DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]

PROCESS FOR THE PREPARATION OF ETORICOXIB

PIRAMAL PHARMA LIMITED, a company incorporated under the Companies Act, 2013, of Ground Floor, Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai 400070, State of Maharashtra, India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed.


FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Etoricoxib (1).

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Etoricoxib belongs to a class of drugs known as COX-2 inhibitors that are used in the treatment of COX-2 mediated disorders.

US5861419 first disclosed processes for the preparation of Etoricoxib and its pharmaceutically acceptable salts such as hydrochloride, pharmaceutical compositions, and method of use as selective cyclooxygenase-2 (COX-2) inhibitors. US'419 patent discloses a process for preparation of etoricoxib, wherein ketosulfone (2) is reacted with the 3-amino-2-chloroacrolein (3) in the presence of an acid followed by work-up to get Etoricoxib, which is shown below in scheme-1.

Scheme-1
US6040319 discloses a process for preparation of Etoricoxib by reacting 2-(4-Methane sulfonyl-phenyl)-1-(6-methyl-pyridin-3-yl)-ethanone (2) with 2-Chloro-1,3-bis (dimethyl amino)tri methinium hexafluoro phosphate (4) in the presence of an equimolar amount of t-BuOK to obtain Etoricoxib. The process is as shown in the scheme-2 given below.

Scheme-2
The above synthetic Schemes for the preparation of Etoricoxib have some drawbacks, which limits its scope on an industrial scale and some of the drawbacks are listed below:
a) Scheme 2 described in patent US`319 for the synthesis of Etoricoxib uses expensive base and expensive solvent like potassium tertiary butoxide and THF respectively.
b) Scheme 1 described in patent US`419 for the synthesis of Etoricoxib uses methane sulfonic acid, which leads to formation of genotoxic impurities.
The literature reported processes inadvertently uses expensive solvents, bases and reagents, which makes the process unfit at large scale operations as it makes manufacturing costly.

Hence, there remains a need for providing efficient, simple, industrially feasible and economically viable process for the manufacture of Etoricoxib (1) to eliminate the problems associated with the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The problem addressed by the present invention is to provide an improved process for preparation of Etoricoxib (1), which permits to avoid use of expensive solvents, bases and reagents to eliminate the problems associated with the processes known in the prior art.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of Etoricoxib (1),

comprising;
(a) reacting 2-(4-Methane sulfonyl-phenyl)-1-(6-methyl-pyridin-3-yl)-ethanone (2) with the 2-Chloro-1,3-bis (dimethyl amino)trimethinium hexafluoro phosphate (4) in a solvent and in presence of a base to give Etoricoxib (1).

The solvent used in step (a) is selected from an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; ketone such as acetone; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene or benzene; water or a mixture thereof.
The base used in step (a) is selected from an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

The complete synthetic scheme of preparation of Etoricoxib (1) according to the present invention is represented below:

Accordingly, the specific embodiment the present invention relates to an improved process for the preparation of Etoricoxib (1),

comprising;
(a) reacting 2-(4-Methane sulfonyl-phenyl)-1-(6-methyl-pyridin-3-yl)-ethanone (2) with the 2-Chloro-1,3-bis (dimethyl amino)trimethinium hexafluoro phosphate (4) in a mixture of N,N-dimethylformamide (DMF) and toluene, and in presence of potassium hydroxide to give Etoricoxib (1).

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1
Preparation of Etoricoxib (1)
2-(4-Methane sulfonyl-phenyl)-1-(6-methyl-pyridin-3-yl)-ethanone (5.0 g), DMF (25 ml) and Toluene (25 ml) were charged in the round bottom flask. Obtained solution was cooled to 0-10 °C. Potassium hydroxide (1.43 g) was charged in the round bottom flask at 0-10 °C. Reaction mixture was stirred for 1 hour at 0-10 °C. 2-Chloro-1,3-bis (dimethyl amino)trimethinium hexafluoro phosphate (6.1 g) was added into the round bottom flask. Reaction mixture was stirred for 1 hour at 0-10 °C. Acetic acid (7.7 g) and Trifluoro acetic acid (2.0 g) were charged in the round bottom flask. Reaction mixture was stirred for 2 hours at 0-10 °C. Ammonium acetate (9.24 g) was charged in the round bottom flask. After the addition, reaction mixture was heated to 55 – 60 °C, maintained for 12 hours and the resulting mass was cooled to 20-25 °C. Toluene (15 ml) and water (25 ml) were charged in the round bottom flask; stirred and layers were separated. Toluene (10 ml) was added in aqueous layer, stirred the reaction mass and layers are separated. Organic layers were combined and washed 2 times with water (20 ml). Organic layer was concentrated under vacuum and isopropyl alcohol (15 ml) was charged into the obtained residue. Reaction mixture was stirred for 2 h at 0-10 °C. Obtained solid was filtered, washed with isopropyl alcohol (10 ml), and dried at 50-55 °C for 10 hours under vacuum to offer Etoricoxib (4.0-5 g having yield: 64.50 to 80.64 %).
Results:
Theoretical Yield: 1.24 w/w
Practical Yield : 0.8 to 1.0 w/w
Yield (%) : 64.50 to 80.64%

,CLAIMS:1. A process for the preparation of Etoricoxib (1),

comprising;
(a) reacting 2-(4-Methane sulfonyl-phenyl)-1-(6-methyl-pyridin-3-yl)-ethanone (2) with 2-Chloro-1,3-bis (dimethyl amino)trimethinium hexafluoro phosphate (4) in a solvent and in presence of a base to give Etoricoxib (1).

2. The process as claimed in claim 1, wherein the solvent used in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; or an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; or a ketone selected from acetone; or an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); or an aromatic solvent such as toluene, xylene or benzene; or water or a mixture thereof.

3. The process as claimed in claim 1, wherein base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; or an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; or an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; or an alkali metal alkoxide selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide; or an organic amine selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

4. A process for the preparation of Etoricoxib (1),

comprising;
(a) reacting 2-(4-Methane sulfonyl-phenyl)-1-(6-methyl-pyridin-3-yl)-ethanone (2) with 2-Chloro-1,3-bis (dimethyl amino)tri methinium hexafluoro phosphate (4) in a mixture of N,N-dimethylformamide (DMF) and toluene, and in presence of potassium hydroxide to give Etoricoxib (1).