WO2005014531A1

WO2005014531A1 - Process for production of n-methacryloyl-4-cyano-3- trifluoromethylaniline, method for stabilization of the same, and process for production of bicalutamide

Info

Publication number: WO2005014531A1
Application number: PCT/JP2004/011800
Authority: WO
Inventors: Kiyoshi Sugi; Tetsuya Shintaku; Tadashi Katsura; Nobushige Itaya
Original assignee: Sumitomo Chemical Company, Limited
Priority date: 2003-08-12
Filing date: 2004-08-11
Publication date: 2005-02-17
Also published as: JP2005060302A

Abstract

A process for the production of N-methacryloyl-4-cyano -3-trifluoromethylaniline which comprises reacting 4-cyano-3-trifluoromethylaniline with methacrylic acid or a reactive derivative thereof in the presence of a polymerization inhibitor; a process for the production of bicalutamide which comprises reacting 4-cyano-3-trifluoromethylaniline with methacrylic acid or a reactive derivative thereof in the presence of a polymerization inhibitor and reacting the obtained N-methacryloyl-4-cyano-3-trifluoromethylaniline with a peroxycarboxylic acid, 4-fluorothiophenol, and a peroxy- carboxylic acid successively; and a method for the stabilization of N-methacryloyl-4-cyano-3-trifluoromethylaniline which comprises incorporating a polymerization inhibitor into N-methacryloyl-4-cyano-3-trifluoromethylaniline.

Description

Specification

Method for producing N-methacryloyl-4-cyano 3-trifluoromethylalanine, method for stabilizing said compound and method for producing bicalutamide

The present invention relates to a method for producing N-methacryloylu 4 _cyano-3-trifluoromethylaniline, a method for stabilizing the compound, and a method for producing bicalutamide via the compound. Background art

N-methylacryloyl-1-cyano-3-trifluoromethylaniline is an intermediate of bicalutamide useful as an anticancer drug.

As shown in Scheme 1 above, N-methacryloyl-14-cyano-3-trifluoromethylaniline is produced by reacting 4-cyano-3_trifluoromethylaniline with methacryloyl chloride ( For example, J. Med. Chem. 1988, 31, 954-959).

However, in the above method, the reaction, post-treatment, isolation and purification, heat melting, and In each stage such as storage at room temperature, the polymerization of N-methacryloyl 4-4-cyano-3-trifluoromethylaniline occurs unexpectedly, and a part of it changes into resinous (polymer-like) impurities, It is feared that the rate and purity are significantly reduced. In addition, when N-methacryloylu-4-cyano-3-trifluoromethylaniline containing such impurities is used for the production of bicalutamide, the yield of the final product, bicalutamide, is reduced for the same reason as described above. Problems such as a drastic decrease could occur. Disclosure of the invention

An object of the present invention is to provide a method for producing N-methacryloyl-4-cyano-3-trifluoromethylaniline, which is an intermediate of bicalutamide useful as an anticancer agent, in a stable and high yield, N-methacryloyl-4 A method for stabilizing cyano-3-trifluoromethylaniline, and a method for producing bicalutamide in a stable and high yield via the compound.

In view of the above problems, the present inventors have found that by reacting 4-cyano-3-trifluoromethylaniline with methacrylic acid or a reactive derivative thereof in the presence of a polymerization inhibitor, N-methacryloyl- The yield and stability of 3-cyano-3-trifluoromethylaniline are improved, and the addition of a polymerization inhibitor to N-methacryloyl-14-cyano-13-trifluoromethylaniline is improved. It has been found that its stability is improved. Further, as a result, they have found that the use of these N-methacryloylue 4-cyano 3-trifluoromethylaniline in the synthesis of bicalutamide improves the overall yield, thereby completing the present invention. That is, the present invention is as described below.

<1> 4-N-methacryloylyl 4-N-methacrylate, which includes reacting 3-trifluoromethylaniline with methacrylic acid or a reactive derivative thereof in the presence of a polymerization inhibitor. 3—Method for producing trifluoromethylaniline.

<2> The method according to <1>, wherein the reactive derivative of methacrylic acid is methacryloyl chloride.

<3> The polymerization inhibitor is at least one compound selected from the group consisting of 2,6-di-tert-butyl-4-methylphenol and butylated hydroxyazole. The method according to <1> or <2>.

<4> The method according to any one of <1> to <3>, wherein the weight of the polymerization inhibitor added to the reaction system is from 500 to 3,000 ppm based on 4-cyano 3-trifluoromethylaniline.

<5> N-methacryloyl 4- 4-cyano-3-trifluoromethylaniline which includes mixing a polymerization inhibitor with N-methacryloyl 4- 4-cyano-3-aniline Stabilization method.

<6> The method according to <5>, wherein the mixing weight of the polymerization inhibitor is 0.001 g to 0.5 g per 1 g of N-methylacryloylur 4_cyano_3-trifluoromethylaniline.

<7> The polymerization inhibitor according to <5> or <6>, wherein the polymerization inhibitor is at least one compound selected from the group consisting of 2,6-di-tert-butyl-4-methylphenol and butylated hydroxyanisole. The described method.

<8> Reaction of 4_cyano_3-trifluoromethylaniline with methacrylic acid or a reactive derivative thereof in the presence of a polymerization inhibitor to form the compound represented by the formula (1)

Step A of obtaining a compound (1) represented by

The compound (1) is reacted with a percarboxylic acid to form a compound of the formula (2)

A process for obtaining the compound (3) represented by (:, and

Formula (4) including a step D of reacting the compound (3) with a percarboxylic acid to obtain bicalutamide

A method for producing bicalutamide represented by the formula:

<9> The method described in <8>, wherein the reactive derivative of methyl acrylic acid is methyl acryloyl chloride.

<10> The polymerization inhibitor in the reaction of the step A is at least one compound selected from the group consisting of 2,6-di-tert-butyl-4-methylphenol and butylated hydroxyazole. > Or gag 9>. <11> The method according to any one of <8> to <10>, wherein the weight of the polymerization inhibitor added in the reaction in the step A is 500 to 3000 ppm based on 4-cyano 3-trifluoromethylaniline.

<12> The method according to any one of 8> to 11>, wherein step A further comprises adding a polymerization inhibitor to the obtained compound (1).

13. The method according to <12>, wherein the polymerization inhibitor added in the reaction of Step A and the polymerization inhibitor further added to the obtained compound (1) are the same polymerization inhibitor.

14. In the step A, the weight of the polymerization inhibitor further added to the obtained compound (1) is 0.001 g to 0.5 g per lg of the compound (1), and is preferably described in 12> or <13>. Method.

15. The method according to any one of 12> to <14>, wherein the step A comprises storing the compound (1) obtained after adding a polymerization inhibitor to the obtained compound (1) at 0 to 40 ° C. for 1 to 60 days. . BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in detail with reference to the following SCHEME 2.

Formula (1) of the present invention

The method for producing N-methacryloyl 4-cyano-3-trifluoromethylaniline (hereinafter, referred to as compound (1)) (hereinafter, referred to as production method 1 of the present invention) represented by the formula (I) is carried out in the presence of a polymerization inhibitor. , 4-cyano 3-trifluoromethylaniline (hereinafter, referred to as compound I) and methacrylic acid or a reactive derivative thereof (hereinafter, referred to as compound II). SCHEME 2

Compound I Compound II

Compound (1)

In the production method 1 of the present invention, methacrylic acid can be used as the compound II, and the compound II can be reacted with the compound I by reacting an amidating agent such as DCC. Derivatives are commonly used. The reactive derivative of methacrylic acid is not particularly limited as long as it has reactivity with an amino group. For example, in the compound II in the above Scheme 2, in which X is a halogen (for example, chlorine, bromine, iodine, etc.), for example, methacrylic acid halides such as methacrylic acid chloride, methacrylic acid bromide, methacrylic acid iodide, Methacrylic anhydride and the like.

Examples of the polymerization inhibitor include 2,6-di-tert-butyl_4-methylphenol (abbreviation: BHT) and butylated hydroxyanisole (abbreviation: BHA). , 2,6-Di-tert-butyl-4-methylphenol is preferred.

Two or more polymerization inhibitors may be used in combination.

The weight of the polymerization inhibitor added in the production method 1 of the present invention is usually 100 to 500 ppm, preferably 500 to 300 ppm, more preferably 500 to 2 ppm with respect to the compound I. 500 ppm.

By making the addition weight of the polymerization inhibitor in the production method 1 of the present invention 100 ppm or more, preferably 500 ppm or more with respect to the compound I, the deterioration of the target product and the yield due to side reactions such as polymerization can be achieved. Reduction and the like can be suppressed.

The amount of compound II to be used is generally 1 to 1.6 mol, preferably 1.3 to 1.4 mol, per 1 mol of compound I. As the compound II, a commercially available product may be used, or its reactive derivative may be separately prepared from methacrylic acid and used. For example, when the reactive derivative of methacrylic acid is methacrylic acid halide, the methacrylic acid halide is separately prepared from methacrylic acid and a halogenating agent such as thionyl chloride according to a known method. Can be used.

For example, when methacrylic acid halide is separately prepared, the amount of the halogenating agent used is usually 1 to 1.2 mol, preferably 1 to 1.1 mol, per 1 mol of methacrylic acid. The solvent used is preferably N, N-dimethylacetoamide (DMAC). The reaction temperature varies depending on the reaction conditions, but is usually −20 to + 5 ° C., preferably −12 to + 12 ° C. The reaction time varies depending on the reaction conditions, but is usually 0.5 to 4 hours, preferably 1 to 2 hours.

As the reactive derivative of methacrylic acid, from the viewpoint of reactivity, a methacrylic acid halide is preferable, and a methacrylic acid chloride is particularly preferable.

The method 1 of the present invention can be carried out by preparing a reactive derivative of methacrylic acid in advance and adding the compound I to the solution of the prepared reactive derivative of methacrylic acid. In this case, the production of the compound (1) from the preparation of the reactive derivative of methacrylic acid to the production of the compound (1) can be performed in one reaction vessel, which is industrially preferable.

In addition, as described above, in the case where the process from preparation of the reactive derivative of methacrylic acid to production of the compound (1) is performed in one reaction vessel, a polymerization inhibitor is added in advance before the preparation of the reactive derivative of methacrylic acid. If a reactive derivative of methacrylic acid is prepared in the presence of a polymerization inhibitor and used in the reaction with compound I, the production method 1 of the present invention can be carried out without adding a polymerization inhibitor separately.

In the production method 1 of the present invention, a solvent is usually used. Examples of the solvent include N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, and the like. Amides are preferred.

The amount of the solvent to be used is generally 2 to 5 parts by weight, preferably 3.5 to 4.5 parts by weight, per 1 part by weight of compound I.

The reaction temperature in the production method 1 of the present invention varies depending on the type of the compound II, the reaction conditions, and the like. However, when methyl methacrylate is used, the reaction temperature is usually 15 to 110 ° C. The temperature is preferably between 12 and 12 ° C.

The reaction time also varies depending on the type of compound II and reaction conditions, but when using methyl methacrylate halide, it is usually 0.5 to 4 hours, preferably 1 to 2 hours.Presence of polymerization inhibitor By reacting compound I with compound II below, side reactions (eg, polymerization reaction, decomposition reaction, etc.) in the reaction system can be suppressed, and an intermediate of bicalutamide useful as an anticancer agent Can be produced with a high yield and purity of 88-98% and a purity of 99.5-99.9%, for example, when using methacrylic acid halide. .

The compound (1) obtained by the production method 1 of the present invention is subjected to post-treatments such as quenching (reaction stop) and liquid separation, and is isolated and purified by a known method such as crystallization, recrystallization, or separation by chromatography. Can be.

The solvent used to stop the reaction is not particularly limited as long as the purpose is achieved.

From the viewpoint of neutralization of the acid content and removal of the reaction solvent (for example, N, N-dimethylacetamide and the like), it is preferable to use a mixture of an aqueous sodium carbonate solution and ethyl acetate. In addition, when the reaction is stopped under the above conditions, at the time of liquid separation, for example, the reaction solvent (eg, N, N-dimethylacetamide, etc.) can be removed from an organic extraction solvent such as ethyl acetate. In order to distribute to the water side, it is preferable to perform extraction and liquid separation using a saline solution (preferably, a 10% saline solution). The extraction and liquid separation are usually performed once to three times, preferably two to three times.

At the time of the extraction and liquid separation, the extract may be filtered using diatomaceous earth (for example, Celite trade name) from the viewpoint of improving the liquid separation rate. Activated carbon may be added in addition to the diatomaceous earth from the viewpoint of improving the hue of the target substance and improving the liquid separation property (removing the emulsion).

During the extraction and liquid separation, the temperature may be generally maintained at 20 to 50 ° C, preferably 30 to 40, more preferably 35 to 40 ° C.

After liquid separation, the organic layer is concentrated usually at 30 to 60 kPa, preferably 30 to 40 kPa, usually at 80 T or less, preferably at 40 to 80 ° C, more preferably at 50 to 60 ° C. It is desirable. Further, from the viewpoint of removing impurities, once concentration, the crystallization solvent described in detail below may be added, diluted, and concentrated again, and dilution and concentration may be repeated.

The compound (1) produced by the production method 1 of the present invention can be isolated and purified by adding a crystallization solvent to the concentrate obtained by the above-mentioned concentration and crystallizing in the solvent. Since the liquid contains a polymerization inhibitor, the isolation and purification can be carried out without substantially causing side reactions such as polymerization and decomposition.

Examples of the crystallization solvent include benzene and toluene with a mono-mouth, a mixed solvent of ethyl acetate and heptane, and the like. From the viewpoint of the crystallization yield and the effect of removing impurities, benzene and toluene are used. preferable.

As a method for isolating and purifying the compound (1) by crystallization, specifically, a solution of the above-mentioned crystallization solvent containing the compound (1) and a polymerization inhibitor (for example, a concentration obtained by concentration in the above-mentioned post-treatment) The solution obtained by adding the above-mentioned crystallization solvent to the product is heated (preferably heated to 70 to 85 ° C, more preferably to 75 to 85 ° C), and then the compound (1) crystal is formed. Concentrate to such an extent that precipitation does not occur (for example, 15 to 30 kPa, preferably 15 to 20 kPa, for example, 75 to 80 ° C., preferably 75 to 78 ° C.), and cool (for example, 15 to 20, preferably Is cooled to 15 to 17 ° C) to crystallize compound (1).

At the time of heating, for example, alumina or activated carbon may be added from the viewpoint of decolorization and removal of metallic impurities. In this case, the added alumina, activated carbon and the like are usually removed by filtration or the like before crystallization of compound (1).

When monochlorobenzene is used as the crystallization solvent, the yield in the crystallization step is 96 to 98%. Compound (1) can be stabilized by mixing a polymerization inhibitor with compound (1) (hereinafter, this method is referred to as the present stabilization method). That is, decomposition and polymerization of the compound (1) can be prevented.

In the present invention, “mixing the polymerization inhibitor with the compound (1)” means not only “mixing the polymerization inhibitor with the compound (1) itself” but also, for example, the compound (1) of the production method 1 of the present invention. By adding a polymerization inhibitor to the raw materials during the production of 1), An embodiment showing an effect substantially equivalent to or very similar to that obtained by mixing a polymerization inhibitor with the product (1) "is also included.

For example, in the crystallization of compound (1), compound (1) can be stabilized by mixing compound (1) with a polymerization inhibitor.

As a specific mixing mode, a polymerization inhibitor may be added to the solution or the reaction solution before crystallization and mixed, or after the compound (1) is crystallized, for example, the crystal (including the crude crystal) Mixing can also be performed by contact with a solution containing a polymerization inhibitor. As a specific method of contacting the crystals with a solution containing a polymerization inhibitor, a method of filtering the crystals and then washing the crystals with a solution containing a polymerization inhibitor can be mentioned.

As the polymerization inhibitor, those mentioned in the above-mentioned Production method 1 of the present invention can be similarly used. From the viewpoint of economy, 2,6-ditert-butyl-1-butyl-4-methylphenol is preferred.

Two or more polymerization inhibitors may be used in combination.

In the present stabilization method, the mixed weight of the polymerization inhibitor is usually 0.001 to 0.5 g, preferably 0.005 to 0.5 lg, and more preferably 0.01 to 0.05 per gram of the compound (1). g.

When a solution containing a polymerization inhibitor is used in the present stabilization method, the solvent for forming the solution must have high solubility in the polymerization inhibitor and wash the crystal of compound (1). There is no particular limitation as long as it can be obtained, but ethyl acetate, toluene, and monochlorobenzene are preferred. Among them, toluene and monochlorobenzene are particularly preferred from the viewpoint of suppressing dissolution loss of crystals due to washing.

The amount of the solvent used in the solution containing the polymerization inhibitor is not particularly limited as long as it can wash the crystals of compound (1), but preferably 2 to 6 parts by weight per part by weight of compound (1) Department.

By mixing compound (1) with a polymerization inhibitor, decomposition and polymerization of compound (1) can be prevented, and the compound can be stabilized. A step of obtaining the compound (1) by the production method 1 of the present invention (hereinafter, sometimes referred to as step A), reacting the compound (1) with a percarboxylic acid to obtain a compound of the formula (2)

A step of obtaining a compound (3) represented by (hereinafter, referred to as step C), and

By reacting the compound (3) with a percarboxylic acid to obtain bicalutamide (hereinafter referred to as step D), the compound of formula (4)

Can be produced stably and in a high yield (hereinafter, the production method is referred to as production method 2 of the present invention).

(Process

Step B is a step of obtaining a compound (2) represented by the formula (2) by oxidizing the compound (1). In step B, an oxidizing agent, percarboxylic acid, is added to compound (1) in a suitable reaction solvent.

Examples of the percarboxylic acid include m-chloroperbenzoic acid and monoperphthalic acid. Monoperphthalic acid is preferred from the viewpoint of safety and reactivity.

Monoperphthalic acid can be easily prepared, for example, by reacting phthalic anhydride with hydrogen peroxide.

Specifically, monoperphthalic acid is prepared by mixing phthalic anhydride and hydrogen peroxide in a suitable solvent in the presence of a base in approximately equimolar amounts. Preferably, a small excess of hydrogen peroxide is used relative to anhydrous phthalic acid. Specifically, hydrogen peroxide is generally used in an amount of 1 to 1.5 mol, preferably 1 to 1.3 mol, per 1 mol of fluoric anhydride.

Phthalic anhydride is inexpensive, has no hygroscopicity, and is easy to handle, and is therefore preferred as a raw material for monoperphthalic acid.

As the hydrogen peroxide, it is preferable to use aqueous hydrogen peroxide from the viewpoint of easy handling. The aqueous hydrogen peroxide is usually used at a concentration of 20 to 50%, preferably 30 to 35%. Hydrogen peroxide at a concentration of 30 to 35% is preferred because it has a low risk of explosion, is generally commercially available, and is inexpensive.

Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide and the like. From the viewpoint of economy, sodium carbonate is preferred. The amount of the base to be used is generally 1 to 1.3 mol, preferably 1 to 1.2 mol, per 1 mol of phthalic anhydride. Solvents to be used include solvents such as water.Among them, metals that may exhibit catalytic activity for decomposition of hydrogen peroxide are not contained, and solubility and economy of hydrogen peroxide are low. From the viewpoint of properties, deionized water is preferred. The amount of the solvent to be used is usually 2 to 5 m, preferably 3 to 4 ml, per 1 g of phthalic anhydride. The reaction temperature is usually from 15 to + 5 ° C, preferably from -5 to 0 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 5 to 2 hours, preferably 0.5 to 0.75 hours. After completion of the reaction, if necessary, the reaction system is neutralized with an acid such as sulfuric acid (preferably, 98% sulfuric acid), and then isolated and purified by ordinary post-treatment. It can be used for the subsequent oxidation reaction (ie, step B and step D above) without the need. Suitable solvents for the reaction in the step B include, for example, toluene, benzene, ethyl acetate and the like, and among them, ethyl acetate is preferred from the viewpoint of solubility in the compound (1).

The amount of the solvent to be used is usually 2-5 ml, preferably 2.5-4 ml, per 1 g of the compound (1).

The amount of percarboxylic acid to be used is generally 1.5 to 3 mol, preferably 1.8 to 2.5 mol, per 1 mol of compound (1).

As a method for adding the percarboxylic acid, it is preferable to add a percarboxylic acid solution dropwise from the viewpoint of easiness of addition, safety and operability. When the percarboxylic acid solution is dropped, the solution may be dropped in two or more portions.

Suitable solvents for preparing the percarboxylic acid solution include, for example, ethyl acetate, ethers (eg, getyl ether, etc.), and among them, ethyl acetate is preferable from the viewpoint of safety. It is desirable to use the same solvent as the reaction solvent. The amount of the solvent used for preparing the percarboxylic acid solution is usually 3 to; L0m1, preferably 3.5 to 7 ml per 1 g of the percarboxylic acid.

When dropping a percarboxylic acid solution, the dropping rate depends on the concentration of the dropping solution, the temperature of the dropping solution and the temperature of the solution to be dropped, but usually 1 to 4 mlZ minutes per 1 g of the compound (1), preferably 1 to 4 mlZ. 5 to 3 mlZ min.

When the percarboxylic acid solution is added dropwise, the temperature of the solution is usually 0 to 35 ° (: preferably 10 to 30 ° C).

When dropping a percarboxylic acid solution, the temperature of the solution to be dropped is usually 20 to 60 ° C. The temperature is preferably 40 to 55 ° C.

The reaction temperature is usually 20-60 ° C, preferably 45-55 ° C.

The reaction time varies depending on the reaction temperature and other reaction conditions, but is usually 5 to 15 hours, preferably 6 to 9 hours.

After the reaction is completed, if necessary, the reaction system is made weakly basic (for example, pH = 8) with a base such as potassium hydroxide or potassium carbonate, and isolated and purified by ordinary post-treatment. Good.

(Process C)

Step C is a step of reacting the compound (2) of the formula obtained in the above step B with 4-fluorothiophenol to obtain a compound (3). The reaction is usually carried out in the presence of a base. It is performed in.

In step C, examples of the base include sodium hydride, sodium hydroxide, sodium carbonate, potassium hydroxide and the like. From the viewpoint of economy, sodium hydroxide is preferred. As the sodium hydroxide, an aqueous sodium hydroxide solution is preferable because of easy handling. A commercially available aqueous sodium hydroxide solution may be used as it is, or a commercially available aqueous sodium hydroxide solution may be diluted. The concentration of the aqueous sodium hydroxide solution used is usually 5 to 20% by weight, preferably 15 to 20% by weight.

In step C, from the viewpoint of operability, a base is added in advance to a solution of 4-fluorothiophenol in a suitable reaction solvent (preferably, a solution containing a base is added dropwise). In advance, a method of adding the compound (2) to the mixture (preferably by adding a solution containing the compound (2) dropwise) is preferable. '

Suitable reaction solvents include polar solvents such as THF and t-butanol, and among them, THF is preferred from the viewpoint of solubility in compound (2).

The amount of the reaction solvent to be used is generally 1-40 ml, preferably 2-20 ml, per 1 g of compound (2).

The amount of the base to be used is generally 1 to 1.3 mol, preferably 1 to 1.2 mol, per 1 mol of 4-fluorothiophenol.

The addition temperature of the base is usually 0 to 30, preferably 0 to 20 ° C. The temperature at which the compound (2) is added is generally 0 to 15 ° (preferably 0 to 10 ° C.) When the compound (2) is added dropwise as a solution, an aprotic solvent such as THF is used as a solvent. Of these, THF is preferred from the viewpoint of solubility in compound (2), and the same solvent as the above reaction solvent is desirable, and the amount of the solvent to be used is generally 1 to 10 m per 1 g of compound (2). 1, preferably 2 to 6 m1.

The reaction temperature is usually 0 to 30 ° C, preferably 0 to 20 ° C.

The reaction time varies depending on the reaction temperature and other reaction conditions, but is usually 1 to 20 hours, preferably 2 to 15 hours.

After completion of the reaction, ordinary post-treatment may be performed, and if necessary, isolation and purification may be performed.

(Process D)

Step D is a step of reacting compound (3) with a percarboxylic acid to obtain bicalixamide (hereinafter sometimes referred to as compound (4)) represented by formula (4).

As the percarboxylic acid, those exemplified in Step B can be similarly used, and preferably, monoperphthalic acid can be used.

In step D, percarboxylic acid is added to compound (3) in a suitable reaction solvent. As a reaction solvent in the reaction of Step D, ethyl acetate is preferred from the viewpoint of operability.

The amount of the solvent used is usually 1 to 3 ml, preferably 1.5 to 2.5 ml, per 1 g of the compound (3).

The amount of percarboxylic acid to be used is generally 3-5 mol, preferably 3.5-4.5 mol, per 1 mol of compound (3).

As a method for adding the percarboxylic acid, dropping of a percarboxylic acid solution is preferable from the viewpoint of easiness of addition, safety, and operability. When the percarboxylic acid solution is added dropwise, the solution may be added in two or more portions.

Suitable solvents for preparing the percarboxylic acid solution include, for example, ethyl acetate, ethers (eg, getyl ether, etc.). Thus, ethyl acetate is preferred. It is desirable to use the same solvent as the above reaction solvent. The amount of the solvent used for preparing the percarboxylic acid solution is usually 3 to L0m1 per gram of percarboxylic acid, preferably 3.5 to 7 ml. It is.

When dropping a percarboxylic acid solution, the dropping rate depends on the concentration of the dropping solution, the temperature of the dropping solution and the temperature of the solution to be dropped, but usually 1 to 4 ml / min. Preferably 1.5-3. Oml // minute.

When the percarboxylic acid solution is added dropwise, the temperature of the solution is usually 0 to 30 ° C, preferably 10 to 25 ° C.

When the percarboxylic acid solution is added dropwise, the temperature of the solution to be added is usually 0 to 20 ° C, preferably 0 to 1 ° C.

The reaction temperature is generally 0-20 ° C, preferably 0-10 ° C.

The reaction time varies depending on the reaction temperature and other reaction conditions, but is usually 0.5 to 5 hours, preferably 1 to 3 hours.

After the completion of the reaction, for example, after the completion of the reaction, an extraction solvent (for example, an organic solvent such as ethyl acetate) is added to the reaction mixture, stirred, and allowed to stand. After standing, the extract (organic layer) obtained by separation is washed and concentrated, whereby compound (4) can be isolated. If necessary, it can be purified by recrystallization or the like.

When about 0.001 to 0.5 g of a polymerization inhibitor to compound (1) lg is further added to compound (1) obtained in step A, compound (1) Is not completely removed by washing solvent, for example, when stored under so-called diet conditions containing about 5 to 15% of washing solvent, for example, at 0 to 40 ° C for a period of about 1 to 60 days, Almost no quality deterioration due to polymerization, decomposition, etc. occurs. Therefore, for example, in the production of bicalutamide by the production method 2 of the present invention, after the compound (1) is produced in the step A, the production method 2 of the present invention is interrupted for some reason, or the reaction scale of the step A and the step B is different. Temporary storage of compound (1), which occurs when compound (1) obtained after repeating step A several times and combined and used in step B, can be performed without any problem under normal conditions. Example 1

To methacrylic acid (29.5 g) was added N, N-dimethylacetamide (85.5 g) and 2,6-di (tert-butyl) -4-methylphenol (0.05 g). Then, thionyl chloride (40.8 g) was added dropwise at a temperature of 15 ± 7 ° C (-12 to 2 ° C). The mixture was stirred at the same temperature for 1 hour.

A solution prepared by dissolving 4-cyano-3-trifluoromethylaniline (48.0 g) in N, N-dimethylacetamide (112.4 g) was added to a solution of 15 ± 7 ° C (−12 ° C ~ 2 ° C). C), the mixture was added dropwise to the above reaction solution at the temperature of C), and the mixture was stirred at the same temperature for 1 hour. High-performance liquid chromatography (HPLC) confirmed the disappearance of the raw material (4-cyano 3 _trifluoromethylaniline).

The above reaction solution was added dropwise to a mixture of a 17% aqueous sodium carbonate solution (907 g) and ethyl acetate (310 g). Separate, add activated carbon (2.4 g) and 10% saline (720 g) to the organic phase, filter through Nutsche pre-coated with Celite (6.7 g), and filter Nutsche with ethyl acetate (43 g). Washed. The filtrate was separated, 10% saline (720 g) was added to the organic phase, the mixture was kept at 35 ° C to 40 ° C, and then separated. The organic phase was concentrated (ethyl acetate) at about 30 kPa and an internal temperature of 80 ° C or less, and benzene (494 g) was added thereto. The content of ethyl acetate in the concentrate was 0.8%.

To the concentrated solution, benzene (595 g) was added, and at about 75 ° C., alumina (6.5 g) was added. After stirring for 15 minutes, the mixture was filtered. Alumina was washed with benzene (33 g), and the combined benzene solution was concentrated at 15 kPa and an internal temperature of 75 ° (: up to 78 ° C. The distillation amount of benzene was 511 ml to 538 ml. When the concentration reached, the concentration was stopped, the concentrate was cooled to 15 ° C to 20 ° C, and N-methacrylonitrile 4-cyano-3-trifluoromethylaniline was crystallized. The crystals were collected by filtration and washed with monochlorobenzene (159 g) in which 2,6-di (tert-butyl) -14-methylphenol (0.73 g) was dissolved, and the crystals were dried and N-methacryloyl was removed. There was obtained 4-41-cyano-3-trifluoromethylaniline (58.34 g), yield 89%.

IR (KB r): 3387, 3063, 2992, 2229, 1693, 1528 , 1330, 1171, 1129, 1050, 928, 907, 854 cm- ¹ . Example 2

To methacrylic acid (29.5 g) were added N, N-dimethylacetamide (85.5 g) and 2,6-di-tert-butyl-4_methylphenol (0.05 g). Thionyl chloride (40.8 g) was added dropwise at ± 7 ° C. The mixture was stirred at the same temperature for 30 minutes.

A solution of 4-cyano-3-trifluoromethylaniline (48.0 g) dissolved in N, N-dimethylacetamide (112.4 g) was dropped into the previous reaction solution at −5 ± 7 ° C. The mixture was stirred at the same temperature for 1 hour. The disappearance of the raw material (4-cyano 3-trifluoromethylaniline) was confirmed by high-performance liquid chromatography (HPLC).

The above reaction solution was added dropwise to a mixture of water (336 g) and ethyl acetate (367.6 g). Next, a mixed solution of water (480 g) and sodium carbonate (91.0 g) was added until the pH reached 7.1.

After liquid separation, the obtained organic layer was washed twice with 10% saline (720 g), and chlorobenzene (265.4 g) was added, followed by concentration under reduced pressure. The distillate at that time was 287.2 g.

Next, chlorobenzene (743.2 g), activated carbon (2.4 g) and alumina (6.5 g) were charged, and after stirring at 80 ° C for 30 minutes, the activated carbon and alumina were filtered off, and chlorinated. Washed with benzene (53.1 g). Thereafter, the mixture was concentrated under reduced pressure. The distillate at that time was 703.0 g.

Then, it was cooled to 65 ° C, and after crystallization, cooled to 20 ° C and kept at the same temperature for 1.5 hours.

Thereafter, the obtained crystals were separated by filtration and washed with monochlorobenzene (159 g) in which 2,6-di-tert-butyl-4-methylphenol (0.73 g) was dissolved.

'The crystals were dried to obtain N-methacryloylue 4-cyano 3-trifluoromethylaniline (60.0 g, yield: 91.5%. When DSC (differential scanning calorimetry) was measured. An exothermic peak was observed at 205. The calorific value was 4.8 ca 1 Zg. DSC measurement: Shimadzu DSC-60 Example 3

To N, N-dimethylacetamide (32.8 g) and 2,6-di-tert-butyl-4-monomethylphenol (0.02 g) were added to methacrylic acid (11.4 g). Then, at −5 ± 7 ° C., thionyl chloride (15.8 g) was added dropwise. The mixture was stirred at the same temperature for 30 minutes.

A solution of 4-cyano-3-trifluoromethylaniline (18.6 g) dissolved in N, N-dimethylacetamide (38.4 g) was added dropwise to the previous reaction solution at 15 ± 7 ° C and the same temperature For 1 hour. High-performance liquid chromatography (HPLC) confirmed the disappearance of the raw material (4-cyano-3-trifluoromethylaniline).

The reaction solution was dropped into a mixture of water (130 g) and ethyl acetate (142.4 g). Then, a mixed solution of water (186 g) and sodium carbonate (35.3 g) was added until the pH reached 7.1.

After liquid separation, the obtained organic layer was washed three times with 15% saline (295.3 g), and then concentrated to obtain crude N-methacryloyl-1-cyano 3-tritrifluoromethylaniline 25.0 g. Got.

When DSC (differential scanning calorimetry) was measured, an exothermic peak was observed at 206 ° C. The calorific value was 7.2 calLZg.

DSC measurement: Shimadzu DSC-60 Comparative Example 1

N, N-Dimethylacetamide (345.3 g) was added to methacrylic acid (94.7 g), and then thionyl chloride (130.9 g) was added dropwise at 0 ± 2 ° C. The mixture was stirred at the same temperature for 2 hours.

A solution of 4-cyano-3-trifluoromethylaniline (153.6 g) dissolved in N, N-dimethylacetamide (360.0 g) was dropped into the previous reaction solution at 0 ± 2 ° C. The mixture was stirred at the same temperature for 1 hour. The disappearance of the raw material (4-cyano-3-trifluoromethylaniline) was confirmed by high performance liquid chromatography (HPLC). The reaction solution was added dropwise to a mixture of a 10% aqueous sodium carbonate solution (2912 g) and ethyl acetate (990 g). After liquid separation, the obtained organic layer was washed three times with 10% saline (573 g), and then 580 g of ethyl acetate was distilled off by concentration. Monochlorobenzene (1259 g) was charged, and the mixture was further concentrated to 664 g. Distill.

1356 g of monochlorobenzene was added to the concentrated solution, and after dissolving at about 75 ° C, alumina (21.5 g) was added and the mixture was stirred for 30 minutes.

The alumina was filtered off, washed with monochlorobenzene (102.9 g), and concentrated to distill off 1645 g of monochlorobenzene.

Then, N-methacryloylue 4-cyano 3_trifluoromethylaniline was crystallized by cooling. After cooling to 15 and stirring at the same temperature for 2 hours, the crystals were collected by filtration and washed with 203.5 g of monochlorobenzene.

The crystals were dried to give N-methacryloylu-4-cyano-13-trifluoromethylaniline (180.8 g). Yield 87.2%. When D S C (differential scanning calorimetry) was measured, an exothermic peak was observed at 155 ° C. The calorific value was 7.68 c a 1 Zg.

DSC Measurement: Shimadzu Seisakusho DSC-60 According to the present invention, N-methacryloyl-4-1-cyano-3-trifluoromethylaniline, an intermediate of bicalutamide, which is useful as an anticancer agent, is produced in a stable and high yield. In addition, N-methacryloyl-14-cyano-3-trifluoromethylaniline can be stabilized. As a result, bicalutamide can be stably supplied with high yield and high purity. The method for producing and stabilizing N-methacryloylu 4-cyano-13-trifluoromethylaniline is useful for industrial production of bicalutamide.

Claims

The scope of the claims

1. N-methacryloyl 4-4-cyano-3-trifluoro comprising reacting 4-cyano 3-trifluoromethylaniline with methacrylic acid or a reactive derivative thereof in the presence of a polymerization inhibitor A method for producing romethylaniline.

2. The method according to claim 1, wherein the reactive derivative of methacrylic acid is methacryloyl chloride.

3. The method according to claim 1, wherein the polymerization inhibitor is at least one compound selected from the group consisting of 2,6-di-tert-butyl-4-monomethylphenol and butylated hydroxyanisole. the method of.

4. The method according to claim 1, wherein the weight of the polymerization inhibitor added to the reaction system is 500 to 3000 ppm based on 4-cyano 3-trifluoromethyl diamine.

5. A method for stabilizing N-methacryloylu-4-1-cyano-13-trifluoromethylaniline, which comprises mixing a polymerization inhibitor with N-methacryloylu-4-cyano-3-trifluoromethylaniline.

6. The method according to claim 5, wherein the mixing weight of the polymerization inhibitor is 0.001 g to 0.5 g per 1 g of N-methacryloyl 4-cyano-3-trifluoromethylaniline.

7. The method according to claim 5, wherein the polymerization inhibitor is at least one compound selected from the group consisting of 2,6-di-tert-butyl-4-methylphenol and butylated hydroxyanisole.

8. 4-Icano_3_trifluoromethylaniline and methacrylic acid or a reactive derivative thereof are reacted in the presence of a polymerization inhibitor to obtain the formula (1)

Step A of obtaining a compound (1) represented by

Step B of obtaining a compound (2) represented by

The compound (2) is reacted with 4-fluorothiophenol to form a compound of the formula (3)

A step C of obtaining a compound (3) represented by

A method for producing bicalutamide represented by the formula:

9. The method according to claim 8, wherein the reactive derivative of methacrylic acid is methacryloyl chloride.

10. The method according to claim 8, wherein the polymerization inhibitor in the reaction of Step A is at least one compound selected from the group consisting of 2,6-di-tert-butyl-4-methylphenol and butylated hydroxydisole. The described method.

11. The method according to claim 8, wherein the weight of the polymerization inhibitor added in the reaction in the step A is 500 to 3000 ppm based on 4-cyano-3-trifluoromethylaniline.

12. The method of claim 8, wherein step A further comprises adding a polymerization inhibitor to the resulting compound (1).

13. The method according to claim 12, wherein the polymerization inhibitor added in the reaction of the step A and the polymerization inhibitor further added to the obtained compound (1) are the same polymerization inhibitor.

14. The method according to claim 12, wherein in Step A, the weight of the polymerization inhibitor further added to the obtained compound (1) is 0.001 g to 0.5 g per 1 g of the compound (1).

15. The method of claim 12, wherein step A comprises storing the compound (1) at 0-40 ° C for 1-60 days after adding a polymerization inhibitor.