Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2003-02-24
2004-05-25
Tsang, Cecilia (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C558S414000
Reexamination Certificate
active
06740770
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a crystal of bicalutamide having a defined form and a production method thereof.
BACKGROUND ART
Bicalutamide represented by the formula (I):
(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):
(hereinafter sometimes referred to as compound of the formula (3) or compound (3)) in methylene chloride solution with m-chloroperbenzoic acid is known (Howard Tucker et al, J. Med. Chem., Vol. 31, 954-959 (1988), and WO01/28990). In this method, methylene chloride is used as a solvent. Halogenated organic solvents such as methylene chloride and the like are generally harmful for human body, and the possibility of carcinogenicity thereof has been suggested. Furthermore, they may produce dioxin during waste treatments. Halogenated organic solvents such as methylene chloride and the like are associated with the problems of economic burden for the cost of waste treatment after use, and of corrosion of incinerator used for the waste treatment.
In recent years, “Green Chemistry” has been drawing attention as one of the measures for risk reduction of chemical substances, and industrial application of environmentally benign type chemical reactions (or reaction not using substances potentially harmful to human body and the environment (e.g., halogen-containing substances etc.) as much as possible, and not emitting them as much as possible) has become a very important object. From this aspect, the above-mentioned production method using methylene chloride as an organic solvent is not entirely a preferable production method of bicalutamide. Therefore, the development of a production method of bicalutamide, which is superior in environmental benignity, is desired.
In addition, the above-mentioned method uses m-chloroperbenzoic acid as an oxidizing agent. m-Chloroperbenzoic acid is highly explosive and is not preferable for industrial processes. Furthermore, m-chloroperbenzoic acid is expensive and poses an economic problem.
Accordingly, industrial practice of the above-mentioned method at a large scale gives rise to the problems not only in environmental benignity, but also safety and economic aspect, due to the use of a halogenated organic solvent as the solvent and of m-chloroperbenzoic acid as the oxidizing agent.
At the moment, as a synthetic method of bicalutamide, which is free of the use of m-chloroperbenzoic acid as an oxidizing agent, the method described in, for example, WO01/00608 is known. According to this method, compound (3) is oxidized with aqueous hydrogen peroxide as an oxidizing agent, in acetic acid or formic acid, for the synthesis of bicalutamide. Thus, this method is considered to be environmentally, economically and industrially superior. In this method, however, synthesis of precursor compound (3) requires many steps (at least 4 steps), which makes this method not an economically and industrially superior synthetic method for the total synthesis of bicalutamide. Furthermore, this method includes steps using a halogenated solvent (e.g., methylene chloride etc.) for the synthesis of compound (3). Thus, it is difficult to say that this method is sufficiently environmentally conscious.
As a synthetic method of bicalutamide free of use of m-chloroperbenzoic acid as an oxidizing agent, a method described in WO02/24638 is also known. The method described in WO02/24638 includes adding aqueous hydrogen peroxide to compound (3), cooling (e.g., −55° C.) the mixture, and adding trifluoroacetic anhydride to the mixture to give bicalutamide. However, this method uses expensive trifluoroacetic anhydride as a reagent, and requires cooling when trifluoroacetic anhydride is added, and is not an economically superior method. Furthermore, because of the corrosive and hygroscopic property of trifluoroacetic anhydride, the method is unsuitable for the industrial production of bicalutamide.
Accordingly, the development of an economical and industrially practical production method of bicalutamide, which is superior in environmental benignity and safety, is desired in this field.
For efficient granulation of a crystal in the field of the production of pharmaceutical drugs, it is desirable that the form of the crystal be defined. However, the form of the crystal of bicalutamide is not defined in any of the above-mentioned references, and therefore, those of ordinary skill in the art of the production of pharmaceutical drugs strongly desire provision of bicalutamide crystals having a defined form.
DISCLOSURE OF THE INVENTION
It is therefore an object of the present invention to provide bicalutamide having a defined crystal form, as well as an economical and industrially practical production method of bicalutamide and a crystal thereof, which is superior in environmental benignity and safety.
As a result of intensive studies by the present inventors in an attempt to solve the above-mentioned problems, they have found that bicalutamide having high purity can be produced in a large amount by reacting a compound of the above-mentioned formula (3) with aqueous hydrogen peroxide, which is an oxidizing agent, using ethyl acetate as a solvent, in the presence of sodium tungstate (or a solvate thereof), phenylphosphonic acid and a phase transfer catalyst. This method is superior in environmental benignity, economic aspect and safety, and is industrially practicable. The present inventors have also found that mono-perphthalic acid as an oxidizing agent prepared from phthalic anhydride and hydrogen peroxide is highly effective as an oxidizing agent for oxidation of olefin to epoxide, and for oxidation of thioether to sulfone, based on which fact they have found production methods of bicalutamide and a crystal thereof, which are mainly based on oxidation reactions and which are capable of finally deriving bicalutamide, which is a sulfone, sequentially via olefin, epoxide and thioether (compound (3)) from a simple starting material, as well as the specific form of the crystal of bicalutamide, which resulted in the completion of the present invention. Accordingly, the present invention provides the following.
[1] A production method of bicalutamide represented by the formula (I):
which comprises a step of reacting a compound represented by the formula (1):
with mono-perphthalic acid to give a compound represented by the formula (2):
[2] The production method of the above-mentioned [1], further comprising use of methanesulfonyl chloride.
[3] A production method of bicalutamide represented by the formula (I):
which comprises reacting a compound represented by the formula (3):
with mono-perphthalic acid.
[4] The production method of any of the above-mentioned [1] to [3], which comprises preparing the mono-perphthalic acid from phthalic anhydride and hydrogen peroxide.
[5] A production method of bicalutamide represented by the formula (I):
which comprises the following Steps (A)-(C):
(A) a step of reacting a compound represented by the formula (1):
with mono-perphthalic acid to give a compound represented by the formula (2):
(B) a step of reacting the compound of the formula (2) obtained in Step (A) with 4-fluorothiophenol to give a compound represented by the formula (3):
(C) a step of reacting the compound of the formula (3) obtained in Step (B) with mono-perphthalic acid to give bicalutamide.
[6] The production method of the above-mentioned [5], wherein the Step (A) further comprises use of methanesulfonyl chloride.
[7] The production method of the above-mentioned [5] or [6], which comprises a step of pr
Itaya Nobushige
Katsura Tadashi
Shintaku Tetsuya
Sackey Ebenezer
Sumika Fine Chemicals Co., Ltd.
Tsang Cecilia
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