WO2005085218A1

WO2005085218A1 - A novel process for preparing valdecoxib

Info

Publication number: WO2005085218A1
Application number: PCT/IN2004/000053
Authority: WO
Inventors: Chandiran Thakashinamoorthy; Mercy Gnanadeepam Jesudoss; Meera Hariharasubramanian; Subramanian Sankara Seetharaman
Original assignee: Chandiran Thakashinamoorthy; Mercy Gnanadeepam Jesudoss; Meera Hariharasubramanian; Seetharaman Subramanian Sankar
Priority date: 2004-03-05
Filing date: 2004-03-05
Publication date: 2005-09-15

Abstract

The present invention relatesto a novel process for making 4-[5-methyl -3-phenylisoxazol-4-yl] benzenesulphonamide

Description

A NOVEL PROCESS FOR PREPARING VALDECOXIB

FIELD OF THE INVENTION

The present invention relates to a novel process for making 4-[5-methyl-3- phenylisoxazol-4-yl] benzenesulphonamide (hereinafter referred as valdecoxib).

BACKGROUND OF THE INVENTION

US Patent 5,633,272 which is incorporated herein by reference, discloses substituted isoxoazolyl compounds, particularly 4-[5-methyl-3-phenylisoxazol- 4-yl] benzenesulphonamide of the Formula 1,

useful in the treatment of inflammation.

Compounds of formula I are useful for but not limited to the treatment of inflammation in a subject and for the treatment of other inflammation associated disorders such as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. Methods for preparing substituted iso-oxazol -4-yl benzenesulfonamide compounds are also described in US Patent No. 5,859,257. This patent describes processes for making valdecoxib by treatment of the 3,4 di-phenyl - 4-hydrido-5-hydroxy-5-methylisoxazole with large excess chlorosulfonic acid to make aromatic sulphonyl chloride and adding liquid ammonia to this sulphonyl chloride to get the desired compound

However, insolubility of the isoxazoline compound in chlorosulphonic acid poses reactivity issues. International publication WO 03/029230, describes a process for preparing aromatic sulfonyl halides by contacting a substituted phenyl compound with a halosulfonic with trifluororacetic acid. This invention discloses a process for preparing valdecoxib by reacting 3,4-diphenyl-5- methylisoxazole or 5-hydroxy-5-methyl-3,4-diphenylisoxazoline with halosulfonic acid in the presence of trifluoroacetic acid to produce a halosulfonated product and then contacting the halosulfonated product with a source of ammonia to produce valdecoxib. This process overcomes the reactivity issues by using trifluoroacetic acid as a medium for dissolution before adding chlorosulfonic acid. Although adding trifluoroacetic acid also aids halosulfonation reaction to be carried out at higher temperatures and thereby shortens reaction time, it is to be noted that performing this halosulfonation reaction at higher temperatures causes formation of isomeric impurity (meta sulphonyl chloride). Clearly there is a need for alternate processes for making valdecoxib that overcome these problems of reactivity and impurities. The object of the present invention is therefore to provide for a process for preparing valdecoxib, which reaction can be carried out at a lower temperature thus avoiding formation of isomeric impurities, while also overcoming reactivity issues.

SUMMARY OF THE INVENTION

The aforesaid objective is achieved by the present invention which provides a novel method for the preparation of 4-[(5-methyl-3-phenyl)-4- isoxazolyl]benzenesulfonamide (hereinafter referred as valdecoxib) consisting of:

- sulfonation of either 3,4-diphenyl-5-methylisoxazole or 5-hydroxy-5- methyl-3,4-diphenylisoxazoline using oleum to get the sulfonic acid derivative; - purification of the sulphonic acid derivative as its sodium salt; halogenating the sodium salt to the corresponding sulfonylhalide; and - treating the aromatic sulphonyl halide with ammonia to get the desired compound.

Further the scope and applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modification within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Brief description of the figure

Figure 1 shows a process by which 4-[5-methyl-3-phenylisoxazol-4- yl]benzenesulphonamide of formulal can be prepared according to the present invention.

Detailed description of the preferred embodiments

The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit and scope of the present invention.

The contents of each reference cited herein including the contents of the references cited within these primary references are herein incorporated by reference in their entirety.

The synthesis of valdecoxib can be summarized by the following reaction scheme as shown in figure 1: Step la: sulfonation of either 3,4-diphenyl-5-methylisoxazole or 5-hydroxy-5- methyl-3,4-diphenylisoxazoline using oleum to get corresponding sulfonic acid; which is then converted in to 4-[(5-methyl-3-phenyι)-4- isoxazolyl]benzenesulfonate sodium salt using sodium chloride. (step lb) The sodium salt is then converted into the corresponding sulphonyl halide using a halogenating agent (Step2), which is then treated with ammonia to get valdecoxib (step 3).

The starting materials for use in the methods of preparation of the invention are known and can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art. The requisite starting isoxazole or isoxazoline can also be obtained commercially by synthesis using methods disclosed as in EP 0026928 and in US Patent No. 5,859,257.

The sulfonation of isoxazole or isoxazoline (step la) is carried out using 10 - 40 % oleum as sulfonating agent in sulfuric acid medium to get 4-[(5-methyl-3- phenyl)-4-isoxazolyl]benzenesulfonic acid. Sulfuric acid is used to dilute the oleum as well as act as the reaction medium for the sulfonation reaction. For sulfonation around 1 to 6 mol of S0₃ is used, and preferably 2 to 3 mol of S0₃ is used, and the reaction can be carried out above the freezing point of the reaction mass. In general the sulfonation of the present invention is carried out at 0 to 40°C, preferably at 5 to 15°C. The product is obtained from the reaction mixture by diluting the reaction mass with water till concentration of the sulfuric acid after dilution is around 30 to 70%. And more preferably, the sulfuric acid concentration is adjusted to 40 to 60% precipitate the product from the reaction mixture. The precipitation of the 4-[(5-methyl-3-phenyl)-4- isoxazolyl]benzenesulfonic acid is carried out at 0 to 40°C and more preferably at 10 to 20° C, and the product is separated by filtration or centrifugation of the slurry. Advantage of using oleum as the sulfonating agent is that it allows for reaction to be carried out at a lower temperature thus avoiding formation of isomeric impurities. Further the reactivity issues are also overcome, as the starting material is freely soluble in oleum.

The obtained sulfonic acid is then converted in its corresponding sodium salt by dissolving it in water at 0 to 40 °C, and then treating with sodium chloride (step lb). The dissolution may be carried in 2 to 10 ml water per 1 g of the sulfonic acid and preferably in 4 to 5 ml of water at 25 to 30°C. The sulfonic acid solution is then saturated with sodium chloride and cooled to 0 to 10°C to crystallize the 4-[(5-methyl-3-phenyl) -isoxazolyl]benzenesulfonate sodium salt from the reaction mixture. The product is filtered, dried under vacuum and analyzed. (HPLC purity analysis: greater than 99%). Making the sulfonic acid sodium salt has several advantages since the sulphonic acid is very hygroscopic in nature, and thus cannot be taken directly for the halogenation step. Further isolating it is a sodium salt enables purification of the sulphonic acid, and this being non-hygroscopic allows for ease in drying and handling of the material.

The sulfonate sodium salt is then converted in to sulfonyl halide using halogenating agents such as SOCl₂, SOBr₂, PC1₅, POCl₃, etc. In a preferred embodiment of the present invention 4-[(5-methyl-3-phenyl)-4- isoxazolyl]benzenesulfonate sodium is converted to 4-[(5-methyl-3-phenyl)-4- isoxazolyl]benzenesulfonyl chloride using SOCl₂ in the presence of catalytic amount of dimethylformamide (step 2). The halogenating agent is used in 1.0 to 4.0 mol per mole of the sulfonate salt. The halogenation reaction may be carried out in chlorinated solvents such as dichloromethane, chlorobenzene and hydrocarbon solvents such as toluene or in the excess of halogenating agent itself as solvent. The halogenation reaction may be carried out at 30 to 120°C and preferably at 60 to 90°C. The reaction mixture may be washed with water after completion of the halogenation to remove the excess halogenating agent and sodium chloride to get the sulfonyl halide in the solution.

The 4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonyl halide solution may be as such taken for the reaction with ammonia or if preferred the 4-[(5- methyl-3-phenyl)-4-isoxazofyl]benzenesulfonyl halide can be isolated from the solution by evaporation of the solvent and then it is purified before further reaction with ammonia. Isolation of the sulphonyl chloride allows for color removal and also purification prior to the last step, so as to obtain pharmaceutically acceptable final product directly without need for further re- crystallization steps to remove impurities.

Pure sulfonyl halide obtained from the above step is reacted with ammonia in a suitable solvent to get valdecoxib. In a preferred embodiment dichloromethane or toluene is used as solvent for the reaction to obtain valdecoxib. The reaction may be carried out by adding aqueous ammonia or anhydrous ammonia in to the solution of 4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonyl halide, or by passing ammonia gas in to the solution of 4-[(5-methyl-3-phenyl)-4- isoxazolyl]benzenesulfonyl halide. In another embodiment of the present invention the solution of 4-{(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonyl halide is added in to aqueous ammonia. The reaction may be carried out at -10 to 40° C and preferably at 0 to 10°C. The reaction mixture is washed with water and then the solvent is partially removed by distillation to get the product crystallized. The product is then filtered and dried to obtain valdecoxib. The following examples are intended to be illustrative of the many embodiments of the present invention and are not meant to be limiting in scope.

Generally, the process methods of the present invention can be performed as follows. Larger scale preparation can be performed, for example, by proportionately increasing ingredient quantities.

EXAMPLE 1:

4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzene sulfonic acid, (step la)

Charged concentrated sulfuric acid (98% w/w, 74ml) in a dry 250 ml four neck RB flask. Added in to it 5-methyl-3,4,diphenylisoxazole (37g, 0.1575 mol) at 25°C. After the addition, the mass is stirred for 15 to 20 min. at 25°C to obtain a clear solution. The reaction mass is cooled to 5° C and oleum (20% w/w, 81.4ml) is added drop-wise by maintaining the temperature 5 - 10°C. After the addition the mass is stirred at 5 - 10°C for an hour. HPLC showed completion of reaction. The reaction mass is then slowly added in to ice water (187 ml) drop by drop by maintaining the temperature 10 to 20° C. The content is then stirred for 5-7 hr at 0 - 5°C to complete the precipitation of the product. The product obtained is then filtered and suck dried to obtain a 4-(5-methyl-3- phenyl-4-isoxazolyl)benzene sulfonic acid as wet product (48g, HPLC purity 99.2%)

EXAMPLE 2: 4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonate sodium salt, (step lb)

The sulphonic acid obtained in example 1 is dissolved in 185 ml water and sodium chloride (37 g, 0.6324 mol) is added portion wise at a temperature of 25-30 °C. The turbid reaction mass is then cooled to 0-5 °C, stirred for 2 h and filtered. The wet material is then washed with chilled water (74 ml) and dried at 70-75 °C under vacuum for 8-10 h to yield white solid. (38 g, HPLC purity = 99.5%, Moisture content = 4.6% )

EXAMPLE 3:

Preparation of 4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenesulfonyl chloride (step 2)

4-(5-methyl-3-phenyl-4-isoxazolyl)benzene sulfuric acid sodium salt (15 g, 0.0445 mol), toluene (300 ml), thionyl chloride (11.3 ml, 0.1548 mol) & catalytic quantity of DMF(0.8 ml) are taken together and heated to 70-75 °C temperature for 2hours. HPLC analysis of the reaction mass showed starting material less than 2%. The reaction mass is then cooled to 5- 10 °C and water (100 ml) is added and stirred for 15 min. The aqueous and organic layers are separated, the organic layer washed with water (100 ml). The organic layer is dried over sodium sulphate and filtered. The organic layer is distilled under vacuum to remove toluene completely to get crude product (14g). To the crude product (14g) is dissolved in diisopropyl ether (250 ml) at reflux and treated with activated carbon (0.8g) for 15 min. The content is then filtered through flash silica gel (230-400 mesh). The mother liquor is cooled to 0-5°C and stirred for an hour to get the crystallization completed. The product is filtered, washed with diisopropyl ether (50 ml). The product obtained is then dried under vacuum at 50-55°C (8.3g, HPLC purity = 97.7%)

EXAMPLE 4

4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide (step 3)

Charged 400 ml of dichloromethane in a dry 1L four neck round bottom flask, into this 7.8 g of sulfonyl chloride from example 3 (0.02296 mol) was added at room temperature and stirred well. Reaαion mass cooled to 0°C and ammonia gas was purged for an hour, during this white solid was formed in the reaction mass. After one hour analysed by HPLC showed completion of reaction. Reaction mass allowed to come to room temperature and dichloromethane layer is washed thrice with water (3 x 100 ml). Dried over anhydrous sodium sulfate and filtered. Dichloromethane is distilled to obtain a one fourth of the initial volume and then cooled to 0 to 5°C to get the product crystallised. The product is then filtered and washed with pre-cooled dichloromethane (2 x 10 ml) and the product dried under vacuum at 60 to 70 °C to obtain a crystalline product (5.6 g, HPLC purity = 99.7%).

Claims

We claim;

1. A method of preparing 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulphonamide of formula 1 comprising: contacting a precursor compound selected from the group consisting of Formula 2 and Formula 3 with a sulfonating agent to form 4-[5-methyl-3- phenylisoxazolyl] benzenesulfonic acid,

2 3 - optionally, treating 4-[5-methyl-3-phenylisoxazolyl] benzenesulphonic acid with a source of alkali metal to obtain 4-[5-methyl-3-phenylisoxazolyl] benzenesulfonate sodium salt; converting 4-[5-methyl-3-phenylisoxazolyl] benzenesulfonate sodium salt or 4-[5-methyl-3-phenylisoxazolyl] benzenesulfonic acid to 4-[5-methyl-3- phenylisoxazolyl] benzenesulfonyl chloride by contacting the sulfonate salt or sulfonic acid, with a halogenating agent, and contacting the 4-[5-methyl-3-phenylisoxazolyl] benzenesulfonyl chloride with a source of ammonia to produce 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulphonamide.

2. The method according to claim 1 wherein the sulfonating agent is oleum.

3. A method according to claim 1 wherein the source of alkali metal is sodium chloride.

4. A method according to claim 1 wherein the halogenating agent is selected from SOCl₂,SOBr₂,PCl₅,POCl_3.

5. A method according to claim 1 wherein the halogenating agent is thionyl chloride.

6. A method according to claim 1 wherein the source of ammonia is selected from ammonium hydroxide or anhydrous ammonia.

7. A method according to claim 6 wherein the source of ammonia is ammonium hydroxide .

8. A method according to claim 6 wherein the source of ammonia is anhydrous ammonia.

9. A method according to claim 1 wherein sulfonation is carried out using 10 - 40 % oleum as sulfonating agent in sulfuric acid medium

10. A method as claimed in claim 1 wherein the amount of halogentaing agent used is between about 1.0 to 4.0 mol per mole of the sulfonate salt.

11. A method as claimed in any one of claims 1,4,5 or 10 wherein the halogenation reaction is carried out in chlorinated solvents

2. A method as claimed in claim 11 wherein chlorinated solvent include dichloromethane, chlorobenzene and toluene