FORM 2
THE PATENTS ACT, ] 970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - : PROCESS FOR THE PREPARATION OF HIGHLY PURE
ETORICOXIB
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention and the manner in which is to be performed :

Field of the invention
The present invention relates to a process for the purification of Etoricoxib. More particularly present invention provides process for the preparation of highly pure Etoricoxib which is substantially free of 6-chloro-2-(6-methylpyridne-3-yl)-3-[4-(methylsulfonyl) phenyl]-1,8-naphthyridine of formula I.
Background of the invention
Selective inhibitors of cyclooxygenase-2 are a sub-class of drugs known as non-steroidal antiinflammatory drugs (NSAIDs). Conventional NSAIDs block both forms of the cyclooxygenase enzyme and although active in reducing pain and swelling associated with the inflammatory process can produce severe side effects. The identification of the COX-2 enzyme associated with inflammation has provided a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
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 .
Certain heteroatom containing cycloalkyl substituted p-chlorovinamidinium salts are disclosed in J. Org. Chem.. Vol. 66, No. 1, p. 251-255, 2001. The method disclosed for the preparation of substituted β - chlorovinamidinium salt comprises, addition of chloroacetic acid to N-formyl compound containing a cycloalkyl group which optionally contains a hetero atom and the mixture was heated at 70 °C and then to it was added phosphorus oxychloride which after suitable work up gave the substituted β -chlorovinamidinium salt.
US6040319 (US' 319) discloses a process for preparing a series of 2-pyridyl-3-(4-methylsulfonyl)phenylpyridines. US 319 disclose a process for preparing these compounds by reacting ketosulfone with the vinamidinium salt under basic conditions. This was followed by treatment with ammonia to obtain the pyridine ring. This patent exemplifies the preparation of etoricoxib by reacting 2-chloro- N, N-dimethylamino trimethinium hexafluorophosphate with ketosulfone in the presence of equimolar amount of tertiary butoxide in tetrahydrofuran and quenching the resultant adduct in a mixture of acetic acid and trifluoroacetic acid. Ring closure of the pyridine ring occurred upon heating at reflux in the presence of aqueous ammonium hydroxide.

Accordingly there remains a need for highly pure Etoricoxib substantially free of impurities, as well as purification process obtaining thereof.
There is need in the art for a process of preparing Etoricoxib, having sufficient purity and yield to meet quality and regulatory standards for pre-clinical and commercial use. The present invention provides a process for purification of Etoricoxib. The present invention also provides a process for improving the color of the final product thereby removing colored impurities. The ensuing product from the present invention herein described, conforms to ICH grade purity specifications for bulk drugs, which requires that known impurity should not be more than 0.15% and unknown impurity should not be more than 0.1%.
Present inventors have focused on the problems associated with the prior art process and have developed an improved process for the preparation of highly pure Etoricoxib substantially free of naphthyridine impurity of formula I. The process of present invention removes further purification steps and provides Etoricoxb in high yield and purity.
Object of the invention:
It is an object of the present invention is to provide process for the preparation of Etoricoxib comprising naphthyridine of formula I in an amount of less then 0.15%.

Further object of present invention is to provide process for the purification of Etoricoxib substantially free of naphthyridine (Formula I) impurity which comprising steps of
(i) Dissolving Etoricoxib in a mixture of EPA : water by heating
(ii) Cooling the reaction mixture
(iii) Isolating pure Etoricoxib substantially free of naphthyridine impurity.

Another object of the present invention is to provide a process for purification of Etoricoxib which comprising step of
(i) Providing a solution of Etoricoxib in mixture of toluene: water by heating
(ii) Cooling the reaction mixture and stirring
(iii) Filtering the reaction mixture through hyflo bed.
(iv) Isolating pure Etoricoxib from reaction mixture
Further object of present invention is to provide highly pure Etoricoxib having purity about 99% with the content of formula I less then 0.15% as measured by HPLC.
Detailed description of the invention:
An embodiment of the present invention provides a process for the purification of Etoricoxib which provides Etoricoxib substantially free of impurity.
Further embodiment of present invention provides process for the preparation of Etoricoxib comprising 6-chloro-2-(6-methyIpyridne-3-yl)-3-[4-(methylsulfonyl)phenyI]-1,8-naphthyridine of formula I in an amount of less then 0.15%.

Another embodiment of present invention provides for the purification of Etoricoxib substantially free of naphthyridine (Formula I) impurity which comprising steps of
(i) dissolving Etoricoxib in a mixture of IP A -. water by heating
(ii) cooling the reaction mixture
(iii) isolating pure Etoricoxib substantially free of naphthyridine impurity.
Further embodiment of the present invention provides process for purification of Etoricoxib which comprising step of
(i) Providing a solution of Etoricoxib in mixture of toluene: water by heating

Further embodiment of the present invention provides process for purification of Etoricoxib which comprising step of
(i) Providing a solution of Etoricoxib in mixture of toluene: water by heating
(ii) cooling the reaction mixture and stirring
(iii) filtering the reaction mixture through hyflo bed.
(iv) isolating pure Etoricoxib.
Yet, another embodiment of the present invention provides highly pure Etoricoxib having purity about 99% with the content of formula I less then 0.15% as measured by HPLC.
The term "substantially free" as used hereinabove means Eetoricoxib comprising naphthyridine (Formula I) is less then 0.15%
Present inventors have developed an advance work up process that is very smooth for isolation of pure Etoricoxib substantially free of naphthylpyridine impurity.
The process of the present invention has following advantage
(i) It eliminates the requirement of chromatographic purification method of Etoricoxib and provides a process which is economical and industrially applicable.
(ii) The process provides a less number of purification steps
(iii) The process is simple and easy to handle and does not require special handling care or critical temperature conditions.

Claims
1. A process for the preparation of Etoricoxib comprising naphthyridine impurity of formula I in an amount of less then 0.15%.

2. The process for the purification of Etoricoxib substantially free of naphthyridine (Formula I)
impurity which comprising steps of
(I) Dissolving Etoricoxib in a mixture of IP A : water by heating
(II) Cooling the reaction mixture
(III) Isolating pure Etoricoxib substantially free of naphthyridine impurity.
3. A process for purification of Etoricoxib comprising the step of
(I) Providing a solution of Etoricoxib in mixture of toluene: water by heating
(II) Cooling the reaction mixture and stirring
(III) Filtering the reaction mixture through hyflo bed.
(IV) Isolating pure Etoricoxib from reaction mixture