FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR THE PREPARATION OF
ETORICOXIB"

We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad 380 015, Gujarat, India.
The following specification describes the invention.

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FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Etoricoxib and also a process for preparing substituted p-chlorovinamidinium salts with cyclic alkyi group (with or without hetero atom), which is one of the intermediate of Etoricoxib. BACKGROUND OF THE INVENTION
Etoricoxib is a selective COX-2 inhibitor which has been shown to be as effective as non¬selective non-steroidal anti-inflammatory drugs in the management of chronic pain in rheumatoid arthritis, osteoarthritis and other COX-2 mediated disorders. Etoricoxib is 5-chloro-6'-methyl-3-[4-methylsulfonyl)phenyl]-233'-bipyridine having structural formula I.

Etoricoxib belongs to a class of drugs known as COX-2 inhibitors that are used in the treatment of COX-2 mediated disorders. The therapeutic application of Etoricoxib as a COX-2 inhibitor is disclosed in WO 9610012 and WO 9616934.
Compounds of general formula (X) which includes Etoricoxib are disclosed in WO9803484 (US 5861419). Process for the preparation of Compound of formula (X) involves bromination of 2-amino pyridine derivative with bromine in acetic acid to provide the bromide of 2-amino pyridine derivative. Coupling of this bromide derivative is then done with 4-(methylthio)phenyI-boronic acid in presence of a suitable base, which is then oxidized to give the corresponding sulphon. Then the amino group of sulphon is converted to corresponding halide. A second palladium catalyzed coupling of sulphon halide derivative with an appropriately substituted metal containing aromatic give compound of formula (X).

Scheme-I WO9803484 application also discloses a second method for the preparation of compound of formula (X), which is as per scheme II.

Scheme II US 6812346 discloses a method for the preparation of Etoricoxib which comprises reacting a compound of formula B, wherein X is Br or CI, with compound of formula C, wherein, M is B(OITb or SnMe-u in the nresence of a palladium catalvst to vield Etoricoxib.

Process for the preparation of Etoricoxib as desribed in scheme III, is disclosed in US6040319, wherein X represents phosphates, sulfates, acetates, perchlorate, borates, antimonates, halides, benzoate, napsylate, particularly, hexafluorophosphate, sulfate, mesylate, tosylate, triflate, acetate, trifluoroacetate, tetrafluoroborate, tetraphenyl borate,

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hexafluoroantimonate, chloride, bromide, fluoride, iodide, benzolate and napsylate. Base used is Na and K hydroxide; Cs carbonate; Li. Na and K C1_6 alkoxide: Li, Na and K amides. Li, Na and K hydrides.

Scheme III WO 0137833 discloses different polymorphs of Etoricoxib, specifically disclosed are forms II, III and IV, hemihydrate of form IV and sesquihydrate of form I. WO 0192230 discloses polymorphic form V of Etoricoxib and process for its preparation.
WO 0296877 discloses pharmaceutical composition comprising 10-50% of polymorphic form V and remainder of the compound comprising at least one polymorph selected from forms I, II, III and IV.
WO 2005085199 discloses different other polymorph of Etoricoxib, specifically disclosed forms IX, X, XI, XII, XIII, XIV, XV and XVI.
US 6252116 (divisional of US 6040319) discloses process for preparing intermediate of formula (III), particularly CDTH salt with hexafluorophosphate, tetraphenyl borate, hexafluoroantimonate as it counterion (X").

According to formula (III) R2 through R5 each independently represents C|_6 alky I, aryl or aralkyl group.
Certain heteroatom containing cycloalkyl substituted p-chlorovinamidinium salts for the preparation of Etoricoxib are disclosed in J. Org. Chem., Vol. 66, No. 1, p. 251-255, 2001. But a large number of limitations are also reported. The method disclosed for the preparation of substituted p-chlorovinamidinium salt comprises, addition of chloroacetic acid to N-formyl compound & cycloalkyl group with or without hetero atom and mixture was heated at 70 °C and then to it was added phosphorus oxychloride which after suitable work up gave the substituted p-chlorovinamidinium salt. This document also states that the p-

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chlorovinamidinium salt using N-formylmorpholine was obtained with very low yield
(<10%) and pure sample could not be obtained by using this method. Thus, there exists a
need to prepare substituted p-chlorovinamidinium salts containing a cycloalkyl group
optionally containing a heteroatom, which is one of the intermediate for the preparation of
Etoricoxib, in a pure form and high yield.
We herein disclose an improved process for preparation of differently substituted p-
chlorovinamidinium salts containing a cycloalkyl group optionally containing a heteroatom,
and also process for the preparation Etoricoxib using the substituted p-chlorovinamidinium
salts thus obtained.
OBJECTS OF THE INVENTION
The objective of the present invention is to provide improved process for preparing Etoricoxib.
In an embodiment is provided an improved process for preparing substituted p-chlorovinamidinium salts containing a cycloalkyl group, optionally containing a heteroatom.
The above and other embodiments are further described in the following paragraphs. DETAILED DESCRIPTION
As used herein, the term "reflux temperature" refers to the boiling point of the solvent.
As used herein, the term "THF" refers to tetrahydrofuran, the term "DMF" refers to dimethyl formamide, the term "DIPE:' refers to di-isopropyl ether, the term "DMSO" refers to dimethyl sulphoxide. the term "MTBE" refers to methyl t-butyl ether, the term "MEK" refers to methyl ethyl ketone, the term 'LHJV1DS' refers to lithium bis (trimethylsilyl)amide, the term 'KHMDS' refers to potassium bis (trirnethylsilyl)amide, the term 'LDA' refers to lithium diethylamide
The improved process for preparing Etoricoxib is described in the following Scheme 4:

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and the counterion (X") is selected from hexafluorophosphate, tetraphenyl borate, hexafluoroantimonate. In one of the embodiment of the invention is disclosed a process for the preparation of substituted p-chlorovinamidinium salt of formula (III) which comprises addition of chloroacetyl chloride to phosphorus oxychloride and the reaction mixture was cooled to 0-5 °C and then the N-formyl compound having substituted cycloalkyl group optionallycontaining a heteroatom was added and the reaction mixture was heated to 50-110 °C for 5-20 hrs. The reaction mixture was dumped in to sodium salt of corresponding acid at 0-10 °C. After maintaining at 0-10 °C, reaction mass filtered and washed with water to gave corresponding p-chlorovinamidinium salt..
The p-chlorovinamidinium salt thus obtained was reacted with a ketosulfone compound of formula II in presences of suitable base and in suitable solvents to obtain crude mixture of Etoricoxib, which on purification give pure Etoricoxib.
The suitable base used may be selected from suitable inorganic or organic bases and may be selected from alkali hydroxides, alkali carbonates, alkali metal alkoxides alkali amides or alkali hydrides, LHMDS, KHMDS, LDA and like.

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The suitable solvent used may be selected from alcohols like methanol, ethanol, isopropanol, butanol. 1,2-dimethoxy ethanol. 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol, esters like ethyl acetate and isopropyl acetate, chlorinated solvents like chloroform, dichloromethane, nitriles like acetonitrile, hydrocarbons like toluene, xylene, chlorobenzene, ketones like acetone, methyl ethyl ketone, ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF, aprotic polar solvents such as DMF, DMSO, DMA, water and their suitable mixtures. More preferably, THF and DMF.
In a further embodiment of the invention is disclosed a pharmaceutical composition of Etoricoxib with a liquid or solid carrier, excipients as is known in the art wherein the Etoricoxib is produced by the above disclosed process.
The invention is further described by the following examples, which are provided for illustration only and should not be construed to limit the scope of invention. Example 1
Preparation of 4-(2-chloro-3-morpholinoallylidene) morpholin-4-ium.PF6 salt (IB): (bismorpholino derivative of p-chlorovinamidinium salt)
Phosphorous oxychloride (6.6g) was added in to N-formyl morpholine (5g) at -5 to 10 C and subsequently chloroacetyl chloride (5g) was added at room temperature and the reaction mixture was stirred. Further, N-formyl morpholine (5g) was added to the reaction mixture at room temperature and heat the reaction mass at 55-110 °C for 3 to 24 hrs. The reaction mixture was then cooled to room temperature to obtain a semi solid mass, which was dissolved in dichloromethane and subsequently a solution of NaPFg was added at 0-10 °C over a period of one hour. Then into it 50 ml water was added, organic layer was separated, dried and concentrated til) dry at less than 50 °C, to give 4-(2-chloro-3-morpholinoaI]ylidene) morpholin-4-ium.PF6 salt (4 g). HPLC purity - 44.63 %. Example 2 Preparation of Etoricoxib
Potassium tert. butoxide (1.4g) was dissolved in THF and the solution was maintained at 5-25 C for 10 minutes. Subsequently, a solution containing the sulfone compound of formula II (3g) in THF was added and kept this at 25-30 °C for 1 hr. 4-(2-chloro-3-morpholinoallylidene) morpholin-4-ium.PF6 salt of (formula III) (4g) in THF, obtained above, was added to the previously prepared solution of ketosulfone and heat the reaction mixture at 30-55 C for 2-24 hrs. The reaction mixture was dumped into a mixture of trifluoroacetic acid (0.6 g), acetic acid (4.4g) and THF. The reaction mixture was further heated at 55-60 C for 6-20 hrs. Then cooled the reaction mixture to room temperature after

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adding aqueous ammonia solution (30 ml) and ammonium acetate (0.8g). The reaction
mixture was dumped into water and extracted with ethyl acetate and washed with 10%
aqueous sodium bicarbonate solution. The organic layer was separated, dried & concentrated
till dry at temperature less than 50 C to obtain Etoricoxib (3.1 g).
% purity by HPLC-15.36 % (Etoricoxib), 64.15 % (ketosulfone compound of formula II)
Example 3
Preparation of l-(2-chloro-3-(piperidin-l-yl) allylidene) piperidinium.PFfi salt
(Bispiperidine derivative of p-chlorovinamidinium salt)
Chloroacetic acid (4.75g, 0.05 mole) was added to N-formyl piperidine (13.5g, 0.119 mole) and the reaction mixture was heated to 70-75 °C to give a clear solution. Subsequently, Phosphorous oxychloride (9.5 ml, 0.1 mole) was added over a period of 2 hrs and maintained at 70-75 C for 3 hrs. The reaction mixture was cooled to room temperature and diluted with absolute alcohol (10 ml) and this reaction mass was added into the solution of NaPF6. The reaction mass was stirred for 30 minutes at 0-10 C, filtered and washed with water, to obtain l-(2-chloro-3-(piperidin-l-yl) allylidene) piperidinium.PF6 salt (2 g), yield = 10.42 % HPLC purity = 83.63% Example 4
Preparation of l-(2-chloro-3-(piperidin-l-yl) allylidene) piperidinium.PFs salt (Bispiperidine derivative of p-chlorovinamidinium salt)
Chloroacetyl chloride (20g) solution was cooled and phosphorous oxychloride (27.2g) was added into it at -10 to 0 C. Subsequently, N-formyl piperidine (40g) was added over a period of 1 hrs, maintained the reaction mass at 55-110 C for 6-20 hrs. Then the reaction mixture was cooled to room temperature and diluted with DMF (40 ml). This reaction mass was added into the solution of NaPF6 over a period of 1 hr and was stirred for 60 minute at 0-10 °C. The reaction mixture was filtered and washed with water to obtain crude l-(2-chloro-3-(piperidin-l-yl) allylidene) piperidinium.PFe salt (37.2 g) HPLC purity = 83.24%.
Crude mass was purified by successive purification using methanol: water treatment to obtain l-(2-chloro-3-(piperidin-l-yl) allylidene) piperidinium.PFg salt (18.8 g), yield = 27.48 %. HPLC purity = 99.19%. Example-5 Preparation of Etoricoxib
Potassium tert. butoxide (2.1g) was dissolved in THF (20ml) and the solution was maintained at 5-25 C for 10 minutes. Subsequently, solution of ketosulfone compound of formula II (5g) in THF was added and kept the mixture for lhr at 25-30 °C. l-(2-chIoro-3-

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(piperidin-1-yl) allyhdene) piperidinium.PF6 salt of formula (III) (8g), obtained in Example 4 above, in THF, was added to the previously prepared solution of ketosulfone and heat the reaction mixture at 30-55 C for 2-24 hrs. The reaction mixture was dumped into a mixture of triiloroaceticacid (lg), acetic acid (7.5g) and THF. The reaction mixture was further heated to 55-60 °C for 6-20 hrs, after adding ammonia solution (125 ml). Then cooled the reaction mixture to room temperature. The reaction mixture was dumped into water and extracted with ethyl acetate & washed with 10% aqueous sodium bicarbonate solution. The organic layer was separated & concentrated to dryness at less than 50 C to give Etoricoxib 8.6 g. HPLC purity- 91.28 % (Etoricoxib). Crude mass was purified to obtain Etoricoxib (4.7g). yield = 75.9 % HPLC purity =,96.31 % .

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