WO2004094397A1

WO2004094397A1 - Process for producing glycidyl sulfonate derivative

Info

Publication number: WO2004094397A1
Application number: PCT/JP2004/005224
Authority: WO
Inventors: Takeshi Kondo; Natsuki Mori; Naoaki Taoka; Noboru Ueyama
Original assignee: Kaneka Corporation
Priority date: 2003-04-21
Filing date: 2004-04-12
Publication date: 2004-11-04

Abstract

A glycidyl sulfonate derivative of high quality useful as an intermediate for medicines can be produced by a simple procedure comprising a small number of steps without yielding a large amount of wastes. The process comprises: (1) reacting 3-chloro-1,2-propanediol with a sulfonyl halide derivative in the presence of a base to produce a glycidyl sulfonate derivative; or (2) producing glycidol from 3-chloro-1,2-propanediol in an organic solvent in the presence of the hydroxide of an alkali metal and/or alkaline earth metal and subsequently reacting the glycidol with a sulfonyl halide derivative in the presence of a base to produce a glycidyl sulfonate derivative; or (3) producing glycidol from 3-chloro-1,2-propanediol in the presence of a base and subsequently reacting the glycidol with a nitrobenzenesulfonyl halide using an inorganic base as the only base to produce a glycidyl sulfonate derivative.

Description

Specification

Method for producing glycidyl sulfonate derivative

Technical field

The present invention relates to a method for producing a glycidyl sulfonate derivative, which is important as a raw material for pharmaceuticals and agricultural chemicals. Background art

The following method is known as a conventional method for producing a glycidyl sulfonate derivative.

(1) A method in which glycidol previously isolated is reacted with a sulfo-yurc-mouth derivative in an organic solvent in the presence of a tertiary amine (journa 1 of Organic Chemistry, 1989, 54, 1295-1). 304).

(2) In an organic solvent, 3-chloro-1,2-propanediol is reacted with at least a species selected from alkali metal carbonates, bicarbonates, and alkaline earth metal carbonates, and then p —A method of reacting with toluenesulfonyl chloride, tertiary amine and 4-dimethylaminopyridine (Japanese Patent No. 3250350).

(3) A method in which glycidol is reacted with nitrobenzenesulfoylculic chloride in an organic solvent / water two-phase solvent in the presence of tertiary amine (JP-A-6-306067).

(4) Glycidol is dissolved in an organic solvent / water two-phase system solvent at least one inorganic base selected from hydroxides, carbonates or bicarbonates of alkali metal or alkaline earth metal and tertiary. A method of reacting with a sulfonyl chloride derivative in the presence of a base consisting of a combination of an amine or a pyridine derivative (Japanese Patent No. 3253634). However, the above method has the following problems.

In the method (1), glycidol which has been isolated in advance is used. I However, the necessity of the isolation step is industrially disadvantageous, and in addition, glycidol is unstable and decomposes at the time of isolation or storage, and has the problem of reduced yield and quality. This is a problematic method for industrial adoption.

In the method (2), when 3-chloro-1,2-propanediol is reacted with a base, the solution viscosity increases during the reaction with an organic solvent other than a halogen-based organic solvent that has a large environmental load, and the solution is not suitable for practical use. Difficult and, in addition, the speed of the reaction is slow. As a result, a side reaction proceeds, and a large amount of impurities are contained. As a result, the obtained glycidyl p-toluenesulfonate has a problem that the quality is not sufficient, and crystallization must be performed twice, which is a problematic method for industrial adoption.

The method of (3) requires a step of extracting glycidol obtained as an intermediate in an organic solvent with water. The increase in the number of processes is industrially disadvantageous, and in addition, there is a problem that the quality of the obtained glycidyl dinitrobenzenesulfonate is not sufficient. It is.

In the method (4), it is necessary to use both an inorganic base and an organic base, and the operation is complicated.In addition to the large amount of waste, the industrial This is a problematic method to adopt. Further tests revealed that the quality of the obtained glycidyl nitrobenzenesulfonate was not sufficient. Thus, any of the conventional production methods has problems to be solved as industrial production methods. An object of the present invention is to provide a method for producing a glycidyl sulfonate derivative which is efficient, economical, and industrially suitable in view of the above situation. Disclosure of the invention

The inventors of the present invention have conducted various studies to solve such problems. As a result, the number of steps is small, the operation is simple, the amount of waste is small, and the quality is high. The present inventors have found a method for producing a glycidyl acid derivative, and have completed the present invention. That is, the first invention relates to a method for producing a glycidyl sulfonate derivative, which comprises reacting 3-chloro-1,2-propanediol and a sulfonyl halide derivative in the presence of a base.

Further, the second invention is to produce glycidol by reacting 3-chloro-1,2-propanediol in an organic solvent in the presence of an alkali metal hydroxide or an alkaline earth metal hydroxide. A method for producing a glycidyl sulfonate derivative, which comprises producing a glycidyl sulfonate derivative without isolating glycidol, followed by reacting with a sulfonyl halide derivative in the presence of a base group. Further, a third invention is a method for producing glycidyl nitrobenzenesulfonate by reacting glycidol and nitrobenzene sulfuryl halide in the presence of a base, wherein the method comprises using only an inorganic base as the base. The present invention relates to a method for producing glycidyl sulfonate. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. In the present specification, ammonia (NH ₃ ) hydrogen atoms substituted with one atom other than hydrogen are replaced with primary amines, those substituted with two atoms with secondary amines, those substituted with three atoms Defined as tertiary amine. If the nitrogen atom has an unsaturated bond, calculate for each bond. For example, pyridine is a tertiary amine.

In a preferred embodiment of the first invention, there is provided a method for producing a glycidyl sulfonate derivative, which comprises reacting 3-chloro-1,2-propanepandiol and a sulfonylno, lide derivative in the presence of a base. Is done.

In this method, a compound in which the sulfonyl halide derivative is bonded only to the terminal hydroxyl group of the two hydroxyl groups of 3-chloro-1,2-propanediol is preferred. It is surprising that the compound obtained earlier and bonded to two hydroxyl groups or the compound bonded only to the 2-position hydroxyl group has less by-product.

As the 3-chloro-1,2-propanediol used in the present invention, any of a racemic form and an optically active form can be used. It is preferable to use an optically active substance because the desired glycidyl sulfonate derivative can be directly obtained as an optically active substance.

The sulfonyl halide derivative to be used is not particularly limited, and alkylsulfonyl halide having 1 to 20 carbon atoms, aryl alkylsulfonyl halide having 7 to 20 carbon atoms, and aryl having 6 to 20 carbon atoms. And sulfuryl halide in which one or more of these hydrogens are substituted with another functional group such as a halogen, a nitro group, a cyano group, and the like. For example, methanesnorefoylk mouth ride, ethanesulfoyurk mouth ride, benzylsulfonylchloride, phenethylsnorefoninolechloride, benzenesulfjork mouth ride, one toluenesulfjork mouth ride, dodecylbenzenesulfuride Elk mouth ride, naphthene snorehonyle / chloride, trifrenoleolomethanes honolehoninolechloride, 2-black benzene snolehoninolechloride, 2-bromobenzene snolehoninolechloride, 3—black benzene snolehonolechloride Henolechloride, 3-Bromobenzenes-nolehoninolechloride, 4-methylbenzenebenzenesnorlehonylchloride, 4-Promobenzenes-norrehoechloride, 4-methoxybenzenesulfonyl chloride, 4-hydroxybenzenesulfonyl chloride Rye , 2-Ditrobenzenesulfonuric mouth ride, 3-2-Nitrobenzenesulfonuric mouth ride, 4-12-trobenzenesulfoninolek mouth ride, 4-Chloro-3-dinitrobenzenesulfoyurc mouth ride, 2 —Methyl-5-nitrobenzene benzenesnorefonolechloride, 2-methoxy-5-nitrobenzenesnorefonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, etc. Among these, inexpensive From the viewpoints of availability, safety and safety, methanesulfoyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4-chlorobenzenesnolehoninolek, 3— Preferred is 2-nitrobenzene benzene-snolephoninolelide, and the amount of sulfuryl halide used is 3-chloro-1,2-propanediol. In contrast, 0.7 to 2 equivalents, preferably 0.8 to 1.5 equivalents der You. If the amount is less than 0.7 equivalents, the yield is reduced due to the insufficient amount of the sulfonyl halide derivative.If the amount exceeds 2 equivalents, an excess amount of the sulfonyl halide derivative remains in the reaction solution, and when the target product is isolated, the yield decreases. It is not preferable because it lowers the quality or lowers the quality.

The base used in the reaction is not particularly limited, and only an organic base may be used, or only an inorganic base may be used. In addition, an organic base or an inorganic base can also be used. From the viewpoint of suppressing side reactions and allowing the target reaction to proceed preferentially, it is preferable to use only an inorganic base, or an organic base and an inorganic base.

Examples of the organic base include primary amine, secondary amine, and tertiary amine. For example, monoalkylamines such as t-butylamine, dialkylamines such as di-t-butylamine, aromatic secondary amines such as imidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, and dicycloamine. Xylmethylamine, Ν, Ν, Ν ', Ν'-tetramethylethylenediamine. Ν, Ν—Trialkylamine derivatives having 3 to 18 carbon atoms, such as dimethylalanine ester, Ν, Ν— Dialkyl phenylene, Ν, Ν-diethyl aniline and other trialkylamines having 8 to 18 carbon atoms such as dialkylphenyl or monoalkyl diphenylamine and triphenylamine, Ν-methylpyrrolidine, Ν-methylpyridine Carbon such as ぺ lysine, Ν-methylmorpholine, Ν-ethylmorpholine, DBU, DABC 0, and quinuclidine 3 to 18 cyclic amines, such as pyridine, picoline, lutidine, collidine, 2-methoxypyridine, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 4-dimethylaminopyridine, 4-dimethylaminopyridine, etc. Examples thereof include pyridine derivatives having 5 to 18 carbon atoms, aromatic amines having 4 to 18 carbon atoms such as pyrazine, pyrimidine, pyridazine, and quinoline. These can be used alone or in combination. When used as a mixture, the mixing ratio is not particularly limited. Among them, pyridine derivatives are preferable, and 4-dimethylaminopyridine is more preferable, from the viewpoint that the effect is exhibited by using a small amount.

Examples of the inorganic base include oxides, hydroxides, carbonates, bicarbonates, and potassium hydroxides, alkali metal hydrides, alkali metal or alkaline earth metals. Sulfate and the like. For example, sodium, sodium hydride, magnesium oxide, calcium oxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, hydrogen carbonate Lithium, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate and the like. These can be used alone or in combination. When used as a mixture, there is no particular limitation on the mixing ratio. Among them, sodium hydroxide, potassium hydroxide, sodium carbonate and carbonated lime are preferred from the viewpoint of low cost and easy handling, and sodium hydroxide and hydroxylated lime are preferred from the viewpoint of increasing the reaction rate. More preferred.

When only an organic base or only an inorganic base is used in the reaction, the amount of the base used is 1.5 to 11 equivalents, preferably 2 to 5 with respect to 3-chloro-1,2-propanediol. Is equivalent. If the amount is less than 1.5 equivalents, the reaction is not completed and the yield decreases. If the amount exceeds 11 equivalents, side reactions such as decomposition of glycidol are not preferred.

When an organic base and an inorganic base are used in the reaction, the mixing ratio of the organic base and the inorganic base is not particularly limited, but the ratio of the organic base to 3-chloro-1,2-propanediol is 0.00. 1 to 4 equivalents, preferably 0.01 to 0.5 equivalents, more preferably 0.01 to 0.1 equivalents, when the inorganic base is 0.5 to 50 equivalents based on 3-chloro-1,2-propanediol. 11 equivalents, preferably 2 to 5 equivalents. If the amount of the organic base used is less than 0.001 equivalent, the addition effect does not appear, and the reaction rate is slow.If the amount exceeds 4 equivalents, the excess organic base remains in the reaction solution and the target product is isolated. In this case, the yield is lowered and the quality is deteriorated, which is not preferable. If the amount of the inorganic base used is less than 0.5 equivalent, the reaction is not completed and the yield is reduced, and if it exceeds 11 equivalents, side reactions such as decomposition of glycidol are not preferred.

These bases may be added in the entire amount at the start of the reaction, or may be added in portions during the reaction.

When the reaction is performed in a state in which part or all of the inorganic base is not dissolved, the diameter of the particles is preferably 5 mm or less, and the diameter is preferably 3 mm or less from the viewpoint of increasing the surface area and increasing the reaction rate. More preferably, the diameter is 1 mm or less. The solvent is not particularly limited as long as it does not inhibit the reaction, and the reaction can be carried out in a mixed solvent of an organic solvent / water or an organic solvent. From the viewpoint of suppressing the hydrolysis of the sulfonyl halide derivative during the reaction, the reaction is preferably carried out in a two-phase solvent of an organic solvent / water or an organic solvent, suppressing side reactions and giving priority to the intended reaction. From the viewpoint of progressing to a second phase, an organic solvent / water two-phase solvent is more preferable.

In the two-phase organic solvent / water system, the organic solvent used is not particularly limited as long as it does not hinder the reaction, and is an organic solvent that forms a two-phase with water at the start of the reaction. Aliphatic hydrocarbon solvents such as hexane, heptane, cyclohexane, and petroleum ether; ester solvents such as ethyl acetate, methyl acetate, propyl acetate, and methyl propionate; and aromatic carbons such as toluene, benzene, and xylene Hydrogenated solvents, ether solvents such as t-butyl methyl ether, methyl ether, diisopropyl ether, etc., ketone solvents such as methyl ethyl ketone, diisopropyl ketone, methyl isobutyl ketone, methylene chloride, chloroform, 1 , 2 Dichloroethane, 1,1-dichloroethane, carbon tetrachloride, Hydrocarbon solvents and the like. These organic solvents may be used alone or in combination of two or more. Among these, from the viewpoint of low cost, easy handling, and solubility of the sulfonyl halide derivative, aromatic hydrocarbon solvents, methyl ethyl ketone, methyl isobutyl ketone, methylene chloride, or a mixture of two or more of them are used. Organic solvents are preferred, and benzene and toluene are more preferred. When a mixed organic solvent is used, the mixing ratio is not particularly limited. Although the mixing ratio of the organic solvent Z water is not particularly limited, it is preferably 10: 1 to 1/10 (by volume), more preferably 5/1 to 1/5 (by volume).

When the reaction is carried out in an organic solvent, the organic solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic carbons such as pentane, hexane, heptane, cyclohexane, and petroleum ether. Hydrogen solvents, ester solvents such as ethyl acetate, methyl acetate, propyl acetate, and methyl propionate; aromatic hydrocarbon solvents such as toluene, benzene, and xylene; t-butyl methyl ether; δ

Ethenolate solvents such as ethenoleate, diisopropynoleate, THF, and dioxane; ketone solvents such as acetone, methylethylketone, diisopropylketone, and methylisobutinoleketone; methylene chloride, chlorophonolem, 1,2- Halogenated hydrocarbon solvents such as dichloroethane, 1,1-dichloroethane, carbon tetrachloride, and chlorobenzene; nitrile solvents such as acetonitrile and propionitrile; and highly polar aprotic solvents such as DMF and DMSO. No. These organic solvents may be used alone or as a mixture of two or more. When a mixed organic solvent is used, the mixing ratio is not particularly limited. In addition, the concept of an organic solvent includes that water does not form a two-phase phase and does not hinder the reaction. Of these, toluene, benzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methylene chloride, or a mixture of two or more of these are considered from the viewpoint of low cost, easy handling, and solubility of the sulfonyl halide derivative. Organic solvents are preferable, and acetone, methyl ketone, methyl isobutyl ketone, or an organic solvent obtained by mixing two or more thereof is more preferable.

The amount of the solvent to be used is preferably llOO vo lZw t times (1- to LO Oml) for 3-chloro-1,2-propanediol, and 3 to 30 V o 1 / wt times. More preferred. If the amount of solvent used is less than 1 Vo 1 t, the yield will decrease or handling will be difficult due to precipitation of insolubles or increase in solution viscosity, and if it exceeds 100 V o 1 / wt, It is not preferable because the reaction rate decreases or the productivity decreases.

The reaction can be carried out at a temperature of usually from 30 to 60 ° C, preferably from 110 to 30 ° C. If the temperature is lower than 30 ° C, the progress of the reaction is slow or the solvent solidifies, which is not preferable. If the temperature is higher than 60 ° C, decomposition and side reactions increase, which is not preferable. The reaction is usually completed in 2 to 24 hours.

The method of addition and the order of addition at the time of the reaction are not particularly limited. For example, (1) 3-chloro-1,2-propanediol or a mixture thereof with a sulfonyl halide derivative or a solvent thereof may be used. A method of adding a base or a mixture thereof with a solvent after adding the mixture, (2) a sulfonyl halide derivative or a mixture thereof. A method in which 3-chloro-1,2-propanediol or a mixture with the solvent is added to the mixture with the solvent, and then a base or a mixture with the solvent is added. (3) 3-chloro-1, A method of adding a base or a mixture thereof with a solvent to 2-propanediol or a mixture thereof with a solvent, and then adding a sulfonyl halide derivative or a mixture thereof with the solvent; (4) 3-chloro-1, Examples thereof include a method in which a sulfonyl halide derivative or a mixture with the solvent and a base or a mixture with the solvent are simultaneously added to 2-propanediol or a mixture with the solvent. Among them, the method (1), (2) or (4) is preferable from the viewpoint of suppressing side reactions and allowing the target reaction to proceed preferentially.

After the reaction, the post-treatment method of the reaction solution is not particularly limited, and examples thereof include the following methods. (1) In the case of an organic solvent system in which no solid is precipitated from the reaction solution, no special post-treatment is required, and in the case of a two-phase system of an organic solvent z water in which no solid is precipitated from the reaction solution By removing the aqueous phase, a solvent mixture of the target substance can be obtained. (2) When only the target solid is precipitated from the reaction solution, the target solid can be obtained by filtration. (3) When only a non-target solid (such as an inorganic salt) is precipitated from the reaction solution, a solvent mixture of the target can be obtained by removing the solid by filtration. When water is added to the reaction solution, non-target solids (inorganic salts, etc.) are dissolved to form an organic solvent / water two-phase system. A solvent mixture can also be obtained. (4) If a solid of the target substance and a solid that is not the target substance (such as an inorganic salt) are precipitated from the reaction solution, add a solvent that dissolves the target substance, or add a solid that is not the target substance (such as an inorganic salt). ) By adding a solvent that dissolves, for example, water, etc., and dissolving either one preferentially, and then performing operation (2) or (3), or performing operation (1) after dissolving both. By doing so, you can obtain the desired object. The operations (1) to (4) may be performed in combination.

During the operations (1) to (4), or prior to the operations (1) to (4), an organic solvent and / or water may be added, if necessary, or the reaction solution may be concentrated. Or may be heated or cooled. (1) In the case of two-phase organic solvent water, From the viewpoint of improving the releasability, the temperature is preferably adjusted to 10 to 60 ° C. If the temperature is lower than 10 ° C, the liquid-liquid separation property is not sufficient, which is not preferable. If the temperature is higher than 60 ° C, decomposition and side reactions are not preferable. Additives (acidic substances, basic substances, salts, etc.) may be added as long as they do not affect the quality of the target product.

The following operation may be further performed on the obtained solvent mixture of the target substance, if necessary. When water is added to the solvent mixture of the target substance, if water forms an organic solvent / water two-phase system, water and / or an acidic aqueous solution such as citric acid, hydrochloric acid, or sulfuric acid, and Z or baking soda or water It may be washed with an alkaline aqueous solution such as sodium oxide or potassium hydroxide. If two phases of organic solvent / water are not formed, washing may be performed after replacing with an organic solvent that forms two phases with water. At the time of washing, the temperature is preferably adjusted to 10 to 60 ° C. from the viewpoint of improving liquid-liquid separation properties. If the temperature is lower than 10 ° C, the liquid-liquid separation property is not sufficient, which is not preferable. If the temperature is higher than 60 ° C, decomposition and side reactions are not preferable. Thereafter, high-purity glycidyl sulfonate derivatives can be easily isolated by ordinary operations such as concentration and crystallization.

Next, in a preferred embodiment of the second invention, glycidol is reacted by reacting 3-chloro-1,2-propanediol in an organic solvent in the presence of an alkali metal and / or alkaline earth metal hydroxide. The present invention provides a process for producing a glycidyl sulfonate derivative, which comprises producing the glycidyl sulfonate derivative without isolating the glycidol and subsequently reacting the sulfonyl halide derivative in the presence of a base.

In this method, alkali metal and hydroxide of alkaline metal or alkaline earth metal are used in the reaction of 3-chloro-1,2-propanediol, so that it can be practically used without using a halogenated solvent. It is surprising that there is no problematic increase in solution viscosity and, in addition, the speed of the reaction is high. Furthermore, in this method, water is produced in an equimolar amount to glycidol during the production of glycidol, but a compound in which the sulfonyl halide derivative binds to the glycidol hydroxyl group over the hydroxyl group of water is obtained preferentially. The point is surprising. First, a method for producing glycidol obtained as an intermediate will be described. As the 3-chloro-1,2-propanediol used in the present invention, any of a racemic substance and an optically active substance can be used. It is preferable to use an optically active substance because the desired glycidyl sulfonate derivative can be directly obtained as an optically active substance.

Examples of the alkali metal or alkaline earth metal hydroxide used as the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. These can be used alone or in combination, and the mixing ratio is not particularly limited. Of these, sodium hydroxide and potassium hydroxide are preferred from the viewpoint of low cost and ease of handling. The amount of the base to be used is 0.5 to 10 equivalents, preferably 1 to 4 equivalents, relative to 3-chloro-1,2-propanediol. If the amount is less than 0.5 equivalent, the reaction is not completed and the yield decreases, and if it exceeds 10 equivalents, side reactions such as decomposition of glycidol increase, which is not preferable. These may be added all at the beginning of the reaction, or may be added in portions during the reaction. When the reaction is performed in a state in which part or all of the base is not dissolved, from the viewpoint of increasing the surface area of the base and increasing the reaction rate, the diameter of the particles is preferably 5 mm or less. It is more preferably at most 3 mm, particularly preferably at most l mm.

The organic solvent to be used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbon solvents such as pentane, hexane, heptane, cyclohexane, petroleum ether, ethyl acetate, and the like. Estenole solvents such as methyl acetate, propyl acetate, and methyl propionate; aromatic hydrocarbon solvents such as tonolenene, benzene, and xylene; t-butyl methyl ether, getyl ether, diisopropyl ether, THF, and dioxane Solvents, ketone solvents such as acetone, methyl ethyl ketone, diisopropyl ketone, and methyl isobutyl ketone; salts; halogens such as methylene chloride, chlorophonolem, 1,2-dichloroethane, 1,1-dichloroethane, carbon tetrachloride, and chlorobenzene Hydrocarbon solvent, acetonitrile And tolyl solvents such as propionitrile, and highly polar nonproton solvents such as DMF and DMSO. These organic solvents may be used alone or as a mixture of two or more. When using mixed organic solvents, the mixing ratio is particularly limited There is no. The term “organic solvent” includes the inclusion of water that does not inhibit the reaction without forming two phases. Among these, ketone solvents, THF, acetonitrile, methylene chloride, and the like, from the viewpoint of low cost, easy handling, solubility of 3-chloro-1,2-propanediol, and dispersibility of bases and inorganic salts during the reaction. Alternatively, an organic solvent obtained by mixing two or more thereof is preferable.

Further, in the production of glycidol and the reaction with a sulfonyl halide derivative among these organic solvents, ketones are preferred from the viewpoint that the reaction proceeds promptly in the same organic solvent without changing the kind of the organic solvent. A system solvent is preferable, and acetone, methyl ethyl ketone, methyl isobutyl ketone, or an organic solvent obtained by mixing two or more thereof is more preferable.

The amount of the solvent used is preferably 1 to: LOO vo 1 / wt (1-to 1 g: LO Oml) based on 3-chloro-1,2-propanediol, and 3 to 30 V o. 1 / wt times is more preferred. If the amount of the solvent used is less than 1 Vo 1 t, the yield becomes lower or the handling becomes difficult due to the precipitation of insolubles or the increase in the solution viscosity, and if it exceeds 100 V o 1 / wt, However, it is not preferable because the reaction rate decreases or the productivity decreases.

The reaction can be carried out at a temperature of usually 30 to 50 ° C, preferably 120 to 30 ° C, more preferably 110 to 20 ° C. When the temperature is lower than 30 ° C, the reaction progresses slowly or the organic solvent solidifies, which is not preferable. When the temperature is higher than 50 ° C, side reactions such as decomposition of daricidol increase, which is not preferable. The reaction is usually completed in 30 minutes to 5 hours.

The method of addition and the order of addition during the reaction are not particularly limited. For example, (1) a method of adding a base or a mixture thereof with an organic solvent to 3-chloro-1,2-propanediol or a mixture thereof with an organic solvent, or (2) a method of adding a base or a mixture thereof with an organic solvent thereof A method of adding 3-chloro-1,2-propanediol or a mixture thereof with an organic solvent to the mixture is exemplified. The glycidol obtained as an intermediate can be reacted with a sulfonyl halide derivative in the presence of a base without isolation to produce a glycidyl sulfonate derivative.

Next, a method for producing a glycidyl sulfonate derivative by reacting the obtained glycidol with a sulfonyl halide derivative in the presence of a base will be described.

If a non-target solid (inorganic salt, etc.) is precipitated from the reaction mixture during glycidol synthesis, if necessary, remove the solid by filtration, obtain a glycidol solvent mixture, and then continue with the sulfonyl halide derivative. May be reacted.

The sulfonyl halide derivative to be used is not particularly limited, and the alkylsulfonyl halide having 1 to 20 carbon atoms, the arylsulfonyl halide having 7 to 20 carbon atoms, and the arylsulfonyl halide having 6 to 20 carbon atoms Halides, and sulfonyl halides in which one or more of these hydrogens are substituted with another functional group such as a halogen, a dinitro group, a cyano group, and the like. For example, methanes-norefoninochloride, ethanes-norefole-chloride, penzinoles-norefonolechloride, phenethylsulfoylurk, benzenesulfoyluku, p-toluenesulfonyl chloride , Dodecylbenzenesulfonyl chloride, naphthylene selenoinochloride, trifnorolenomethane snorefoninochloride, 2-chlorobenzene snoleshonolinochloride, 2-bromobenzenesnolehoninochloride Benzene, snolephoninolechloride, 3-bromobenzenes / lehoninolechloride, 4-bromobenzenes / lehoninolechloride, 4-bromobenzenes / lehoninolechloride, 4-methoxy Benzens-no-Henorechloride Fluorochloride, 2-nitrobenzenesulfonylc mouth ride, 3-nitrobenzenesulfonylc mouth ride, 4-12 trobenzenesulfoeruku mouth ride, 4-chlorotolone 3-nitrobenzenesnorehoninorek Mouth Ride, 2-Methynolee 5-Nito Mouth Benzenes Nolehoninolechloride, 2-Methoxy-5-nitrobenzenes / Lehonyl Chloride, 2,4-Dinitrobenzenesulfonyl Chloride and the like. Among them, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfuryl chloride, Preferred are benzene snorehoninolek monolide and 3-nitrobenzene snorehoninolek ride. The amount of the sulfonyl halide derivative to be used is 0.7 to 2 equivalents, preferably 0.8 to 1.5 equivalents, relative to 3-chloro-1,2-propanediol. If the amount is less than 0.7 equivalents, the yield decreases due to the insufficient amount of the sulfonyl halide derivative, and if it exceeds 2 equivalents, an excess amount of the sulfohalide derivative remains in the reaction solution, and the yield decreases when isolating the target product. It is not preferable because the quality deteriorates.

The base used is not particularly limited, and may be an organic base alone, an inorganic base alone, or an organic base and an inorganic base. Examples of the organic base include primary amine, secondary amine, and tertiary amine.

For example, monoalkylamines such as t-butylamine, dialkylamines such as di-t-butylamine, aromatic secondary amines such as imidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, Dicyclohexylmethylamine, N, N, Ν ', Ν'-tetramethylethylenediamine Ν, Ν-dimethylalanine ester and other trialkylamine derivatives with 3 to 18 carbon atoms, Ν, Ν-dimethyla Dilinolequinolepheninoleamine or monoa / req ^^ diphene / reamine, triarylamines such as triphenylamine, phenylmethylpyrrolidine, Ν-methylpyrrolidine, etc. —Total carbon such as methylpiperidine, Ν-methylmorpholine, Ν-ethylmorpholine, DBU, DABC 0, quinuclidine 3 to 18 cyclic amines, such as pyridine, picoline, lutidine, collidine, 2-methoxypyridine, 2-dimethylaminopyridine, 3-dimethyl ^^ aminoviridine, 4-dimethylaminopyridine, and 4-ethylaminopyridine Examples thereof include pyridine derivatives having 5 to 18 carbon atoms, aromatic amines having 4 to 18 carbon atoms such as pyrazine, pyrimidine, pyridazine, and quinoline. These can be used alone or in combination. Of these, triethylamine, diisopropylethylamine, and pyridine derivatives are preferable from the viewpoint of low cost and ease of handling. Further, from the viewpoint that the effect is exhibited by using a small amount, a pyridine derivative is preferable, and 4-dimethylaminopyridine is particularly preferable. Examples of the inorganic base include an alkali metal, an alkali metal hydride, an alkali metal or an alkaline earth metal, an oxide, a hydroxide, a carbonate, a hydrogen carbonate or a borate. For example, sodium, sodium hydride, magnesium oxide, calcium oxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, lithium carbonate, calcium carbonate, hydrogen carbonate Lithium, sodium bicarbonate, lithium bicarbonate, calcium bicarbonate and the like. These can be used alone or in combination. Of these, sodium hydroxide, potassium hydroxide, sodium carbonate, and carbonated carbonate are preferred from the viewpoint of low cost and ease of handling, and sodium hydroxide and potassium hydroxide are more preferred from the viewpoint of increasing the reaction rate. Replying to

When only an organic base or only an inorganic base is used in the reaction, the amount of the base to be used is 0.5 to 10 equivalents, preferably 1 to 4 equivalents, to dalicidol. If the amount is less than 0.5 equivalent, the reaction is not completed and the yield is reduced. If the amount exceeds 10 equivalents, side reactions such as decomposition of dalicidol are undesirably increased.

When an organic base and an inorganic base are used in the reaction, the mixing ratio of the organic base and the inorganic base is not particularly limited, but the organic base is preferably used in an amount of 0.001 to 3 equivalents, preferably 0.00, based on dalicidol. The amount is from 1 to 0.5 equivalent, more preferably from 0.01 to 0.1 equivalent, and the amount of the inorganic base is from 0.5 to 10 equivalent, preferably from 1 to 4 equivalent to glycidol. If the amount of the organic base used is less than 0.001 equivalent, the addition effect does not appear, and the reaction rate is slow.If the amount exceeds 3 equivalents, an excessive amount of the organic base remains in the reaction solution and the desired product is isolated. In this case, the yield is reduced and the quality is deteriorated, which is not preferable. If the amount of the inorganic base is less than 0.5 equivalent, the reaction is not completed and the yield is lowered. If it exceeds 10 equivalents, side reactions such as decomposition of daricidol increase, which is not preferable.

These may be added all at the beginning of the reaction, or may be added in portions during the reaction. When the reaction is carried out in a state where part or all of the inorganic base is not dissolved, from the viewpoint of increasing the surface area and increasing the reaction rate, the diameter of the particles is preferably 5 mm or less, and the diameter of the particles is 3 mm. The following is more preferable, and the diameter is preferably 1 mm or less. When an inorganic base is used for producing a glycidyl sulfonate derivative from glycidol, the necessary inorganic base may be added in advance when synthesizing glycidol, if necessary. These may be added in total at the start of the glycidol synthesis reaction, or may be added in portions during the reaction. When adding an inorganic base required for the synthesis of glycidyl sulfonate when synthesizing glycidol, make sure that the amount of the inorganic base is not more than 10 equivalents with respect to 3-chloro-1,2-propanediol so as not to inhibit glycidol synthesis. To

The solvent is not particularly limited as long as it does not inhibit the reaction, and the organic solvent described in the section of glycidol synthesis or a mixed solvent of the organic solvent and water may be used alone or as a mixture of two or more. Can be used. From the viewpoint of suppressing the hydrolysis of the sulfonyl halide derivative during the reaction, the reaction is preferably carried out in a two-phase solvent of an organic solvent / water or an organic solvent. In a reaction in an organic solvent, the concept of an organic solvent includes the presence of water that does not inhibit the reaction without forming two phases.

The amount of the solvent is not particularly limited, but the total amount of the solvent is 1 to glycidol.

It is preferable that the ratio be up to 100 V o 1 / wt (1 to 100 g / g).

The reaction can be carried out at a temperature of usually from 130 to 60 ° C, preferably from 10 to 30 ° C. If the temperature is lower than 30 ° C., the progress of the reaction is slow or the solvent solidifies, which is not preferable. If the temperature is higher than 60 ° C., decomposition and side reactions increase, which is not preferable. The reaction is usually completed in 2 to 24 hours.

The method of addition and the order of addition during the reaction are not particularly limited. For example, (1) After adding a sulfonyl halide derivative or a mixture of the solvent to a mixture of glycidol and a solvent, the base or the solvent is added. (2) a method of adding a mixture of glycidol and a solvent to a sulfonyl halide derivative or a mixture of the solvent, and then adding a base or a mixture of the solvent and the solvent; (3) A method of adding a base or a mixture thereof with a solvent to a mixture of glycidol and a solvent, and then adding a sulfonyl halide derivative or a mixture thereof with the solvent. (4) A method of simultaneously adding a sulfonyl halide derivative or a mixture of the solvent and a base or a mixture of the solvent to a mixture of the glycidol and the solvent.

After the reaction, the post-treatment method of the reaction solution is not particularly limited, and examples thereof include the following methods. (1) In the case of an organic solvent system in which no solid is precipitated from the reaction solution, no special post-treatment is required, and in the case of a two-phase system of organic solvent / water in which no solid is precipitated from the reaction solution By removing the aqueous phase, a solvent mixture of the target substance can be obtained. (2) When only the target solid is precipitated from the reaction solution, the target solid can be obtained by filtration. (3) When only a solid (inorganic salt, etc.) that is not the target substance is precipitated from the reaction solution, a solvent mixture of the target substance can be obtained by filtering to remove the solid. When water is added to the reaction solution, non-target solids (inorganic salts, etc.) are dissolved to form an organic solvent / water two-phase system. A solvent mixture can also be obtained. (4) If a solid of the target substance and a solid that is not the target substance (such as an inorganic salt) are precipitated from the reaction solution, add a solvent that dissolves the target substance, or add a solid that is not the target substance (such as an inorganic salt). ) Is dissolved by adding a solvent such as water, etc., and either one is preferentially dissolved, and then the operation of (2) or (3) is performed, or the operation of (1) is performed after dissolving both. By doing so, you can obtain the desired object. The operations (1) to (4) may be performed in combination.

During the operations (1) to (4) or prior to the operations (1) to (4), if necessary, an organic solvent and z or water are added, and the reaction solution is concentrated. Or may be heated or cooled. In the case of the organic solvent / water two-phase system (1), the temperature is preferably adjusted to 10 to 60 ° C. from the viewpoint of improving liquid-liquid separability. If the temperature is lower than 10 ° C, the liquid-liquid separation property is not sufficient, so that it is not preferable. Additives (acidic substances, basic substances, salts, etc.) may be added as long as they do not affect the quality of the target product.

The following operation may be further performed on the obtained solvent mixture of the target substance, if necessary. When water is added to the target solvent mixture, the organic solvent z water When forming a two-phase system, wash with water and / or an acidic aqueous solution such as citric acid, hydrochloric acid, or sulfuric acid, and / or an alkaline aqueous solution such as baking soda, sodium hydroxide, or potassium hydroxide. May be. If two phases of organic solvent / water are not formed, washing may be performed after replacing with an organic solvent that forms two phases with water. At the time of washing, the temperature is preferably adjusted to 10 to 60 ° C from the viewpoint of improving the liquid-liquid separation property.

If the temperature is lower than 10 ° C, the liquid-liquid separation property is not sufficient, so that it is not preferable. Thereafter, high-purity glycidyl sulfonate derivatives can be easily isolated by ordinary operations such as concentration and crystallization.

Next, in a preferred embodiment of the third invention, a method for producing glycidyl nitrobenzenesulfonate by reacting glycidol with nitrobenzenesulfonyl halide in the presence of a base, wherein only an inorganic base is used as the base A process for producing glycidyl nitrobenzenesulfonate is provided.

Until now, the reaction between glycidol and nitrobenzenesulfonyl halide was carried out only with an organic base or a combination of an organic base and an inorganic base, and the quality of the target product was not sufficient, but the cost was low and the burden on the environment was low. It is surprising that the reaction proceeds with only a small amount of inorganic base, and a higher quality target product can be obtained.

Glycidol used in the present invention can be either racemic or optically active. It is preferable to use an optically active substance since the target glycidyl ditrobenzenesulfonate can be directly obtained as an optically active substance.

First, a method for synthesizing glycidol obtained as an intermediate will be described. As the 3-chloro-1,2-propanediol used in the present invention, any of a racemic form and an optically active form can be used. It is preferable to use an optically active substance because the target glycidyl nitrobenzenesulfonate can be directly obtained as an optically active substance.

The base used is not particularly limited, and may be an organic base alone, an inorganic base alone, or an organic base or an inorganic base. Examples of the organic base include primary amine, secondary amine, and tertiary amine. For example, monoalkylamines such as t-butylamine, dialkylamines such as di-t-butylamine, aromatic secondary amines such as imidazole, and trimethylamine , Triethylamine, tripropylamine, diisopropylethylamine, dihexylmethylamine, N, N, N ', N'-tetramethylethylenediamine, N, N-dimethylalanine ester, etc. Trialkylamine derivative having 3 to 18 carbon atoms, N, N-dimethylaniline, N, N-getylaniline, etc.Dialkylphenylamine or monoalkyldiphenylamine having 8 to 18 carbon atoms , Triarylamines such as triphenylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N-ethylmorpholine, DBU, DABC0, quinuclidine and the like. Pyridine, picoline, lutidine, collidine, 2-methoxypyridine, 2-dimethylaminopyridine, 3-dimethylaminopyridine, 4-diamine Examples thereof include pyridine derivatives having a total number of carbon atoms of 5 to 18 such as methylamino pyridine and 4-getylaminopyridine, and aromatic amines having a total number of carbon atoms of 4 to 18 such as pyrazine, pyrimidine, pyridazine and quinoline. These can be used alone or in combination. Of these, triethylamine, diisopropylethylamine, and pyridine derivatives are preferable from the viewpoint of low cost and ease of handling. Examples of the inorganic base used include an alkali metal, an alkali metal hydride, an oxide, a hydroxide, a carbonate, a hydrogen carbonate or a borate of an alkali metal or an alkaline earth metal. For example, sodium, sodium hydride, magnesium oxide, calcium oxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, lithium hydrogen carbonate , Sodium bicarbonate, potassium bicarbonate, calcium bicarbonate and the like.

These can be used alone or in combination. Of these, hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals are preferred from the viewpoint of inexpensiveness and ease of handling, and sodium hydroxide, potassium hydroxide, sodium carbonate, Potassium carbonate is more preferred.

In addition, inorganic bases that do not adversely affect the subsequent reaction of glycidol with utrobenzenesulfonyl halide are preferred over organic bases. Guri If the organic base remains after the synthesis of cidol, the reaction between glycidol and nitrobenzenesulfonyl halide can be carried out without problems by eliminating the organic base by an operation such as neutralization with an acid.

When using only an organic base, only an inorganic base, or an organic base and an inorganic base, the total amount of these bases used is 0.5 to 10 equivalents based on 3-chloro-1,2-propanediol. It is preferably 1 to 4 equivalents. If the amount is less than 0.5 equivalent, the reaction is not completed and the yield is lowered.

These bases may be added all at the beginning of the reaction or may be added in portions during the reaction.

When the reaction is performed in a state in which part or all of the inorganic base is not dissolved, the diameter of the particles is preferably 5 mm or less, and 3 mm in diameter, from the viewpoint of increasing the surface area and increasing the reaction rate. The following is more preferred, and the diameter is particularly preferably 1 mm or less.

Examples of the solvent used include water, an organic solvent, and an organic solvent Z water mixed solvent. In the case of an organic solvent / water mixed solvent, both a one-phase system and a two-phase system are suitably carried out. When reacting in an organic solvent or an organic solvent / water mixed solvent, the organic solvent used is not particularly limited as long as it is an organic solvent that does not inhibit the reaction, and examples thereof include pentane, hexane, heptane, and cyclohexane. Aliphatic hydrocarbon solvents such as xane and petroleum ether; ester solvents such as ethyl acetate, methyl acetate, propyl acetate, and methyl propionate; alcohol solvents such as methanol, ethanol, and isopropanol; toluene, benzene, xylene, etc. Aromatic hydrocarbon solvents, ether solvents such as t-butyl methyl ether, getyl ether, diisopropyl ether, THF, and dioxane; ketone solvents such as acetone, methyl ethyl ketone, diisopropyl ketone, and methyl isobutyl ketone , Methylene chloride, black mouth form, 1, Examples include halogenated hydrocarbon solvents such as 2-dichloroethane, 1,1-dichloroethane, carbon tetrachloride, and chlorobenzene; nitrile solvents such as acetonitrile and propionitrile; and highly polar aprotic solvents such as DMF and DMSO. Can be These organic solvents may be used alone or as a mixture of two or more. You may use it. When a mixed organic solvent is used, the mixing ratio is not particularly limited. Among these, THF, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methylene chloride, or, from the viewpoint of low cost, easy handling, and solubility of 3-chloro-1,2-propanediol Organic solvents in which two or more of them are mixed are preferred. The mixing ratio of the organic solvent is not particularly limited, but is preferably 10/1 to 1 × 10 (volume ratio), and more preferably 5Zl to 1/5 (volume ratio).

The amount of the solvent to be used is preferably 1 to: L O O v o 1 / wt relative to 3-chloro-1,2-propanediol (1 to 100 m 1 per 1 g).

The reaction can be carried out at a temperature of usually from 130 to 120 ° C, preferably from 0 to 100 ° C. If the temperature is lower than 30 ° C, the reaction progresses slowly or the solvent solidifies, which is not preferable. If the temperature exceeds 120 ° C, side reactions such as decomposition of glycidol increase, which is not preferable. The reaction is usually completed in 30 minutes to 24 hours.

The method of addition and the order of addition during the reaction are not particularly limited. For example, (1) a method of adding a base or a mixture thereof with a solvent to 3-chloro-1,2-propanediol or a mixture thereof, or (2) a method of adding a base or a mixture thereof to a solvent thereof. -Chloro-1,2-propanediol or a method of adding a mixture thereof with a solvent can be used.

The glycidol obtained as an intermediate can be subsequently reacted with trobenzenesulfonyl halide in the presence of an inorganic base to produce glycidyl ditrobenzenesulfonate.

Glycidol may be isolated by evaporation of the solvent, distillation, or the like, or may be used in the next step as it is as a mixed solvent containing glycidol. Non-isolation is preferred because of high reaction efficiency and high yield and quality.

If a solid (inorganic salt, etc.) that is not the target substance is precipitated from the reaction solution during the synthesis of dalicidol, if necessary, remove the solid by filtration and obtain a glycidol solvent mixture, and then continue with nitrobenzenesulfonyl halide May be reacted.

The nitrobenzenesulfonyl halide to be used only needs to have at least one nitro group on the benzene ring. For example, 2-nitrobenzenesulfonyl- Norechloride, 3—Nitrobenzenesnolehoninolechloride, 4 12-Trobenzene snorehoninolek mouth light, 4—1-chloro-3—2-tooth benzene snorehoninolek mouth light, 2-Methyl-5,12-nitrobenzenesulfo Examples include Juruku's mouth, 2-Methoxy-5-2 Trovenzens / Lefoninolechloride, and 2,4-dinitrobenzenesnolehoninolechloride. Among these, from the viewpoint of availability and safety, 312-nitrobenzenesulfonyl chloride is preferred. Nitrobenzenesulfonyl halide is used in an amount of 0.7 to 2 equivalents, preferably 0.8 to 1.0, based on glycidol.

5 equivalents. If the amount is less than 0.7 equivalents, the yield will decrease due to the insufficient amount of nitrobenzenesulfonyl halide.If the amount exceeds 2 equivalents, excess nitrobenzenesulfonyl halide will remain in the reaction solution, and when isolating the target product, the isolation yield It is not preferable because the quality is lowered and the quality is reduced.

Examples of the inorganic base used include alkali metal, alkali metal hydride, alkali metal or alkaline earth metal oxides, hydroxides, carbonates, hydrogen carbonates and borates. For example, sodium, sodium hydride, magnesium oxide, calcium oxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, hydrogen carbonate Lithium, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium hydrogencarbonate and the like can be mentioned. These can be used alone or in combination. Among them, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate are preferred from the viewpoint of low cost and ease of handling, and sodium hydroxide and potassium hydroxide are more preferred from the viewpoint of increasing the reaction rate. preferable. The amount of the inorganic base to be used is 0.5 to 10 equivalents, preferably 1 to 4 equivalents, relative to glycidol. If the amount is less than 0.5 equivalent, the reaction is not completed and the yield decreases, and if it exceeds 10 equivalents, side reactions such as decomposition of glycidol increase, which is not preferable. There is no particular limitation on the method of adding these inorganic bases, and they may be added in the entire amount at the start of the reaction or may be added in portions during the reaction. If necessary, an inorganic base necessary for producing a derivative of glycidyl nitrobenzenesulfonate from glycidol may be added in advance when synthesizing glycidol. These are the synthesis of glycidol The total amount may be added at the beginning of the reaction, or may be added in portions during the reaction. When adding the entire amount of the inorganic base required for the synthesis of daricidyl nitrobenzenesulfonate when synthesizing glycidol, the inorganic base should be 10 equivalents or less based on 3-chloro-1,2-propanediol so as not to inhibit glycidol synthesis. So that

The solvent is not particularly limited as long as it does not inhibit the reaction, and the organic solvent mentioned in the section of glycidol synthesis or the organic solvent / water mixed solvent can be used alone or as a mixture of two or more. From the viewpoint of suppressing hydrolysis of the sulfonyl halide derivative during the reaction, the reaction is preferably carried out in a two-phase solvent of the organic solvent Z water or an organic solvent. In a reaction in an organic solvent, the concept of an organic solvent includes the presence of water to such an extent that the reaction does not hinder the reaction without forming two phases.

The amount of the solvent is not particularly limited, but the total amount of the solvent should be 1 to: L 0 V o 1 / wt times for glycidol (1 to 100 ml for 1 g). Is preferred.

The reaction can be carried out at a temperature of usually from 130 to 60 ° C, preferably from 110 to 30 ° C. If the temperature is lower than 30 ° C., the progress of the reaction is slow or the solvent solidifies, which is not preferable. If the temperature is higher than 60 ° C., side reactions such as decomposition of glycidol are not preferable. The reaction is usually completed in 30 minutes to 24 hours.

The method of addition and the order of addition during the reaction are not particularly limited. For example, (1) a method of adding nitrobenzenesulfonyl halide or a mixture with the solvent to glycidol or a mixture with the solvent, and then adding an inorganic base or a mixture with the solvent, (2) nitrobenzenesulfonyl halide Or glycidol, or a mixture with the solvent, and then a mixture with the solvent, and then adding an inorganic base or a mixture with the solvent. (3) Glycidol, or a mixture with the solvent, After adding the inorganic base or the mixture with the solvent, add the nitrobenzenesulfol halide or the mixture with the solvent. PT / JP2004 / 005224

twenty four

And (4) a method of simultaneously adding nitrobenzenesulfonyl halide or a mixture of the solvent and a mixture of an inorganic base or a solvent thereof to glycidol or a mixture thereof with a solvent.

After the reaction, the post-treatment method of the reaction solution is not particularly limited, and examples thereof include the following methods. (1) In the case of an organic solvent system in which no solid is precipitated from the reaction solution, no special post-treatment is required, and in the case of a two-phase system of an organic solvent in which no solid is precipitated from the reaction solution and water By removing the aqueous phase, a solvent mixture of the target substance can be obtained. (2) When only the target solid is precipitated from the reaction solution, the target solid can be obtained by filtration. (3) When only a solid (inorganic salt, etc.) that is not the target substance is precipitated from the reaction solution, a solvent mixture of the target substance can be obtained by filtering to remove the solid. When water is added to the reaction solution, non-target solids (inorganic salts, etc.) are dissolved to form an organic solvent / water two-phase system. A solvent mixture can also be obtained. (4) If a solid of the target substance and a solid that is not the target substance (such as an inorganic salt) are precipitated from the reaction solution, add a solvent that dissolves the target substance, or add a solid that is not the target substance (such as an inorganic salt). ) Is dissolved by adding a solvent such as water, etc., and either one is preferentially dissolved, and then the operation of (2) or (3) is performed, or the operation of (1) is performed after dissolving both. By doing so, you can obtain the desired object. The operations (1) to (4) may be performed in combination.

During the operations (1) to (4) or prior to the operations (1) to (4), if necessary, an organic solvent and water or water are added, or the reaction solution is concentrated. Or may be heated or cooled. In the case of the organic solvent / water two-phase system (1), the temperature is preferably adjusted to 10 to 60 ° C. from the viewpoint of improving liquid-liquid separability. If the temperature is lower than 10 ° C, the liquid-liquid separation property is not sufficient, so that it is not preferable. Additives (acidic substances, basic substances, salts, etc.) may be added as long as they do not affect the quality of the target product.

The following operation may be further performed on the obtained solvent mixture of the target substance, if necessary. When water is added to the target solvent mixture, the organic solvent / water If a two-phase system is formed, wash with water and / or an acidic aqueous solution such as citric acid, hydrochloric acid, or sulfuric acid, and an alkaline aqueous solution such as Z or baking soda, sodium hydroxide, or potassium hydroxide. Is also good. When the organic solvent / water two phase is not formed, washing may be performed after replacing the organic solvent with an organic solvent which forms two phases with water. At the time of washing, the temperature is preferably adjusted to 10 to 60 ° C from the viewpoint of improving the liquid-liquid separation property. If the temperature is lower than 10 ° C, the liquid-liquid separation property is not sufficient, which is not preferable. If the temperature is higher than 60 ° C, decomposition and side reactions increase, which is not preferable. Thereafter, high-purity glycidyl ditrobenzenesulfonate can be easily isolated by ordinary operations such as concentration and crystallization.

Example

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. The optical purity was analyzed by high performance liquid chromatography under the following conditions.

Analysis column: CH I RALP AK AS (manufactured by Daicel)

Mobile phase: Hexane Z-isopropanol = 80/20 (vol)

Flow rate: 1.2 ml / in. Wavelength: 220 nm. Force ram temperature: 30 ° C

HPLC purity was defined as the following formula, and analyzed by high performance liquid chromatography under the following conditions.

HPLC purity (%) = Glycidyl nitrobenzenesulfonate area (total area-solvent area-nitrobenzenesulfonyl chloride area) XI 00 Analytical column: YMC Pack ODS-AA-303 (manufactured by YMC) Mobile phase : Acetonitrile / potassium phosphate buffer ( _PH = 2.5) = 50/50 (vol%) Flow rate: 1.0 ml / min. Wavelength: 210 nm. Column temperature: 40 ° C The content was calculated by comparing the weight and area with a standard with a known content, and analyzed under the same conditions as for HP LC purity. PT / JP2004 / 005224

26

Example 1 Synthesis of Optically Active Glycidyl 3-Nitrobenzenesulfonate Under a nitrogen atmosphere, to (R) -3-chloro-1,2-propanediol (optical purity 98% ee), 10.0 g (90.5 mmol) Add 4 Om 1 of distilled water, dissolve with stirring, add a solution of 3-ethylbenzenesulfonyl chloride 20.1 (90.5 mol) dissolved in 90 ml of toluene, and cool to about 2 ° C did. Under stirring and at the same temperature, the addition of 24.1 g (18 lmmol) of 30% aqueous sodium hydroxide was started. After the addition over about 1 hour, the mixture was stirred at 0 to 7 ° C for 7 hours to synthesize the desired product. At the end of the reaction, crystals of the target substance had precipitated, and were heated to 35 ° C. to dissolve. Upon standing, the solution separated into two phases with good liquid-liquid separation properties, and the toluene solution of the target product was obtained by removing the lower layer (aqueous phase). Thereafter, this toluene solution was washed with about 10% aqueous citric acid (4 Oml) at about 35 ° C., and further washed with 5% aqueous sodium bicarbonate (25 ml). During the washing, the liquid-liquid separation property was good. Thereafter, the mixture was concentrated under reduced pressure using an evaporator. To the concentrate was added 19 ml of ethyl acetate, and the mixture was dissolved at 37 ° C. with stirring. When 3 lm 1 of hexane was added at the same temperature, crystals of the target product gradually precipitated. Then, after cooling to 110 ° C, filtration was performed to obtain crystals. Vacuum drying was performed to obtain 15.2 g (pure content) of (S) -3-nitrobenzenesulfonic acid glycidyl (yield: 65%). The content was 100 wt% and the optical purity was 99.2% ee.

Example 2 Synthesis of Optically Active Dalicidyl 3-Nitrobenzenesulfonate Under a nitrogen atmosphere, (S) _3-chloro-1,2-propanediol (optical purity 98% ee), 10.0 g (90.5 mmol) Add 40 ml of distilled water, dissolve with stirring, and add 4-methyldimethylaminopyridine, 167 mg (1.4 mmol), 312-port benzenesulfoerck-cap, 20.1 g (90.5 mmol) in toluene 9 Oml Was added thereto, and the mixture was cooled to about 2 ° C. At the same temperature under stirring, the addition of 25.4 g (19 Oramol) of 30% aqueous sodium hydroxide was started. After the addition over about 10 minutes, the mixture was stirred at 2 to 5 ° C for 8 hours to synthesize the desired product. At the end of the reaction, crystals of the target substance had precipitated, so the mixture was heated to 30 ° C. and dissolved. Upon standing, the solution separated into two phases with good liquid-liquid separation properties, and the toluene solution of the target product was obtained by removing the lower layer (aqueous phase). Thereafter, this toluene solution was washed with 10% aqueous citric acid 4 Om 1 at about 35 ° C., and further washed with 5% aqueous sodium bicarbonate 4 Om 1. During the washing, the liquid-liquid separation property was good. Thereafter, the mixture was concentrated under reduced pressure to 44 g using an evaporator. Analysis of the concentrate at this stage showed that the yield of (R) -3 glycidyl 3- (2-nitrobenzenesulfonate) was 15.0 g (pure), the yield was 64%, and the optical purity was 96.5% ee. there were. Hexane (1 ml) was added to the concentrate at 37 ° C. with stirring, and the mixture was gradually cooled. As a result, desired crystals were precipitated at 30 ° C. Thereafter, at the same temperature, 14 ml of hexane was added, and the mixture was cooled to 0 ° C and filtered to obtain crystals. Vacuum drying was performed to obtain 13.8 g (pure) of glycidyl (R) -3-nitrobenzenesulfonate (59% yield). The content was 93.7 wt% and the optical purity was 97.5% ee.

(Example 3) Optical activity-Synthesis of glycidyl toluenesulfonate

Under a nitrogen atmosphere, 4 Om 1 of distilled water was added to 10.0 g (90.5 mmol) of (R) -3-chloro-1,2-propanediol (98% ee of optical purity), and dissolved under stirring. A solution prepared by dissolving 173 mg (1.4 mmol) of paminopyridine, 17.3 g (90.5 mmol) of p-toluenesulfonyl chloride in 9 Oml of toluene was added, and the mixture was cooled to about 2 ° C. . At the same temperature under stirring, the addition of 30% aqueous sodium hydroxide, 25. 3 g (19 Ommol) was started. After the addition over about 5 minutes, the mixture was stirred at 2-4 ° C. for 3 hours to synthesize the desired product. At the end of the reaction, crystals of the desired product had precipitated, and were heated to 30 ° C. to dissolve. Upon standing, the solution was separated into two phases with good liquid-liquid separation properties, and the lower layer (aqueous phase) was removed to obtain a toluene solution of the desired product. Thereafter, the toluene solution was washed with 10% aqueous citric acid 4 Om 1 at about 30 ° C., and further washed with 5% aqueous sodium bicarbonate 4 Om 1. During the washing, the liquid-liquid separation property was good. Thereafter, the solvent was distilled off under reduced pressure, and the concentrate was analyzed. As a result, the yield of glycidyl (S) -p-toluenesulfonate was 15.7 g (pure), the yield was 76%, and the optical purity was 98%. 2% ee. 47 ml of isopropanol was added to the concentrate and dissolved at 35 ° C under stirring. When cooled gradually, the desired product crystallized out at about 25 ° C. At the same temperature, 8 ml of hexane was added, and then cooled to 0 ° C, followed by filtration to obtain crystals. 04005224

28

. After vacuum drying, 14.2 g (pure) of glycidyl (S) -p-toluenesulfonate was obtained (yield 69%). The content was 99.7 wt% and the optical purity was 98.7 ° / oee.

(Example 4) Synthesis of optically active p-toluene sulfonate dalicidyl

Under a nitrogen atmosphere, stirring at about 10 ° C, sodium hydroxide (shape: granular, about 1 mm in diameter) 3.79 g (95.Ommol) was added to methyl isobutyl ketone (MI BK, water content 761). (R) -3_chloro-1,2-propanediol (98% ee in optical purity) and 10.0 g (90.5 bunol) were added. Glycidol was synthesized by reacting at about 10 ° C for 2 hours. During the reaction, the slurry was in a good slurry state with sufficient stirring, and no increase in solution viscosity that would cause a problem in practice was observed. Thereafter, 17.3 g (90.5 mmol) of p-toluenesulfonyl chloride was added under stirring at about 0 ° C. in a slurry state in which a non-target substance was precipitated. Subsequently, sodium hydroxide (shape: granular, about lmm in diameter), 3.82 g (95.Ommol) and 167 mg (1-4mmol) of 4-dimethylaminopyridine were added. The mixture was stirred at 0 to 8 ° C for 10 hours to synthesize the desired product. Thereafter, 40 ml of water was added to the slurry in which the non-target solid was precipitated, and the mixture was heated to 40 ° C. with stirring. As a result, the precipitated solid was dissolved. Upon standing, the solution separated into two phases with good liquid-liquid separation. The MIBK solution of the target substance was obtained by removing the lower layer (aqueous phase). Thereafter, this solution was washed at 35 to 45 ° C. with (1) 10% aqueous solution of citric acid 4 Om 1 and (2) 4% of sodium bicarbonate solution 4 Oml. During washing, the liquid-liquid separation property was good. After that, the solvent was distilled off under reduced pressure, and the concentrate was analyzed. As a result, the yield of (S) -p-toluenesulfonate daricidyl was 14.2 g (pure), the yield was 69%, and the optical purity was 98. It was 0% ee. (Example 5) Synthesis of optically active glycidyl p-toluenesulfonate

Under a nitrogen atmosphere, at about 10 ° C, while stirring, sodium hydroxide (shape: granular, about 1 mm in diameter) 3.83 g (95.Ommol) was added to methyl ethyl ketone (MEK, water content 78 (p pm) 10 Om 1 and disperse, then add (S) -3 5224

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10.0 g (90.5 mmol) of pandiol (98% ee optical purity) was added. Glycidol was synthesized by reacting at about 10 ° C for 1 hour. During the reaction, the slurry was in a good slurry state with sufficient agitation, and no increase in solution viscosity that would cause a problem in practice was observed. Then, with stirring, at about o ° C, in a slurry state in which a solid that was not the target substance was precipitated, 10.1 g (99.5 benzyl) of triethylamine, and 172 mg of 4-dimethylaminoviridine ( 1.4 Image 1) was added. Subsequently, 17.3 g (90.5 benzyl) of p-toluenesulfonyl chloride were added. The mixture was stirred at 1 to 3 ° C for 7 hours to synthesize the desired product. Thereafter, 40 ml of water was added to the solution in a slurry state in which a non-target solid precipitated, and the mixture was heated to 30 ° C. with stirring. As a result, the precipitated solid was dissolved. Upon standing, the solution separated into two phases with good liquid-liquid separation. The MEK solution of the target substance was obtained by removing the lower layer (aqueous phase). Thereafter, the solution was washed at about 30 ° C. with (1) 40 ml of 10% aqueous citric acid, (2) 40 ml of 5% aqueous sodium bicarbonate, and (3) washing with 40 ml of water. During the washing, the liquid-liquid separation property was good. Thereafter, the solvent was distilled off under reduced pressure, and the concentrate was analyzed. As a result, the yield of glycidyl (R) -p-toluenesulfonate was 16.5 g (pure), and the yield was 80 ° /. The optical purity was 97.4% ee.

(Example 6) Synthesis of optically active glycidyl 3-nitrobenzenesulfonate Sodium hydroxide (shape: plate-like, diameter of about 3 to 5 mm) under nitrogen atmosphere at about 20 ° C while stirring 3.04 g (76.0 thighs) ol) was added to and dispersed in 70 ml of methyl isobutyl ketone (MI BK, water content 761 pm), and (R) -3-chloro-1,2-propanediol (optical purity 98% ee), 7.00 g ( 63.3 mmol). Glycidol was synthesized by reacting at 20 to 25 ° C for 1.5 hours. During the reaction, the slurry was in a good slurry state with sufficient stirring, and there was no increase in solution viscosity that would pose a practical problem. Thereafter, the mixture was stirred for 0 while the non-target solid was precipitated. At C, 14.0 g (63.3 mmol) of 3-nitrobenzenesulfonyl chloride was added. Subsequently, 2.79 g (69.7 mmol) of sodium hydroxide (shape: plate, about 3-5 mm in diameter) were added. The mixture was stirred at 0 ° C overnight (about 15 hours) to synthesize the desired product. Then, the slurry in which solids not intended 5224

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To the solution, 45 ml of water was added with stirring, and the mixture was heated to 40 ° C. As a result, the precipitated solid was dissolved. When the stirring was stopped and allowed to stand, the solution was separated into two phases with good liquid-liquid separation properties. By removing the lower layer (aqueous phase), the MIBK solution of the target substance was obtained. Thereafter, the solution was washed with 26 ml of 10% aqueous citric acid at 40 to 50 ° C., and further washed with 3 Oml of 5% aqueous sodium bicarbonate. During the washing, the liquid-liquid separation property was good. Thereafter, the solvent was distilled off under reduced pressure. As a result of analyzing the concentrate, the yield of (S) -3-glycidyl trobenzenesulfonate was 12.0 g (pure), the yield was 73%, and the optical purity was 96.3% ee. Example 7 Synthesis of Optically Active Glycidyl 3-Nitrobenzenesulfonate Under a nitrogen atmosphere at about 10 ° C. with stirring, sodium hydroxide (shape: granular, about lmm in diameter) 2.66 g (66 .5 mmol) was added to and dispersed in 7 Om1 of methyl ethyl ketone (MEK, water content 78 ppm), and (R) -3-chloro-1,2-propanediol (optical purity 98% ee), 7.00 g (63.3 mmol) was added. Glycidol was synthesized by reacting at about 10 ° C for 1 hour. During the reaction, the slurry was in a good slurry state with sufficient agitation, and no increase in solution viscosity that would pose a practical problem was observed. After that, at a temperature of about o ° c with stirring, with the slurry in which the non-target substance precipitated

Then, 14.0 g (63.3 mmol) of 3-nitrobenzenesulfonyl chloride was added to the mixture. Subsequently, sodium hydroxide (shape: granular, about lmm in diameter), 2.66 g (66.5 cellulose) was added. The mixture was stirred at about 0 ° C for 3 hours to synthesize the desired product. Thereafter, 33 ml of water was added to the solution in a slurry state in which a non-target substance precipitated, and the mixture was heated to 30 ° C. with stirring. As a result, the precipitated solid was dissolved. Upon standing, the solution separated into two phases with good liquid-liquid separation. By removing the lower layer (aqueous phase), a MEK solution of the target substance was obtained. Thereafter, this solution was washed at 35 to 45 ° C with (1) 29 ml of 10% aqueous citric acid, (2) 28 ml of 5% aqueous sodium bicarbonate, and (3) 28 ml of water. During the washing, the liquid-liquid separation property was good. Thereafter, the solvent was distilled off under reduced pressure, and the concentrate was analyzed. As a result, the yield of glycidyl (S) -3-12-nitrobenzenesulfonate was 13.4 g (pure), the yield was 81%, and the optical purity was 81%. 97.7% ee. 2004/005224

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Example 8 Synthesis of Optically Active Dalicidyl 3-Nitrobenzenesulfonate Under a nitrogen atmosphere, (R) -3-chloro-1,2-propanediol (optical purity 98% ee), 7.00 g (63. ol), 10.5 g (76.0 mmol) of potassium carbonate and 70 ml of acetone were added, and the mixture was heated under reflux for 3 hours to synthesize glycidol. In a slurry state in which a solid that was not the target substance was precipitated, 14.0 g (63.3 t ol) of 3-nitrobenzenesulfyurokulide was added at 18 ° C. with stirring. Subsequently, 2.79 g (69.7 mmol) of sodium hydroxide (shape: plate-like, about 3-5 mm in diameter) was added. The mixture was stirred at 5 to 10 ° C for about 3 hours to synthesize the desired product. The precipitated solid which was not the target substance was separated by filtration, and the filtrate was distilled off under reduced pressure. As a result of analyzing this concentrate, the yield of glycidyl (S) -3-nitrobenzenesulfonate was 10.4 g (pure), the yield was 64%, and the optical purity was 96.9% ee.

Example 9 Synthesis of Optically Active Glycidyl 3-Nitrobenzenesulfonate Under a nitrogen atmosphere, (R) -3-chloro-1,2-propanediol (optical purity 98% ee), 10.0 g (90. Distilled water (4 Om1) was added to 5 mL of the mixture, dissolved under stirring, and cooled to about 3 ° C. Under stirring and at the same temperature, the addition of 12.1 g (90.5 mmol) of 30% aqueous sodium hydroxide was started. After the addition over about 30 minutes, the mixture was further stirred at 0 to 3 ° C. for 4 hours to synthesize glycidol. To this glycidol aqueous solution was added a solution prepared by dissolving 20.1 g (90.5 mmol) of 3-nitrobenzenesnoreffoninolecule in 90 ml of toluene at about 0 ° C under stirring. . Subsequently, 13.3 g (99.5 mmol) of 30% aqueous sodium hydroxide was added. After stirring at 0 to 6 ° C for 6 hours, the target compound was synthesized. At the end of the reaction, crystals of the target substance had precipitated, so the mixture was heated to 30 ° C. and dissolved. Upon standing, the solution was separated into two phases with good liquid-liquid separation properties, and the toluene solution of the target product was obtained by removing the lower layer (aqueous phase). Thereafter, this toluene solution was washed with 40 ml of 10% aqueous citric acid at about 30 ° C., and further washed with 30 ml of 5% aqueous sodium bicarbonate. During the washing, the liquid-liquid separation property was good. Thereafter, the mixture was concentrated under reduced pressure to 19 g using an evaporator. At this stage, a part of the concentrate was withdrawn and subjected to quantitative analysis. As a result, the yield of glycidyl (S) -3-dinitrobenzenesulfonate was 7 T / JP2004 / 005224

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4%, HP LC purity was 98.7%, and optical purity was 96.9% ee. 25 ml of ethyl acetate was added to the concentrate and dissolved at 40 ° C. with stirring. When 28 ml of hexane was added at the same temperature, crystals of the target product gradually precipitated. Then, after cooling to 0 ° C, filtration was performed to obtain crystals. After vacuum drying, 15.7 g (pure) of glycidyl (S) -3-nitrobenzenesulfonate was obtained (yield 67%). The content was 99.6 wt% and the optical purity was 99.1% ee.

(Example 10) Synthesis of optically active 3-dicose daricidyl benzenesulfonate Under a nitrogen atmosphere, (R) -3-chloro-1,2-propanediol (optical purity 98.8% ee), 20.0 Distilled water (54.0 g) was added to g (178.4 mmo 1), dissolved under stirring, and cooled to about 3 ° C. At the same temperature under stirring, the addition of 35.7 g (178.4 mmo 1) of a 20% aqueous sodium hydroxide solution was started. After the addition over about 1 hour, the mixture was stirred at 3-5 ° C. for another 3 hours to synthesize glycidol. This glycidol aqueous solution is stirred for about 5 minutes. At C, a solution of 39.5 g (178.4 mmo 1) of 3-2-nitrobenzenesulfouric-mouth chloride in 174 g of toluene was added. Subsequently, 39.2 g (196.2 mmo 1) of a 20% aqueous sodium hydroxide solution was added. The mixture was stirred at 15 ° C for 16 hours to synthesize the desired product. At the end of the reaction, crystals of the target substance had precipitated, so the mixture was heated to 35 ° C and dissolved. Upon standing, the solution was separated into two layers with good liquid separation properties, and the lower layer (aqueous layer) was removed to obtain the target toluene solution. Thereafter, the toluene solution was washed at about 35 ° C. with 72 g of water. During the washing, the liquid-liquid separation property was good. Thereafter, the mixture was concentrated under reduced pressure to 85.6 g (about 40 wt%) using an evaporator. At this stage, a part of the concentrate was sampled and quantitative analysis was performed. As a result, the yield of glycidyl (S) -3-nitrobenzenesulfonate was 74%, and the optical purity was 97.5% ee. Toluene was added to this solution to make a 35 wt% toluene solution of glycidyl 3_ ditrobenzenesulfonate, and then the temperature was raised to 35 ° C. At the same temperature, 6 g of hexane was added, and then seed crystals of (S) dalicidyl (1-)-3-nitrobenzenesulfonate were added. As a result, crystals of the target product gradually precipitated. After stirring at the same temperature for 1 hour, 28 g of hexane was added over 1 hour. JP2004 / 005224

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Then, after cooling to 20 ° C., the crystals were obtained by filtration, and after drying in vacuo, 30.2 g of (S) glycidyl 1,3-ditrobenzenesulfonate was obtained (yield 63%). The content was 99.6 wt% and the optical purity was 99.6% ee. (Example 11) Synthesis of glycidyl 3-to-mouth benzenesulfonate

Under a nitrogen atmosphere, add 26.3 g (1 90 mol ol) of potassium carbonate and 21 Om 1 of acetone to 21.0 g (1 90 mmol) of 3-chloro-1,2-propanediol for 2 hours. The mixture was heated under reflux to synthesize glycidol. The precipitated non-target solid was filtered to obtain an acetone solution of the target. After evaporating the solvent under reduced pressure, 100 ml of distilled water was added to prepare an aqueous glycidol solution. This aqueous solution was divided into three portions, and one of them was mixed with a solution prepared by dissolving 14.0 g (63.3 mmol) of 3-nitrobenzenesulfoyluricide in 63 ml of toluene under stirring at about 2 ° C. Was added. Subsequently, 9.3 g (69.7 mmol) of 30% aqueous sodium hydroxide were added. The mixture was stirred at 0 to 5 ° C for 9 hours to synthesize the desired product. Thereafter, the mixture is heated to 30 ° C with stirring, then left standing, and the lower layer (aqueous phase) is removed. did. During the washing, the liquid-liquid separation property was good. Thereafter, the solvent was distilled off under reduced pressure. As a result of analyzing the concentrate, the HPLC purity of daricidyl 3-to-2 mouth benzenesulfonate was 94.2%. (Comparative Example 1)

Example 11 14.0 g (63.3 mmol) of 3-nitrobenzenesulfonyl chloride was added to one of the aqueous glycidol solutions obtained by dividing into three at a temperature of about 0 ° C with stirring in toluene. A solution dissolved in 63 ml was added. Subsequently, 6.4 g (63.3 mmol) of triethylamine were added. The mixture was stirred at 0 to 5 ° C for 9 hours to synthesize the desired product. Thereafter, the mixture is heated to 30 ° C with stirring, and then left standing. The lower layer (aqueous phase) is removed, and washed at about 30 ° C with 40 ml of 10% aqueous citric acid and 30 ml of 5% aqueous sodium bicarbonate. Thereafter, the solvent was distilled off under reduced pressure. As a result of analyzing this concentrate, the HPLC purity of glycidyl 3-nitrobenzenesulfonate was 51.0%. 05224

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(Comparative Example 2)

Example 1 14.0 g (63.3 mmol) of 3-nitrobenzenesulfoyl cucumide was dissolved in 63 ml of toluene under stirring at about 0 ° C. in one of the glycidol aqueous solutions obtained by dividing into three parts. The allowed solution was added. Subsequently, dimethylaminopyridine, 0.12 g (0.95 thigh.1), 30% aqueous sodium hydroxide, and 9.3 g (69.7) were added. The mixture was stirred at 0 to 5 ° C for 9 hours to synthesize the desired product. After that, the mixture was heated to 30 ° C under agitation, allowed to stand, and the lower layer (aqueous phase) was removed. After washing at about 30 ° C, 40 ml of 10% aqueous citric acid and 30 ml of 5% aqueous sodium bicarbonate were washed. The solvent was distilled off under reduced pressure. As a result of analyzing the concentrate, the HP LC purity of glycidyl 3-nitrobenzenesulfonate was 86.2%. Industrial applicability

The present invention relates to (1) reacting 3-chloro-1,2-propanediol and a sulfonyl halide derivative in the presence of a base, or (2) reacting an alkali metal or alkaline earth in an organic solvent. Production of glycidol from 3-chloro-1,2-propanediol in the presence of a metal hydroxide, followed by reaction with a sulfonyl halide derivative in the presence of a base, or (3) A method for producing glycidyl sulfonate derivatives, which comprises producing glycidol from 3-chloro-1,2-propanediol in the presence of glycidol and then reacting it with nitrobenzenesulfonyl halide using only an inorganic base as a base. Since the number of processes is small and the operation is simple, the amount of waste is small, and the quality is high, it can be industrially suitably carried out.

Claims

The scope of the claims

1. A method for producing a daricidyl sulfonate derivative, which comprises reacting a 3-chloro-1,2-propanediol and a sulfonyl chloride derivative in the presence of a base.

2. The method according to claim 1, wherein the reaction is carried out in a two-phase solvent of an organic solvent Z water or in an organic solvent.

3. The production method according to claim 1 or 2, wherein only an inorganic base is used as the base.

4. The method according to claim 1 or 2, wherein only an organic base is used as the base.

5. The method according to claim 1 or 2, wherein an inorganic base and an organic base are used as the base.

6. The method according to claim 1, wherein the base is at least one selected from hydroxides, carbonates, and hydrogencarbonates of alkali metal Z or alkaline earth metal. The method according to any one of the second, third and fifth aspects.

7. The method according to any one of claims 1, 2, 3, or 5, wherein a hydroxide of an alkali metal or alkaline earth metal is used as the base. Manufacturing method.

8. The method according to any one of claims 1, 2, 3 and 5, wherein sodium hydroxide and / or potassium hydroxide are used as the base.

9. The method according to any one of claims 1, 2, 4, and 5, wherein a tertiary amine is used as the base.

10. The production method according to any one of claims 1, 2, 4, and 5, wherein a pyridine derivative is used as the base.

11. The method according to any one of claims 1, 2, 4 and 5, wherein 4-dimethylaminopyridine is used as the base.

12. The method according to any one of claims 1 to 11, wherein an aromatic hydrocarbon solvent is used as the organic solvent.

13. The method according to claim 12, wherein at least one of benzene and toluene is used as the aromatic hydrocarbon solvent.

1 4. Glycidol is produced by reacting 3-chloro-1,2,2-propanediol in the presence of an alkali metal and / or alkaline earth metal hydroxide in an organic solvent to produce glycidol and isolate glycidol. Subsequently, a method for producing a daricidyl sulfonate derivative, wherein the derivative is produced by reacting a sulfo-halide derivative in the presence of a base.

15. The production method according to claim 14, wherein the hydroxide of the alkali metal is sodium hydroxide and / or a hydroxide lithium.

16. The method according to claim 14 or 15, wherein a ketone solvent is used as the organic solvent.

17. The production method according to any one of claims 14 to 16, wherein at least one of acetone, methyl ethyl ketone, and methyl isobutyl ketone is used as the organic solvent.

18. The method according to any one of claims 14 to 17, wherein the reaction of glycidol and the sulfonyl halide derivative is carried out in a two-phase solvent of an organic solvent / water or in an organic solvent.

19. The process according to any one of claims 14 to 18, wherein only an inorganic base is used as the base used in the reaction between glycidol and the sulfonyl halide derivative.

20. The method according to any one of claims 14 to 18, wherein only an organic base is used as the base used in the reaction between glycidol and the sulfonyl halide derivative.

21. The method according to any one of claims 14 to 18, wherein an inorganic base and an organic base are used as the base used in the reaction between glycidol and the sulfonyl halide derivative.

22. As the base used in the reaction between glycidol and the sulfonyl halide derivative, it is necessary to use at least one selected from hydroxides, carbonates and hydrogencarbonates of alkali metal Z or alkaline earth metal. The method according to any one of claims 14, 15, 16, 17, 18, 19, or 21, characterized by the features.

23. Claims 14, 15 and 16 characterized in that a hydroxide of an alkali metal and / or an alkaline earth metal is used as the base used in the reaction of glycidol with the sulfonyl halide derivative. , A manufacturing method according to any of the seventeenth, the eighteenth, the nineteenth, the twenty-first, or the twenty-second.

24. The scope of the claims, characterized in that sodium hydroxide and Z or potassium hydroxide are used as the base used in the reaction of the glycidol with the sulfonyl halide derivative. 18. The production method according to any one of 18, 18, 19, 22, and 23.

25. A tertiary amine as a base used in the reaction between glycidol and a sulfonyl halide derivative, wherein the tertiary amine is used. 21. The production method according to any one of 21, 22, 23 or 24.

26. Claims 14, 15, 15, 16, 17, 18, 20, 21, 21 characterized by using a pyridine derivative as a base used in the reaction of glycidol and a sulfonyl halide derivative. The manufacturing method according to any one of the 22nd, 23rd, 24th and 25th.

27. The method according to claim 14, characterized in that 4-dimethylaminopyridine is used as the base used in the reaction between dalicidol and the sulfonyl halide derivative. A manufacturing method according to any one of the 21, 21, 22, 23, 24, 25 or 26.

28. A method for producing glycidyl nitrobenzenesulfonate by reacting glycidol with nitrobenzenesulfonyl halide in the presence of a base, comprising the steps of: A process for producing glycidyl utrobenzenesulfonate, wherein only an inorganic base is used.

29. The production method according to claim 28, wherein the reaction is carried out in a two-phase solvent of Z water or an organic solvent.

30. The production method according to claim 29, wherein an aromatic hydrocarbon solvent is used as the two-phase solvent of the organic solvent / water.

31. The method according to claim 30, wherein at least one of benzene and toluene is used as the aromatic hydrocarbon solvent.

32. A ketone-based solvent is used as the organic solvent.

29. The production method according to item 9.

33. The method according to claim 32, wherein at least one of acetone, methyl ethyl ketone, and methyl isobutyl ketone is used as the ketone solvent.

34. The method according to claim 28, wherein the inorganic base is at least one selected from hydroxides, carbonates, and hydrogencarbonates of alkali metals and Z or alkaline earth metals. The production method according to any one of the third to third aspects.

35. The method according to any one of claims 28 to 34, wherein the inorganic base is a hydroxide of an alkali metal and / or an alkaline earth metal.

36. The method according to any one of claims 28 to 35, wherein the inorganic base is sodium hydroxide and / or potassium hydroxide.

37. The method according to any one of claims 28 to 36, wherein glycidol is obtained by reacting 3-chloro-1,2-propanediol in the presence of a base.

38. The process according to claim 37, wherein the glycidol is reacted with benzenesulfonyl halide without isolation, without isolation.

39. The process according to claim 37 or 38, wherein glycidol is synthesized in water, an organic solvent, or a mixed solvent of organic solvent Z and water.

40. Glycidol synthesis in the presence of at least one inorganic base of hydroxides, carbonates or bicarbonates of alkali metals and / or alkaline earth metals, claims 37 to 3 9. The production method according to any one of 9.

41. The production method according to any one of claims 37 to 40, wherein the dalicidol is synthesized in the presence of sodium hydroxide and / or a hydroxylase.

4 2. The sulphonylenolide derivative is methanesulphonyl chloride, benzenes sulphonyl chloride, p-tonolene sulphonyl chloride / p-toluene sulphonyl chloride, nitrosulphonyl halide or nitrobenzenesulphonyl halide. The production method according to any one of claims 1 to 27, wherein

4 3. The claim that the nitrobenzene snorehoninolehalide is a 2-nitrobenzene snorehoninolek mouth ride, a 3-nitrobenzene snorehoninolechloride mouth ride, or a 4-nitrobenzene snorehononylek mouth ride. The method according to any one of Items 28 to 42.

44. The method according to any one of claims 1 to 43, wherein the optically active glycidyl sulfonate derivative is produced using optically active 3-chloro-1,2-propanediol or optically active dalicidol. Manufacturing method.