FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for the preparation of 2-(6-chloro-9H-carbazol-2-yl)propanoic acid
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at 301, 'Dosti Pinnacle', 3rd Floor,
Plot No.E7, Road No.22, Wagle Industrial Area,
Thane(W)-400 604
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

Field of Invention
The present invention relates to a novel process for the preparation of a non-steroidal anti-inflammatory drug, commonly known as carprofen.
Background of the Invention
Carprofen is a non-steroidal anti-inflammatory drug marketed under the trade names as "Rimadyl", "Imadyl", "Novox" and "Imafen" manufactured by Pfizer Animal Health, which is prescribed by veterinarians as a supportive treatment for various conditions. It provides day-to-day treatment for pain and inflammation from arthritic in geriatric dogs, joint pain, osteoarthritis, hip dysplasia, and other forms of joint deterioration.
Carprofen is also used to relieve short-term post-operative pain, inflammation, and swelling after spaying, neutering, and other procedures. Carprofen reduces inflammation by inhibition of COX-2 and other sources of inflammatory prostaglandins. This is targeted protection, in that it does not interfere with COX-1 activity.
The chemical name of carprofen is 2-(6-chloro-9H-carbazol-2-yl)propanoic acid represented by formula I,

There are few process reported for the preparation of this compound. US 4264500 patent discloses a method for making 6-chloro-a-methyl-carbazole-2-acetic acid. The process comprises reacting methyl-malonic acid diethyl ester with 2-cyclohexen-l-one in presence of a solvent to form α-methyl-3-oxocyclohexane-malonic acid diethyl ester. Reacting the obtained a-methyl-3-oxocyclohexane-

malonic acid diethyl ester with p-chlorophenyl-hydrazine hydrochloride using a solvent to form 6-chloro-1,2,3,4-tetrahydro-2-carbazolyl)-methyl-malonic acid diethyl ester. Further reacting the obtained 6-chloro-1,2,3,4-tetrahydro-2-carbazolyl)-methyl-malonic acid diethyl ester with chlorine gas in toluene to form (6-chloro-2-carbazolyl)-methyl-malonic acid diethyl ester. Finally decarboxylating (6-chloro-2-carbazolyl)-methyl-malonic acid diethyl ester using acid gives 6-chloro- a -methyl-carbazole-2-acetic acid.
EP0008446 patent describes a process for preparing carprofen which comprises reacting diethyl methyl malonate with 2-cyclohexen-l-one in presence of an alcohol to form a-methyl-3-oxocyclohexane-malonic acid diethyl ester. It involves the dissolution of the residue in ether, washing with water, removing the ether at reduced pressure and distillation of the residual oil. Reacting the obtained a-methyl-3-oxocyclohexane-malonic acid diethyl ester with p-chlorophenyl-hydrazine hydrochloride using an alcohol to form 6-chloro-I,2,3,4-tetrahydro-2-carbazolyl)-methyl-malonic acid diethyl ester. Further reacting the obtained 6-chloro-l,2,3,4-tetrahydro-2-carbazolyl)-methyl-ma!onic acid diethyl ester with chloranil in xylene and treating with benzene and carbon tetrachloride to form (6-chloro-2-carbazolyl)-methyl-malonic acid diethyl ester. Finally decarboxylating (6-chloro-2-carbazolyl)-m ethyl-ma Ionic acid diethyl ester using acid to give 6-chloro-a -methyl-carbazole-2-acetic acid.
The said conventional processes for the preparation of carprofen involve the distillation of residual oil containing a-methyl-3-oxocyclohexane-malonic acid diethyl ester, which requires high vacuum and high temperature. Moreover, the prior art process uses carcinogenic solvent such as benzene and class-1 solvent such as carbon tetrachloride for the work up of (6-chloro-2-carbazolyl)-methyl-malonic acid diethyl ester. Hence these processes are not environment friendly.
Thus it is highly desirable to develop a process which overcomes most of the drawbacks of the prior art. The present inventors have developed a very cost effective process which avoids the distillation of residual oil and avoids the use of carcinogenic solvent benzene and other hazardous class-1 solvents.

Summary of the invention
The principal aspect of the present invention is to provide a process for the preparation of 2-(6-chloro-9H-carbazol-2-yl)propanoic acid of formula I, which comprises:
a) condensation of 2-cyclohexen-l-one of formula VI with diethyl methylmalonate of formula VII using a reagent in presence of a solvent without distillation of the formed dimethyl methyl(3-oxocyclohexyl)malonate of formula IV;
b) reaction of dimethyl methyl(3-oxocyclohexyl)malonate of formula IV with (4-chlorophenyl)hydrazine or its hydrochloride salt of formula V in presence of solvent to form dimethyl (6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)methylmalonate of formula HI;
c) dehydrogenation of dimethyl (6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yI)methylmalonate of formula III using chloranil in presence of a solvent to form dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate of formula II wherein workup is carried out by xylene; and
d) hydrolysis as well as decarboxylation of the obtained dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate of formula II using acid to obtain 2-(6-chloro-9H-carbazoI-2-yl)propanoic acid formula I.
The present invention can be illustrated by the below reaction scheme:


Detail Description of the Invention
Accordingly in an embodiment of the invention, the condensation of 2-cyclohexen-1-one of formula VI with diethyl methylmalonate of formula VII is carried out using a reagent selected from sodium methoxide, sodium ethoxide, sodium propoxide and the like, preferably sodium methoxide. The solvent for the said condensation is an alcoholic solvent selected from the group consisting of methanol, ethanol, propanol, butanol, isopropanol and the like. Preferably methanol is used as solvent for the condensation. The condensation is carried out at a temperature in the range of about 20-40°C, preferably at 25 °C.
In another embodiment of the invention, reaction of dimethyl methyl(3-oxocyclohexyl)malonate of formula IV with (4-chlorophenyI)hydrazine or its hydrochloride salt of formula V is carried out in presence of solvent selected from the group consisting of methanol, ethanol, propanol, butanol, isopropanol, xylene

and mixture thereof. The reaction is carried out preferably in methanol. The reaction is carried out at a temperature in the range of about 20-70°C.
In yet another embodiment of the invention, dehydrogenation of dimethyl (6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)methylmalonate of formula III using chloranil is carried out in presence of a solvent selected from the group consisting of toluene, xylene, monochlorobenzene and the like, preferably in xylene to form dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate of formula II. The reaction is carried out at reflux temperature in the range of about I20-160°C, preferably at 135-140 °C. In further embodiment of the invention the obtained dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate is isolated using repeated work up with xylene and use of carcinogenic solvent benzene and crystallisation using class-l solvent carbon tetrachloride is avoided.
In another embodiment of the invention, hydrolysis as well as decarboxylation of the obtained dimethyl (6-chloro-9H-carbazol-2-yl)methyImalonate of formula II is carried out using an acid selected from hydrochloric acid, sulphuric acid, acetic acid and the mixture thereof preferably the mixture of hydrochloric acid and acetic acid to give 2-(6-chloro-9H-carbazol-2-yl)propanoic acid formula I. The reaction is carried out at reflux temperature in the range of about 80-120°C, preferably at 95-105 °C.
In another embodiment, some of the key advantages of the present invention are as below:
1, The process of the present invention avoids the distillation of dimethyl
methyl(3-oxocyclohexyl)malonate which in turn requires high vacuum
and high temperature whereas in the present invention the solvent is
distilled which doesn't require high vacuum and high temperature.
2. The process of the present invention doesn't use the carcinogenic benzene
and hazardous class-l solvent viz. carbon tetrachloride instead uses xylene
for the isolation and workup of dimethyl (6-chloro-9H-carbazol-2-
yl)methylmalonate.

3. The workup process of dimethyl (6-chloro-9H-carbazol-2-yl) methylmalonate is comparatively easy.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of 2-(6-chloro-9H-carbazol-2-yl)propanoic acid of formula I:
(a) Preparation of dimethyl methyl(3-oxocyclohexyl)malonate
Methanol (200 ml) and sodium methoxide (5.89 g) were stirred for 15 minutes at 25 °C in a RB flask. Diethyl methylmalonate (200 g) was added slowly into it and stirred for one hour at 25 °C. A solution of 2-Cyclohexen-l-one (100 g) in methanol (130 ml) was added slowly and stirred for 16 hrs. After completion of reaction, the reaction mass was quenched with acetic acid (20 ml) at 25 °C, stirred for 30 minutes. Solvent and low volatiles present in reaction mass were distilled at 50 °C to get syrupy liquid. Xylene (400 ml) was added to the syrup, stirred for 15 minutes and washed with DM water (230 ml X 3). Xylene layer was separated and distilled at 68 - 72 °C to get a residue.
Yield: 263g
(b) Preparation of (6-chIoro-2,3,4,9-tetrahydro-lH-carbazoI-2-yl)methyl
malonate
Methanol (300 ml), dimethyl methyl(3-oxocyclohexyl)malonate(100g; weight of crude material, 106.04g) obtained in stage (a) and p-Chlorophenyl hydrazine hydrochloride (74 g) were stirred for 1.5 hr at 25 °C in a RB flask. Further the reaction mixture was heated to 65°C and temperature was maintained for 1.5 hrs. After completion of reaction, the reaction mixture was cooled to 0 °C, and filtered. The product was washed with chilled mixture of 1:1 ratio of methanol and hexane (200 ml) and suck dried. The wet product was stirred in 500 ml of DM water at 25 °C for 30 minutes, cooled to 5-10 °C for 1 hr and filtered. The solid

obtained was washed with cold (5-10°C ) DM water (100 ml), suck dried for two hours and dried under vacuum at 50 °C till M.C is less than 0.5% and LOD is less than 1%.
Yield: 88.8 g
(c) Alternative preparation of (6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-
yI)methyImaIonate
Xylene layer of dimethyl methyl(3-oxocyclohexyl)malonate obtained in (a) was distilled at 68-72 °C to get anhydrous xylene solution (equivalent to 251.7g of stage 1 product). Xylene (405 ml) and P-chlorophenyl hydrazine hydrochloride (186.11 g) was added and stirred for 1.5 hr at 25 °C. After completion of reaction, the reaction mixture was heated to 65 °C and maintained for 1.5 hour. The reaction mixture was cooled to 0 °C and filtered. The product was washed with chilled mixture of 1:1 ratio of methanol and hexane (503 ml) and suck dried for two hours. The wet product obtained was stirred in DM water (1259 ml) at 25 °C for 60 minutes and filtered. The solid obtained was washed with DM water (252 ml), suck dried for two hours and dried under vacuum at 50 °C till moisture content is less than 0.5% and LOD is less than 1%.
Yield: 194.28 g
(d) Alternative preparation of (6-chIoro-2,3,4,9-tetrahydro-lH-carbazol-2-
yl)methylmalonate
Xylene layer of dimethyl methyl(3-oxocyclohexyl)malonate obtained in (a) was distilled at 68-72 °C to get anhydrous xylene solution (equivalent to 251.7g of stage 1 product). Methanol (251 ml), xylene (153 ml) and P-chlorophenyl hydrazine hydrochloride (186.11 g) was added and stirred for 1.5 hr at 25 °C. After completion of reaction, the reaction mixture was heated to 65 °C and maintained for 1.5 hour. The reaction mixture was cooled to 0 °C under stirring for one hour and filtered. The product was washed with chilled mixture of 1:1 ratio of methanol and hexane (503 ml) and suck dried for two hours. The wet product obtained was stirred in DM water (1259 ml) at 25 °C for 60 minutes and filtered. The solid

obtained was washed with DM water (252 ml), suck dried for two hours and dried under vacuum at 50 °C till moisture content is less than 0.5% and LOD is less than 1%.
Yield: 199.19 g
(e) Preparation of dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate
Xylene (1.0 L), (6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)methyl malonate (100 g) and Chloranil (168.84 g) were heated to reflux (~138°C) and maintained for 6 hours in RB Flask. After completion of reaction, the reaction mixture was cooled to 40 °C and filtered. Insolubles were washed with hot xylene and suck dried. Suck dried insolubles were taken in an RBF, slurried with xylene at 60oC for 30 minutes and filtered. This process was repeated twice or thrice. Finally the combined filtrate was heated to 40-45 °C to get clear solution. Xylene solution was stirred with 2N sodium hydroxide solution (400 m! X 4) for 30 minutes each, layers were separated [The aqueous layer contains dark coloured solid material which was stirred successively three times with DM water (465 ml) to get 18g of crude dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate. This crude dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate is combined later with worked up xylene layer]. Organic layer was washed with water (370 ml X 4) till neutral pH is obtained. Organic layer was decolourised with of 2g activated carbon at 70-75 °C for 1 hr and slurry was filtered through hyflow. The hyflow bed was washed with hot xylene (180 ml). Filtrate and hyflow bed washings were combined. Crude dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate obtained above were added to the filtrate and concentrated till a residual volume of 150 ml by distilling xylene at 60-65 °C. Residue was chilled to 0±2 °C for 1 hr and filtered. The product was washed with chilled xylene (0±2 °C) (100ml), suck dried for 2 hrs and dried at 50 °C under vacuum till LOD is less than 0.5%
Yield: 71.7g

(f) Preparation of 2-(6-chloro-9H-carbazol-2-yl)propanoic acid
Dimethyl (6-chloro-9H-carbazol-2-yl)(methyl)malonate(100g), acetic acid (770ml) and 6N HC1 (770 ml) were heated to reflux (100°C) for 10 hours in a RB Flask. After completion of reaction, reaction mass was cooled to 0-5 °C, maintained for 30 minutes. Reaction mass was filtered, solids were washed with 1:1 ratio of acetic acid and DM water cold (0-5°C) mixture (80 ml X 3). Solids are again washed with cold DM water (0-5 °C) (120 ml x 1) and suck dried for 2 hour. The crude wet material obtained was charged into RBF containing 10% KOH solution (575 ml) at 25-30 °C, stirred for 1 hour at 25-30 °C. The reaction mass was transferred to the separating funnel, washed with MTBE (140 ml x 4). Aqueous layer was charged to the RB flask, activated carbon (2.7g) was added, stirred at 25-30°C for 1 hour and filtered through hyflow bed. The bed was washed with DM water (100ml), filtrate was once again charged to the RBF, cooled to 5-10°C. 2N HC1 (276 ml) was slowly added to adjust the pH to 3-4, stirred for 1 hour at 5-10°C and filtered through cloth. The solid was then washed with DM water (200ml) and suck dried for 2 hours. Wet material and DM water (700 ml) was charged into another RBF, stirred and heated to 50°C for 1 hour. Filtered, washed the solid with DM water (400 ml) and sucked dried for 2 hours. This is repeated once again.
Yield: 60 g Purity: NLT 99.5%

We claim:
1. A process for the preparation of 2-(6-chloro-9H-carbazol-2-yl)propanoic acid of formula I, which comprises:

a) condensation of 2-cyclohexen-l-one of formula VI with diethyl methylmalonate of formula VII using a reagent in presence of a solvent without distillation of the formed dimethyl methyl(3-oxocyclohexyl)malonate of formula IV;

b) reaction of dimethyl methyl(3-oxocyclohexyl)malonate of formula IV with (4-chlorophenyl)hydrazine or its hydrochloride salt of formula V in presence of solvent to form dimethyl (6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)methylmalonate of formula III;

c) dehydrogenation of dimethyl (6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)methylmalonate of formula III using chloranil in presence of a solvent to

form dimethyl (6-chloro-9H-carbazol-2-yl)methylmaIonate of formula II wherein workup is carried out by xylene; and

d) hydrolysis as well as decarboxylation of the obtained dimethyl (6-chloro-9H-carbazol-2-yl)methylmalonate of formula II using acid to obtain 2-(6-chloro-9H-carbazol-2-yl)propanoic acid formula I.
2. A process according to claim 1, wherein the reagent for condensation in step (a) is selected from sodium methoxide, sodium ethoxide or sodium propoxide.
3. A process according to claim 1, wherein the solvent for condensation in step
(a) and in step (b) is selected from methanol, ethanol, propanol, butanol or
isopropanol.
4. A process according to claim 1, wherein the solvent for the reaction in step
(b) is selected from the group consisting of methanol, ethanol, propanol,
butanol, isopropanol, xylene and mixture thereof.
5. A process according to claim 1, wherein the condensation in step (a) and reaction in step (b) is carried out at the temperature in the range of about 20-70°C.
6. A process according to claim 1, wherein the solvent for dehydrogenation in step (c) is selected from toluene, xylene, monochlorobenzene and the like.
7. A process according to claim 1, wherein the dehydrogenation in step (c) is carried out at the temperature of about 120-160°C.

8. A process according to claim 1, wherein the acid for decarboxylation in step (d) is selected from hydrochloric acid, sulphuric acid, acetic acid and the mixture thereof.
9. A process according to claim 1, wherein the acid for decarboxylation in step (d) is hydrochloric acid and acetic acid.
10. A process according to claim 1, wherein the decarboxylation in step (d) is carried out at the temperature of about 80-120°C.