Claims:Claims:

1. A process for preparing Etoricoxib comprising of following steps:

a) reacting ketosulfone compound of formula (II) with CDT-Phosphate compound of formula (III) in presence of suitable base and suitable solvent(s);
b) treating the reaction mixture obtained from step (a) with hydroxylamine hydrochloride in presence of suitable solvent(s);
c) optionally isolating the salt of etoricoxib using conventional techniques;
d) further treating the reaction mixture of step (b) or salt of step (c) using suitable base and suitable solvent(s);
e) optionally seeding the reaction mixture obtained in step (e) to obtain the desired product of formula (I).

2. The process as claimed in claim 1, wherein the suitable base are selected NaOH, KOH, NaHCO3, K2CO3, Na2CO3, NaH, aq.NH3.
3. The process as claimed in claim 1, wherein suitable solvent(s) are selected from alcohols, acetates, ethers, ketones, amides, hydrocarbons, halogenated solvents, DMSO, DMF, DMA, dimethyl acetamide, glacial acetic acid and mixtures thereof.
4. The process as claimed in claim 3, wherein the suitable alcohols are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-hexanol, n-pentanol and like.
5. The process as claimed in claim 3 wherein the suitable acetates are selected from Ethylacetate, methyl acetate, isopropyl acetate, n-Butyl acetate, Isobutyl actetate, amyl acetate, isoamyl acetate and like.
6. The process as claimed in claim 3 wherein the suitable ethers are selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, Diisopropylether, methyl tert-butyl ether and like.
7. The process as claimed in claim 3 wherein the suitable ketone solvents are selected from acetone, Methylisobutyl ketone, methylethyl ketone and like.
8. The process as claimed in claim 3 wherein the suitable amide solvents are selected from Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea and like.
9. The process as claimed in claim 3 wherein the suitable halogenated solvents are selected from dichloromethane, chlorobenzene, ethylenedichloride, chloroform, benzotrifluoride, carbon tetrachloride and like.
10. The process as claimed in claim 3 wherein the suitable hydrocarbons are selected from hexane, heptane, pentane benzene, cyclohexane, toluene, xylene and like.

Date this 25th day of February 2015.

, Description:Field of the invention
The present invention is directed towards process for preparing Etoricoxib of Formula-I.

Formula-I

Background of the invention:

Cyclooxygenase-2 selective inhibitors constitute an important class of non-steroidal anti-inflammatory drug substances (NSAIDs), especially due to their improved safety profile. Commonly used NSAIDs, for example aryl propionic acid or aryl acetic acid derivatives are known to cause gastric irritation and ulcerations upon prolonged use of such drugs. Cyclooxygenase-2 inhibitors, which act on mechanism of isozyme expression in inflamed tissues, show better safety in this regard.
Etoricoxib selectively inhibits isoform 2 of cyclooxygenase enzyme (COX-2) and currently it is approved in more than 70 countries for therapeutic indications like treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, chronic low back pain, acute pain, osteoarthritis and gout.
Compound of general formula (A) including Etoricoxib are disclosed in US 5861419 as depicted in scheme below:

An alternate process is also disclosed in US 5861419 as depicted in the following scheme:

The process described in US 5861419 comprises multi-step synthesis resulting in poor yield of final product.

US 6040319 describe a process for the preparation of Etoricoxib according to the scheme below. It involves condensation between a compound of Formula-II and a compound of Formula-IIIa, wherein X may be selected from phosphates, sulfates, acetates, perchlorate, borates, benzoates, napsylate, particularly, hexafluorophosphate, sulfate, mesylate, tosylate, triflate, acetate, trifluoroacetate, tetrafluoroborate, tetraphenylborate, hexafluoroantimonate, chloride, bromide, fluoride, iodide, benzolate and napsylate. Sodium and potassium hydroxides, cesium, carbonate, alkoxides, amides and hydrides of lithium, sodium and potassium depicted as suitable base.

WO 99/55830 describes a process for preparing COX-2 inhibitors including Etoricoxib. It involves condensation between a vinaminidium salt and a substituted benzyl pyridyl ketone derivative, which in turn is made by employing a Grignard reaction between a pyridyl amide derivative and a thiomethyl benzyl halide, followed by oxidation step.
Nevertheless, there always exists a need to work out a newer synthetic approach that may lead to an improved and cost effective process for preparation of the said drug substance.

Object of the invention:
In one aspect, the present invention relates to a process for preparing Etoricoxib, comprising the steps of:
a) reacting ketosulfone compound of formula (II) with CDT-Phosphate compound of formula (III) in presence of suitable base and suitable solvent(s);
b) treating the reaction mixture obtained from step (a) with hydroxylamine hydrochloride in presence of suitable solvent(s);
c) optionally isolating the salt of Etoricoxib using conventional techniques;
d) further treating the reaction mixture of step (b) or salt of step (c) using suitable base and suitable solvent(s);
e) optionally seeding the reaction mixture obtained in step (e) to obtain the desired product of formula (I).
In another aspect, the present invention is to provide process for the preparation of Etoricoxib Hydrochloride.

Reaction Scheme:

Detailed description of the invention:
Present invention relates to a process for preparing an Etoricoxib, comprising of following steps:
a) reacting ketosulfone compound of formula (II) with CDT-Phosphate compound of formula (III) in presence of suitable base and suitable solvent(s);
b) treating the reaction mixture obtained from step (a) with hydroxylamine hydrochloride in presence of suitable solvent(s);
c) optionally isolating the salt of Etoricoxib using conventional techniques;
d) further treating the reaction mixture of step (b) or salt of step (c) using suitable base and suitable solvent(s);
e) optionally seeding the reaction mixture obtained in step (e) to obtain the desired product of formula (I).
In one aspect the term suitable base may be selected from suitable organic or inorganic base selected from NaOH, KOH, aq.ammonia and like; carbonates such as NaHCO3, K2CO3, Na2CO3; hydrides such as NaH, LHMDS, KHMDS and like; alkali metal alkoxides such as sodium, potassium, lithium, t-butoxide and like; sodium, potassium, lithium isopropoxide and like.
In another aspect the solvents used herein includes but not limited to alcohols, Acetates, Ethers, ketones, amides, hydrocarbons, aprotic solvents such as DMF, dimethyl acetamide, DMSO, glacial acetic acid and like or mixture thereof.
In another aspect the suitable alcohols are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-hexanol, n-pentanol and like.
In another aspect the suitable acetates are selected from Ethylacetate, methyl acetate, isopropyl acetate, n-Butyl acetate, Isobutyl actetate, amyl acetate, isoamyl acetate and like.
In another aspect the suitable ethers are selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, Diisopropylether, methyl tert-butyl ether and like.
In another aspect the suitable ketone solvents are selected from acetone, Methylisobutyl ketone, methylethyl ketone and like.
In another aspect the suitable amide solvents are selected from Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea and like.
In another aspect the suitable halogenated solvents are selected from dichloromethane, chlorobenzene, ethylenedichloride, chloroform, benzotrifluoride carbon tetrachloride and like.
In another aspect the suitable hydrocarbons are selected from hexane, pentane, heptane, benzene, cyclohexane, toluene, xylene and like.
The term "conventional techniques" as used herein includes but not limited to distillation, distillation under reduced pressure or vacuum, filtration, evaporation, solvent-anti solvent, spray drying, lyophilization or freeze drying.
The term seeding as used herein includes using seed of Form-1 of Etoricoxib.
The following examples are provided to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

Preparation of Etoricoxib
Example-1:
Step-I: Preparation of Etoricoxib hydrochloride (IV)
Ketosulfone (II) (100 gm) was added to flask containing DMSO (200 ml) and Toluene (800 ml) at ambient temperature under nitrogen atmosphere and stirred for about 10 minutes. The reaction mixture was cooled and sodium hydride (60%) (16.6 gm) was added over a period of one hour under nitrogen. Further CDT-Phosphate (127.16 gm) was added to the reaction mixture and stirred for about 30 minutes. After completion of reaction, the mixture was quenched into the flask containing glacial acetic acid (133 ml) and the reaction mixture was stirred for 120 minutes. Further liq. Ammonia solution (280 ml) was added to the reaction mixture over a period of 30 minutes. The reaction mixture was refluxed for about 4 hours and then charged with DM water (1500 ml) and toluene (400 ml) and stirred for about 30 minutes. The organic layer was separated and filtered through Hyflo bed. NaOH (12.0 gm) in process water (120 ml) was added to organic layer and the reaction mixture was heated to 65 + 5oC. Solution of hydroxyl amine hydrochloride (10.0 gm) in water (50 ml) was added to reaction mixture over a period of 45-60 minutes and the reaction mixture was stirred for 2 hours. The reaction mixture was allowed to cool and organic layer was separated from aqueous layer.

Step-2: Preparation of Etoricoxib (I)
5% caustic solution (300 ml) was added to organic layer obtained in step-1 and stirred for about 15 minutes. The organic layer was separated and toluene was distilled under vacuum till the residual volume remains to 1000-1050 ml. Further isopropyl alcohol hydrochloride (120 ml) was added to the reaction mixture along with stirring to adjust pH 1.0-2.5 under nitrogen. The solid obtained was filtered and washed with toluene and dried in VTD/ATD at 75 + 5oC to obtain the desired product.
Yield: 75.0 g (75.0%)

Step-2: Preparation of Etoricoxib (I) (Seeding technique)
Charge Etoricoxib hydrochloride (100 gm) with process water (800 ml). Add toluene (1000 ml) to this mixture followed by ammonia solution (50 ml) over a period of 30 minutes at 45+ 5oC till the clear solution is observed. The pH of the solution should not be less than 9. Separate organic layer. Distill out toluene under vacuum at 70oC and degas reaction mixture for 2-3 hours at same temperature. Charge IPA (400 ml) to the reaction mixture and heat the reaction mixture till clear solution obtained. Distill out IPA under vacuum and degas the reaction mixture for 2-3 hours at same temperature. Add mixture of IPA and hexane (700 ml) at 70oC under nitrogen atmosphere. Heat the reaction mixture again till clear solution obtained. Add activated carbon (5 gm) to reaction mixture at 80 + 5oC and filter through hyflo bed under nitrogen. Wash the hyflo bed with mixture of IPA and hexane. Cool the reaction mixture at 55+ 2oC. Add seed of Etoricoxib Form-1 (10 mg) to the reaction mixture under nitrogen and allow the reaction mixture to stand for one hour. Filter the reaction mixture and wash the solid with mixture of IPA and hexane. Dry the solid under vacuum.
Yield: 80.0 g (80.0%)

Date this 25th day of February 2015.