Abstract:
Valdecoxib Form A is prepared by a process comprising adding aqueous ammonia to a solution of 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonyl chloride in a halogenated hydrocarbon or water.

Description:
CROSS-REFERENCE TO RELATED APPLICATION  
       [0001]     This application derives priority from U.S. Provisional Application 60/572,597 filed May 19, 2004, the entire content of which is hereby incorporated by this reference. 
     
    
     INTRODUCTION TO THE INVENTION  
       [0002]     The present invention relates to a process for the preparation of crystalline Form A of valdecoxib. Valdecoxib, which is chemically known as 4-(5 methyl-3-phenyl-4-isoxazolyl) benzene sulfonamide, is represented by Formula (I)  
                         
 
         [0003]     The present invention also relates to a process for the purification of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride, an intermediate in the preparation of valdecoxib, and its subsequent conversion to valdecoxib. Valdecoxib obtained by this process is substantially free of its meta-isomer.  
         [0004]     Valdecoxib is a potent and specific inhibitor of cyclooxygenase-2, and is used for the treatment of rheumatoid arthritis, osteoarthritis, and dysmenorrhea pain. A commercial pharmaceutical product containing valdecoxib has the trademark BEXTRA.  
         [0005]     U.S. Pat. No. 5,633,272 discloses valdecoxib specifically, its pharmaceutical formulations and use in the treatment of rheumatoid arthritis, osteoarthritis, and dysmenorrhea pain. The &#39;272 patent discloses a process for the preparation of valdecoxib, which comprises the reaction of desoxy benzoin with hydroxylamine hydrochloride in the presence of potassium hydroxide to give desoxybenzoin keto-oxime, which further reacts with acetic anhydride in the presence of N-butyl lithium in tetrahydrofuran to give 3,4-diphenyl-4-hydrido-5-hydroxy-5-methyl isoxazole. Successive treatment of the resultant solid with chlorosulfonic acid and saturated ammonium hydroxide solution gives 4-(5-methyl-3-phenyl isoxazol-4-yl) benzene sulfonamide.  
         [0006]     U.S. Patent Application No. 2003/0162813 A1 also discloses a process for the preparation of valdecoxib, which comprises the reaction of 4-acetyl benzene sulfonyl chloride with ammonium hydroxide in ether to form 4-sulfonyl acetophenone, which on reaction with lithium diisopropylamide and hexamethyl phosphoramide yields 1-(4-sulfonyl phenyl)-1-propyne. Benzaldehyde oxime is reacted with chloramine-T in methanol and upon refluxing gives benzonitrile oxide. The resultant benzonitrile reacts with 1-(4-sulfonyl phenyl)-1-propyne in ethanol at reflux temperature to give 4-(5-methyl-3-phenyl-isoxazol-1-yl) benzene sulfonamide.  
         [0007]     U.S. Pat. No. 6,441,014 discloses the process for the preparation of crystalline Form A (Example 6) and Form B (Example 1) of valdecoxib.  
         [0008]     U.S. Patent Application No. 2003/0105334 A1 discloses a preparation of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride in the presence of toluene and further recrystallization from heptane. The product has a purity of about 85 percent.  
         [0009]     The processes disclosed in the art suffer from the disadvantages such as being costly, using pyrophoric reagents, and provide a poor yield, and are therefore not suitable for scale-up and commercial manufacturing.  
         [0010]     Accordingly, there is a need for a process for the preparation of valdecoxib crystalline forms, which is simple, provides high yield, is industrially feasible, environmentally friendly and easy to scale-up.  
     
    
     BRIEF DESCRIPTION OF THE DRAWING  
       [0011]      FIG. 1  is an X-Ray powder diffraction (XRD) pattern of crystalline Form A of valdecoxib. 
     
    
     SUMMARY OF THE INVENTION  
       [0012]     The present invention relates to a process for the preparation of crystalline forms of valdecoxib, particularly Form A of valdecoxib.  
         [0013]     One aspect of the present invention provides a process for the purification of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride (an intermediate of valdecoxib) and its subsequent conversion to valdecoxib.  
         [0014]     A process for the preparation of crystalline Form A of valdecoxib comprises: 
        (a) adding aqueous ammonia to a solution of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride in a solvent;     (b) optionally adding seed crystals of Form A of valdecoxib to the reaction mass of step (a) and stirring;     (c) filtering the separated solid of step (b);     (d) washing the solid of step (c) by solvent of step (a); and     (e) drying the solid of step (d) to obtain crystalline Form A of valdecoxib.        
 
         [0020]     A process for purifying 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride comprises: 
        (1) dissolving 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride in an organic solvent(s) accompanied by continuous stirring;     (2) cooling the solution of step (1) accompanied by stirring;     (3) separating the resultant solid by filtration;     (4) washing the solid with the solvent used in step (1); and     (5) drying the solid to obtain the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride.        
 
         [0026]     The processes of the present invention are simple, cost effective, industrially feasible, environmentally friendly, and commercially suitable over prior processes.  
       DETAILED DESCRIPTION  
       [0027]     One embodiment of the present invention is a process for the preparation of crystalline Form A of valdecoxib.  
         [0028]     A process for the preparation of crystalline Form A of valdecoxib comprises: 
        (a) adding aqueous ammonia to a solution of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride in a solvent;     (b) optionally adding seed crystals of Form A of valdecoxib to the reaction mass of step (a) accompanied by stirring to form a solid;     (c) separating the solid of step (b), such as by filtration;     (d) washing the solid of step (c) with the organic solvent of step (a);     (e) drying the solid of step (e) to obtain crystalline Form A of valdecoxib.        
 
         [0034]     The solvents useful in the invention can be halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, or mixtures thereof, or water. It is preferred to use dichloromethane or water.  
         [0035]     The reaction is performed at temperatures below about 50° C., preferably about 25 to 35° C.  
         [0036]     The quantity of solvent used in the above process can be varied from 5-30 times, preferably 10 times, of the weight of the 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride.  
         [0037]     Crystalline Form A of valdecoxib as seeding material can be used optionally from about 2-10 percent by weight of the 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride.  
         [0038]     Another embodiment of the present invention is a process for the purification of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride (an intermediate of valdecoxib) and subsequent conversion of this intermediate to valdecoxib.  
         [0039]     The process for the purification of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride comprises: 
        (1) dissolving 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride in an organic solvent(s) accompanied by continuous stirring;     (2) cooling the solution of step (1), accompanied by stirring to form a solid;     (3) separating the resultant solid by filtration;     (4) washing the solid with solvent used in step (1);     (5) drying the solid to obtain the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride.        
 
         [0045]     The purified 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride can be dissolved in a solvent to form the starting solution for the process described above to prepare valdecoxib Form A.  
         [0046]     Examples of useful organic solvents include cyclohexane, dichloromethane, dichloroethane, chloroform, ethyl acetate, acetone and hexane or mixtures thereof.  
         [0047]     It is also possible to start the reaction using crude 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride. The obtained pure compound 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride obtained from the process can be converted to valdecoxib crystalline Form A which is substantially free from its meta isomer.  
         [0048]     4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride obtained by the present process generally has a purity of at least 99.5% by HPLC.  
         [0049]     The processes of the present invention are further described by the following examples. These examples are provided for illustration only and should not be construed as a limitation of the scope of the invention.  
       EXAMPLE 1  
       [0050]     25 ml of 19.5% w/v aqueous ammonia solution were added slowly to a solution of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride (5 grams) in dichloromethane (50 ml) at 25-30° C. 0.5 grams of crystalline Form A of valdecoxib (as seeding material) was charged to the reaction mass at 25-30° C. and the reaction mass was stirred for 35-45 minutes. The separated solid was filtered and washed with dichloromethane (5 ml). The compound was suction dried under reduced pressure followed by drying at 35-40° C. under reduced pressure to obtain the desired crystalline Form A of valdecoxib. The yield of the compound was 4 grams and the X-ray diffraction pattern for the product is shown in  FIG. 1 .  
       EXAMPLE 2  
       [0051]     25 ml of 19.5% w/v aqueous ammonia solution were added slowly to a solution of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride (5 grams) in water (25 ml) at 25-35° C. The reaction mass was heated to 55-60° C. and stirred at this temperature until completion of the reaction. The reaction mass was cooled to about 20-30° C. The solid was filtered and washed with water (30 ml). The compound was suction dried under reduced pressure followed by drying at 25-35° C. under reduced pressure to obtain the desired crystalline Form A of valdecoxib. The yield of the compound was 4.2 grams.  
       EXAMPLE 3  
     PROCESS FOR PURIFICATION OF 4-(5-METHYL-3-PHENYL-4-ISOXAZOLYL) BENZENE SULFONYL CHLORIDE  
       [0052]     5.0 grams of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride were added to 5 ml of ethyl acetate and heated to 55-60° C. Charged 45 ml of cyclohexane and stirred at 55-60° C. for about 45 minutes. Cooled the reaction mass to 25-30° C. accompanied by stirring for 30-45 minutes. Filtered the solid and washed with 5 ml of cyclohexane. Dried the compound at 50° C. to get about 3.4 grams of the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride.  
       EXAMPLE 4  
     PROCESS FOR PURIFICATION OF 4-(5-METHYL-3-PHENYL-4-ISOXAZOLYL) BENZENE SULFONYL CHLORIDE  
       [0053]     5.0 grams of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride were added to 5 ml of dichloromethane and heated to 35-45° C. and stirred for 30 minutes. 45 ml of cyclohexane was charged and the reaction mass was cooled to 25-30° C. accompanied by stirring for 30-45 minutes. The solid was filtered and washed with 5 ml of cyclohexane. The compound was dried at 50° C. to get the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride. (Yield 3.9 grams).  
       EXAMPLE 5  
     PROCESS FOR PURIFICATION OF 4-(5-METHYL-3-PHENYL-4-ISOXAZOLYL) BENZENE SULFONYL CHLORIDE  
       [0054]     5.0 grams of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride were added to 50 ml of cyclohexane and heated to reflux temperature and stirred for 30 minutes. The reaction mass was cooled to 25-30° C. accompanied by stirring for 45-60 minutes. The solid was filtered and washed with 5 ml of cyclohexane. The resultant compound was dried at 50° C. to get the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride. (Yield 3.9 grams).  
       EXAMPLE 6  
     PREPARATION OF CRYSTALLINE FORM-A OF VALDECOXIB FROM FORM B  
       [0055]     Dissolve 100 gm of valdecoxib Form B in the mixture of 7.5 L of dichloromethane and 500 ml of aqueous ammonia under stirring. Separate the dichloromethane layer and distill off completely at 35° C. without stirring in a Rota Vapour flask. Dry the compound under reduced pressure at 35° C. in a Rota Vapour flask for 22-26 hours with rotation at 115-125 rpm. Further dry the compound at 100° C. under reduced pressure for 2.5 to 3.5 hours while rotating at 115-125 rpm. Cool to 25-35° C. and unload the compound, yielding 90.4 g of valdecoxib Form A (90.4%).