This application claims priority to Indian patent application No. 2292/CHE/2013 filed on May 27, 2013 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Etoricoxib. The present invention particularly related to Etoricoxib polymorphic Form-I process by drying the mixture of its polymorphs.

BACK GROUND OF THE INVENTION

Etoricoxib is a potent and selective COX-2 inhibitor, which is effective in the management of chronic pain in rheumatoid arthritis, osteoarthritis and other COX-2 mediated disorders. Etoricoxib is designated chemically as 5-chloro-3-[4-methylsulfonyl) phenyl]-2-(2-methyl-5-pyridinyl) pyridine and is represented by the compound of formula (I). Etoricoxib is sold by Merck Sharp & Dohme Limited under the brand name ARCOXIA® US5861419 first discloses Etoricoxib and its hydrochloride, processes for their preparation, pharmaceutical compositions comprising the compounds, and method of use as selective cyclooxygenase-2 (COX-2) inhibitors. US'419 disclose a process for preparation of etoricoxib by reacting ketosulfone(ll) with the 3-amino-2-chloroacrolein(X) in the presence of acidic condition. The step wise process is as shown in the scheme-l given below.

Scheme-I US6040319 discloses a process for preparing a series of 2-pyridyl-3-(4-methylsulfonyl)pheny!pyridines. US'319 discloses a process for preparation of etoricoxib by reacting ketosulfone(ll) with the vinamidinium hexafluorophoshate (III) in the presence of basic condition. This was followed by treatment with ammonia to obtain etoricoxib. The step wise process is as shown in the scheme-ll given below. The present invention provides improved process for the preparation of Etoricoxib by reacting ketosulfone with vinamidinium salt in the presence of an acid.

SUMMARY OF THE INVENTION

In one aspect of the present invention is to provide a process for preparation of pure etoricoxib form-l comprising the steps of;

a) keeping wet etoricoxib containing polymorphic mixture at about 25-35°C,

b) drying at about 60-70°C, optionally in the presence of humidity,

c) optionally milling, and

d) further drying the milled product at about 90-100°C to get pure etoricoxib form-l.

Another aspect of the present invention is to provide a process for preparation of pure etoricoxib form-l comprising the steps of;

a) keeping wet etoricoxib containing polymorphic mixture at about 25-35°C,

b) drying at about 60-70°C, optionally in the presence of humidity,

c) optionally milling and continue drying at about 60-70°C to get pure etoricoxib form-l.

Another aspect of the present invention is to provide a process for preparation of pure etoricoxib form-l comprising the steps of;

a) keeping wet etoricoxib containing polymorphic form-l & IV mixture at about 25-35°C,

b) drying at about 60-70°C, optionally in the presence of humidity,

c) optionally milling, and

d) further drying the milled product at about 90-100°C to get pure etoricoxib form-l.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation pure etoricoxib form-l by drying the mixture of etoricoxib form-l & IV in the presence of a moisture, followed by milling and further drying to get pure Form-l. One embodiment of the present invention is to provide a process for preparation of pure etoricoxib form-l comprising the steps of;

a) keeping wet etoricoxib containing polymorphic mixture at about 25-35°C,

b) drying at about 60-70°C, optionally in the presence of humidity,

c) optionally milling, and

d) further drying the milled product at about 90-100°C to get pure etoricoxib form-l.

Another embodiment of the present invention is to provide a process for preparation of pure etoricoxib form-l comprising the steps of;

a) keeping wet etoricoxib containing polymorphic mixture at about 25-35°C,

b) drying at about 60-70°C, optionally in the presence of humidity,

c) optionally milling and continue drying at about 60-70°C to get pure etoricoxib form-l.

Another embodiment of the present invention is to provide a process for preparation of pure etoricoxib form-l comprising the steps of;

a) keeping wet etoricoxib containing polymorphic form-l & IV mixture at about 25-35°C,

b) drying at about 60-70°C, optionally in the presence of humidity,

c) optionally milling, and further drying the milled product at about 90-100°C to get pure etoricoxib form-l.

According to the present invention the wet etoricoxib obtained from the reaction containing the polymorphic mixture is dried initially at 20-35°C and raised the temperature to 60-65°C and maintained the drying for about 10-15hrs in the presence of a moisture/humidity. The obtained semidried material is milled to break the lumps and further dried at 90-100°C for about 6-10hrs to get pure etoricoxib form-l. According to the present embodiment etoricoxib polymorphic mixture may be the combination of etoricoxib form-l and form-IV or etoricoxib form-l and hemihydrate. According to the present embodiment, the drying is carried out in the presence of related humidity at 60-90% under reduced pressure. During this process, etoricoxib polymorphic form-IV is converted to its hydrated form, preferably hemihydrate in the presence moisture/humidity and in the further drying this hemihydrate is totally converted to pure etoricoxib form-l. The following example is provided to illustrate the process of the present invention. How ever, they are not intended to limit the scope of an invention.

EXAMPLES

Example-1: Preparation of 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)-pyridine 2-(4-Methanesulfonylphenyl)-1-(6-methylpyridin-3-yl)ethanone (100 g) was dissolved in a mixture of propionic acid (250 ml) and methanesulfonic acid (30 g). Ammonium acetate (170 g) was added to the solution. To the viscous reaction mass 2-chloro-1, 3-bis(dimethylamino)trimethinium hexafluorophosphate (Vinamidinium Hexaflurophosphate salt, 150 g) was added. The contents were heated to 128-134°C.and progress of reaction was monitored by qualitative HPLC analysis. After completion of reaction, it was cooled to 22-35°C and diluted with water (750 ml) and toluene (1000 ml). The pH of reaction mass was raised to about 6.0 with aqueous ammonium hydroxide and filtered through hyflow to remove any insoluble matter. The filtrate was heated to 40-45°C to have better layer separation and organic layer was separated. Organic layer/ toluene extract was washed with aqueous sodium hydroxide followed by with water (200 ml) to remove any unreacted ethanone derivative. The organic extract was treated with carbon and filtered over celite.

The filtrate was concentrated under reduced pressure at below 50°C to remove toluene completely. The concentrate was diluted with ethanol (450 ml) and p-Toluene sulfonic acid monohydrate (49 g) dissolved in 150 ml of ethanol was added. The solution was seeded with Etoricoxib PTSA salt (0.2 g) to initiate the crystallization. The product slurry was heated to reflux and continued reflux for about 15min. Product slurry was cooled to 25-35 CC and stirred to complete the crystallization. Product was filtered and washed with ethanol (100 ml) and suck thoroughly to obtain Etoricoxib p-toluene sulfonic acid salt (~ 150 g - wet). The above obtained Etoricoxib p-toluene sulfonic acid salt (~ 150 g - wet) was taken into isopropyl alcohol (600 ml) and Triethylamine (24.8 g) diluted with 60 ml isopropyl alcohol was added slowly at 25-60°. Stirring was continued at 55-60 °C to obtain a clear solution and the solution was treated with activated carbon. Carbon was removed by filtration through hyflow in hot condition. The clear filtrate was concentrated below 50 °C under reduced pressure to ~350 ml. The concentrate was gradually cooled to 7-10°C and stirred for 60 min to complete thecrystallization. Product was filtered and washed with pre-chilled isopropyl alcohol (80 ml). The above obtained product can be as such taken for drying or optionally slurried in hot water to remove any inorganics/ salts. The product (wet) was added to pre-heated water (270 ml, ~ 60 °C) and stirred for 30 min. Product slurry was cooled to RT, filtered, washed with water (80 ml) and dried under reduced pressure at 50-55 °C till water content is NMT 1.0 % w/w to obtain Etoricoxib (58 g).

The above obtained product is mixture of different polymorphs

Example-2: Preparation of 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)-pyridine (Etoricoxib Form-I) Etoricoxib (58 g, as obtained in example -1) was taken in isopropyl alcohol (380 ml) and heated to 70-75cto obtain a clear solution. The clear solution was slowly added to pre-cooled (8-15°C) n-heptane (450 ml) containing seed of Etoricoxib Form-I (0.5 g) while maintaining temperature at 12-25°C to precipitate/crystallize the product. The product slurry was aged for about 2 hrs and product was filtered, washed with n-heptane (60 ml) and sucked thoroughly to get 65 g of wet product. The wet product was dried initially at 25-35 °C under reduced pressure for about 2 hrs. Thereafter, drying was continued at 60-65 °C under reduced pressure. Further, the product was milled and drying continued at 95±3°C till the polymorphic quality (by XRPD) met the requirement. Example-3: Preparation of 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)-pyridine (Etoricoxib Form-I) Etoricoxib (58 g, as obtained in example-1) was taken in isopropyl alcohol (380 ml) and heated to 70-75°to obtain a clear solution. The clear solution was slowly added to pre-cooled (8-15°C) n-heptane (450 ml) while maintaining temperature at 12-25°C to precipitate/crystallize the product. The product slurry was aged for about 2 hrs and product was filtered, washed with n-heptane (60 ml). The wet product was dried initially at 25-35 °C under reduced pressure for about 2 hrs. Thereafter, the semidried product was milled and drying was continued at 60-65 °C under reduced pressure for the milled product till the polymorphic quality (by XRPD) met the requirement.

Example-4:

Preparation of 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)-pyridine (Etoricoxib Form-I) Etoricoxib (58 g, as obtained in example -1) was taken in isopropyl alcohol (380 ml) and heated to 70-75°to obtain a clear solution. The clear solution was slowly added to pre-cooled (8-15°C) n-heptane (450 ml) containing seed of Etoricoxib Form-I (0.5 g) while maintaining temperature at 12-25°C to precipitate/crystallize the product. The product slurry was aged for about 2 hrs and product was filtered, washed with n-heptane (60 ml) and sucked thoroughly to get 65 g of wet product. Part of the wet product (~ 35 g) was dried initially at 25-35 °C under reduced pressure for about 2 hrs. Thereafter, the semi dried product was exposed to humidity (RH ~ 85) for 2-3 hr and then drying was continued at 60-65 °C under reduced pressure till the polymorphic quality (by XRPD) met the requirement

Example-5: Preparation of 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)-pyridine (Etoricoxib Form-I) The remaining wet product (~30 g, from example-4) was dried initially at 25-35 °C under reduced pressure for about 2 hrs. Thereafter, the semi dried product was exposed to humidity (RH ~ 85) for 2-3 hr and then drying was continued at 60-65 °C under reduced pressure for 3-4 hrs. The drying temperature was raised and drying continued at 95±3°C till the polymorphic quality (by XRPD) met the requirement.

We claim

1. Process for preparation of pure etoricoxib form-l comprising the steps of;

a) keeping wet etoricoxib containing polymorphic form mixture at about 25-35°C,

b) drying at about 60-70°C, optionally in the presence of humidity,

c) optionally milling, and

d) further drying the milled product at about 90-100°C to get pure etoricoxib form-l.

2. The process according to claim 1, polymorphic mixture contains etoricoxib form-l and IV.

3. The process according to claim 1 step b), drying is carried out in the presence of humidity at 85%.

4. The process according to claim 3, the drying is carried out at the temperature of 60-65°C for 3-4hours.

5. The process according to claim 4, the drying temperature further raised to 95±3 to get pure etoricoxib form-l.