DESC:Field of the invention

The present invention encompasses an improved process for the preparation of 2-chloro-3-amino acrolein which is used in the synthesis of Etoricoxib of formula (I). More particularly present invention provides process for the preparation of Etoricoxib which gives Etoricoxib in high yield and purity.

Formula (I)

Background of the invention

Selective inhibitors of cyclooxygenase-2 are a sub-class of drugs known as non-steroidal anti-inflammatory 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 and is represented by the compound of formula I.

EP0975596 disclose a process for preparing Etoricoxib by reacting ketosulfone with the chloro malonaldehyde under acidic condition conditions in the presence of toluene at reflux temperature.

Pure sample of Etoricoxib could not be obtained by using this prior art process, because reaction is employed at higher temperature (136 0C), 2-chloro-malonaldehyde decompose at such higher temperature, which makes the reaction very sluggish and generates so many impurities which requires many purification and reduce the yield of product.

There is need in the art for a process of preparing compounds of formula I having sufficient purity and yield to meet quality and regulatory standards for pre-clinical and commercial use. The present invention provides a process for preparing compound of formula I using compound of formula II and III. 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%.

Formula II Formula III

Present inventors have focused on the problems associated with the prior art process and have developed an improved process for the preparation of Etoricoxib using cyclohexane as a solvent at 70-100 0C which minimize the decomposition of 3-amino-2- chloro acrolein. The process of present invention removes further purification steps and provides Etoricoxib in high yield and purity.

Object of the invention:

It is an object of the present invention is to provide an improved process for the preparation of Etoricoxib having purity of about 99%.

Further object of present invention is to provide an improved process for the preparation of Etoricoxib which comprising step of reacting compound of formula II and compound of formula III in the under acidic condition in the presence of cyclohexane at 75 to 90 0C.

Formula II Formula III

Another object of present invention to provides a process for preparation 3-amino-2- chloro acrolein (formula II) comprising a step of reacting CDT phosphate (Formula IV) with metal hydroxide to give metal salt of 2-chlorormalonaldehyde, which is further reacted with acid to give 2-chloromalonaldehyde, which is reacted with isopropyl alcohol and ammonia to give 3-amino-2-chloro acrolein (formula II).

Detailed description of the invention:
An embodiment present invention provides an improved process for the preparation of Etoricoxib comprising, reacting compound of formula II with compound of formula III under acidic condition and in the presence of cyclohexan as a solvent.

Formula II Formula III

For purposes of this specification acidic condition includes methanesulfonic acid, acetic acid, propionic acid and mixture thereof.
The molar ratio of compound of formula II to compound of formula III can typically be varied form 1:1 to 2:1; preferably 1:1. The reaction step may be conducted at a temperature range of 70 to 1000C; preferably at 80 to 900C.

The work up process in the present invention is very smooth for isolation of pure Etoricoxib as there is very less decomposition of 3-amino-2-chloro acrolein at lower temperature.

In another embodiment present invention provides a process for preparation 3-amino-2-chloro acrolein (formula II) comprising a step of reacting CDT phosphate (Formula IV) with metal hydroxide to give metal salt of 2-chlorormalonaldehyde, which is further reacted with acid to give 2-chloromalonaldehyde, which is reacted with isopropyl alcohol and ammonia to give 3-amino-2-chloro acrolein

For purposes of this specification metal hydroxide includes sodium hydroxide and potassium hydroxide. More Preferable is aq. solution of metal hydroxide.
The reaction step may be conducted at a temperature range of 100 to 120 0C; preferably at 80 to 1000C.
Further the compound of formula II is reacted with compound of formula III in the presence of methansulfonic acid and cyclohexane at 70 to 100 0C. Preferably at 80 to 90 0C. The process of present invention provides Etoricoxib substantially free of ketosulfone (compound of formula III) 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.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

Examples:
Example-1 Preparation of 2-chloromalonaldehyde

CDT Phosphate (Formula-IV) (100g) was charged to a solution of NaOH (39.13g) in Water (150ml) at room temperature. Reaction mass was heated up to 80-90°C till completion. Reaction mass was cooled to 25-35°C and was filtered. Solid was suspended in water and pH was adjusted to acidic with conc. hydrochloric acid. Precipitated solid was filtered and dried at 35-45°C.
Yield: 18-27g.

Example-2 Preparation of 3-amino-2-chloroacrolein

IPA (600ml) and 2-chloro-3-hydroxy prop-2-enal (100g) were charged to a stirring apparatus at room temperature. IPA was distilled atmospherically and the residue was cooled to 25-30°C. The residue was added to the mixture of Aqueous Ammonia (100ml) in IPA (200ml). After 1 hour stirring of reaction mass at 20-30°C, it was cooled to 1-5°C and stirred for 1 hour. Solid was filtered and washed with cold IPA (25ml) and dried the solid at 50-60°C.
Yield- 57-72g

Example-3 Preparation of Etoricoxib hydrochloride salt

Propionic acid (500ml), Cyclohexane (500ml), Ketosulfone (Formula-III) (100g), Methanesulfonic acid (66.4g) and 3-amino-2-chloro acrolein (91g) were charged to a stirring apparatus at room temperature. Reaction mass was heated up to 80-90°C, water was removed azeotropically. After completion of the reaction, Cyclohexane and Propionic acid were distilled out under reduced pressure up to 95°C. Water (600ml) was added to the residue and basify with a solution of NaOH (100g) in water (100ml) till pH~10-14 up to 60°C. Toluene (1500ml) added, reaction mass was heated at 65-75°C and stirred for 15 mins. Cooled reaction mass to 15-19°C and reaction mass was filtered. The filtrate was as such used for next step. Filtrate comprising of Etoricoxib and ketosulphone.

A solution of NaOH (5.53g) in water (50ml) was added to the organic layer at 15-30°C and heated at 60-70°C. Solution of Hydroxyl amine hydrochloride (7.2g) in water (50ml) was added in hot and stirred for 2 hrs at 65-75°C. Cooled solution at 35-45°C, charged NaOH solution (100 g in 500 ml of water) to reaction mass. Cooled reaction mass and Organic layer was separated. Organic layer further cooled to 14-20°C and added IPA HCl (92g). Solid was filtered and dried.
Yield- 95-100g.

Example-4 Preparation of Etoricoxib

DM water (800ml), Toluene (1000ml) and Etoricoxib HCl (100g) were charged to a stirring apparatus. Ammonia solution (50ml) was added slowly till clear solution. Organic layer was separated and distilled up to 70°C. IPA (705.6ml) and Hexane (14.4ml) mixture were charged to the residue and heated at 75-85°C. Mixture was stirred till clear solution obtained. Reaction mass was cooled to 10-14°C and Solid was filtered and dried.
Yield- 68-80g
,CLAIMS:1. A process for the preparation of Etoricoxib of formula I comprising the step of reacting compound of formula II

Formula II

with compound of formula III

Formula III

in the presence of methansulfonic acid and cyclohexane at 75 to 90 0C.

2. A process for the preparation of 3-Amino-2-chloro acrolene of formula-II comprising a step of
a) reacting compound of formula IV with the with metal hydroxide to give metal salt of 2-chlorormalonaldehyde, which is further reacted with acid to give 2-chloromalonaldehyde.

2-chlorormalonaldehyde

b) 2-chloromalonaldehyde is further reacted with isopropyl alcohol and ammonia to give 3-Amino-2- chloro acrolene of formula II.

3. Process for the preparation of Etoricoxib of formula I

Formula (I)

a) The process comprising of reacting compound of formula-IV


Formula-IV
With the metal hydroxide to give metal salt of 2-chlorormalonaldehyde, which is further reacted with acid to give 2-chloromalonaldehyde.

2-chloromalonaldehyde

b) 2-chloromalonaldehyde is further reacted with isopropyl alcohol and ammonia to give 3-Amino-2- chloro acrolene of formula II.

Formula-II
c) Reacting compound of formula-II With the compound of formula-III

Formula (III)
in the presence of methansulfonic acid and cyclohexane at 75 to 90 0C.

4. A process according to claim 2 to 3 where in metal hydroxide is sodium hydroxide or potassium hydroxide.