WO2005014531A1 - Procede de production de n-methacryloyl-4-cyano-3-trifluoromethylaniline, procede de stabilisation de ce compose, et procede de production de bicalutamide - Google Patents

Procede de production de n-methacryloyl-4-cyano-3-trifluoromethylaniline, procede de stabilisation de ce compose, et procede de production de bicalutamide Download PDF

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Publication number
WO2005014531A1
WO2005014531A1 PCT/JP2004/011800 JP2004011800W WO2005014531A1 WO 2005014531 A1 WO2005014531 A1 WO 2005014531A1 JP 2004011800 W JP2004011800 W JP 2004011800W WO 2005014531 A1 WO2005014531 A1 WO 2005014531A1
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compound
polymerization inhibitor
cyano
trifluoromethylaniline
reaction
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Japanese (ja)
Inventor
Kiyoshi Sugi
Tetsuya Shintaku
Tadashi Katsura
Nobushige Itaya
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

Definitions

  • 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.
  • N-methylacryloyl-1-cyano-3-trifluoromethylaniline is an intermediate of bicalutamide useful as an anticancer drug.
  • 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).
  • 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.
  • 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.
  • 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.
  • ⁇ 2> The method according to ⁇ 1>, wherein the reactive derivative of methacrylic acid is methacryloyl chloride.
  • the polymerization inhibitor is at least one compound selected from the group consisting of 2,6-di-tert-butyl-4-methylphenol and butylated hydroxyazole.
  • ⁇ 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.
  • 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.
  • the compound (1) is reacted with a percarboxylic acid to form a compound of the formula (2)
  • Formula (4) including a step D of reacting the compound (3) with a percarboxylic acid to obtain bicalutamide
  • 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>.
  • step A further comprises adding a polymerization inhibitor to the obtained compound (1).
  • 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>.
  • 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.
  • 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.
  • 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).
  • 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.
  • an amidating agent such as DCC.
  • the reactive derivative of methacrylic acid is not particularly limited as long as it has reactivity with an amino group.
  • X is a halogen (for example, chlorine, bromine, iodine, etc.)
  • methacrylic acid halides such as methacrylic acid chloride, methacrylic acid bromide, methacrylic acid iodide, Methacrylic anhydride and the like.
  • polymerization inhibitor examples 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.
  • 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.
  • a commercially available product may be used, or its reactive derivative may be separately prepared from methacrylic acid and used.
  • 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.
  • 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).
  • DMAC N, N-dimethylacetoamide
  • 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.
  • 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.
  • 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.
  • 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.
  • a solvent is usually used.
  • 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
  • side reactions eg, polymerization reaction, decomposition reaction, etc.
  • 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.
  • the reaction solvent for example, N, N-dimethylacetamide and the like
  • the reaction solvent eg, N, N-dimethylacetamide, etc.
  • the reaction solvent can be removed from an organic extraction solvent such as ethyl acetate.
  • 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.
  • the extract may be filtered using diatomaceous earth (for example, Celite trade name) from the viewpoint of improving the liquid separation rate.
  • diatomaceous earth for example, Celite trade name
  • 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).
  • the temperature may be generally maintained at 20 to 50 ° C, preferably 30 to 40, more preferably 35 to 40 ° C.
  • 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.
  • crystallization solvent examples 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.
  • 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.
  • cool for example, 15 to 20, preferably Is cooled to 15 to 17 ° C to crystallize compound (1).
  • alumina or activated carbon may be added from the viewpoint of decolorization and removal of metallic impurities.
  • the added alumina, activated carbon and the like are usually removed by filtration or the like before crystallization of compound (1).
  • 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.
  • 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.
  • compound (1) in the crystallization of compound (1), can be stabilized by mixing compound (1) with a polymerization inhibitor.
  • 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.
  • a 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.
  • 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.
  • 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.
  • the solvent for forming the solution must have high solubility in the polymerization inhibitor and wash the crystal of compound (1).
  • 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.
  • step A By mixing compound (1) with a polymerization inhibitor, decomposition and polymerization of compound (1) can be prevented, and the compound can be stabilized.
  • step A 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)
  • step C A step of obtaining a compound (3) represented by (hereinafter, referred to as step C), and
  • step D By reacting the compound (3) with a percarboxylic acid to obtain bicalutamide (hereinafter referred to as step D), the compound of formula (4)
  • production method 2 of the present invention Can be produced stably and in a high yield (hereinafter, the production method is referred to as production method 2 of the present invention).
  • Step B is a step of obtaining a compound (2) represented by the formula (2) by oxidizing the compound (1).
  • an oxidizing agent percarboxylic acid
  • percarboxylic acid examples 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.
  • 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.
  • a small excess of hydrogen peroxide is used relative to anhydrous phthalic acid.
  • 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.
  • aqueous hydrogen peroxide 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.
  • 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).
  • the percarboxylic acid solution dropwise from the viewpoint of easiness of addition, safety and operability.
  • 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.
  • 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.
  • the temperature of the solution is usually 0 to 35 ° (: preferably 10 to 30 ° C).
  • 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.
  • 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.
  • 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.
  • sodium hydroxide is preferred.
  • 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.
  • 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).
  • 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.)
  • an aprotic solvent such as THF is used as a solvent.
  • 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.
  • 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).
  • percarboxylic acid those exemplified in Step B can be similarly used, and preferably, monoperphthalic acid can be used.
  • step D percarboxylic acid is added to compound (3) in a suitable reaction solvent.
  • 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).
  • dropping of a percarboxylic acid solution is preferable from the viewpoint of easiness of addition, safety, and operability.
  • 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.
  • 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.
  • the temperature of the solution is usually 0 to 30 ° C, preferably 10 to 25 ° C.
  • 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.
  • an extraction solvent for example, an organic solvent such as ethyl acetate
  • an organic solvent such as ethyl acetate
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the alumina was filtered off, washed with monochlorobenzene (102.9 g), and concentrated to distill off 1645 g of monochlorobenzene.
  • 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.
  • N-methacryloyl-4-1-cyano-3-trifluoromethylaniline an intermediate of bicalutamide, which is useful as an anticancer agent
  • N-methacryloyl-14-cyano-3-trifluoromethylaniline can be stabilized.
  • 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.

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Abstract

L'invention concerne un procédé de production de N-méthacryloyl-4-cyano-3-trifluorométhylaniline consistant à faire réagir le composé 4-cyano-3-trifluorométhylaniline avec de l'acide méthacrylique ou un dérivé réactif de celui-ci, en présence d'un inhibiteur de polymérisation. Cette invention concerne en outre un procédé de production de bicatulamide consistant : à faire réagir le composé 4-cyano-3-trifluorométhylaniline avec de l'acide méthacrylique ou un dérivé réactif de celui-ci, en présence d'un inhibiteur de polymérisation, et ; à faire réagir le composé N-méthacryloyl-4-cyano-3-trifluorométhylaniline obtenu, successivement avec de l'acide peroxycarboxylique, le composé 4-fluorothiophénol et de l'acide peroxycarboxylique. La présente invention se rapporte par ailleurs à un procédé de stabilisation du composé N-méthacryloyl-4-cyano-3-trifluorométhylaniline qui consiste à incorporer un inhibiteur de polymérisation dans le composé N-méthacryloyl-4-cyano-3-trifluorométhylaniline.
PCT/JP2004/011800 2003-08-12 2004-08-11 Procede de production de n-methacryloyl-4-cyano-3-trifluoromethylaniline, procede de stabilisation de ce compose, et procede de production de bicalutamide Ceased WO2005014531A1 (fr)

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JP2003-292498 2003-08-12
JP2003292498A JP2005060302A (ja) 2003-08-12 2003-08-12 Ｎ−メタクリロイル−４−シアノ−３−トリフルオロメチルアニリンの製造方法および安定化方法

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WO2022249994A1 (fr) * 2021-05-28 2022-12-01 富士フイルム株式会社 Procédé de production de composés n-(hétéro)aryl(méth)acrylamide

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