth regulator, fertilizer, soil improving agent, In addition, such a mixture may be mixed with other pesticides or used at the same time. The application amount of the herbicide of the present invention may be appropriately selected according to the kind of the active ingredient, target weed, treatment period, treatment method, or soil properties. Usually, the effective amount per 1 hectare is 20 to 2000 grams, preferably 50 To 1000 grams.

The optical isomer mixture of the present invention has an excellent herbicidal activity as compared with the corresponding racemate as described in JP-A-2-304043. Further, the water-solubility of the racemate is remarkably improved, so that it has a particularly excellent field soil treatment activity. The herbicide of the present invention comprising the optical isomer mixture of the present invention having the excellent herbicidal activity of the present invention as an active ingredient exhibits a powerful weed activity against the annual weeds of rice paddies such as barnyard grass, , Barley, beet and the like are remarkably less vulnerable to crops. In addition, the herbicide of the present invention is effective also for the perennial weeds of weeds such as weed killer, weed killer weed, weed killer weed, weed killer weed, weed killer, weed killer, weed killer weed, weed killer weed,

The herbicide of the present invention can be used in combination with other herbicides to significantly broaden the width of the herbicidal spectrum. Thus, it is possible to provide a herbicide which is effective, for example, in the annual growth of light-grown broad-leaved weeds and perennial weeds, and can further stabilize the herbicidal effect. Herbicides which can be mixed with the herbicides of the present invention in a preferable manner include, for example, the generic names listed in the following mixture list. However, the herbicides which can be mixed properly are not limited to those listed in the following list.

<Mixed list>

Group A

Chloroacetamide system; Alachlor, methorachlor, acetochlorine

Carbamate type; Triallyrate

Dinitroaniline series; Tripluralin, pendimethalin

Group B

Phenoxy propionate type; Methyl, fenoxaprop-ethyl, fluazipopod-butyl, quizalofop-ethyl

Cyclohexanedione system; Cetoxydim, Cleptodim, Tralcoxidim, Butroxhidim

C group

Amide system; Diflufenicane, UBH-820

Sulfonamide system; Flumethsulam

Sulfonylurea type; Halosulfuron

Imidazolidinone; Imajarun

D group

Sulfonylurea type; Chlorimuron, thifensulfuron, prosulfuron, methsulfuron methyl, amidosulfuron, indosulfuron

Sulfonamide system; Dichlorosulam

Phenolic; Bromoxynyl, ioxynil

Phenok watch; 2,4-D, methoprotein

Diphenyl ether type; Lactophene, acifluorfen-sodium, bifenox, oxyfluorfen

Other; Dicamba, bentazon, fluoxam, flimiclol-ethyl, BAS 61500H

E group

Triazines; Atrazine, cyanazine,

Urea system; Chlorotoluron, isoprothrone, diuron, linuron, fluoromuten

Sulfonylurea type; Chlorsulfuron, lymsulfuron, nicosulfuron, flupyrsulfuron

Imidazolidinone; Imazetapyr, imajamox, imazametaphyr

Amide system; Dimetheneamide

Other; Fluomycin, here tetrapolene, sulcotrione, nolflurazone, clomazone, JV 485 (isopropazole)

F group

Organic phosphorus; Glyphosate, glufosinate, biaraphos

Other; Paracuart

G group

Chloroacetamide system; Butyrochlor, pretilachlor, tenyl chloride

Amide system; Mepenacet, carpentol, etobenzionide, NBA-061 (pentrazamide), propanyl

Phenoxy propionate type; Siallofort-butyl

Carbamate type; Benzothiocarb, esprocarb, molinate, pyridine butyrate,

Other; Oxaziclomepine, pyriminobut-methyl

H group

Sulfonylurea type; Benzisulfuron-methyl, pyrazosulfuron-ethyl, imazosulfuron, cyclosulfamuron, cinosulfuron, ethoxysulfuron, azimsulfuron, halosulfuron

Phenok watch; N-proanilide, cromeprov, phenothiol, MCPB, MCPA

Pyrazolate; Pyrazolate, pyrazoxifene, benzofenaf &lt; RTI ID = 0.0 &gt;

Diphenyl ether type; Bifenox

Other; Oxadiargyl, pentoxazone

I group

Amide system; Bromobutide

Urea system; Dimuron (dimuron), cumyluron

Other; Benfuresate; SB-500

In the herbicide for soil treatment of the present invention, it is preferable to use the herbicide as a mixed herbicide or a mixed herbicide in the C group or the E group, among the above-mentioned herbicides.

(III) Production method of optically active 1,2-disubstituted-2,3-epoxypropane

(III-1) Preparation of olefins by subtropic epoxidation

The optical isomer mixture of the present invention (hereinafter sometimes referred to as optically active 1,2-disubstituted-2,3-epoxypropane represented by the general formula (1)) is, for example,

(In the formula, A and B are the same as in the formula (1)), by epoxidizing the 2,3-disubstituted-1-propene.

The method of subjecting the 2,3-disubstituted-1-propene represented by the formula (4) to sub-epoxidation is not particularly limited, and for example, a method of reacting an oxidizing agent in the presence of an optically active manganese complex is used.

As the optically active manganese complex, for example, the following formula (5)

(Wherein, R ² each independently represent an alkyl group or an aryl group having 1 to 10 carbon atoms or and may be bonded to form a hydrocarbon ring together, R ³ and R ⁴ are alkyl groups having 1 to 10 carbon atoms, each independently, an alkoxy group, A trialkylsiloxy group or an aryl group), and the like. Among them, those represented by the following formula (21) or (22) are preferable.

(Wherein t-Bu represents a tert-butyl group, i-Pr represents an isopropyl group, and Ph represents a phenyl group.)

The amount of the optically active manganese complex used is 0.0001 to 1.5 mol per mol of the 2,3-dihydro-1-propene represented by the formula (4) as the reaction raw material.

As the oxidizing agent, any of conventionally known ones may be used, and preferably, an excessively high iodine compound such as C ₆ H ₅ IO, an inorganic oxidizing agent such as sodium hypochlorite and hydrogen peroxide, a percarboxylic acid such as methachloro and benzoic acid, have. The amount of the oxidizing agent to be used may be appropriately selected depending on the reaction conditions. Usually, the equivalent amount of the 2,3-dihydroxy-1-propene may be used.

In the oxidation reaction by the above-mentioned optically active manganese complex, the reaction is carried out in the presence of the N-oxide compound to obtain the optically active 1,2-disubstituted-2,3-epoxypropane of the formula (1) The optical purity is increased. As the N-oxide compound to be used, any conventionally known compounds can be used, and examples thereof include N-oxide of heterocyclic amines such as 4-phenylpyridine-N-oxide, N-methylmorpholine- And N-oxides of aliphatic amines. The amount of the N-oxide compound used is in the range of 0.0001 to 1.5 mol per mol of the 2,3-dicarboxylic acid-1-propene.

The subtitle epoxidation reaction may be carried out in the presence of a solvent. Any solvent may be used as the solvent. Aliphatic hydrocarbon solvents such as hexane and heptane; aromatic solvents such as benzene, toluene and xylene; halogen solvents such as dichloromethane, chloroform and chlorobenzene; and water. They may be used singly or as a mixed solvent. The amount of the solvent to be used is preferably 0 to 100 times by weight, more preferably 1 to 20 times by weight, based on the weight of the 2,3-disubstituted-1-propene represented by the formula (4) used for the reaction. When a functional solvent is used as the solvent, the reaction is preferably carried out under an alkaline condition because the decomposition of the optically active 1,2-disubstituted-2,3-epoxypropane, which is a product, is suppressed.

The reaction temperature of the subtitle epoxidation reaction is in the range of -50 to 100 占 폚, preferably -20 to 70 占 폚, and the reaction time is usually within 100 hours. When an optically active manganese complex is used, after completion of the reaction, the reaction mixture is extracted with an organic solvent and purified by crystallization, distillation or column chromatography to obtain optically active 1,2-disubstituted-2,3-epoxypropane Can be obtained.

(III-2) Preparation of optically active 1,2-disubstituted-2,3-dihydroxypropanes by ring closure

The optically active 1,2-disubstituted-2,3-epoxypropane represented by the above-mentioned formula (1)

(In the formula, A and B are the same as those in the formula (1)), by stereoselectively ringing the optically active 1,2-disubstituted-2,3-epoxypropane.

The stereoselective ring closure is not particularly limited. For example, optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-described formula (6) The method of making active sulfonic acid esters and ring closure thereof in the presence of a base is preferable because of its simple and low cost.

(Wherein A and B are the same as in the formula (1), and R ⁵ represents an alkyl or aryl group having 1 to 10 carbon atoms which may have a substituent.)

Examples of the alkyl group having 1 to 10 carbon atoms which may have a substituent represented by R ⁵ in the formula (7) include a methyl group, a chloromethyl group, an ethyl group, a n-propyl group, , an n-heptyl group and the like. Examples of the aryl group (preferably having 6 to 10 carbon atoms) which may have a substituent include a phenyl group, a tolyl group, a nitrophenyl group, a chlorophenyl group and a naphthyl group. R ⁵ is preferably a methyl group or a p-tolyl group.

As the base used in the reaction, any conventionally known one can be used. Specific examples include 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, potassium hydroxide, Potassium and sodium carbonate, and the like. Among them, metal alkoxides and inorganic bases are preferable. The amount of the base to be used may be equal to or more than the equivalent amount of the optically active sulfonic acid esters represented by the formula (7), preferably 1.0 to 1.5 equivalents.

The ring-closure reaction may be carried out suitably in the presence of a solvent. As the solvent to be used, any solvent can be used, and examples thereof include 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 , Halogenated solvents such as chloroform and chlorobenzene, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, alcohols such as methanol, ethanol and butanol, nitriles such as acetonitrile, propionitrile and butyronitrile, And polar solvents such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and water. They may be used singly or as a mixed solvent. The amount of the solvent to be used may be 0 to 10 times the weight of the optically active sulfonic acid ester.

The reaction temperature is in the range of -50 to 100 ° C, preferably 0 to 70 ° C, and the reaction time is usually 30 hours or less.

The optically active sulfonic acid esters represented by the above-mentioned formula (7) are novel compounds, and for example, the optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned formula (6) With a sulfonic acid derivative represented by the following formula (8) or (9) in the presence of a base.

R ⁵ SO ₂ Y

(R ⁵ SO _{2) 2} O

(Wherein R ⁵ is the same as in the formula (7), and Y represents a halogen atom.)

As the sulfonic acid derivative represented by the formula (8) or (9), any one can be used, and as the sulfonic acid derivative represented by the formula (8), methanesulfonyl chloride and p-toluenesulfonyl chloride can be exemplified , And the sulfonic acid derivative represented by the formula (9) include methanesulfonic anhydride and p-toluenesulfonic anhydride. Of these, inexpensive methanesulfonyl chloride and p-toluenesulfonyl chloride are preferable.

The amount of the sulfonic acid derivative to be used may be equal to or more than the equivalent amount of the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (6), preferably 1.0 to 1.5 equivalents.

As the base to be used, any one can be used, and examples thereof include 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, potassium hydroxide, potassium carbonate, sodium carbonate and the like. Of these, amines and pyridines are preferable. The amount of the base to be used may be equal to or more than the equivalent amount of the optically active 1,2-disubstituted-2,3-dihydroxypropane, and usually 1.0 to 2.0 equivalents may be used.

In this reaction, the reaction may be suitably carried out in the presence of a solvent. As the solvent to be used, any solvent can be used, and examples thereof include 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 , Halogen solvents such as chloroform and chlorobenzene, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile, propionitrile and butyronitrile, dimethylformamide, N-methylpyrrolidone , A polar solvent such as dimethylsulfoxide and water, and the like. These solvents may be used alone or as a mixed solvent. When amines or pyridines are used as the base, the reaction may be carried out using the base itself as a solvent. The amount of the solvent to be used may be 0 to 10 times the weight of the optically active 1,2-disubstituted-2,3-dihydroxypropane. The reaction temperature is in the range of -50 to 100 ° C, preferably -20 to 50 ° C, and the reaction time is usually 30 hours or less.

As described above, optically active 1,2-disubstituted-2,3-dihydroxypropanes are used as optically active sulfonic acid esters and then ring-closed in the presence of a base to obtain optically active 1,2-disubstituted-2,3 - Epoxy propane can be prepared. At this time, the optically active sulfonic acid esters may be subjected to a cyclization reaction successively without isolation. Also, the reaction of optically active 1,2-disubstituted-2,3-dihydroxypropanes as optically active sulfonic acid esters and the reaction of optically active sulfonic acid esters with optically active 1,2-disubstituted-2,3-epoxypropanes May be carried out at the same time. When the reaction is performed in such a competitive manner, it is preferable to use an inorganic base such as sodium hydroxide as a base.

(IV) Preparation of optically active 1,2-disubstituted-2,3-dihydroxypropanes

The production method of the optical isomer mixture of the present invention is as described above. In the present invention, by stereoselectively ringing the optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned formula (6), the 1,2- It is also as described above that dihydroxy-2,3-epoxypropane can be produced.

In the present invention, the optically active 1, 2, or 3-epoxypropane represented by the formula (6), which is an intermediate for the production of the 1,2-disubstituted-2,3-epoxypropane represented by the formula (1) 2,3-dihydroxypropanes are efficiently and at high optical purity. By combining these production methods, an optical isomer mixture of the present invention and an agricultural chemical, especially a herbicide, containing the same as an effective ingredient can be produced industrially advantageously. Hereinafter, a method for producing the 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (6) will be described.

(IV-1) Preparation of olefins by subtly dihydroxylation

The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned formula (6)

[Chemical Formula 4]

(In the formula, A and B are the same as in the formula (1)) by diethoxylation of 2,3-disubstituted-1-propene.

The method for diethoxylating 2,3-dihydroxy-1-propene is optional, but a method of subtitle dihydroxylation using an osmium compound is preferable. Among them, it is preferable to carry out dihydroxylation in the presence of optically active tertiary amines and osmium compounds. In addition, it is preferable to carry out subtitle dihydroxylation by oxidizing a tertiary amine, such as N-oxide or a potassium carboxylate, in combination.

In the presence of tertiary amines, in an asymmetric dihydroxylation reaction using an osmium compound, a reducing agent such as sodium sulfite is added after completion of the reaction to extract the product with an organic solvent, which is subjected to acid treatment to remove tertiary amines , Crystallization, distillation or column chromatography to obtain optically active 1,2-disubstituted-2,3-dihydroxypropanes of interest as high optical purity.

As the osmium compound to be used in the subtitle dihydroxylation reaction, an octyl or octavalent osmium compound is preferable. Specific examples thereof include K ₂ OsO ₂ (OH) ₄ and osmium tetraoxide. The amount of the osmium compound to be used may be 0.0001 to 1.5 mole times the amount of the reaction raw material, 2,3-dihydroxy-1-propene.

As optically active tertiary amines, any of them may be used. Specifically, optically active substances of amines such as N, N'-tetrasubstituted ethylenediamines, N, N'-tetrasubstituted-1,4-butanediamines and 1,4-phthaladinediethers, . Among them, optically active substances of 1,4-phthalazinediyl diethers are preferable, and hydroquinine 1,4-phthalazinediyl diether represented by the following formula (23) is preferable Do.

The amount of optically active tertiary amines may be used in an amount of 0.0001 to 1.5 mol per mol of the reaction raw material, 2,3-dihydroxy-1-propene.

In the subtitle dihydroxylation reaction, the amount of the osmium compound and the optically active tertiary amines used can be reduced by using a co-oxidizing agent in combination, which is preferable.

As the co-oxidizing agent, any one can be used, and preferred examples thereof include N-oxide of tertiary amine or potassium ferricyanide [K ₃ Fe (CN) ₆ ]. The amount of the co-oxidizing agent used may be at least the molar amount of 2,3-dihydroxy-1-propene. It is also preferred to carry out the subtitle dihydroxylation reaction in the presence of a base in addition to the co-activator. As the base, any of them can be used. Specific examples thereof include metal alkoxides such as sodium methoxide and sodium ethoxide, inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate. Of these, inorganic bases, in particular carbonates, are preferred, and potassium carbonate is particularly preferred. The amount of the base to be used may be equal to or more than the equivalent amount of 2,3-dihydro-1-propene.

The subtitle dihydroxylation reaction may be carried out suitably in the presence of a solvent. As the solvent used in the present reaction, any solvent can be used, and examples thereof include diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, tetrahydropyran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, Aliphatic hydrocarbon solvents such as ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and diethylene glycol dibutyl ether; aliphatic hydrocarbon solvents such as hexane and heptane; benzene, toluene, xylene, Aromatic hydrocarbon solvents, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, halogen solvents such as dichloromethane and chloroform, nitrile solvents such as acetonitrile, propionitrile and butyronitrile, Amide, N-methylpyrrolidone and the like, amide solvents such as methyl acetate, ethyl acetate, propionic acid Butyl ester solvent such as methanol, ethanol, propanol, in can be a t- butyl alcohol, t- amyl alcohol solvents such as alcohols, dimethyl sulfoxide and the like. They may be used singly or as a mixed solvent. Among them, it is preferable to use a mixed solvent of an alcohol solvent and water, particularly a mixed solvent of t-butyl alcohol and water. The amount of the solvent to be used is preferably 0 to 100 times by weight, more preferably 1 to 20 times by weight, based on the weight of the reaction raw material, 2,3-dihydroxy-1-propene.

The reaction temperature is in the range of -50 to 100 占 폚, preferably -20 to 70 占 폚, and the reaction time is usually within 100 hours.

(IV-2) Enzyme Reaction Preparation by stereoselective ester cleavage

The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned formula (6)

(In the formula, A and B are the same as in the formula (1)) in the presence of an enzyme having a stereoselective ester interchangeability with 1,2-disubstituted 2,3-dihydroxypropanes of the formula (11)

(R ⁶ CO ₂ ) _m R ⁷ _m

(Wherein R ⁶ represents an alkyl group, an alkenyl group, an aralkyl group or an aryl group having 1 to 20 carbon atoms which may have a substituent and R ⁷ represents an alkyl group, an alkenyl group, an aralkyl group, an aryl group Or an acyl group, or R ⁶ and R ⁷ may combine to form a ring, and m represents an integer of 1 to 3) to produce a compound represented by the following formula Disubstituted-2-hydroxy-3-acyloxypropanes represented by the formula (12) and the compound represented by the formula (12) are optically active 1, 2,3-dihydroxypropanes, which are optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (13), which is an optical isomer having a desired stereostructure That is, the same as in the formula (6) .

Or optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes have a desired stereostructure, they are further subjected to solvolysis after the reaction to obtain optically active 1,2-disubstituted rings represented by the formula (6) -2,3-dihydroxypropanes, and fractionating the same.

In the enzymatic reaction, the stereostructure (R, S) of the compound generated depending on the stereoselectivity of the enzyme used in the reaction changes, and therefore, one of the above-mentioned methods may be selected. In addition, as the notation of the chemical structure, the stereochemistry may be different as described above. Therefore, the chemical structure is denoted by "*" in the subtitle carbon atom. This also applies to (IV-3) described later.

(Wherein A and B are the same as in the formula (1), R ⁶ is the same as in the formula (11), and * represents an asymmetric carbon atom.)

Here, the 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the general formula (12) and the compound represented by the general formula (12) 2-iodihydro-2,3-dihydroxypropanes are important intermediates for optically active 1,2-disubstituted-2,3-epoxypropanes in the optical isomer mixtures of the present invention as novel compounds.

As the enzyme used in this enzyme reaction, any enzyme may be used as long as it has an ability of sterically selective ester exchange with 1,2-disubstituted-2,3-dihydroxypropanes of the racemate described above. Specific examples thereof include lipases derived from microorganisms belonging to the genus Penicillium, Pseudomonas, Alcaligenes, Rhizopus or Aspergillus, Among them, preferred are lipases derived from microorganisms belonging to the genus Penicillium and Pseudomonas. These enzymes may be those which have been treated with the enzyme, such as acetone treatment or freeze-drying, or those immobilized on a carrier. An enzyme obtained by a suitable expression system by gene recombination may be used.

Specific examples of the lipase derived from microorganisms belonging to the genus Penicillium, Pseudomonas, Alzheimer's, Rhizopus or Aspergillus include Lipase R (penicillium genus, Amano Seiyaku Co., Ltd.) Lipase AK (Pseudomonas, manufactured by Amano Seiyaku), Lipase AKG (Pseudomonas, Amano Seiyaku), Toyozime LIP (Pseudomonas, manufactured by Toyobo Co., Ltd.) , Lipase Q (manufactured by Amano Seiyaku Co., Ltd.), Lipase PL (Lipase PL, Lipase QL), Lipase PL (manufactured by Meito Sanayoku Co., Ltd.) AP6 (genus Aspergillus, manufactured by Fluka), and the like.

These enzymes vary in reactivity and selectivity depending on the type of 1,2-dihydroxy-2,3-dihydroxypropane of the racemate as a raw material of the reaction. Therefore, the amount of the enzyme to be used may be appropriately set, Preferably 0.01 to 5 times by weight, more preferably 0.05 to 2 times by weight.

In the formula (11), R ⁶ in the carboxylic acid ester or acid anhydride represented by the chemical formula (11) used in this enzyme reaction is preferably a methyl group, ethyl group, n-propyl group, Butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-undecyl group, n-tridecyl group, A straight chain or branched chain alkyl group having 1 to 20 carbon atoms such as a t-butyl group; An alkenyl group having 2 to 20 carbon atoms such as a vinyl group, an isopropenyl group, a 2-pentenyl group and an 8-heptadecenyl group; A phenyl group, a naphthyl group and the like, preferably an aryl group having 6 to 20 carbon atoms; Benzyl group, phenethyl group and the like, preferably an aralkyl group having 7 to 20 carbon atoms. As R ⁷ , in addition to the group represented by R ⁶ described above, a group represented by formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, caproyl, An acyl group having 1 to 20 carbon atoms such as a methyl group, an acryloyl group, a methacryloyl group, a crotonoyl group, an isocrotonoyl group, and an oleyl group. These R ⁶ and R ⁷ may further have a substituent. m represents an integer of 1 to 3; That is, as the carboxylic acid ester represented by the formula (11), a monocarboxylic acid ester, a dicarboxylic acid ester, or a glyceride may be used.

Specific examples of the carboxylic acid esters include vinyl acetate, vinyl chloroacetate, vinyl propionate, vinyl butyrate, vinyl caproate, vinyl caprylate, vinyl caprate, vinyl laurate, vinyl myristate, vinyl palmitate, stearic acid Vinyl propionate, methyl caprate, methyl caprate, caprylate, methyl caprate, methyl laurate, myristyl acid, and methyl myristate. Methyl methyl palmitate, methyl stearate, methyl pivalate, methyl 2-ethylhexanoate, methyl methacrylate, isopropenyl acetate and the like.

Examples of the acid anhydrides include the anhydrides of the carboxylic acids constituting the carboxylic acid esters, specifically acetic anhydride, anhydrous propionic acid, anhydrous butyric acid, anhydrous isobutyric acid, anhydrous isophthalic acid, anhydrous isovaleric acid, anhydrous caproic acid, Acid, maleic anhydride, caprylic anhydride, lauric anhydride, succinic anhydride, maleic anhydride, and benzoic anhydride.

Among these carboxylic acid esters and acid anhydrides, vinyl esters and acid anhydrides are preferable, and vinyl esters such as vinyl acetate, vinyl butyrate, and vinyl caprate, anhydrous caproic acid and anhydrous benzoic acid are preferable because they are inexpensive and highly reactive . In particular, vinyl butyrate is preferable because it is inexpensive, has high stereoselectivity in the enzymatic reaction, and has a fast reaction speed.

These carboxylic acid esters and acid anhydrides may be used in an amount of 0.5 equivalents or more based on 1,2-dihydroxy-2,3-dihydroxypropane of the racemate used for the reaction.

This enzyme reaction is carried out, for example, by suspending an enzyme in a solvent in which racemic 1,2-dihydroxy-2,3-dihydroxypropanes and carboxylic acid esters or acid anhydrides are dissolved and stirring or shaking. Only one side of the optically active isomer of the racemic 1,2-dihydroxy-2,3-dihydroxypropane reacts with the carboxylic acid ester or the acid anhydride to form the optically active 1,2-disubstituted Hydroxy-3-acyloxypropanes. When the ester is an optical isomer having a desired stereostructure, the enzyme is removed by filtration or centrifugation after the completion of the enzyme reaction. If necessary, the resulting filtrate is concentrated and extracted from it, crystallized or subjected to column chromatography to give an ester The optically active 1,2-disubstituted-2,3-dihydroxypropanes of high optical purity can be obtained by purifying the sieve and then solvolyzed by an acid or an alkali. Furthermore, isolation of the optically active 1,2-disubstituted-2,3-dihydroxypropane (ester form of the optical isomer) after the completion of the enzymatic reaction by crystallization or the like is preferable because the subsequent operation becomes easy.

When the optically active substance having the desired stereostructure is not esterified after the enzyme reaction, that is, when the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (6) is obtained , It may be separated from the reaction solution by crystallization or the like.

Further, by conducting this enzyme reaction repeatedly, the optical purity of the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (6) can be further increased, which is preferable.

As the solvent used in this enzyme reaction, any solvent can be used. Examples thereof include ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran; aliphatic hydrocarbon solvents such as hexane and heptane; aromatic solvents such as toluene and xylene; Ester solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; halogen solvents such as chloroform and chlorobenzene; acetonitrile, ; Amide solvents such as dimethylformamide and N-methylpyrrolidone; dimethylsulfoxide; and the like. In addition, it is preferable to conduct the reaction using the carboxylic acid ester or the acid anhydride used as the solvent for the enzyme reaction because the reaction rate is increased.

The amount of the solvent to be used may be 0 to 20 times by weight based on 1,2-dihydroxy-2,3-dihydroxypropane of the racemate as the raw material of the reaction.

The reaction is carried out at a temperature of 0 to 100 ° C, preferably 10 to 50 ° C, and a reaction time of 5 hours to several days.

The 1,2-dihydroxy-2,3-dihydroxypropane of the racemate represented by the formula (10) used in this enzyme reaction may be prepared by a known production method. The production method thereof can be easily produced, for example, by oxidizing the corresponding olefin derivative as described in JP-A-2-304043.

(IV-3) Enzyme Reaction Preparation by stereoselective solvolysis

The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned formula (6)

(Wherein, A and B are the same as in the formula (1), and R ⁶ is the same as in the formula (11)), 1,2-dihydroxyl-2-hydroxy-3-acyloxypropane (15) in the presence of an enzyme having a stereoselective solvolytic ability,

R ⁸ OH

(Wherein R ⁸ represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms which may have a substituent) to obtain a compound represented by the formula (12) as described in the above (IV-2) The optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes and the compound represented by the formula (12) are optically active 1,2-disubstituted-2,3 Dihydroxypropanes, optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (13) (i.e., the optically active 1,2-disubstituted 2,3-dihydroxypropanes represented by the formulas (6) and The same method).

Or optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes have a desired stereostructure, they are subjected to solvolysis again after the reaction to obtain optically active 1,2-disubstituted rings represented by the formula (6) -2,3-dihydroxypropanes, and fractionating the same.

Here, the racemic 1,2-dihydroxy-2-hydroxy-3-acyloxypropane as a reaction raw material of this enzyme reaction is a novel compound, and its preparation method will be described later.

The specific group of R ⁶ in the formula (14) is as described in the above (IV-2). In the enzymatic reaction relating to the solvolysis, an n-propyl group, an i-propyl group or an n-pentyl group is preferable as R ⁶ since the reaction rate and stereoselectivity are high.

As the enzyme used in this enzyme reaction, any enzyme may be used as long as it has an ability of solubilizing the stereoselective solvate to racemic 1,2-dihydroxy-2-hydroxy-3-acyloxypropane. Specific examples thereof include lipases derived from microorganisms belonging to the genus Penicillium, genus Pseudomonas, genus Alcaligenes, genus Rhizopus or genus Aspergillus, among which microorganism-derived microorganisms belonging to genus Penicillium and Pseudomonas Of lipase and the like. These enzymes may be those which have been treated with the enzyme, such as acetone treatment or freeze-drying, or those immobilized on a carrier. In addition, those obtained by appropriate expression systems by genetic recombination may be used.

Specific examples of the lipase derived from the microorganism belonging to the genus Penicillium, Pseudomonas, Algerian genus, Rizophus or Aspergillus include lipase R (penicillium genus, produced by Amano Seiyaku Co., Ltd.) Lipase AK (Pseudomonas, manufactured by Amano Seiyaku Co.), Lipase AKG (Pseudomonas, manufactured by Amano Seiyaku Co., Ltd.), Toyojim LIP (Pseudomonas, manufactured by Toyobo Co.), Lipase QL Lipase PL (Lipase PL, Lipase D, manufactured by Amano Seiyaku Co., Ltd.), Lipase AP6 (Aspergillus sp. Manufactured by Fluka), and the like.

These enzymes vary in reactivity and selectivity depending on the kind of the 1,2-dihydroxy-2-hydroxy-3-acyloxypropane of the racemate as the raw material of the reaction. Therefore, the amount of the enzyme to be used may be suitably set, It is preferably used in an amount of 0.01 to 5 times by weight, preferably 0.05 to 2 times by weight, based on the raw material.

In the compound represented by the formula (15), R ⁸ represents a hydrogen atom; An n-pentyl group, an n-hexyl group, an n-heptyl group, an n-undecyl group, an n-tridecyl group, an n-pentadecyl group, , an n-heptadecyl group, a t-butyl group, and a 2-ethylpentyl group, or a straight chain or branched chain alkyl group having 1 to 20 carbon atoms. Is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group or an n-butyl group, particularly a hydrogen atom, that is, when water is used as a compound represented by the formula (15) It is preferable.

The amount of the compound represented by the formula (15) may be 0.5-fold moles or more relative to the 1,2-disubstituted-2-hydroxy-3-acyloxypropanes of the racemate.

In the enzymatic reaction, for example, an enzyme is added to a solution or a mixture obtained by dissolving or suspending a racemic 1,2-dihydroxy-2-hydroxy-3-acyloxypropane and a compound represented by the formula (15) Stirring or shaking.

Depending on the enzyme used, only one side of the optically active isomer of the racemic 1,2-dihydroxy-2,3-dihydroxypropane reacts with the carboxylic acid ester or the acid anhydride to form the optically active 1,2- 2-hydroxy-3-acyloxypropane.

After completion of the reaction, the enzyme is separated by conventional operations such as separation of filtration, centrifugation or addition of water and separation, and the filtrate or organic layer is concentrated and then purified by extraction, crystallization or column chromatography, Optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the following general formula (12) are obtained. At this time, it is preferable to isolate optically active 1,2-disubstituted-2,3-dihydroxypropanes, which are optical colons, by crystallization or the like because the above-mentioned purification operation becomes simple.

When the ester is optically active having a desired stereostructure, the optically active 1,2-disubstituted-2,3-dihydroxypropane of high optical purity is obtained by purifying and then solubilizing with an acid or an alkyllie .

When the optically active substance having the desired stereostructure is not esterified after the enzyme reaction, that is, when the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (6) is obtained This may be separated by crystallization or the like in a reaction solution.

Further, by conducting this enzyme reaction repeatedly, the optical purity of the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (6) can be further increased, which is preferable.

As the solvent used in this enzyme reaction, any solvent can be used. Examples thereof include ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran; aliphatic hydrocarbon solvents such as hexane and heptane; aromatic solvents such as toluene and xylene; 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; N- Amide solvents such as methyl pyrrolidone; dimethyl sulfoxide; and the like.

Among them, when water is used as the compound represented by the chemical formula (15), when this enzyme reaction is carried out in the presence of an organic solvent, preferably a water-insoluble organic solvent, 1,2-dihydro- It is preferable since the acyloxypropanes can be effectively dispersed in the reaction system and the operability and reactivity can be improved. In particular, the use of an ether-based solvent, an aromatic hydrocarbon-based solvent, a ketone solvent, a halogen-based solvent, or the like as the water-insoluble organic solvent is preferable because the oxygen reaction rate is increased.

The amount of the solvent to be used may be 0 to 10 times, preferably 0 to 5 times, based on the weight of the racemic 1,2-dihydroxy-2-hydroxy-3-acyloxypropane.

The present reaction is carried out at a temperature of 0 to 100 ° C, preferably 10 to 50 ° C, and may be carried out for 5 hours to several days.

The 1,2-dihydroxy-2,3-dihydroxypropane of the racemate represented by the formula (10) used in this enzyme reaction may be prepared by a known production method. The production method thereof can be easily produced by oxidizing the corresponding olefin derivative, for example, as described in JP-A-2-304043.

When water is used as the compound represented by the chemical formula (15), it is preferable to carry out the reaction while maintaining the optimum pH depending on the kind of the enzyme. Usually, the pH is in the range of 6 to 10, preferably 7 to 8 In the range of &lt; / RTI &gt; As a method for maintaining the pH, a reaction may be carried out while neutralizing the carboxylic acid generated in the 1,2-dihydroxy-2-hydroxy-3-acyloxypropane by an enzyme reaction with the addition of a base, or a suitable buffer solution Is preferably used. As the base to be used, any one can be used. Specific examples thereof include amines such as triethylamine and N, N-dimethylaniline, pyridines such as pyridine, picoline and lutidine, sodium methoxide, sodium ethoxide and the like Inorganic bases such as metal alkoxides, sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. Among them, inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate are preferable because they are inexpensive and easy to obtain.

(IV-3-1) Preparation of 1,2-dihydroxy-2-hydroxy-3-acyloxypropanes

Hydroxy-3-acyloxypropanes of the racemate as the reaction raw material of the enzyme reaction in the step (IV-3) are the novel compounds as described above. The process for producing the novel compound may be carried out, for example, as follows.

The carboxylic acid derivative represented by the following formula (16) or (17) is reacted with 1,2-disubstituted-2,3-dihydroxypropanes of the racemate represented by the formula (10) And the like.

R ⁶ COY

(R &lt; ⁶ &gt; CO) ₂ O

(Wherein R ⁶ is the same as in the formula (11), and Y represents a halogen atom.)

This reaction is carried out under strong acylation conditions using acid chloride as a carboxylic acid derivative and triethylamine as a base, and only one side of the hydroxy group of the racemic 1,2-dihydroxy-2,3-dihydroxypropane is reacted with It is an excellent method for producing an object by misfiring.

In formula (16), Y is preferably a chlorine atom or a bromine atom, and particularly preferably a chlorine atom.

Specific examples of the carboxylic acid derivative represented by the formula (16) include acetyl chloride, acetyl bromide, propionyl chloride, propionyl chloride, n-butyryl chloride, i-butyryl chloride, N-octanoyl chloride, n-decanoyl chloride, n-lauroyl chloride, benzoyl chloride, and the like. Specific examples of the carboxylic acid derivative represented by the formula (17) include acetic anhydride, anhydrous propionic acid, anhydrous butyric acid, anhydrous isobutyric acid, anhydrous valeric acid, anhydrous isovaleric acid, anhydrous caproic acid, anhydrous caprylic acid, , Carboxylic anhydrides such as anhydrous lauric acid and anhydrous benzoic acid. Of these, acetyl chloride, propionyl chloride, n-butyryl chloride, i-butyryl chloride, n-caproyl chloride, acetic anhydride, propionic anhydride, anhydrous butanoic acid, anhydrous isobutyric acid and anhydrous caproic acid are preferable, -Butyryl chloride, i-butyryl chloride, anhydrous butyric acid, and anhydrous isobutyric acid are preferred.

The amount of the carboxylic acid derivative to be used may be equal to or more than the equivalent amount of the 1,2-dihydroxy-2,3-dihydroxypropane, preferably 1.0 to 1.5 equivalents.

The base to be used may be any one selected from the group consisting of amines such as triethylamine and N, N-dimethylaniline, pyridines such as pyridine, picoline and lutidine, sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate Inorganic bases and the like. Among them, amines or pyridines are preferable. The amount of the base to be used may be equal to or more than the equivalent amount of the 1,2-dihydroxy-2,3-dihydroxypropane, preferably 1.0 to 2.0 equivalents.

Examples of the solvent used in this reaction include ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, aliphatic hydrocarbon solvents such as hexane and heptane, aromatic hydrocarbons such as toluene and xylene, 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, dimethylsulfoxide, N-methylpyrrolidone, and the like. These may be used alone or in combination.

The amount of the solvent to be used may be 0 to 10 times the amount of 1,2-dihydroxy-2,3-dihydroxypropane of the racemate.

The reaction temperature is in the range of -50 to 150 ° C, preferably -20 to 100 ° C, and the reaction time is usually 30 hours or less.

(IV-4) A stereostructure of an optically active epoxy compound Inversion method by ring opening

The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned formula (6)

Disubstituted 2,3-epoxypropanes represented by the general formula (1) in which A and B are the same as in the formula (1), is hydrolyzed in the presence of (a) an acid, or (b) Ring opening in the presence of an acid, followed by solvolysis.

Production method (a)

In the production process (a), the optically active 1,2-disubstituted-2,3-epoxypropane represented by the formula (18) is reacted with an acid in the presence of water to hydrolyze the epoxy group. After completion of the reaction, the product is appropriately extracted with an organic solvent, and the product is purified by crystallization, distillation, column chromatography or the like, thereby obtaining the optically active 1, 2, 3, 4, - dihydroxy-2,3-dihydroxypropanes are obtained. The production process (a), which is a hydrolysis reaction, has an advantage that an object is produced in a single reaction and its optical yield is good.

Specific examples of the acid used for hydrolysis include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid and boric acid, methanesulfonic acid, trifluoromethanesulfonic acid, And Lewis acids such as organic acids such as toluene sulfonic acid, boron trifluoride, titanium tetrachloride, tin tetrachloride, aluminum chloride, iron chloride, antifluoride, and ytterbium tripraate. Of these, optical purity and yield of optically active 1,2-disubstituted-2,3-dihydroxypropanes, which are products, are all increased, so it is preferable to use inorganic acid, and sulfuric acid is particularly preferable. The amount of the acid to be used is preferably 0.01 to 100 equivalents, more preferably 0.1 to 10 equivalents, based on the optically active 1,2-disubstituted-2,3-epoxypropane represented by the formula (18) as the raw material for the reaction.

The amount of water to be used may be equal to or more than the equivalent amount of the reaction raw materials described above. Among them, the use of 1 to 10 equivalents, particularly 1 to 5 equivalents, is preferable because both the optical purity and the yield of the product are increased. Particularly when inorganic acid, sulfuric acid is used as the acid, it is preferable to use water in an amount of 3 to 6 equivalents relative to the reaction raw material. At this time, if the amount of water used exceeds this range, the optical purity of the product may be lowered. When sulfuric acid is used as the acid, it is preferable to use water and sulfuric acid which have been previously mixed with sulfuric acid, because the optical purity of the product is higher than when water and sulfuric acid are separately used.

As the solvent used in this enzyme reaction, any solvent can be used, and examples thereof include diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc., tetrahydropyran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl Ether solvents such as ethylene glycol diethyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and diethylene glycol dibutyl ether, ester solvents such as ethyl acetate, methyl acetate and methyl propionate, An aliphatic hydrocarbon solvent such as hexane or heptane, an aromatic hydrocarbon solvent such as toluene or xylene, a ketone solvent such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dichloromethane or chloroform solvent such as dichloromethane, , Halogen-based solvents such as chlorobenzene, acetonitrile, propionitrile, butyronitrile and the like Amide solvents such as nitriles, dimethylformamide and N-methylpyrrolidone; dimethylsulfoxide; and the like. They may be used singly or as a mixed solvent.

In the above-mentioned solvents, optically active 1,2-disubstituted-2,3-dihydroxypropanes, which are the products, are preferred because of their high optical purity and yield, and they can be used in ether solvents, ketone solvents, ester solvents, amide solvents Is preferably used. Of these solvents, ether solvents, ketone solvents and ester solvents are preferred because they increase both the optical purity and the yield of the product. Among them, ethylene glycol ethers or ethers having a 6-membered ring structure are preferred, Ethylene glycol diethyl ether is preferred.

The amount of the solvent to be used is preferably 0 to 100 times by weight, more preferably 1 to 20 times by weight, based on the weight of the optically active 1,2-disubstituted-2,3-epoxypropane represented by the formula (18) Do.

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.

Production method (b)

In the production method (b), optically active 1,2-disubstituted-2,3-epoxypropanes represented by the formula (18) are ring-opened in the presence of a carboxylic acid, and the resulting carboxylic acid esters .

After completion of the reaction, the product is extracted with an organic solvent as appropriate, and the product is purified by crystallization, distillation, column chromatography or the like, thereby obtaining optically active 1, 2-iodo-2,3-dihydroxypropanes are obtained. The production method (b) includes a two-step reaction of a ring-opening reaction and a solvolysis reaction. When the solvent is used for the reaction, a hydrophilic solvent is necessarily required It is characterized by not doing. That is, even when the optically active 1,2-disubstituted-2,3-epoxypropane represented by the formula (18) as the reaction raw material of the production method (b) is prepared by using a hydrophobic solvent, Subsequently, the production process (b) can be carried out in the same solvent system. In the production of the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (6) It is an industrially advantageous production method.

As the carboxylic acid used in the production method (b), any one may be used. Specific examples thereof include formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid and caproic acid. Of these, formic acid is preferable because the optical purity and yield of optically active 1,2-disubstituted-2,3-dihydroxypropanes, which are inexpensive and are the products, are both high. The amount of the carboxylic acid to be used may be equal to or more than the equivalent amount of the above-mentioned starting materials, and in particular, 1 to 10 equivalents may be used to obtain the optically active 1,2-disubstituted-2,3-dihydro The optical purity and the yield of the Roxy propane are all increased, which is preferable.

In the production method (b), an acid other than the carboxylic acid may suitably be present. Examples of the acid to be used in combination include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid and boric acid, and organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and p- And Lewis acids such as organic acids, boron trifluoride, titanium tetrachloride, tin tetrachloride, aluminum chloride, iron chloride, antimony pentafluoride, and ytterbium tripraate. The amount of the acid to be used in combination is preferably 0 to 100 equivalents, more preferably 0 to 10 equivalents, relative to the optically active 1,2-disubstituted-2,3-epoxypropane of the reaction source.

The ring-opening reaction in the production method (b) may be carried out again in the presence of a solvent. As the solvent to be used, any solvent can be used, and specific examples include the solvents exemplified in the above-mentioned production method (a), and these solvents may be used singly or as a mixed solvent. Further, do. As the solvent, aromatic solvents such as benzene, toluene, xylene and chlorobenzene are preferable, and chlorobenzene is particularly preferable because the optical purity and yield of the product are increased and post-treatment of the reaction is simple. The amount of the solvent to be used is preferably 0 to 100 times by weight, more preferably 1 to 20 times by weight, based on the weight of optically active 1,2-disubstituted-2,3-epoxypropane as the reaction raw material.

The production process (b) is carried out by ring-opening the optically active 1,2-disubstituted-2,3-epoxypropane as a reaction raw material in the presence of a carboxylic acid as described above, and then solvolyzolizing the obtained carboxylic acid ester do. As the solvent in the solvolysis, water or a protonic solvent such as methanol, ethanol, propanol or butanol is preferably used. The solvolysis reaction may be carried out under acidic conditions or under basic conditions, and it is preferably carried out under basic conditions in view of the high reaction rate and reaction yield.

In the case of conducting under acidic conditions, any acid may be used. Examples of the acid include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chloric acid, hypochlorous acid and boronic acid, and organic acids such as methanesulfonic acid, p- toluenesulfonic acid and formic acid . Among them, sulfuric acid is preferable.

The amount of the acid used in the solvolysis reaction may be 0.01 to 10 equivalents of the optically active 1,2-disubstituted-2,3-epoxypropane, which is a reaction raw material in the ring-opening reaction. The reaction time is in the range of -50 to 100 ° C, preferably -20 to 70 ° C, and the reaction time is usually 48 hours or less.

When the reaction is carried out under basic conditions, any base may be used. Examples of the base include 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, potassium hydroxide, Potassium and sodium carbonate, and the like. Among them, metal alkoxides and inorganic bases are preferable.

The amount of the base used in the solvolysis reaction may be adjusted by neutralizing the excess carboxylic acid remaining after the ring opening reaction and then using the equivalent of the optically active 1,2-disubstituted-2,3-epoxypropane Among them, it is preferable to use 1 to 5 equivalents. The reaction temperature is in the range of -50 to 150 ° C, preferably -20 to 100 ° C, and the reaction time is usually within 48 hours.

(IV-4-1) Preparation of optically active 1,2-disubstituted-2,3-epoxypropane

The optically active 1,2-disubstituted-2,3-epoxypropane represented by the formula (18) used in the above-mentioned production methods (a) and (b) is a novel compound. The production method of this compound can be industrially advantageously produced, for example, by the production routes (1) and (2) shown below. Hereinafter, each manufacturing path will be described.

(Wherein A and B are the same as in the formula (1), R ⁶ and R ⁷ are the same as in the formula (11), and R ⁵ is the same as in the formula (7)

In the production process (1), the optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the chemical formula (20) and the optical isomer 2-hydroxy-3-acyloxypropanes represented by the structural formula (24) are prepared. In this reaction (1), it is preferable to use a lipase derived from a microorganism belonging to the genus Pseudomonas as an enzyme.

Subsequently, the compound (20) is isolated from a mixture of the obtained compound represented by the general formula (20) and the compound represented by the general formula (24) or reacted with a sulfonic acid derivative in the presence of a base without isolation to prepare a compound of the formula (19) ②). This reaction does not substantially react with the sulfonic acid derivative even when the compound of the formula (24) coexists in the reaction (2), and it can be hydrolyzed as it is or partially converted into the optically active 1,2- -Dihydroxypropanes. &Lt; / RTI &gt;

As the sulfonic acid derivative, a sulfonic acid derivative represented by the formula (8) or (9) as described in the above (III-2) may be used.

As the sulfonic acid derivative represented by the formula (8) or (9), any one can be used, and as the sulfonic acid derivative represented by the formula (8), methanesulfonyl chloride and p-toluenesulfonyl chloride are exemplified . Examples of the sulfonic acid derivative represented by the formula (9) include methanesulfonic acid anhydride and p-toluenesulfonic anhydride, and in particular methanesulfonyl chloride and p-toluenesulfonyl chloride are preferable.

The amount of the sulfonic acid derivative to be used may be equal to or more than the equivalent amount of the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (20), and is preferably 1.0 to 1.5 equivalents.

As the base to be used, any one can be used, and examples thereof include 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, potassium hydroxide, potassium carbonate, sodium carbonate and the like. Of these, amines and pyridines are preferable. The amount of the base to be used may be equal to or more than the equivalent amount of the optically active 1,2-disubstituted-2,3-dihydroxypropane, and usually 1.0 to 2.0 equivalents may be used.

The reaction (2) may be carried out suitably in the presence of a solvent. As the solvent to be used, any solvent can be used, and examples thereof include 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 , Halogenated solvents such as chloroform and chlorobenzene, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile, propionitrile and butyronitrile, dimethylformamide, N-methylpyrrolidone , A polar solvent such as dimethylsulfoxide and water, and the like. They may be used singly or as a mixed solvent. When amines or pyridines are used as the base, the reaction may be carried out using the base itself as a solvent. The amount of the solvent to be used may be 0 to 10 times the weight of the optically active 1,2-disubstituted-2,3-dihydroxypropane. The reaction temperature is in the range of -50 to 100 ° C, preferably -20 to 50 ° C, and the reaction time is usually 30 hours or less.

The optically active sulfonic acid ester represented by the formula (19) is isolated from the reaction product of the reaction (2) or isolated by reacting with a base without isolation to obtain the 1,2-dihydroxy-2,3- Dihydroxypropanes are obtained (reaction (3)).

The base used in the reaction (3) may be any one selected from the group consisting of triethylamine, amines such as N, N-dimethylaniline, pyridines such as pyridine, picoline and lutidine, sodium methoxide, sodium ethoxide and the like Inorganic bases such as metal alkoxides, sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. Of these, metal alkoxides or inorganic bases are preferred.

The amount of the base to be used may be equal to or more than the equivalent amount of the optically active sulfonic acid esters, and is preferably 1.0 to 1.5 equivalents. The reaction temperature is in the range of -50 to 100 ° C, preferably 0 to 70 ° C, and the reaction time is usually within 30 minutes.

When the compound of the formula (24) coexists in the reaction (3), as described above, it is hydrolyzed by the action of a base to be a compound represented by the formula (6) or coexists in the reaction product with some unreacted . This coexisting product is hydrolyzed or solvolyzed when the compound of formula (18) is used in the production method (a) or (b) described in (IV-4) There is no. Rather, even if the compound represented by the formula (24) is not isolated, the compound represented by the formula (6) can be efficiently obtained at a high optical purity by a series of reactions, and thus an industrially excellent preparation route to be.

Therefore, the production route (1) is a step in which a product represented by the formula (10) is used as a starting material and a product represented by the formula (6) And the entire process can be carried out in the same reactor, which is an industrially excellent manufacturing route.

(Wherein A and B are the same as in the formula (1), R ⁶ is the same as in the formula (11), and R ⁸ is the same as in the formula (15)

The production route (2) is a process wherein the optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the general formula (20) and the optically active 1,2- Hydroxy-3-acyloxypropanes of the optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the formula (24) having a three-dimensional structure of the colonic is prepared. In this reaction (4), it is preferable to use a lipase derived from a microorganism belonging to the genus Penicillium as an enzyme. Thereafter, the compound represented by the formula (18) can be produced in accordance with the reactions (2) and (3) of the preparation route (1) described above.

(IV-5) Preparation by esterification reaction using optically active nucleophilic catalyst

The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned formula (6) can also be prepared by the following method.

The 1,2-disubstituted-2,3-dihydroxypropanes of the racemate represented by the above-described formula (10) can be obtained by reacting 1,2-disubstituted-2,3-dihydroxypropanes of the racemate represented by the formula (10) Is reacted with a carboxylic acid derivative represented by the formula (16) or (17) to obtain the optically active 1,2-dihydro-2-hydroxy-3-acyloxypropane represented by the formula (12) The compound to be displayed is an optically active isomer having a desired stereostructure by producing an optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the chemical formula (13) Dihydroxypropane (that is, the same as in the formula (6)) is separated from the optically active 1,2-disubstituted-2,3-dihydroxypropane.

When the optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropane has a desired steric structure, the optically active 1,2-disubstituted ring represented by the formula (6) -2,3-dihydroxypropane, which may be separately prepared.

This reaction can be carried out optically in an affordable manner without using an expensive enzyme as described in (IV-2) or (IV-3) above, Dichloro-2,3-dihydroxypropanes represented by the following formula (1). Since this compound is an important intermediate for the production of optically active 1,2-disubstituted-2,3-epoxypropane represented by the chemical formula (1) which is an active ingredient of agricultural chemicals, particularly herbicides as described above, The esterification reaction using a catalyst can be industrially produced by a method for producing an effective component of an agricultural chemical, particularly a herbicide, by combining with the production method described in (III) above.

As the nucleophilic catalyst to be used in the present reaction, any one can be used, and examples thereof include optically active 1,2-diamines, optically active pyridines, optically active pyrrole, optically active peptides and optically active phosphines . Specifically, for example, as the optically active 1,2-diamine, a pyrrolidine derivative represented by the following formula (25) is preferable.

(Wherein, D is -N (R ¹⁰⁾ represents an ^{R 11, R 9, R 10} , R 11 which may have a substituent represents an alkyl group having 1 to 20 carbon atoms, an alkenyl group, an aralkyl group or an aryl group. However, R ¹⁰ and R &lt; ¹¹ &gt; may combine to form a ring. * Represents an asymmetric carbon atom.

Specific examples of the alkyl group having 1 to 20 carbon atoms, the alkenyl group having 2 to 20 carbon atoms, preferably the aralkyl group having 7 to 20 carbon atoms and preferably the aryl group having 6 to 20 carbon atoms in R ⁹ , R ¹⁰ and R ¹¹ Is the same as the description of R ⁶ described in the above (IV-2).

As R ⁹ , an alkyl group having 1 to 5 carbon atoms is preferable, and a methyl group is particularly preferable. As R ¹⁰ and R ¹¹ , an alkyl group having 1 to 20 carbon atoms or an aralkyl group having 7 to 20 carbon atoms is preferable, and among these, R ¹⁰ and R ¹¹ are preferably bonded to form a ring. Specifically, it is preferably an N-alkylbenzyl group which may have a substituent, a pyrrolidyl group, a piperidyl group, a dihydroisoindolyl group or a terahydroisoquinolyl group.

The optically active pyridines and the optically active pyrrole are not particularly limited,

(Wherein R ¹² represents an aryl group having 6 to 10 carbon atoms which may have a substituent and * represents an asymmetric carbon atom), an optically active 4-pyrrolidinopyridine derivative represented by the following formula (27) or (28) And the like.

(Wherein R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represents an alkyl or aryl group having 1 to 6 carbon atoms which may have a substituent, and R ¹⁷ and R ^{18 each} represent an alkyl group having 1 to 10 carbon atoms Or R ¹⁷ and R ¹⁸ may combine to form a ring.)

From the viewpoint of the reaction rate, stereoselectivity and cost, R ¹³ , R ¹⁴ and R ¹⁵ are preferably methyl, ethyl, t-butyl or phenyl. R ¹⁶ is preferably a methyl group or a phenyl group. R ¹⁷ and R ¹⁸ are preferably a methyl group, an ethyl group, or a combination of R ¹⁷ and R ¹⁸ to form a pyrrolidine ring.

Any optically active peptide may be used, and examples thereof include optically active tetrapeptide derivatives represented by the following chemical formula (29).

(Wherein Z 'represents an amino acid residue bonded by a peptide bond, and * represents an asymmetric carbon atom.)

Examples of the amino acid residue bonded by a peptide bond represented by Z 'include racemates or optically active substances such as phenylalanine, valine, glycine and the like.

Of optically active nucleophilic catalysts, optically active 1,2-diamines are preferred from the viewpoints of reaction rate, raw material cost and stereoselectivity. The amount of optically active nucleophilic catalyst to be used in this reaction is 0.00001 to 1.5 molar times, preferably 0.0001 to 1.5 mol, per mol of 1,2-dihydroxy-2,3-dihydroxypropane of the racemate represented by formula (10) To 1.0 mol by mol.

In the carboxylic acid derivative represented by the formula (16) or (17) used in the present reaction, R ⁶ is specifically the same as the description of the formula (11) described in the above (IV- Among them, a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, chloromethyl group, phenyl group, chlorophenyl group, dichlorophenyl group and benzyl group , And Y is preferably a chlorine atom or a bromine atom. Specific examples of the carboxylic acid derivative include acetic anhydride, anhydrous propionic acid, anhydrous butyric acid, anhydrous isobutyric acid, anhydrous isoquinic acid, anhydrous isovaleric acid, anhydrous caproic acid, anhydrous chloroacetic acid, anhydrous benzoic acid, anhydrous chlorobenzoic acid, anhydrous dichlorobenzoic acid, But are not limited to, acetic acid, acetyl chloride, propionic acid chloride, butyric acid chloride, isobutyl acid chloride, valacic acid chloride, isovaleric acid chloride, caproic acid chloride, benzoyl chloride, toluylic acid chloride, dimethylbenzoic acid chloride, dichlorobenzoic acid chloride, , Acetyl bromide, propionic acid bromide, butyrate bromide, isobutyrate bromide, valacic acid bromide, isovaleric acid bromide, caproic acid bromide, benzoyl bromide, toluyl acid bromide, dimethyl benzoic acid bromide, Dichlorobenzoic acid bromide, phenylacetic acid bromide, and the like.

Of these carboxylic acid derivatives, benzoic acid derivatives are preferred, and benzoic acid derivatives are preferred, among which benzoic acid chloride, toluic acid chloride, dimethylbenzoic acid chloride, chlorobenzoic acid chloride, dichlorobenzoic acid chloride, benzoic acid bromide, dimethylbenzoic acid bromide, Bromide and dichlorobenzoic acid bromide are preferable, and benzoic acid chloride, toluenic acid chloride, dimethylbenzoic acid chloride, chlorobenzoic acid chloride and dichlorobenzoic acid chloride are preferable.

The amount of the carboxylic acid derivative to be used is usually 0.01 to 1.0 mole times the amount of the 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (10), and may be appropriately selected depending on the stereoselectivity of the reaction . That is, the optically active substance produced without reacting with the carboxylic acid derivative represented by the formula (16) or (17) (that is, the optically active 1,2-disubstituted-2,3-dihydrogenphosphate represented by the formula (20) In order to obtain a high optical purity, it is sufficient to increase the content of the carboxylic acid derivative to increase the conversion rate of the reaction. Further, by reducing the content of the carboxylic acid derivative and lowering the conversion rate of the reaction, the optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the above-mentioned formula (24) It can be obtained in optical purity.

In the present reaction, the reaction may be suitably carried out using a solvent. Examples of the solvent to be used include halogenated solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene, aromatic hydrocarbon solvents such as benzene, toluene, xylene and ethylbenzene, aliphatic hydrocarbon solvents such as n-hexane, n-heptane and isooctane , Ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, ketone solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, diglyme, diethylene glycol diethyl ether And the like; nitrile solvents such as acetonitrile, propionitrile and butyronitrile; tertiary alcohols such as t-butanol and t-amyl alcohol; ketones such as dimethylformamide, dimethylacetamide, Amide solvents such as dimethylformamide, N, N-dimethylimidazolinone, etc .; nitroalkanes such as nitromethane, nitroethane and nitropropane; sulfoxides such as dimethylsulfoxide; Drew and the like. Among them, a halogenated solvent, an ether solvent, a ketone solvent, a nitrile solvent, an ester solvent, an amide solvent and a nitroalkane are preferable, and a ketone solvent, a nitrile solvent, an amide solvent, desirable.

In the present reaction, when tertiary amines or pyridine bases are used as bases described further below, the reaction may be carried out using these as a solvent.

The amount of the solvent to be used is preferably 0 to 100 times by weight, more preferably 0 to 50 times by weight, based on the weight of the 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (10).

In the present reaction, the reaction is preferably carried out in the presence of a base, preferably an acicular base, because the reaction rate can be improved and the amount of the optically active nucleophilic catalyst can be reduced.

As the acidic base, any one can be used, and examples thereof include tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, N, N-dimethylaniline and N, N-diethylaniline, pyridine, 2 Pyridine bases such as picoline, 3-picoline, 4-picoline, 2,6-lutidine, 2,4,6-collidine, 2- chloropyridine, 4- chloropyridine, cesium carbonate, potassium carbonate, Inorganic bases such as sodium carbonate, sodium hydrogencarbonate, lithium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate and barium carbonate. Preferred are tertiary amines or inorganic bases, more preferably inorganic bases When used, high stereoselectivity is obtained. The amount of the optically active nucleophilic catalyst to be used when the reaction is carried out in the presence of a base is 0.00001 to 0.2 mol per mol of the 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (10) It is preferable to use 0.0001 to 0.1 mol by mol.

The amount of the acidic base to be used is usually 0.01 to 1.0 mole times the amount of the 1,2-dihydroxy-2,3-dihydroxypropanes represented by the formula (10), and when appropriately selected according to the stereoselectivity of the reaction do. That is, the optically active substance produced without reacting with the carboxylic acid derivative represented by the formula (16) or (17) (that is, the optically active 1,2-disubstituted-2,3-dihydrogenphosphate represented by the formula (20) In order to obtain a high optical purity, it is sufficient to increase the content of the base to increase the conversion rate of the reaction. In addition, by reducing the content of the base to lower the conversion rate of the reaction, the optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the above-described formula (24) You can get it.

The present reaction is preferably carried out at a low temperature in order to obtain high stereoselectivity. The present reaction is industrially low cost because it can obtain high stereoselectivity in an industrially preferable temperature range.

Concretely, when an organic base is used as an acidic base, particularly when tertiary amines are used, it is preferable to carry out the reaction at -150 to 100 占 폚, particularly -100 to 50 占 폚. On the other hand, in the case of using an inorganic base as an acidic base, it is preferably carried out at -50 to 100 占 폚, preferably -10 to 50 占 폚.

In the present invention, it is preferable to carry out the reaction in the presence of an inorganic porous material such as zeolite (hereinafter simply referred to as &quot; zeolite &quot;) because the reaction yield can be improved. As the zeolite, any one can be used. For example, the zeolite may have a pore diameter of 1 Å or more, particularly 3 Å or more. Specifically, the molecular sieve 4A (manufactured by Linde) may be used. The zeolite coexisting in the reaction system is preferably in the form of powder, pellet or the like, or powder. The amount of zeolite to be used may be 1% by weight or more based on the weight of 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (10) as a raw material for the reaction, and usually 5 to 100% do.

The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-described formula (6) can also be produced according to the production route (3) shown below.

Wherein A and B are the same as in the formula (1), R ⁶ and Y are the same as in the formula (16), and R ⁵ is the same as in the formula (19).

The production route (3) is a process wherein the optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the general formula (20) and the optically active 1,2- Optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the formula (24), which is a large intestine, is prepared. In this reaction (5), an optically active nucleophilic catalyst is used as described above. Thereafter, the compound represented by the formula (18) can be produced according to the reactions (2) and (3) of the preparation route (1) described in the above (IV-41).

That is, the production route (3) is a step of separating and purifying the product in each step in a series of steps of producing the target compound represented by the formula (6) using the compound represented by the formula (10) And the entire process can be carried out in the same reactor, which is an industrially excellent manufacturing route.

In the compounds represented by the formulas (6), (7), (10), (12), (13), (14), (19), (20) In the case where the group represented by A in the chemical formula is a group having an indanthione structure represented by the general formula (2), as shown below, there is a case in which the compound is in an equilibrium state with the hemicetal ring- have. Specifically, when a compound represented by the above-described formula is used in the reaction, depending on the reaction conditions and the solvent used in the reaction, the carbonyl group of the indanedione and the hydroxyl group bonded to the asymmetric carbon atom in the reaction system bind to each other, It is in an equilibrium state with the cyclized cyclic compound and crystallized as a hemiketal upon crystallization. Therefore, in the present invention, in the compounds represented by the formulas (6), (7), (10), (12), (13), (14), (19), (20) The same method is applied to the purification method of optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the chemical formula (6) described below.

(V) Method for purifying optically active 1,2-disubstituted-2,3-dihydroxypropanes

The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-described formula (13) (including the compound represented by the formula (6) is of course also included) 1-disubstituted-2,3-epoxypropane, which is an optically active 1,2-disubstituted-2,3-epoxypropane. Increasing the optical purity of these optically active 1,2-disubstituted-2,3-dihydroxypropanes is important for increasing the optical purity of the objective optical isomer mixture and the like. Hereinafter, the purification method of the optically active 1,2-disubstituted-2,3-dihydroxypropane will be described.

The optically active organic compounds are roughly classified into the following two types of properties: (a) a property that optically isomerized optically with each other in pairs grows and crystallizes (hereinafter referred to as "racemic compound"), And b) only one side of the optical isomer grows and crystallizes (hereinafter referred to as "racemic mixture"). That is, in the crystallization of a substance (racemic compound) having a property of a), one kind of racemic crystals is precipitated, whereas in a substance having a property of b) (racemic mixture) Which is suitable for obtaining a desired optical isomer.

However, in the crystal of the racemic compound in which one of the optical isomers is enriched, crystals of a racemate in which crystals of optically isomeric optically isomerized in a pair are grown, and crystals in which only one optical isomer is grown are mixed Is known.

Conventionally, when the optically enriched racemic compound is crystallized and taken out from the solution, crystals of the racemate grown by pairing optical isomers of the optically optically enantiomer are precipitated, only one optically active isomer is then grown, It is generally known to precipitate. Therefore, in order to obtain crystals of desired high optical purity, a method of increasing the purity of the solution containing the solute to be crystallized has been adopted. For example, crystals having low optical purity such as racemic crystals are precipitated and removed, The optical purity of the optically isomer in the optically active compound is increased and then the optically purity is determined.

On the other hand, recently, in the case of pharmaceuticals, the use of an optically active compound as an active ingredient has been increasing in response to requests for high activity, dose reduction, and the like. In this manufacturing method, a simple and inexpensive manufacturing method has been studied. Likewise, in pesticides, when an asymmetric carbon atom is present in the chemical structure of an active ingredient compound, only an optical isomer having higher activity is considered to be an effective ingredient.

For example, as described above, the 1,2-dihydroxy-2,3-epoxypropane is an effective ingredient of an excellent pesticide showing excellent herbicidal effect, and the compound may have an asymmetric carbon in some cases. There are various methods for producing 1,2-dihydroxy-2,3-epoxypropane, but for example, 1,2-dihydroxy-2,3-dihydroxypropane is used as an intermediate raw material, There is a way. In this production process, it is important to improve the optical purity of 1,2-dihydroxy-2,3-dihydroxypropanes in obtaining 1,2-disubstituted-2,3-epoxypropane of high optical purity It is as described above.

However, in order to obtain an optical isomer of high optical purity as described above, it is necessary to repeatedly precipitate and remove low-purity crystals containing a crystal of a racemate to increase the optical purity of the optically active substance in the mother liquid, Therefore, a multistage process water was required. Therefore, the yield is not high, and it is industrially inexpensive and difficult to manufacture easily. This is generally because the optically active moieties remaining in the mother liquor have higher solubility than the crystals of the racemic crystals, and crystals of the racemic crystals precipitate first, and it is very difficult to take crystals of the optically active substance with high purity first.

There is also a method of separating an optical isomer using an optically active segmentation agent or the like. However, since an optically active segmentation agent is generally expensive and slow in processing speed, it is not satisfactory as an industrial production method.

Further, as a method for producing an optically active substance, a racemate may be chemically modified, and the racemate may be isolated by crystallizing the optically isomer of the racemate as a derivative having a racemic mixture, and then removing the chemical formula A method of obtaining an optically active substance of a target substance with high optical purity is known. However, in this method, too, the number of steps is increased, which is also industrially inexpensive and problematic to manufacture easily.

Therefore, in order to obtain the optical isomer mixture or the optically active 1,2-disubstituted-2,3-epoxypropane of the present invention with high optical purity, the present inventors have found that the optically active 1,2- 3-dihydroxypropanes were extensively studied in order to obtain a high optical purity with a small number of process water without using a simple and expensive optical resolving agent.

As a result, by crystallizing an optical isomer mixture of 1,2-dihydroxy-2,3-dihydroxypropanes having a specific structure with an aromatic compound which may have a substituent as a solvent, And succeeded in separation and purification as solvate crystals of 2-iodo-2,3-dihydroxypropanes. The obtained solvate is a novel compound. By using this solvate crystal, 1,2-dihydroxy-2,3-epoxypropane, which is an effective ingredient of herbicide, can be easily produced with high optical purity.

Specifically, an optically active 1,2-disubstituted-2,3-dihydroxypropane mixture of optical isomers is dissolved in a solvent containing an aromatic compound which may have a substituent and then cooled to obtain optically active 1,2-disubstituted -2,3-dihydroxypropanes are purified by high optical purity.

Hereinafter, a solvate and a production method thereof (i.e., a method for purifying optically active 1,2-disubstituted-2,3-dihydroxypropanes) will be described.

(V-1) solvate

(-) - 2- [2- (3-chlorophenyl) -2,3-dihydroxypropyl] -2,3-dihydroxypropyl] Ethyl-indan-1,3-dione are preferred.

The aromatic compound which may have a substituent (hereinafter referred to as &quot; aromatic compound &quot;) used in the purification method may be any as far as it exhibits aromaticity,

Ar-A _'n

(Wherein Ar represents a phenyl group and A 'represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms , A halogen atom, n represents an integer of 0 to 6, and when there are a plurality of substituents, the substituents may be bonded to each other to form a ring).

Examples of A 'include alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl and pentyl; An alkoxy group having 1 to 5 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group and n-butoxy group; An alkenyl group having 2 to 5 carbon atoms such as a vinyl group and an allyl group; An alkynyl group having 2 to 5 carbon atoms such as an ethynyl group and a propargyl group; A haloalkyl group having 1 to 5 carbon atoms such as a chloromethyl group, a dichloromethyl group, a trifluoromethyl group, and a fluoroethyl group; A halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, among which an alkyl group having 1 to 5 carbon atoms and a halogen atom are preferable.

Examples of the aromatic compound which may have a substituent include benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, isopropylbenzene, tetralin, chlorobenzene, dichlorobenzene, bromobenzene, styrene, Among them, benzene, toluene, o-xylene, m-xylene and chlorobenzene are particularly preferable because o-xylene, m-xylene and chlorobenzene are stable solubilized at high optical purity.

The solvate is composed of an optically active 1,2-disubstituted-2,3-dihydroxypropane and an aromatic compound, and a ratio of 2: 1 is preferable because it can be obtained as crystals of high optical purity. In this case, 2-dihydroxypropane-2,3-dihydroxypropane and one aromatic compound are stacked, and B (aryl (meth) acrylate of the compound represented by the above-described formula (13) And the aromatic compound are considered to form some bonds. In the present invention, the solvent is referred to as a solvate even if such a definite bond is not formed. The solvate of the present invention contains 1,2-dihydroxy-2,3-dihydroxypropanes having a high optical purity, specifically 80% ee or more.

As described above, in the formula (13), a compound in which A is a group having an indanthione structure represented by the formula (2) may be in an equilibrium state with a hemicetal cyclic compound. Therefore, Also in the purification method and the solvate, the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula (13) includes such a cyclic compound or a mixture thereof.

(V-2) Solvate (Method for purifying optically active 1,2-disubstituted-2,3-dihydroxypropanes)

The optical isomer mixture of 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (13) used in this production method (hereinafter, simply referred to as an optical isomer mixture) And an optical isomer of L-isomer. The mixture ratio of each optical isomer is arbitrary. Preferably, the content of the desired optical isomer is high. For example, the optical purity is preferably 60% ee or more.

The aromatic compound used in this production method is the same as the aromatic compound constituting the solvate and preferable ones are the same. The aromatic compound is preferably used in an amount of 0.5 molar or more, preferably 0.7 to 30 molar times relative to 1,2-disubstituted-2,3-dihydroxypropane.

The solvates can be produced, for example, by dissolving an optically isomer mixture of 1,2-dihydroxy-2,3-dihydroxypropanes as crystals in an aromatic compound and cooling them to prepare a solvate of high optical purity Further, an aromatic compound may be used as a solvent in the synthesis of 1,2-dihydroxy-2,3-dihydroxypropanes. Alternatively, 1,2-dihydroxy-2,3-dihydroxypropanes may be prepared as solvates of high optical purity by adding an aromatic compound to the reaction product solution obtained by the synthesis and then cooling.

Therefore, a solvate may be prepared using a mixed solvent with a solvent other than the aromatic compound. Examples of the solvent used in addition to the aromatic compound include ether such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran Based solvents such as hexane, heptane, octane and isooctane; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl; halogen solvents such as chloroform and chlorobenzene; acetonitrile, propionitrile, butyrolactone; Nitriles such as nitrile, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like. Of these, aliphatic hydrocarbon-based solvents such as hexane, heptane, octane, and isooctane are preferred.

The amount of the solvent to be used is preferably such that the optical isomer mixture can be completely dissolved, specifically 0 to 100 times by weight, preferably 0 to 50 times by weight, of the optical isomer mixture.

The temperature at which the optical isomer mixture is completely dissolved in the aromatic compound-containing solvent is usually set at a temperature ranging from 0 ° C to the boiling point of the mixture. From the viewpoint of the yield of the solvent, the compound is preferably dissolved at room temperature or higher, Deg.] C or higher, and particularly preferably 60 deg. C or higher.

The cooling rate of the optical isomer mixture solution is usually 1 to 50 ° C per hour, preferably 3 to 20 ° C. The cooling rate is not necessarily constant, and may be changed continuously or stepwise. The temperature at which the solution reaches the cooling (the temperature at which the solution reaches the cooling temperature) may be appropriately set, and is usually -30 to 30 캜, preferably -10 to 30 캜, more preferably 0 to 30 캜.

As described above, the obtained solvate contains 1,2-dihydroxy-2,3-dihydroxypropanes having a high optical purity, specifically 80% ee or more, and the solvate is dissolved in an alcohol system such as ethanol 1,2-dihydroxy-2,3-epoxypropane, which is a herbicide component, can be easily obtained with high optical purity by cyclizing it by a reaction such as decomposition with a percarboxylic acid or by over-solvolysis.

EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples, preparation examples and test examples. However, the present invention is not limited to the following examples unless the gist thereof is exceeded.

The structures of the compounds used in the following examples are shown in Tables 2 to 4. The analysis conditions used in the examples are as follows.

Analysis of reaction results;

High performance liquid chromatography (column: Inertsil ODS 2, eluting solvent methanol: water mixed solvent (70:30), flow rate 0.6 mL / min, detection 220 nm).

Analysis of optical purity;

(Chiralcel-OJ manufactured by Daicel Chemical Industries, Ltd., eluent: n-hexane: isopropanol mixed solvent (85:15 to 90:10) or n-hexane: ethanol: methanol mixed solvent : 3: 6), flow rate 1.0 mL / min, detection 220 nm or 254 nm).

And, as an index of the kinetic optical splitting efficiency, the known literature [C. S. Chen, Y. Fujimoto, G. Girdaukas, and C. J. Sih, J. Am. Chem. Soc. 104, 7294 (1982), etc.) is used.

(1-ee (P)]] / ln [1-c [1-ee

TECHNICAL FIELD The present invention relates to a novel optical isomer mixture, a process for producing the same, a herbicide containing the same as an active ingredient, a preparation intermediate thereof and a process for producing the same, and more specifically to an optically active 1,2- An isomer mixture, a process for producing the same, a herbicide containing the same as an active ingredient, a production intermediate, and a production method thereof.

Example 1

The reaction vessel was charged with 1.17 g of 2- [2- (3-chlorophenyl) -2-propenol-2-ethylindan- 57.3 mg of (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminomanganese (III) chloride (compound represented by the above formula (21) (PH 11.3, 0.6 M aq. NaOCl, 0.05 M aq. Na2HPO4, 1.0 M aq. NaOH) was added to the ice-cooled mixture, and the mixture was stirred at 0 ° C for 10 hours , And stirred again at room temperature for 4 hours.

The reaction solution was analyzed by high performance liquid chromatography (column: Inertsil ODS 2, eluting solvent methanol: water mixed solvent (70:30), flow rate 0.6 ml / min, detection 220 nm) (3-chlorophenyl) -2,3-epoxypropyl] -2-propyl] -2-ethylindan- Ethyl indan-l, 3-dione [Compound No. (-) - 16] was produced in a yield of 95% and an optical purity of 40% ee. The physical properties of this compound are as follows:

mp 52-56 C; [?] D25-23.8 (C 0.566, CHCl3)

Example 2

235 mg of 2- [2- (3-chlorophenyl) -2-propane] -2-ethylindan-1,3-dione and 487 mg of N- methylmorpholine- R, R) - (-) - N, N'-bis (3,5-di-tert- butylsalicylidene) -1,2-cyclohexanediaminomagnesium (Ⅲ) chloride and dichloromethane 8.0 Ml, and the mixture was cooled to -78 ° C. To the mixture was added 251 mg of methachlorobenzoic acid, and the mixture was stirred at -78 ° C for 5 hours.

The reaction solution was analyzed by high performance liquid chromatography (column: Inertsil ODS 2, eluting solvent methanol: water (70:30), flow rate 0.6 ml / min, detection 220 nm). As a result, 2- [2- ) -2-propane] -2-ethylindan-1,3-dione was 94% and the conversion of (-) - 2- [2- (3- chlorophenyl) Ethyl indan-l, 3-dione [Compound No. (-) - 16] was produced in a yield of 92% and an optical purity of 62% ee.

Example 3

The reaction vessel was charged with AD-mix-α [hydroquinine 1,4-phthalazinediyl ether, K ₃ Fe (CN) ₆ , K ₂ CO ₃ , K ₂ OsO ₄ .2H ₂ O, ], 280 mg of t-butanol, 1.0 mL of t-butanol and 1.0 mL of water. To the ice-cooled mixture was added a solution of 2- [2- (3-chlorophenyl) -2- propane] 65 mg, and the mixture was stirred at 0 占 폚 for 10 minutes and then at room temperature for 14 hours.

The reaction solution was analyzed by high performance liquid chromatography (column: Inertsil ODS 2, eluent methanol: water (70:30), flow rate 0.6 mL / min, detection 220 nm) 3-chlorophenyl) -2,3-dihydroxylpropyl] -2-ethylindan-1,3-dione was produced in a yield of 14%.

Sodium sulfite was added and extracted with dichloromethane. The organic layer was washed with aqueous sulfuric acid, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated by silica gel column chromatography to obtain (-) - 2- [2 The optical purity of Compound No. (-) - 1 was measured by high performance liquid chromatography (column: dichexyl (Chiralcel-OJ manufactured by Takeda Chemical Industries, Ltd., eluent: n-hexane: ethanol: methanol (91: 3: 6), flow rate 1.0 mL / min, detection 220 nm). The analytical values of this compound are as follows.

[[alpha]] D &lt; 25 &gt; -17.1 (C 0.507, CHCl3)

Example 4 <Optical resolution (1) of Compound No. (±) -1>

To 50 mg of (±) 2- [2- (3-chlorophenyl) -2,3-dihydroxylpropyl] -2-ethylindan-1,3-dione (Compound No. (±) (Manufactured by Amano Seiyaku Co., Ltd.) and 5.0 ml of vinyl acetate are mixed and stirred at room temperature for 5 days. After completion of the reaction, the enzyme was separated by filtration and the filtrate was analyzed by high performance liquid chromatography to find that (-) 2- [2- (3-chlorophenyl) -2,3-dihydroxypropyl] (Yield: 50%, optical purity 83% ee) and (+) - 2- [2- (3- chlorophenyl) -2-hydroxy- -Acetoxypropyl] -2-ethylindan-1,3-dione (Compound No. (+) - 2) (yield 50%, optical purity 83% ee).

Examples 5 to 13 <Optical resolution (2) of Compound No. (±) -1>

The reaction was carried out in the same manner as in Example 4 except that 100 mg of the enzyme shown in Table 5 (100 mg) was used instead of 100 mg of the lipase R (derived from Penicillium laurocortin, manufactured by Amano Seiyaku Co., Ltd.) used in Example 4 Conduct. After completion of the reaction, the enzyme was separated by filtration, and the filtrate was analyzed by high performance liquid chromatography. The results are shown in Table 5.

Example 14 <Optical resolution (3) of Compound No. (±) -1>

To the flask, 100 mg of the compound number (±) -1, 100 mg of Lipase R and 1.0 ml of vinyl acetate were added and the mixture was stirred at room temperature for 19 hours. After completion of the reaction, the enzyme was separated by filtration and the filtrate was analyzed by high performance liquid chromatography to find that the compound number (-1) -1 (yield 75%, optical purity 32% ee) and compound number (+ 52%, optical purity 95% ee).

Examples 15 to 24 <Optical resolution (4) to (13) of Compound No. (±) -1>

The reaction was carried out in the same manner as in Example 14, except that 1.0 ml of the ester shown in Table 6 was used instead of 1.0 ml of the vinyl acetate used in Example 14. After completion of the reaction, the enzyme was separated by filtration and the filtrate was purified by high performance liquid chromatography And the results shown in Table 6 were obtained.

Example 25 <Optical resolution of Compound No. (±) -1 (14)>

To the flask was added 100 mg of the compound number (±) -1, 100 mg of Lipase R (Penicillium roqueforti, manufactured by Amano Seiyaku Co., Ltd.), 0.2 ml of vinyl acetate and 1.0 ml of diisopropyl ether, Stir 19 hours. After completion of the reaction, the enzyme was separated by filtration and the filtrate was analyzed by high performance liquid chromatography to give Compound No. (-1) -1 (yield 95%) and compound No. (+) -2 (yield 5% .

Examples 26 to 30 <Optical resolution (15) to (19) of Compound No. (±) -1>

The reaction was carried out in the same manner as in Example 25 except that 1.0 ml of the solvent shown in Table 7 was used instead of 1.0 ml of diisopropyl ether. After completion of the reaction, the enzyme was separated by filtration, and the filtrate was analyzed by high performance liquid chromatography The results shown in Table 7 are shown.

Example 31 <Optical resolution (20) of Compound No. (±) -1>

To the flask was added 100 mg of the compound number (±) -1, 100 mg of Lipase R (Penicillium roqueforti, manufactured by Amano Seiyaku Co., Ltd.), 1.0 mL of diisopropyl ether and 0.2 mL of acetic anhydride, Stir 19 hours. After completion of the reaction, the enzyme was separated by filtration and the filtrate was analyzed by high performance liquid chromatography to obtain Compound No. (-1) -1 (yield 99%) and compound No. (+) -2 (yield 1% .

Examples 32 to 38 <Optical resolution (21) to (31) of Compound No. (±) -1>

The reaction was carried out in the same manner as in Example 31 except that 0.2 ml of the acid anhydride shown in Table 8 was used instead of 0.2 ml of acetic anhydride. After completion of the reaction, the enzyme was separated by filtration and the filtrate was analyzed by high performance liquid chromatography 8 shows the result shown in Fig.

Example 39 <Synthesis of Compound No. (-) -1 and Compound No. (+) -2>

Lipase R (5.00 g, manufactured by Amano Seiyaku Co., Ltd.) and 50 ml of vinyl acetate are placed in the compound number (±) -1 (5.00 g) and the mixture is stirred at room temperature for 5 days. After completion of the reaction, the enzyme was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 to 2: 1) to obtain 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). The analytical values of Compound No. (+) - 2 are as follows:

Example 40 <Synthesis of Compound No. (-) -1>

Lipase R (1.00 g, Penicillium roqueforti, Amano Seiyaku Co., Ltd.) and 10 ml of vinyl acetate were added to the compound number (±) -1 (1.00 g, optical purity 78% ee) Lt; / RTI &gt; After completion of the reaction, the enzyme was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 to 2: 1) to give 279 mg (yield: 25% Yellow liquid), compound number (-1) -1 (719 mg, yield 72%, optical purity 95% ee, white solid). Compound number (-) - 1 thus obtained was recrystallized from toluene / n-hexane to obtain Compound No. (-) - 1 (738 mg, yield 90%, optical purity> 99% ee, white solid).

The analytical values of the compound number (-) - 1 are as follows:

Example 41 <Synthesis of Compound No. (-) - 14>

387 mg of Compound No. (-) - 1 (optical purity> 99% ee) was dissolved in 8.0 ml of pyridine, and 186 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, ethyl acetate was added, and the mixture was washed with water, 10% hydrochloric acid, water and saturated brine successively and concentrated to give Compound No. (-) - 14 (473 mg, , Optical purity &gt; 99% ee, yellow liquid).

The analytical values of the compound number (-) - 14 are as follows:

Example 42 <Synthesis of Compound No. (-) - 16>

473 mg of Compound No. (+/-) -14 (optical purity &gt; 99% ee) was dissolved in 10 ml of methanol, and 218 mg of potassium carbonate was added at room temperature. After completion of the reaction, the solvent is evaporated under reduced pressure, water and ethyl acetate are added, and the separated organic layer is washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain Compound No. (-) - 16 (331 mg, yield 90%, optical purity> 99% ee, yellow liquid) . This is added with n-hexane and ice-cooled to obtain a white solid.

The analytical values of the compound number (-) - 16 are as follows:

Example 43 Synthesis of Compound No. (-) - 15

1.00 g of Compound No. (-) - 1 (optical purity> 99% ee) was dissolved in 4.0 ml of pyridine, and 640 mg of p-toluenesulfonyl chloride was added dropwise under ice cooling. After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour, ethyl acetate was added, and the mixture was washed successively with water, 10% hydrochloric acid, water and saturated brine, and then concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give Compound No. (-) - 15 (1.35 g, yield 94%, optical purity> 99% ee, colorless liquid) . The analytical values of the compound number (-) - 15 are as follows:

Example 44 <Synthesis of Compound No. (-) - 16>

500 mg of Compound No. (±) -15 (optical purity> 99% ee) was dissolved in 5.0 ml of methanol, 161 mg of potassium carbonate was added at room temperature, and the mixture was reacted for 1 hour. After completion of the reaction, the solvent is evaporated under reduced pressure, water and ethyl acetate are added, the organic layer is separated, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain Compound No. (-) - 16 (306 mg, yield 92%, optical purity> 99% ee, yellow liquid) . This is added with n-hexane and ice-cooled to obtain a white solid.

Example 45 <Synthesis of Compound No. (-) - 1>

160 g of Compound No. (±) -1 is dissolved in 160 ml of vinyl acetate, 160 g of Lipase R is added to this solution, and the mixture is stirred at 30 ° C for 2 days. After completion of the reaction, the enzyme is separated by filtration, and the filtrate is washed successively with saturated aqueous sodium chloride, water, and saturated saline solution. After the solvent is evaporated under reduced pressure, 160 ml of toluene and 480 ml of n-hexane are added to the concentrate, and the mixture is frozen. The precipitated crystals were filtered and washed by shaking with a mixed solvent of toluene 40 ml and n-hexane 120 ml, followed by drying to obtain Compound No. (-) - 1 (64 g, yield 40%, optical purity 97% ee, White solid).

Example 46 <Synthesis of Compound No. (-) - 14>

226 g of Compound No. (-) - 1 (optical purity> 97% ee) was dissolved in 750 ml of pyridine, and 98 g of methanesulfonyl chloride was added dropwise under ice-cooling. After the dropwise addition, the reaction mixture was reacted at room temperature for 1 hour and then ethyl acetate was added thereto. The reaction mixture was washed with water, 10% hydrochloric acid, water and saturated brine and then concentrated to obtain 290 g (yield: 100% Optical purity 97% ee, yellow liquid).

Example 47 <Synthesis of Compound No. (-) - 16>

The crude (±) -14 (290 g) obtained in the compound 46 was dissolved in 100 ml of methanol, 119 g 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 is evaporated under reduced pressure, water and ethyl acetate are added to extract, and the organic layer is washed with water and saturated brine. The organic layer was collected and the solvent was evaporated under reduced pressure to obtain Compound No. (-) - 16 (210 g, yield 98%, optical purity 97% ee, yellow liquid). This is added with n-hexane and ice-cooled to obtain a white solid.

Example 48 <Synthesis of Compound No. (-) - 16>

To a mixture of 5.0 g of the compound No. (-) - 1 (optical purity> 85% ee), 2.7 g of p-toluenesulfonyl chloride and 25 ml of chlorobenzene, 12 g of 25% sodium hydroxide aqueous solution was added dropwise at room temperature. After the dropwise addition, the mixture was reacted at room temperature for 2 hours, and the organic layer was separated, washed with water and brine, and then concentrated to give Compound No. (-) - 16 (4.7 g, yield 98%, optical purity 85% ee) . This is added with n-hexane and ice-cooled to obtain a white solid.

Example 49 <Optical resolution (1) of Compound No. (-) - 2>

To 100 mg of 2- [2- (3-chlorophenyl) -2-hydroxy-3-acetoxypropyl] -2-ethylindan- (100 mg), 100 mg of penicillium roqueforti, manufactured by Amano Seiyaku Co., Ltd., 70 mg of n-heptanol and 2 mL of diisopropyl ether, and the mixture is stirred at room temperature for 24 hours. After completion of the reaction, the enzyme was separated by filtration and the filtrate was analyzed by high performance liquid chromatography to find that Compound No. (-) - 2 (yield: 95%) and (+) - 2- [2- 2,3-dihydroxypropyl] -2-ethylindan-1,3-dione (Compound No. (+) - 1) (yield 5%, optical purity 77% ee). The filtrate was concentrated, the compound number (-) - 2 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain the compound number (-) - 1 (optical purity: 4% ee).

The analytical values of the compound number (-) - 1 are as follows:

Example 50 <Optical resolution (2) of Compound No. (±) -2>

100 mg of Compound No. (±) -2 was added to 100 mg of Lipase R (Penicillium Roqueforti, Amano Seiyaku Co., Ltd.), 1.0 ml of diisopropyl ether and 10 ml of phosphate buffer solution (pH 7.2) And stirred at room temperature for 72 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that the compound number (-) - 2 (yield: 79%) and the compound number (+ ) Was generated. The organic layer was concentrated, the compound number (-) - 2 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain compound number (-) - 1 (optical purity 21% ee).

Example 51 &lt; Optical resolution of Compound No. (+/-) -3 &gt;

Except that 100 mg of 2- [2- (3-chlorophenyl) -2-hydroxy-3-propionyloxypropyl] -2-ethylindan-1,3-dione (Compound No. The reaction was carried out in the same manner as in Example 50, and after completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that (-) - 2- [2- (3- chlorophenyl) -2- (Yield: 72%) and Compound No. (+) - 1 (yield: 28%, optical purity: 97%) was obtained in the same manner as in Reference Example 1, 69% ee) was generated. The organic layer was concentrated, the compound number (-) - 3 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain the compound number (-) - 1 (optical purity 27% ee).

Example 52 <Optical resolution of Compound No. (占) -4>

Except that 100 mg of 2- [2- (3-chlorophenyl) -2-hydroxy-3-butyryloxypropyl] -2-ethylindan-1,3-dione (Compound No. The reaction was carried out in the same manner as in Example 50, and after completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that (-) - 2- [2- (3- chlorophenyl) -2- (Yield: 36%) and Compound No. (+) - 1 (yield: 64%, optical purity: 56% ee). The organic layer was concentrated and the compound number (-) - 4 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain the compound number (-) - 1 (optical purity> 99% ee).

Example 53 &lt; Optical resolution of Compound No. (占 -5)

(100 mg) of 2- [2- (3-chlorophenyl) -2-hydroxy-3-isobutyryloxypropyl] -2-ethylindan- The reaction was carried out in the same manner as in Example 50 except that the reaction was completed and the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that (-) - 2- [2- (3- chlorophenyl) -2- (Yield: 54%) and compound number (+) - 1 (yield: 46%, yield: 54%). An optical purity of 96% ee) was produced. The organic layer was concentrated, the compound number (-) - 5 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain the compound number (-) - 1 (optical purity 82% ee).

Example 54 <Optical resolution of Compound No. (±) -6>

Except that 100 mg of 2- [2- (3-chlorophenyl) -2-hydroxy-3-valeryloxypropyl] -2-ethylindan-1,3-dione (Compound No. The reaction was carried out in the same manner as in Example 50, and after completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that (-) - 2- [2- (3- chlorophenyl) -2- (Yield: 96%) and Compound No. (+) - 1 (yield: 4%, optical purity: 96% ee) was generated. The organic layer was concentrated, the compound number (-) - 6 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain the compound number (-) - 1 (optical purity: 4% ee).

Example 55 <Optical resolution of Compound No. (占) -7>

100 mg of 2- [2- (3-chlorophenyl) -2-hydroxy-3-isobaryloxypropyl] -2-ethylindan-1,3-dione (Compound No. The reaction was carried out in the same manner as in Example 50 except that the reaction was completed and the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that (-) - 2- [2- (3- chlorophenyl) -2- (Yield: 94%) and compound number (+) - 1 (yield: 6%, optically active substance: optically active substance) Purity 97% ee) was produced. The organic layer was concentrated, and the compound number (-) - 7 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain compound number (-) - 1 (optical purity: 6% ee).

Example 56 &lt; Optical resolution of Compound No. (+/-) -8 &gt;

100 mg of 2- [2- (3-chlorophenyl) -2-hydroxy-3-caproyloxypropyl] -2-ethylindan-1,3-6 on The reaction was carried out in the same manner as in Example 50 except that the reaction was completed and the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that (-) - 2- [2- (3- chlorophenyl) -2- (Yield: 20%) and compound number (+) - 1 (yield: 80%, optically active) in the same manner as in Example 1, Purity 25% ee) was produced. The organic layer was concentrated, the compound number (-) - 8 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain compound number (-) - 1 (optical purity 99% ee).

Example 57 <Optical resolution of Compound No. (占) -4>

To the reaction vessel were added 500 mg of the compound No. (±) -4, 50 mg of Lipase R (Penicillium roqueforti, Amano Seiyaku), 1.0 ml of diisopropyl ether, 2.5 ml of phosphate buffer solution (pH 7.2) And the mixture is stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography to find that (-) - 2- [2- (3-chlorophenyl) -2-hydroxy- (Yield: 84%) and compound number (+) - 1 (yield: 16%, optical purity: 93% ee). The organic layer was concentrated, the compound number (-) - 4 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain the compound number (-) - 1 (optical purity 18% ee).

Example 58 &lt; Optical resolution of Compound No. (±) -5 &gt;

The reaction was carried out in the same manner as in Example 57 except that 500 mg of the compound (±) -5 was used. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was analyzed by high performance liquid chromatography, (Compound No. (-) - 5) (yield: 92%) was obtained in the same manner as in Reference Example 1, except that 2- (2- (3- chlorophenyl) -2-hydroxy-3-isobutyryloxypropyl] And compound number (+) - 1 (yield: 8%, optical purity: 98% ee). The organic layer was concentrated, the compound number (-) - 5 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain the compound number (-) - 1 (optical purity: 9% ee).

Example 59 <Optical resolution of Compound No. (占) -8>

The reaction was carried out in the same manner as in Example 57 except that the compound number (±) -8 (500 mg) was used. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and the organic layer was analyzed by high performance liquid chromatography. 3-dione (Compound No. (-) - 8) (Yield: 64%) was obtained as a colorless oil. ) And compound number (+) - 1 (yield: 36%, optical purity: 91% ee). The organic layer was concentrated, the compound number (-) - 8 was collected by silica gel column chromatography, and treated with methanol and sodium hydroxide to obtain compound number (-) - 1 (optical purity 51% ee).

Example 60 <Synthesis of Compound No. (±) -2>

1.7 g of acetic anhydride was added to a solution of 3.0 g of the compound number (±) -1 and 30 ml of pyridine, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water is added, extraction is performed with ethyl acetate, and the organic layer is washed with water, hydrochloric acid water and water in order. The organic layer was concentrated and purified by silica gel column chromatography to obtain a compound number (±) -2 (3.1 g, colorless liquid). The analytical values of the compound number (±) -2 are as follows:

Example 61 <Synthesis of Compound No. (±) -3>

To a solution of 0.50 g of the compound number (±) -1 and 5.0 ml of pyridine was added 0.37 g of anhydrous propionic acid and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water is added, extraction is performed with ethyl acetate, and the organic layer is washed with water, hydrochloric acid water and water in order. The organic layer was concentrated and purified by silica gel column chromatography to obtain a compound number (±) -3 (0.54 g, colorless liquid). The physical properties of this compound are as follows.

nD23: 1.5533

Example 62 <Synthesis of Compound No. (±) -4>

To a solution of 0.50 g of the compound number (±) -1 and 5.0 ml of pyridine was added 0.44 g of anhydrous butyric acid and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water is added, extraction is performed with ethyl acetate, and the organic layer is washed with water, hydrochloric acid, and water. The organic layer was concentrated and purified by silica gel column chromatography to obtain a compound number (±) -4 (0.56 g, colorless liquid). The analytical values of this compound are as follows. Further, the melting point of the crystal obtained by recrystallizing this liquid from diisopropyl ether was mp: 100 - 105 캜.

Example 63 <Synthesis of Compound No. (±) -4>

(35.2 g) was added dropwise to a solution of 107.6 g of the compound number (±) -1 (107.6 g), 36.4 g of triethylamine and 300 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour do. After the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Sodium sulfate was separated by filtration and concentrated to give Compound No. (+/-) -4 (129.1 g, colorless liquid).

Example 64 <Synthesis of Compound No. (±) -5>

To a solution of Compound No. (±) -1 7.2 g, triethylamine (2.53 g) and tetrahydrofuran (20 ml) under ice-cooling, isobutyl chloride (2.56 g) was added dropwise and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Sodium sulfate was separated by filtration and concentrated to give Compound No. (±) -5 (8.5 g, colorless liquid). Compound number (±) -5 (8.5 g, colorless liquid) is obtained. The analytical values of the compound number (±) -5 are as follows:

Example 65 <Synthesis of Compound No. (±) -6>

To a solution of 0.50 g of the compound number (±) -1 and 5.0 ml of pyridine was added dropwise isopropyl acetic acid chloride (0.34 g), and after completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water is added, extraction is performed with ethyl acetate, and the organic layer is washed with water, hydrochloric acid, and water. The organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain Compound No. (±) -6 (0.55 g, colorless liquid). The analytical values of the compound number (±) -6 are as follows: nD23: 1.5525

Example 66 <Synthesis of Compound No. () -7>

0.34 g of isovaleric acid chloride under ice-cooling was added dropwise to a solution of 0.50 g of the compound number (±) -1 and 5.0 ml of pyridine, and the mixture was stirred at room temperature for 2 hours after completion of dropwise addition. After completion of the reaction, water is added, extraction is performed with ethyl acetate, and the organic layer is washed sequentially with water, saturated sodium carbonate aqueous solution, hydrochloric acid water and water. The organic layer was concentrated and purified by silica gel column chromatography to give a compound number (±) -7 (0.50 g, colorless liquid). The analytical values of the compound number (±) -7 are as follows: nD23: 1.5552

Example 67 <Synthesis of Compound No. () -8>

To a solution composed of 0.50 g of the compound number (±) -1 and 5.0 ml of pyridine, 0.60 g of anhydrous capronic acid was added and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water is added, extraction is performed with ethyl acetate, and the organic layer is washed with water, hydrochloric acid water and water in order. The organic layer was concentrated and purified by silica gel column chromatography to give a compound number (±) -8 (0.56 g, colorless liquid). The analytical values of the compound number (±) -8 are as follows:

Example 68 <Synthesis of Compound No. (±) -8>

44.4 g of caproic acid chloride was added dropwise under ice-cooling to a solution of 107.6 g of the compound number (±) -1, 36.4 g of triethylamine and 300 ml of tetrahydrofuran. After the dropwise addition, the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the organic layer is washed sequentially with hydrochloric acid, sodium bicarbonate, and brine. The organic layer was concentrated to obtain a compound number (±) -8 (133.8 g, pale yellow liquid).

Example 69 <Synthesis of Compound No. (±) -16>

To 5.00 g of Compound No. (±) -1 were added 5.00 g of Lipase R (Penicillium Roqueforti, Amano Seiyaku Co., Ltd.) and 50 ml of vinyl acetate, followed by stirring at room temperature for 5 days. After the reaction, the enzyme is separated by filtration, and the filtrate is concentrated under reduced pressure. The residue was separated by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to obtain Compound No. (-) - 1 (2.55 g, yield 51%, optical purity 78% ee, white solid) Compound number (+) - 2 (2.73 g, yield 49%, optical purity 81% ee, yellow liquid) was obtained.

A solution composed of 90 mg of sodium hydroxide and 10 ml of methanol was dropwise added to 840 mg of the obtained compound number (+) - 2 (optical purity 81% ee) at room temperature. After completion of the reaction by stirring for 1 hour as it is, methanol is evaporated under reduced pressure. Demineralized water was added thereto, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to obtain Compound No. (+) - 1 (690 mg, yield 92%, optical purity 81% ee, white solid).

To 670 mg of the obtained compound number (+) - 1 (optical purity 81% ee), 670 mg of lipase R (penicillium roqueforti, manufactured by Amano Seiyaku Co., Ltd.) and 7.0 ml of vinyl acetate were added and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the enzyme was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to obtain 324 mg (yield: 43%, optical purity: 99% And compound number (+) - 1 (382 mg, yield 57%, optical purity 68% ee, white solid).

The analytical values of Compound No. (+) - 2 are as follows:

To 252 mg of thus obtained compound No. (+) - 2 (optical purity> 99% ee), a solution consisting of 90 mg of sodium hydroxide and 10 ml of methanol was added dropwise at room temperature. After completion of the reaction by stirring for 1 hour as it is, methanol is evaporated under reduced pressure. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. 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 analytical values of Compound No. (+) - 1 are as follows: mp 97.3 - 98.9 캜; [?] D ²⁵ +62.2 (C 0.460, CHCl 3)

168 mg of Compound No. (+) - 1 (optical purity> 99% ee) thus obtained 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, ethyl acetate was added, and the mixture was washed successively with water, 10% aqueous hydrochloric acid, water and saturated brine, and concentrated to obtain Compound No. (+ Optical purity &gt; 99% ee, yellow liquid).

211 mg of Compound No. (+) - 14 thus obtained was dissolved in 5.0 ml of methanol, 95 mg of potassium carbonate was added at room temperature, and the mixture was reacted for 1 hour. After completion of the reaction, the solvent is evaporated under reduced pressure, water and methyl acetate are added to extract, and the organic layer is washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain Compound No. (+) - 16 (152 mg, yield 95%, optical purity> 99% ee, yellow liquid). The analytical value of the compound number (+) - 16 is as follows. : [?] D ²⁵ +58.8 (C 0.464, CHCl 3)

Example 70 <Synthesis of Compound No. (-) -1>

1.0 ml of 1 N hydrochloric acid was added to a solution of 50 mg of the compound (±) -16 (optical purity> 99% ee) in 1.0 ml of methanol, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was analyzed by high performance liquid chromatography to find that the compound number (+) - 16 had a conversion of 100% and a compound number (-) - 1 (yield: 56%, optical purity: 45% ee). The analytical values of the compound number (-) - 1 are as follows:

Example 71 <Synthesis of Compound No. (-) -1>

1.0 ml of 1 N hydrochloric acid was added to a solution of 50 mg of acetone in 1.0 ml of the compound number (占) -16 (optical purity &gt; 99% ee) and the mixture was stirred at 50 占 폚 for 2 hours. The reaction solution was analyzed by high performance liquid chromatography to find that the compound number (+) - 16 had a conversion of 100% and a compound number (-) - 1 (yield: 82%, optical purity: 70% ee).

Example 72 <Synthesis of Compound No. (-) -1>

To a solution of 50 mg of the compound (±) -16 (optical purity> 99% ee) in acetone (1.0 ml) was added 1.0 ml of 10% sulfuric acid and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was analyzed by high performance liquid chromatography to find that the compound number (+) - 16 had a conversion of 100% and a compound number (-) - 1 (yield 94%, optical purity 75% ee).

Example 73 <Synthesis of Compound No. (-) - 1>

1.0 ml of 10% sulfuric acid was added to a solution of 50 mg of the compound (±) -16 (optical purity> 99% ee) in 1.0 ml of diisopropyl ether, and the mixture was stirred at 50 ° C. for 5 hours. The reaction solution was analyzed by high performance liquid chromatography to find that the compound number (+) - 16 had a conversion of 6% and a compound number (-) - 1 (yield: 4%, optical purity: 47% ee).

Example 74 <Synthesis of Compound No. (-) -1>

1.0 ml of 10% acetone in 10 ml of 10% sulfuric acid was added to a solution of 50 mg of compound No. (±) -16 (optical purity> 99% ee) in 1.0 ml of acetone, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was analyzed by high performance liquid chromatography to find that the compound number (+) - 16 had a conversion of 4% and a compound number (-) - 1 (yield 3%, optical purity 79% ee).

The results of Examples 70 to 74 are shown in Table 9.

Example 75 <Synthesis of Compound No. (-) -1>

To a solution of 10.1 g of 20 ml of acetone in 20 ml of 10% sulfuric acid was added the compound number (±) -16 (optical purity> 70% ee) and the mixture was stirred at 50 ° C for 5 hours. After completion of the reaction, sodium carbonate is added to the reaction solution to neutralize. Ethyl acetate was added to separate the layers, and the organic layer was washed with water and saturated brine. After the solvent is evaporated under reduced pressure, 5 ml of toluene and 25 ml of n-hexane are added to the concentrate, and the mixture is frozen. The precipitated crystals were filtered and dried to obtain Compound No. (-) - 1 (9.1 g, yield 86%, optical purity 36% ee, white solid).

Example 76 <Synthesis of Compound No. (-) -1>

10 ml of 10% aqueous acetone solution was added to a solution of 4.67 g of compound No. (±) -16 (optical purity 70% ee) in 10 ml of acetone, and the mixture was stirred at 50 ° C for 5 hours. After completion of the reaction, sodium carbonate is added to the reaction solution to neutralize. Ethyl acetate was added to separate the layers, and the organic layer was washed with water and saturated brine. After the solvent was evaporated under reduced pressure, 2.5 ml of toluene and 12.5 ml of n-hexane were added to the concentrate, and the mixture was ice-cooled. The precipitated crystals were filtered and dried to obtain 4.13 g (yield: 84%, optical purity 33% ee, white solid) of the compound number (-) - 1.

Example 77 <Synthesis of Compound No. (-) - 1>

Compound No. (±) -16 (optical purity> 99% ee) (0.50 g) was dissolved in acetonitrile (5.0 ml), and 65% sulfuric acid aqueous solution (0.15 ml) was added and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, sodium carbonate is added to the reaction solution to neutralize. Ethyl acetate was added to separate the layers, and the organic layer was washed with water and saturated brine. The organic layer was analyzed by high performance liquid chromatography to find that the compound number (+) - 16 had a conversion of 76% and a compound number (-) - 1 (yield 60%, optical purity 38% ee).

Examples 78 to 91 &lt; Synthesis of Compound No. (-) - 1 &gt;

Table 10 shows the results obtained by carrying out the reaction in the same manner as in Example 77, using the solvents shown in Table 10, together with Example 77.

Example 92 <Synthesis of Compound No. (-) -1>

Compound No. (±) -16 (6.28 g, optical purity> 99% ee) was dissolved in chlorobenzene (40.0 g), formic acid (13.8 g) and water (5.4 g) were added and stirred at 50 ° C. for 3 hours . After completion of the reaction, 25% aqueous sodium hydroxide solution (60 g) was added to the reaction solution, and the mixture was stirred at 50 占 폚 for 0.5 hours. The organic layer was washed with water and brine. The organic layer was analyzed by high performance liquid chromatography to find that the compound (+) - 16 had a conversion of 100% and a compound number (-) - 1 (yield 85%, optical purity 55% ee).

Example 93 <Synthesis of Compound No. (-) - 1>

0.50 g of Compound No. (±) -16 (optical purity> 99% ee) was dissolved in 10 ml of chlorobenzene, 0.5 ml of formic acid was added, and the mixture was 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 mixture, and the mixture was stirred at room temperature for 5 hours. The organic layer was washed with water and brine. The organic layer was analyzed by high performance liquid chromatography to find that the compound (+) - 16 had a conversion of 100% and a compound number (-) - 1 (yield: 79%, optical purity: 64% ee).

Example 94 <Synthesis of Compound No. (-) -1>

1.40 g (4.11 mol) of Compound No. (±) -16 (optical purity> 99% ee) was dissolved in 14 ml of diethylene glycol diethyl ether, and 0.1 ml of concentrated sulfuric acid and 0.1 ml (5.56 mmol, H ₂ O-1.35 eq / (+) - 16) is added dropwise, and after the dropwise addition, the mixture is stirred at room temperature for 10 hours. After completion of the reaction, sodium carbonate is added to the reaction solution to neutralize. Ethyl acetate was added to separate the layers, and the organic layer was washed with water and saturated brine. The organic layer was analyzed by high performance liquid chromatography, and the optical purity of Compound No. (-) - 1 was 76% ee.

Example 95 <Synthesis of Compound No. (-) -1>

The organic layer was analyzed by high performance liquid chromatography in the same manner as in Example 94 except that 0.35 ml of concentrated sulfuric acid and 0.35 ml (19.4 mmol, H ₂ O-4.7 eq / (+) - 16) The optical purity of Compound No. (-) - 1 was 83% ee.

Example 96 <Synthesis of Compound No. (-) -1>

The organic layer was analyzed by high performance liquid chromatography in the same manner as in Example 94 except that 0.75 ml of concentrated sulfuric acid and 0.75 ml of water (41.6 mmol, H ₂ O-10 eq / (+) - 16) The optical purity of Compound No. (-) - 1 was 78% ee.

Example 97 <Synthesis of Compound No. (-) -1>

1.40 g (4.11 mol) of Compound No. (±) -16 (optical purity> 99% ee) and 0.1 ml (5.56 mmol, H ₂ O-1.35 eq / (+) - 16) of water were added to diethylene glycol diethyl ether 14 , And 0.1 ml of concentrated sulfuric acid was added dropwise at room temperature. After dropwise addition, the mixture was stirred at room temperature for 10 hours. After completion of the reaction, sodium carbonate is added to the reaction solution to neutralize. Ethyl acetate was added to separate the layers, and the organic layer was washed with water and saturated brine. The organic layer was analyzed by high performance liquid chromatography, and the optical purity of Compound No. (-) - 1 was 70% ee.

Example 98 <Synthesis of Compound No. (-) -1>

1.40 g (4.11 mol) of Compound No. (±) -16 (optical purity> 99% ee) and 0.35 ml (19.4 mmol, H ₂ O-4.7 eq / (+) - 16) of water were added to diethyleneglycol diethyl ether 14 And 0.35 ml of concentrated sulfuric acid was added dropwise at room temperature. After dropwise addition, the mixture was stirred at room temperature for 10 hours. After completion of the reaction, sodium carbonate is added to the reaction solution to neutralize. Ethyl acetate was added to separate the layers, and the organic layer was washed with water and saturated brine.

The organic layer was analyzed by high performance liquid chromatography, and the optical purity of Compound No. (-) - 1 was 75% ee.

Example 99 <Synthesis of Compound No. (-) - 16>

To a mixture of 17.9 g of the compound number (±) -1 (optical purity 80% ee), 2.7 g of p-toluenesulfonyl chloride and 100 ml of toluene, 40 g of a 20% sodium hydroxide aqueous solution was added dropwise at 40 ° C. After completion of the reaction, the mixture was allowed to react at 50 캜 for 3 hours, and the organic layer was separated, washed with water and concentrated to obtain 16.9 g of Compound No. (+) - 16 (yield: 99%, optical purity: 80% ee). This is added with n-hexane and ice-cooled to obtain a white solid of Compound No. (+) - 16. The analytical values of this compound are as follows: mp 41-42 DEG C; [?] D ²⁵ -47.6 (C 0.556, CHCl3)

Hereinafter, embodiments of the production method of the important intermediate of the optical isomer mixture of the present invention represented by the above-mentioned formula (6) will be summarized.

Example 100 &lt; Crystallization purification of Compound No. (-) - 1 &gt;

Compound No. (-) - 1 5.0 g (81% ee, chemical purity 86%, toluene 8%) and toluene 20 ml were dissolved by heating at 70 캜 and then cooled to 0 캜. The precipitated crystals are filtered off and dried to obtain 4.1 g (85% ee) of the solvate crystal of the compound No. (-) - 1.

Examples 101 to 106 <Crystallization and purification of Compound No. (-) - 1>

Crystallization was carried out in the same manner as in Example 100 except that 20 ml of the solvent shown in Table 11 was used instead of 20 ml of toluene and the temperature was lowered to the temperature shown in Table 11, and the results shown in Table 11 were obtained. The solvate crystals obtained herein showed no impurities other than those containing 5-15% by weight of the aromatic compound shown in Table 11.

Comparative Example 1

Crystallization was carried out in the same manner as in Example 100, except that 20 ml of toluene was replaced with 5 ml of ethyl acetate and 15 ml of n-hexane to obtain 3.4 g of a compound (-) - 1 crystal. However, the optical purity was as low as 78% ee and the optical purity was lowered.

In Examples 100 to 106 described above, crystals obtained by single crystal X-ray analysis were analyzed to confirm that they were solvates. For example, the solvate crystal with O-xylene obtained in Example 104 was analyzed to find that it was a solvate having a compound No. (-) - 1 and O-xylene ratio of 2: 1. NMR data and melting point of this crystal are shown.

Ortho-xylene complex of (S) -diol [(S) -diol 0.5 ortho-xylene]: colorless; mp 91-94 [deg.] C;

As can be seen from Table 11, it is found that an optical isomer having a very high optical purity can be easily obtained.

Example 107 <Synthesis of Compound No. (±) -1>

A mixture of 160 g of Compound No. (±) -4, 85 g of Lipase R (Penicillium Roqueforti, Amano Seiyaku Co., Ltd.), 350 ml of diisopropyl ether and 1050 ml of phosphoric acid buffer solution (pH 7.2) Stir at 25 占 폚 for 24 hours. After the reaction mixture was extracted with chlorobenzene, the organic layer was washed with celite, and the organic layer was washed with sodium carbonate water, water and brine in this order, and then the organic layer was analyzed by silica gel column chromatography. (-) - 4 (optical purity of 82% ee) and compound number (+) - 1 (optical purity of 82% ee).

30 g of pyridine was added to the chlorobenzene solution, and 30 g of methanesulfonyl chloride was added dropwise under ice-cooling. Compound (-) - 4 (optical purity 82% ee) and compound number (+) were analyzed by high performance liquid chromatography, and the organic layer was analyzed by high performance liquid chromatography. -14 (optical purity 82% ee).

To this chlorobenzene solution, 320 g of a 25% aqueous sodium hydroxide solution was added at room temperature, and the reaction was continued for 5 hours. After completion of the reaction, the organic layer is washed with water and brine, and the solvent is evaporated under reduced pressure. The residue was analyzed by high performance liquid chromatography to give compound number (-) - 1 (optical purity 82% ee) and compound number (+) - 16 (optical purity 82% ee).

This residue was dissolved in a mixed solvent of diethyleneglycol diethyl ether (350 ml) and water (9.0 ml), and 9.0 ml of concentrated sulfuric acid under ice-cooling was slowly added dropwise, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction solution is neutralized with an aqueous solution of sodium hydroxide, and the organic layer is washed with brine. The solvent was evaporated under reduced pressure and the residue was crystallized from a mixed solvent of toluene and n-hexane to obtain Compound No. (-) - 1 (98 g, Compound No. (±) -4 (optical purity 74% ee, white solid ) In a yield of 73%).

Example 108 <Synthesis of Compound No. (-) - 1>

207 g (4.50 mol) of formic acid was added dropwise at 50 째 C to a mixture of 102 g (0.300 mol) of compound number (짹) -16, 600 g of chlorobenzene and 81.1 g (4.50 mol) After completion of the dropwise addition, the mixture was reacted at 50 DEG C for 2 hours, and 768 g (4.80 mol) of a 25% sodium hydroxide aqueous solution was added thereto, followed by reaction at 50 DEG C for 1 hour. After the reaction, the organic layer is separated and washed with saturated brine. Approximately one third of the chlorobenzene is evaporated under reduced pressure, 200 g of chlorobenzene and 29.7 g (0.37 mmol) of pyridine are added, followed by dropwise addition of 48.5 g (0.360 mol) of caproic acid chloride. After completion of the dropwise addition, the mixture was reacted at 50 ° C for 1 hour, and the organic layer was separated, washed with brine-containing aqueous solution of sodium chloride and saturated brine, and concentrated under reduced pressure to obtain 161 g of crude compound number (±) -8.

The crude compound number (±) -8 (161 g) was dissolved in 250 ml of diisopropyl ether and washed with 1 N aqueous hydrochloric acid solution, sodium carbonate aqueous solution and saturated brine. To this solution, 55 g of lipase R (Penicillium roqueforti, Amano Seiyaku Co., Ltd.) and 750 ml of phosphate buffer solution (pH 7.2) were added and stirred at 25 캜 for 16 hours. After completion of the reaction, 150 g of sodium chloride was added and the mixture was extracted with 375 ml of chlorobenzene. The organic layer was separated by filtration through a gel and washed with brine and brine containing sodium carbonate. The organic layer was analyzed by high performance liquid chromatography, ) -8 was 50%, the compound number (-) - 8 (optical purity 85% ee) and the compound number (+) - 1 (optical purity 85% ee) were produced.

Subsequently, about 1/3 of chlorobenzene is evaporated under reduced pressure, 19.0 g (0.188 mol) of triethylamine is added, and 20.6 g (0.180 mol) of methanesulfonyl chloride is added dropwise under ice-cooling. (Optical purity: 85% ee) and the compound number (+) as a result of analysis by high performance liquid chromatography. As a result, -14 (optical purity 85% ee).

236 g (1.48 mol) of 25% sodium hydroxide aqueous solution was added to the chlorobenzene solution, and the mixture was reacted at 70 DEG C for 2 hours. After completion of the reaction, saline was added, extraction was performed with ethyl acetate, the organic layer was washed with brine, and the solvent was evaporated under reduced pressure. The residue was analyzed by high performance liquid chromatography to give compound number (-) - 1 (optical purity 85% ee) and compound number (+) - 16 (optical purity 85% ee).

The residue is dissolved in 500 ml of diethylene glycol ethyl ether, and a mixed solution of 12.2 mol (0.675 mol) of water and 12.2 ml of concentrated sulfuric acid is slowly dropped under ice-cooling, and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was neutralized by adding an aqueous solution of sodium hydroxide. The organic layer was separated and concentrated under reduced pressure. The residue was crystallized from a mixed solvent of toluene / n-heptane to obtain Compound No. (-) - 1 , Compound number (±) -16 (optical purity 81% ee, white solid: 75%).

Example 109 <Synthesis of Compound No. (-) - 1>

207 g (4.50 mol) of formic acid was added dropwise at 50 째 C to a mixture of 102 g (0.300 mol) of compound number (짹) -16, 600 g of chlorobenzene and 81.1 g (4.50 mol) of water. After completion of the dropwise addition, the mixture was reacted at 50 DEG C for 2 hours, and 768 g (4.80 mol) of a 25% sodium hydroxide aqueous solution was added thereto, followed by reaction at 50 DEG C for 1 hour. After the reaction, the organic layer is separated and washed with brine and water. About 1/3 of the chlorobenzene is evaporated under reduced pressure, 29.7 g (0.37 mol) of pyridine are added, and then 48.5 g (0.360 mol) of caproic acid chloride is 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 brine and brine, and concentrated under reduced pressure to obtain the crude compound number (±) -8. This was dissolved in 250 ml of diisopropyl ether, and the mixture was washed with hydrochloric acid, sodium carbonate, and water. To this solution, 55 g of lipase R (Penicillium roqueforti, Amano Seiyaku Co., Ltd.) and 750 ml of phosphate buffer solution (pH 7.2) were added and stirred at 25 캜 for 16 hours. After completion of the reaction, 150 g of sodium chloride was added and the mixture was extracted with 375 ml of chlorobenzene. The organic layer was separated by filtration through a gel and washed with brine and brine containing sodium carbonate. The organic layer was analyzed by high performance liquid chromatography, ) -8 was 50%, the compound number (-) - 8 (optical purity 85% ee) and the compound number (+) - 1 (optical purity 85% ee) were produced.

(0.157 mol) of p-toluenesulfonyl chloride was added, and 240 g (1.50 mol) of 25% sodium hydroxide aqueous solution was added dropwise. After completion of the dropwise addition, the mixture was reacted at 40 to 50 ° C for 4 hours and at 70 ° C for 2 hours . The mixture is extracted with ethyl acetate, and the organic layer is washed with brine and water and concentrated under reduced pressure. The residue was analyzed by high performance liquid chromatography to give compound number (-) - 1 (optical purity 85% ee) and compound number (+) - 16 (optical purity 85% ee).

The residue is dissolved in 500 ml of diethylene glycol ethyl ether, and a mixed solution of 12.2 mol (0.675 mol) of water and 12.2 ml of concentrated sulfuric acid is slowly dropped under ice-cooling, and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was neutralized by adding an aqueous solution of sodium hydroxide. The organic layer was separated and concentrated under reduced pressure. The residue was crystallized from a mixed solvent of o-xylene / toluene / n-heptane, 1 (81 g, yield 75% from compound number (±) -16 (optical purity 83% ee, white solid).

Example 110

(1.0 g, 2.79 mmol), molecular sieves 4A (manufactured by Linde Corp.), 2- (30 mg, 5.0 mol%) was added to a 50-mL eggplant-shaped flask, followed by the addition of (-) - 2- (N-benzyl- In acetone (5.0 mL) and triethylamine (mg, 50 mol%) were added.

The mixture was cooled to -78 ° C and an acetone solution (5.0 ml) of benzoyl chloride (75 mol%) was added dropwise. After completion of the dropwise addition, the mixture was stirred at -78 ° C for 1 hour. The reaction solution was analyzed by HPLC to find that (±) -2- [2- (3- chlorophenyl) -2,3- dihydroxypropyl] -2- The conversion rate of ethyl indan-1,3-dione was 53%, and (+) - 2- [2- (3- chlorophenyl) -2,3- dihydroxypropyl] Dione (20% ee) and (-) - 2- [2- (3-chlorophenyl) -2-hydroxy-3- benzoyloxypropyl] Was created.

Examples 111 and 112

Except that the optically active diamines (5.0 mol%) shown in Table 12 were used instead of the (-) - 2- (N-benzyl-N-methylaminomethyl) -1-methylpyrrolidine 110 &lt; / RTI &gt; The results are shown in Table 12. From the results in Table 12, it can be seen that all optically active diamines can be optically split. The split efficiency was determined by the same procedure as in Example 1 except that (-) - 1-methyl-2 - [(piperidin- 1 -yl) methyl] pyrrolidine, , 2,3,4-tetrahydroisoquinoline, and (-) - 2- (N-benzyl-N-methylaminomethyl) -1-methylpyrrolidine.

Examples 113 to 120

Acetone (5.0 ml) was subjected to the reaction in the same manner as in Example 110 at the reaction temperature shown in Table 13 instead of the reaction solvent (5.0 ml) shown in Table 13. The results are shown in Table 13.

From the results in Table 13, it can be seen that all the reaction solutions can be optically split. The separation efficiency is high in ketone solvents, ester solvents, amide solvents and nitrile solvents, and in particular, ketone solvents, amide solvents and nitrile solvents are particularly high.

Examples 121 to 128

The reaction was carried out in the same manner as in Example 110, except that acylic bases (50 mol%) shown in Table 14 were replaced with triethylamine (50 mol%) under the conditions of diamine, reaction solvent and reaction temperature shown in Table 14. The results are shown in Table 14.

From the results in Table 14, it can be seen that all the archival bases can be optically split. It can be seen that the partitioning efficiency is lowered when pyridine is used compared to triethylamine, and is improved when an inorganic base is used. Among the bases, sodium carbonate and sodium hydrogencarbonate show particularly high separation efficiency.

Examples 129 to 135

Benzoyl chloride (75 mol%) was subjected to a reaction in the same manner as in Example 110, except that acylating agent (75 mol%) shown in Table 15 was used instead of acyl base, reaction solvent and reaction temperature shown in Table 15. The results are shown in Table 15.

From the results in Table 15, it can be seen that all the acylating agents can be optically split. It can be seen that the partitioning efficiency is improved by using an aromatic carboxylic acid halide.

Examples 136 and 137

The amount of diamine used was reacted in the same manner as in Example 110 under the conditions of the acylal base and the reaction temperature shown in Table 16 instead of the used amount shown in Table 16. The results are shown in Table 16.

From the results in Table 16, it can be seen that even if the amount of the optically active diamine is reduced, the division efficiency is not reduced.

Hereinafter, examples of the preparation of pesticides of the present invention, a production method thereof, and test examples using the same are described. And &quot;% &quot; mean &quot; parts by weight &quot; and &quot;% by weight &quot;, respectively.

Formulation Example 1:

40 parts of the optical isomer mixture of the present invention (the optical purity of Compound No. (-) - 16 is the same in the preparation of 99% ee. Or less), 40 parts of Caplex # 80 (trade name of Shionogyse Iyaku Co., , 35 parts of N, N-kaolin clay (trade name, a product of Tsuchiya Kaolin Co., Ltd.) and 5 parts of a high-alcohol sulfate surfactant Sorbo 8070 (trade name, manufactured by Toho Chemical Industry Co., Ltd.) were mixed and uniformly mixed and pulverized A wettable powder containing 40% active ingredient is obtained.

Formulation Example 2: Granulation

1 part of the optical isomer mixture of the present invention, 45 parts of clay (manufactured by Nippon Talcsha K.K.), 52 parts of bentonite (manufactured by HOJUYON YOKOSHA) and 50 parts of succinate surfactant AirRol CT-1 ) Were blended, mixed and pulverized, and then 20 parts of water was added and kneaded. Then, this is extruded through a hole having a diameter of 0.6 mm by using an extrusion granulator and dried at 60 DEG C for 2 hours. Cut to a length of 1 to 2 mm to obtain a granule containing 1% active ingredient.

Formulation Example 3: Emulsion

The optical isomer mixture of the present invention was dissolved in a mixed solvent consisting of 30 parts of xylene and 25 parts of dimethylformamide, 15 parts of polyoxyethylene surfactant Sorbo 3005X (trade name, manufactured by Toho Chemical Industry Co., Ltd.) To obtain an emulsion containing 30% of the active ingredient.

Formulation Example 4: Floor Blue

30 parts of the optical isomer mixture of the present invention, 8 parts of ethylene glycol preliminarily mixed, 5 parts of sorb AC3032 (trade name, manufactured by Toho Chemical Industry Co., Ltd.), 0.1 part of xanthan gum and 56.9 parts of water are well mixed and dispersed. Subsequently, this slurry-like mixture is wet-pulverized using Dyno Mill (Shinmaru Enterprise Co., Ltd.) to obtain a stable floor blue agent containing 30% of active ingredient.

Test Example 1 Field soil treatment test

The soil of the field volcanic ash was filled in a resin pad having an area of 200 cm 2, and the soil was sprayed with the fertilizer. Then, the soils obtained by uniformly blending the seeds of the maple, Sorghum napacarla, The obtained herbicide (wettable powder) of the present invention is diluted with water, and a predetermined amount is homogeneously treated with a small-sized power sprayer.

(%: The ratio of the dry weight of the upper part of the weeds in the untreated area to 100) was calculated for each of the treatments and the weed species by 28 days after the preparation treatment, and 90% inhibition (The amount of active ingredient: g / ha) was calculated. The results are shown in Table 17 (i.e., 90% inhibition means that the weight of the weed at the top of the weed control area was 10% it means.).

Then, as a comparative example, the test was carried out in the same manner as above using the racemate corresponding to compound number (-) - 16 (Comparative Example A) and commercially available weed active ingredient, and evaluated by the same method, Lt; tb &gt; Comparative Example A, Comparative Example B and Comparative Example C in Table 17 are shown below.

Comparative Example A; Compound No. (±) -16

As can be seen from Table 17, it is clear that the herbicide of the present invention exhibits excellent herbicidal activity at a remarkably low dose with respect to the comparative example, which is a conventional herbicide, while being in a light spectrum for soil treatment.

Test Example 2

The herbicidal effect of the pesticide of the present invention is tested in the same manner as in Test Example 1 except that the optical purity (% ee) and the amount of the pesticide of the present invention are changed as shown in Table 18.

To evaluate the herbicidal effect, the herbicidal effect factor Y is determined by the following equation, and the result is an 11-step evaluation, and the three points of the evaluation result are averaged. The results are shown in Table 18.

Y (%) = (1 -? /?) 100

(In the formula,? Represents the biomass weight of the weed overgraze in the agrochemical treatment area, and? Represents the biomass weight of the weed overgraze in the agrochemical treatment area.)

Herbicidal effect factor Y (%)

0 0

1 1 to 10

2 11-20

3 21 ~ 30

4 31-40

5 41 ~ 50

6 51 ~ 60

7 61 ~ 70

8 71 ~ 80

9 81-90

10 91-100

As shown in Table 18, the herbicide containing the optical isomer mixture of the present invention as an active ingredient has a broad weed spectrum and exhibits excellent herbicidal effect at a low dose. This is because the specific optical isomer content of the racemate is set to a specific value (40% ee or more) to improve the water solubility, thereby exhibiting an excellent effect as a soil treatment agent for the field.

The optically active 1,2-disubstituted-2,3-epoxypropane of the present invention and the optical isomer mixture of the optical isomer exhibit excellent herbicidal activity and remarkably improved water solubility as shown in the above Test Example, It is useful to exhibit excellent herbicidal effects in the treatment.

Further, the production method of the present invention is an industrially inexpensive and excellent process capable of producing a desired compound by a simple process.

Claims (49)

Disclosed is a mixture of optically active 1,2-disubstituted-2,3-epoxypropanes represented by the following formula (1) and an optical isomer mixture of the optically isomeric mixture, wherein the content of the optical isomer represented by the following formula (1) Or more of an isomeric mixture of 1,2-disubstituted-2,3-epoxypropane. [Chemical Formula 1] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent. The optical isomer mixture according to claim 1, wherein the optical isomer mixture has a content of 70% ee or more. The optical isomer mixture according to claim 1, wherein the content is 90% ee or more. The optical isomer mixture according to claim 1, wherein the water solubility is 30 ppm or more. The optical isomer mixture of optically active 1,2-disubstituted-2,3-epoxypropanes of the formula (1), wherein A is a group represented by the formula (2). The optically active 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms of the formula (1), wherein A is a group represented by the formula (2), n in the formula (2) is 0, and B is a phenyl group substituted with a halogen atom, A mixture of optical isomers of 2-iodo-2,3-epoxypropane. 2. The optically active 1,2-disubstituted ring-substituted 1,2,3,4-tetrahydronaphthalene ring represented by the formula (1) wherein A is a group represented by the formula (2), n in the formula (2) is 0 and B is a chlorophenyl group -2,3-epoxypropane. The positive resist composition according to claim 1, wherein the compound represented by the formula (1) is (-) - 2- [2- (3- chlorophenyl) -2,3-epoxypropyl] Lt; / RTI &gt; An agrochemical comprising an optically active mixture of optically active 1,2-disubstituted-2,3-epoxypropanes according to claim 1 as an active ingredient. The pesticide according to claim 9, which is a herbicide. 11. The herbicide according to claim 10, which is a herbicide for soil treatment. (4) [Chemical Formula 4] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent (1), characterized in that the 2,3-dihydroxy-1-propene is epoxidized by subtission, [Chemical Formula 1] (Wherein A and B are the same as in the formula (4)). 13. The process according to claim 12, wherein the sub-epoxidation is carried out by reacting with an oxidizing agent in the presence of an optically active manganese complex. (6) [Chemical Formula 6] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent (1) which stereoselectively cyclizes optically active 1,2-disubstituted-2,3-dihydroxypropanes. [Chemical Formula 1] (Wherein A and B are the same as in the formula (6)). (7) (7) (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), B represents an aryl group which may have a substituent, R ⁵ represents a substituent (1), wherein the optically active sulfonic acid ester represented by the general formula (1) is an alkyl group or an aryl group having 1 to 10 carbon atoms, [Chemical Formula 1] (Wherein A and B are the same as in the formula (7)). (7) (7) (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), B represents an aryl group which may have a substituent, R ⁵ represents a substituent An alkyl group or an aryl group having 1 to 10 carbon atoms which may have a substituent. (8) or (9) is reacted with optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above formula (6) in the presence of a base, [Chemical Formula 8] R ⁵ SO ₂ Y [Chemical Formula 9] (R ⁵ SO _{2) 2} O (Wherein R ⁵ represents an alkyl or aryl group having 1 to 10 carbon atoms which may have a substituent, and Y represents a halogen atom), is reacted with a sulfonic acid derivative represented by the formula (7 ) &Lt; / RTI &gt; (4) [Chemical Formula 4] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent (6), characterized in that 2,3-dihydro-1-propene is diethylazylated by subtission, [Chemical Formula 6] (Wherein A and B are the same as in the formula (4)). The production method of optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 18, wherein the subtitle dihydroxylation reaction is carried out in the presence of an osmium compound. The production method of optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 18, wherein the dihydroxylation reaction is carried out in the presence of optically active tertiary amines. 19. The process for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 18, wherein the subtitle dihydroxylation reaction is carried out by oxidation with a catalytic agent in the presence of an osmium compound. (10) [Chemical formula 10] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent Dihydroxypropanes are reacted with 1,2-dihydroxy-2,3-dihydroxypropanes in the presence of an enzyme having a stereoselective ester interchangeability, (11) (R ⁶ CO ₂ ) _m R ⁷ _m (Wherein R ⁶ represents an alkyl group, an alkenyl group, an aralkyl group or an aryl group having 1 to 20 carbon atoms which may have a substituent and R ⁷ represents an alkyl group, an alkenyl group, an aralkyl group, an aryl group Or an acyl group, or R ⁶ and R ⁷ may combine to form a ring, and m represents an integer of 1 to 3) to produce a compound represented by the following formula Disubstituted-2-hydroxy-3-acyloxypropanes represented by the general formula (12) and the compound represented by the following general formula (12) represented by the general formula (13) Dihydroxypropanes can be produced to prepare optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (13), which is a desired optical isomer, After resuspending, Wherein the optically active 1,2-disubstituted-2,3-dihydroxypropane is represented by the following formula (6). [Chemical Formula 12] [Chemical Formula 13] [Chemical Formula 6] (Wherein A, B and R ⁶ are the same as those of formulas (10) and (11), and * represents an asymmetric carbon atom.) (12) [Chemical Formula 12] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), B represents an aryl group which may have a substituent, R ⁶ represents a substituent An alkenyl group, a benzyl group or an aryl group having 1 to 20 carbon atoms which may have 1 to 20 carbon atoms. (13) [Chemical Formula 13] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent Active 1,2-disubstituted-2,3-dihydroxypropanes. 23. The production method of optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 22, wherein the enzyme is a lipase derived from genus Penicillium or Pseudomonas sp. The production method of optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 22, wherein the compound represented by the formula (11) is vinyl butyrate. (14) [Chemical Formula 14] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), B represents an aryl group which may have a substituent, R ⁶ represents a substituent An alkyl group, an alkenyl group, an aralkyl group or an aryl group having 1 to 20 carbon atoms, which may have 1 to 20 carbon atoms, by reacting 1,2-disubstituted-2,3-dihydroxypropanes represented by the general formula (15) &lt; / RTI &gt; [Chemical Formula 15] R ⁸ OH (Wherein R ⁸ represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms which may have a substituent) to obtain optically active 1,2-disubstituted-2- The hydroxy-3-acyloxypropanes and the compound represented by the formula (12) represented by the following formula (13) can be produced by producing an optically active 1,2-disubstituted-2,3-dihydroxypropane (6), wherein optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (13), which is the desired optical isomer, is isolated or solvolized again after reaction The production of optically active 1,2-disubstituted-2,3-dihydroxypropanes. [Chemical Formula 12] [Chemical Formula 13] [Chemical Formula 6] (Wherein A, B and R ⁶ are the same as in the formula (14), and * represents an asymmetric carbon atom.) 28. The process for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 27, wherein the enzyme is a lipase derived from a microorganism belonging to the genus Penicillium. 28. The process for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 27, wherein the compound represented by the formula (15) is water. (14) [Chemical Formula 14] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), B represents an aryl group which may have a substituent, R ⁶ represents a substituent An alkenyl group, an aralkyl group or an aryl group having 1 to 20 carbon atoms which may have 1 to 20 carbon atoms. (10) [Chemical formula 10] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent Dihydroxypropanes can be prepared by reacting 1,2-dihydroxy-2,3-dihydroxypropanes with the following formula (16) or (17) in the presence of a base, [Chemical Formula 16] R ⁶ COY [Chemical Formula 17] (R &lt; ⁶ &gt; CO) ₂ O (Wherein R ⁶ represents an alkyl group, an alkenyl group, an aralkyl group or an aryl group having 1 to 20 carbon atoms which may have a substituent and Y represents a halogen atom), with a carboxylic acid derivative represented by the formula A process for producing 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the formula (14) according to claim 30. (18) [Chemical Formula 18] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent (6), characterized in that 1,2-dihydroxy-2,3-epoxypropanes are hydrolyzed in the presence of an acid or carboxylic acid is decomposed and then solvolyzed. [Chemical Formula 6] (In the formula, A and B are the same as in the formula (18)), the optically active 1,2-disubstituted-2,3-dihydroxypropanes are produced. (18) [Chemical Formula 18] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent Optically active 1,2-disubstituted-2,3-epoxypropane. The optically active 1,2-disubstituted-2,3-epoxypropane of claim 32, which is obtained by hydrolyzing an optically active 1,2-disubstituted-2,3-epoxypropane represented by the formula (18) Preparation of 3-dihydroxypropanes. 33. The optically active 1,2-disubstituted 2,3-epoxypropane of claim 32, wherein the optically active 1,2-disubstituted-2,3-epoxypropane represented by the formula (18) is decomposed with a carboxylic acid and then solvolyzed. Preparation of dihydroxy-2,3-dihydroxypropanes. (19) (Wherein A and B are the same as in the formula (18), and R ⁵ represents an alkyl group or an aryl group having 1 to 10 carbon atoms which may have a substituent) and a base are reacted with the optically active sulfonic acid ester Of the optically active 1,2-disubstituted-2,3-epoxypropane represented by the chemical formula (18) according to claim 32. The process for producing optically active 1,2-disubstituted-2,3-dihydroxypropanes according to claim 32, wherein the compound represented by the formula (18) is prepared by the process according to claim 36. (19) [Chemical Formula 19] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), B represents an aryl group which may have a substituent, R ⁵ represents a substituent An alkyl group or an aryl group having 1 to 10 carbon atoms which may have a substituent. (20) (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent Optically active 1,2-disubstituted-2,3-dihydroxypropanes, and (8) or (9) [Chemical Formula 8] R ⁵ SO ₂ Y (9) [Chemical Formula 9] (R ⁵ SO _{2) 2} O (Wherein R ⁵ represents an alkyl or aryl group having 1 to 10 carbon atoms which may have a substituent, and Y represents a halogen atom) is reacted with a sulfonic acid derivative represented by the formula (19) ) &Lt; / RTI &gt; The optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (20) according to claim 39, wherein the optically active 1,2-disubstituted-2,3-dihydroxypropanes are represented by the production process according to any one of claims 22, . &Lt; / RTI &gt; (13) [Chemical Formula 13] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent (6), characterized in that an optically active mixture of optically active 1,2-disubstituted-2,3-dihydroxypropanes is dissolved in a solvent containing an aromatic compound which may have a substituent and then cooled. Of the optically active 1,2-disubstituted-2,3-dihydroxypropanes. 42. The method according to claim 41, wherein the aromatic compound, which may have a substituent, (30) Ar-A _'n (Wherein Ar represents a phenyl group and A 'represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms , A halogen atom, and n represents an integer of 0 to 6, and when there are a plurality of substituents, the substituents may be bonded to each other to form a ring. (6) [Chemical Formula 6] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent An optically active 1,2-disubstituted-2,3-dihydroxypropane and an aromatic compound which may have a substituent. 44. The solvate of claim 43, wherein the molar ratio of 1,2-disubstituted-2,3-dihydroxypropanes and aromatic compounds that may have substituents is 2: 1. 44. The method according to claim 43, wherein the aromatic compound, which may have a substituent, (30) Ar-A _'n (Wherein Ar represents a phenyl group and A 'represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms , A halogen atom, and n is an integer of 1 to 6, and when a plurality of substituents are present, the substituents may be bonded to each other to form a ring. 44. The solvate of claim 43, wherein the optical purity is greater than 80% ee. (10) [Chemical formula 10] (Wherein A is a group represented by the following formula (2) (2) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, an alkenyl group or an alkynyl group, Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, Or a cyano group, n represents an integer of 0 to 4) or a group represented by the following formula (3) (3) CX ¹ ₃ (CX ² ₂ ) _p - (Wherein X ¹ and X ² each independently represent a halogen atom or a hydrogen atom, p represents 0 to 2), and B represents an aryl group which may have a substituent Optically active 1,2-disubstituted-2,3-dihydroxypropanes are reacted with an optically active 1,2-disubstituted-2,3-dihydroxypropanes of formula (16) or (17) [Chemical Formula 16] R ⁶ COY [Chemical Formula 17] (R &lt; ⁶ &gt; CO) ₂ O (Wherein R ⁶ represents an alkyl, alkenyl, aralkyl or aryl group having 1 to 20 carbon atoms, which may have a substituent, and Y represents a halogen atom) to obtain a compound represented by the following formula 12-disubstituted-2-hydroxy-3-acyloxypropanes represented by the formula (13) and the compound represented by the formula (12) represented by the formula (13) 2,3-dihydroxypropanes can be produced to prepare 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (13), which is a desired optical isomer, Disubstituted 2,3-dihydroxypropanes represented by the following formula (6), characterized by decomposing the optically active 1,2-disubstituted-2,3-dihydroxypropanes. [Chemical Formula 12] [Chemical Formula 13] [Chemical Formula 6] (Wherein A, B and R ⁶ are the same as those of formulas (10) and (16), and * represents an asymmetric carbon atom.) 48. The process of claim 47, wherein as an optically active nucleophilic catalyst, (25) R ⁹ , R ¹⁰ and R ¹¹ each independently represents an alkyl group, an alkenyl group, an aralkyl group or an aryl group having 1 to 20 carbon atoms which may have a substituent, D represents -N (R ¹⁰ ) R ¹¹ , And R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt; may combine to form a ring. * Represents an asymmetric carbon atom. 48. The process according to claim 47, wherein the reaction is carried out in the presence of an inorganic base.