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AssigneeSumika Fine Chemicals Co., Ltd.
InventorsTetsuya Shintaku, Tadashi Katsura, Nobushige Itaya
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The present invention relates to a crystal of bicalutamide having a defined form, as well as economical and industrially practical production methods of bicalutamide and a crystal thereof, which are superior in environmental benignity and safety. Accordingly, the present invention provides a production method of bicalutamide represented by the formula (I): 1 which includes at least a step of reacting a compound represented by the formula (3): 2 with an oxidizing agent, a production method of a crystal of bicalutamide, as well as a crystal form of bicalutamide as defined by X-ray diffraction (XRD) or solid 13C NMR measurement.
A production method of bicalutamide represented by the formula (I):
A production method of bicalutamide represented by the formula (I):
A production method of bicalutamide represented by the formula (I):
A production method of bicalutamide represented by the formula (I):
A production method of a crystal of bicalutamide, comprising the following Steps (I)-(III):
A crystal of bicalutamide having peaks of δ at 177.08, 168.16, 164.69, 142.31, 136.58, 133.09, 124.80, 118.50, 116.16, 104.68, 75.56, 67.14 and 29.23 ppm in 13C-NMR.
Dependencies are inferred from the claim text.
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Preparation of sulfones; Preparation of sulfoxides: separation; Purification; Stabilisation; Use of additives
Drugs for disorders of the endocrine system
Of the sex hormones: antiandrogens
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
Term end not estimated
The present invention relates to a crystal of bicalutamide having a defined form and a production method thereof.
Bicalutamide represented by the formula (I): 3
(hereinafter sometimes referred to as compound of the formula (I) or compound (I) in the present specification) has been reported to be useful as a compound having an antiangrogenic action (JP-B-4-32061, U.S. Pat. No. 4,636,505 and WO01/34563). As a synthetic method of the compound of the formula (I), for example, a method comprising a reaction of 4′-cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide represented by the formula (3): 4
FIG. 1 is a chart showing solid 13C VACP/MAS NMR spectrum of a crystal of bicalutamide, wherein the symbol * shows a spinning side band.
The present invention is explained in detail by referring to the following Scheme 1. 16
In the present invention, the total synthesis of bicalutamide is started using 4-cyano-3-(trifluoromethyl)aniline as a starting material. 4-Cyano-3-(trifluoromethyl)aniline may be commercially available or may be separately synthesized and used, because its structure is simple (J. Am. Chem. Soc., 76, 1051-1054 (1954); see EP2892). By subjecting 4-cyano-3-(trifluoromethyl)aniline to condensation reaction with methacrylic acid or its reactive derivative (e.g., methacryloyl halide etc., preferably methacryloyl chloride), an olefin compound represented by the above-mentioned formula (1) (hereinafter sometimes referred to as compound (1)) can be obtained. Since methacrylic acid and its reactive derivative are extremely economical as commercially available products and can be easily obtained in large amounts, the condensation reaction may be an industrially and economically effective means. This condensation reaction can be carried out according to conventional amide chemistry. In addition, compound (1) can be used for the next reaction without isolation and/or purification.
Step A and Step C are oxidation steps using an oxidizing agent.