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

“A PROCESS FOR THE PREPARATION OF CARPROFEN”

ZENFOLD SUSTAINABLE TECHNOLOGIES PRIVATE LIMITED an Indian company of 53 C, Praga Square, Bommasandra Industrial Area, Phase 1, Hosur Road, Bengaluru, Karnataka- 560099, India

The following specification particularly describes the invention & the manner in which it is to be performed.

Field of the invention
The present invention relates to a process for the preparation of Carprofen.

Background of the invention
Carprofen is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class that includes ibuprofen, naproxen, and ketoprofen. Carprofen is the nonproprietary designation for a substituted carbazole, 6-chloro-α-methyl-9H-carbazole-2-acetic acid.The chemical structure of carprofen is:

Formula I
Carprofen is a non-narcotic, non-steroidal anti-inflammatory agent with characteristic analgesic and antipyretic activity approximately equipotent to indomethacin in animal models. It is indicated for the relief of pain and inflammation associated with osteoarthritis and for the control of postoperative pain associated with soft tissue and orthopedic surgeries in dogs. It is supplied under the tradenames Rimadyl, Novox, and Vetprofen in the dosages of 25mg, 75 mg, and 100 mg of carprofen per tablet or caplet.

Carprofen is a white, crystalline compound. It is freely soluble in ethanol, but practically insoluble in water at 25°C.

The U.S. Patent No. 4,158,007 discloses preparation of carprofen by using cyclohexanone and 2-methylmalonate as starting materials as follows –

The method known in the art for the preparation of carprofen has various disadvantages such as use of stochiometric amount of chloranil(oxidizing agents), generate huge volume of chemical wastage (chloranil by-product), processes often are tedious as the by-products of oxidizing agents are hard to remove and require intense purification process, result in moderate yields and costly process.

Inventors have surprisingly discovered the novel process of preparation of carprofen which is easy for processing, do not require chloranil and results in higher yields.

Summary of the invention
The specification discloses a process for the preparation of Carprofen having Formula I

Formula I
comprising:
a. converting a compound of Formula II

Formula II
to a compound of Formula III

Formula III
in presence of a copper salt,
b. optionally, crystallizing the compound of Formula III and
c. converting the compound of Formula III to Carprofen.

Brief description of the drawings
Figure I: Synthetic scheme for the preparation of Carprofen.

Detailed description
One embodiment discloses a process for the preparation of Carprofen having Formula I

Formula I
comprising:
a) converting a compound of Formula II

Formula II
to a compound of Formula III

Formula III
in presence of a copper salt,
b) optionally, crystallizing the compound of Formula III and
c) converting the compound of Formula III to Carprofen.

The copper salt used in the present invention is selected from Copper(I) chloride, Copper(I) iodide, Copper(I) bromide, Copper(I) triflate, Copper(II) chloride, Copper(II) iodide, Copper(II) bromide, Copper(II) nitrate, Copper(II) sulfate and Copper(II) acetylacetonate.

The copper salt is used in the reaction in amount from 0.1 to 0.5 molar equivalents of a compound of Formula II, preferably 0.2 molar equivalent of a compound of Formula II.

The conversion of compound of Formula II to compound of Formula III is carried out in a hydrocarbon solvent selected from toluene, ethyl acetate, xylene, or the like.

The reaction can be carried out at about 25°C to there flux temperature of the reaction mixture. Preferably, the reaction is carried out at the reflux temperature of the reaction mixture. The product compound of Formula III is optionally crystallized from the solvent selected from toluene, methanol, ethyl acetate, hexane or mixtures thereof.

The conversion of compound of Formula III to Carprofen is carried out in acetic acid in the presence of hydrochloric acid.

The reaction can be conveniently carried out at a temperature in the range of about 15° to about 150° C.

The process further comprises a process for the preparation of compound of Formula II

Formula II
comprising:
reacting a compound of Formula IV

Formula IV
with 4-chlorophenyl hydrazine of Formula V or its hydrochloride
.
Formula V
The reaction of compound of Formula IV with 4-Chlorophenyl hydrazine of Formula V, particularly4-Chlorophenyl hydrazine hydrochlorideis carried out in the presence of an inert organic solvent, for example, an alkanol selected from methanol, ethanol, propanol, or the like.

The reaction can be conveniently carried out at a temperature in the range of about 15° to about 100° C. The compound of Formula II can be recovered, if desired, utilizing conventional methods. However, it is also possible to utilize the reaction product in situ in the next step of the process of the invention.

The process further comprises a process for the preparation of compound of Formula IV

Formula IV
comprising:
reacting diethyl methylmalonate of Formula VI

Formula VI
with 2-cyclohexen-1-oneof Formula VII
.
Formula VII
The reaction of diethyl methylmalonate of Formula VI with 2-cyclohexen-1-one of Formula VII is carried out in the presence of an inertorganic solvent, for example, an alkanol selected from methanol, ethanol, propanol, or the like. The reaction is carried out in present of alkalialkoxide selected from sodium methoxide or sodium ethoxide.

The reaction can be conveniently carried out at a temperature in the range of about 0° to about 100° C. The compound of Formula IV can be recovered, if desired, utilizing conventional methods. However, it is also possible to utilize the reaction product in situ in the next step of the process of the invention.

The following examples illustrate specific embodiments; however, the full scope of the disclosure is not limited to the examples described below.

Example 1
Preparation of Diethyl 2-methyl-2-(3-oxocyclohexyl)malonate of Formula IV
Sodium methoxide (7.5 g) was added to ethanol (325 mL) and the mixture was stirred till the sodium dissolves. The resulting solution was treated with diethyl 2-methylmalonate (200 g, 1.14 moles) and the mixture was stirred for an hour. Solution of cyclohexanone (100 g, 1.04 moles) in ethanol (125 mL) was added within one hour and the mixture as stirred for 16 hours. Acetic acid (20 mL) was added to the reaction mixture and recovered. The resulting oil was dissolved in Toluene(750 mL) and the organic layer was washed with water (3 x 200 mL). The organic solution was dried over sodium sulphate, filtered and the solvent is recovered to give the crude product diethyl 2-methyl-2-(3-oxocyclohexyl) malonate as a brown oil(260 g, 90 %).

Example 2
Preparation of Diethyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methylmalonate of Formula II
Ethanol (300 mL), diethyl 2-methyl-2-(3-oxocyclohexyl)malonate (100 g, 0.37 mol), 4-Chlorophenyl hydrazine hydrochloride (73g, 0.41 mol. 1.1 equiv.) were stirred for 1.5 h at room temperature. Further the reaction mixture was heated at 70 °C for 2 h. The reaction mixture was cooled to 0 °C and kept at that temperature for 1h then filtered off. The filter cake was washed with cold ethanol and hexane mixture (1:1, 200 mL) and suck dried. The wet material was stirred in water (500mL) at room temperature for 1 h and filtered. The wet material dried under vacuum at 60°C till water content less than 1.0% to obtain the title compound (85 g, 55 %).

Example 3
Preparation of Diethyl 2-(6-chloro-9H-carbazol-2-yl)-2-methylmalonate of Formula III
To a 3 Litre multi neck round bottom flask fitted with a guard tube was charged diethyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methylmalonate (100 g, 0.265 mol, 1 equiv.), toluene (1500 mL) and dimethylsulfoxide (DMSO) (5 mL). The reaction mixture was added copper chloride (0.053 mol, 0.2 equiv.) The reaction mixture was heated to 100°C for 16 h. The reaction mixture was filtered through a celite pad and the filtrate was washed with water (2 x 350 mL) and brine solution (2 x 250 mL).The organic layer was dried over anhydrous sodium sulphate, filtered and the solvent was recovered to yield the title compound as a brown solid which on recrystallization with 20 % ethyl acetate/ Hexane (200 mL) yielded the off white solid (72 g, 73 %).

Example 4
Alternate preparation of Diethyl 2-(6-chloro-9H-carbazol-2-yl)-2-methylmalonate of Formula III
To a 3 Litre multi neck round bottom flask fitted with a guard tube was charged diethyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methylmalonate (100 g, 0.265 mol, 1 equiv.), Ethyl acetate (1500 mL) and dimethylsulfoxide (DMSO) (5 mL). The reaction mixture was added copper chloride(0.053 mol, 0.2 equiv.) The reaction mixture was heated to 80°C for 16 h. The reaction mixture was filtered through a celite pad and the filtrate was washed with water (2 x 350 mL) and brine solution (2 x 250 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and treated with activated carbon. Solvent was partially recovered and then added Hexane (100 mL) to obtain off white solid (71.5 g, 72 %).

Example 5
Preparation of 2-(6-chloro-9H-carbazol-2-yl)propanoic acid of Formula I
A solution of diethyl 2-(6-chloro-9H-carbazol-2-yl)-2-methylmalonate (100 g, 0.268 mol) in acetic acid (750 mL) and 6N hydrochloric acid (HCl) (750 mL) was heated for 16 h at 100 °C. The reaction mixture was cooled to 0 °C and the precipitate obtained was filtered off. The filter cake was washed with 1:1 mixture of Acetic acid and water (3x100 mL). The crude wet material was charged into a flask containing 10 % potassium hydroxide (KOH) solution (550 mL) and stirred for 30min. The reaction mass was washed with dichloromethane (150 mL x 4), 5 g of activated carbon was added to the reaction mass, stirred f or 1 h and filtered through a celite bed. The filter bed was washed with water (100 mL) and the aqueous layer was transferred to the flask again and cooled to 5 °C. The pH of the solution was adjusted to 3-4 and the precipitated solid was washed with water and air dried to afford the product 2-(6-chloro-9H-carbazol-2-yl) propanoic acid (Carprofen) (65 g, 89 %)

Example 6 comparative example

Preparation of Diethyl 2-(6-chloro-9H-carbazol-2-yl)-2-methylmalonate of Formula III
To a solution of diethyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methylmalonate (100 g, 0.264mol, 1 equiv.) in Xylene (1000 mL) was added Chloranil ( 97 g, 0.39 mol, 1.5 equiv.).The reaction mixture was heated for 12 h at 138 °C. The chloranil by-product got crystallized along with a small amount of product. The solid was filtered off and the filter cake was washed with hot xylene. The combined xylene filtrate was washed with 4 x 300 mL of 2N sodium hydroxide (NaOH). To the xylene layer was added 10 of charcoal, heated to 70°C, filtered over a celite while hot and the solvent was recovered. The resultant solid was recrystallised from 20 % ethyl acetate/ Hexane mixture (450 mL). 54 g (54 %) of diethyl 2-(6-chloro-9H-carbazol-2-yl)-2-methylmalonate, was obtained as a pale yellow solid.
, Claims:We claim:

1. A process for the preparation of Carprofen having Formula I

Formula I
comprising:
a. converting a compound of Formula II

Formula II
in presence of a copper salt to a compound of Formula III, and

Formula III
b. converting the compound of Formula III to Carprofen.
2. The process according to claim 1 wherein the copper salt is selected from Copper(I) chloride, Copper(I) iodide, Copper(I) bromide, Copper(I) triflate, Copper(II) chloride, Copper(II) iodide, Copper(II) bromide, Copper(II) nitrate, Copper(II) sulfate and Copper(II) acetylacetonate.

3. The process according to claim 2 wherein the copper salt is Copper(I) chloride or Copper(II) chloride.

4. The process according to claim 1 wherein the copper salt is used in the reaction in amount from 0.1 to 0.5 molar equivalents of a compound of Formula II, preferably 0.2 molar equivalent of a compound of Formula II.

5. The process according to claim 1 wherein the conversion of compound of Formula II to compound of Formula III is carried out in a hydrocarbon solvent selected from toluene, ethyl acetate or xylene.

6. The process according to claim 1 wherein the product compound of Formula III is optionally crystallized from the solvent selected from toluene, methanol, ethyl acetate, hexane or mixtures thereof.

7. The process according to claim 1 wherein the conversion of compound of Formula III to Carprofen is carried out in acetic acid in the presence of hydrochloric acid.

8. The process according to claim 1 further comprising a process for the preparation of compound of Formula II,

Formula II
comprising:
a) reacting diethyl methylmalonate of Formula VI

Formula VI
with 2-cyclohexen-1-one of Formula VII

Formula VII
to obtain compound of Formula IV

Formula IV
b) reacting a compound of Formula IV

Formula IV
with 4-Chlorophenyl hydrazine of Formula V or its hydrochloride

Formula V
to obtain compound of Formula II.

9. The process according toclaim8 wherein the process is carried out in the presence of an inertorganic solvent selected from methanol, ethanol or propanol.

10. The process according to claim 8 wherein the process of step (a)is carried out in the presence of alkalialkoxide selected from sodium methoxide or sodium ethoxide.