FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"A ONE POT PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE"
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, S. V. ROAD,
JOGESHWARI (WEST), MUMBAI-400 102,
MAHARASTRA, INDIA

FIELD OF THE INVENTION:
The present invention relates to a one pot process for the preparation of Teriflunomide of formula (I).
BACKGROUND OF THE INVENTION:
Teriflunomide chemically known as (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoro methyl) phenyl]but-2-enamide has the following structure:
Teriflunomide acts as an immunomodulatory agent by inhibiting pyrimidine synthesis, indicated for the treatment of multiple sclerosis, specifically relapsing forms. Teriflunomide is an immunomodulatory agent that decreases the amount of activated CNS lymphocytes, which results in anti-inflammatory and antiproliferative effects. This drug is currently used in the treatment of rheumatoid arthritis. It is the active metabolite of Leflunomide, and is marketed under the name Aubagio®. The FDA label states an important warning about the risk of hepatoxicity and teratogenicity for patients using Teriflunomide.

Teriflunomide was first disclosed and claimed in US 5,679,709 patent but this application does not mention the process of preparation.
US 5,494,911 patent discloses process for preparation of Teriflunomide of formula (I) which involves reacting 5-methyl-isooxazole-4-carboxylic acid chloride of formula (IV) with 4-trifluoromethyl aniline ("TFMA") of formula (V) in acetonitrile to give Leflunomide of formula (II). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide of formula (I) as shown in Scheme 1.
Journal of Labelled Compounds and Radiopharmaceuticals, 2003, 46 (7), 613-22 gives the process for the synthesis of Teriflunomide of formula (I) involves the chlorination of 5-methylisoxazole-4-carboxylic acid ("MlA")of formula (III) to convert it to the corresponding acyl chloride ("MIA-C1"), which treated with 4-trifluoromethyl aniline ("TFMA") of formula (V) in the presence of sodium bicarbonate in toluene and then converted to Teriflunomide of formula (I) using sodium hydroxide as shown in Scheme 2.

Both the above processes involve a two stage process, involving the isolation of Leflunomide in one stage and conversion of leflunomide so formed to Teriflunomide in the second stage. Also no mention is made about the quality of the product so obtained. Further that the process mentioned in US'911 patent makes use of a molar excess of TFMA in acetonitrile making the preparation uneconomical on a large scale, since acetonitrile is an expensive solvent. TFMA which is used as an acid scavenger in the reaction is also expensive and besides it is considered as a potential genotoxic impurity.
US 6,723,855 patent discloses two step process for the synthesis of Leflunomide of formula (II). The chlorination of 5-methyiisoxazole-4-carboxylic acid of formula (III) to convert it to the corresponding acid chloride of formula (IV), which treated with 4-trifluoromethyl aniline of formula (V) in the presence of alkali metal or alkaline-earth metal bicarbonates, preferably about 40°C to

prepare Leflunomide of formula (II) as shown in Scheme 3. Bicarbonates such as Sodium or Potassium bicarbonates are described for coupling reaction and then use of Sodium hydroxide is prescribed. Bases are used multiple times.
US'855 patent teach chlorination using large excess thionyl chloride, typically in 5 molar excess or greater. The excess of the chlorinating agent is removed by distillation. It also mentioned the drawbacks encountered in the prior art processes during the preparation of Leflunomide of formula (II). One such drawback mentioned is the formation of Teriflunomide of formula (I) as an impurity which is difficult to remove from Leflunomide of formula (II). Use of single base was taught to primarily produce Leflunomide in which Teriflunomide impurity is formed. This is in contrast with the prior art which uses two bases. In the present invention it was surprisingly found that use of single base produces Teriflunomide which is devoid of Leflunomide. Another drawback mentioned in US'855 patent is associated with the preparation of 5-methyl-isooxazole-4-carboxylic acid chloride of formula (IV). To ensure complete conversion of MIA to MIA CI, excess quantities are used. This necessitates distillation. Another drawback was reaction between MIA and TFMA and poor yields. These drawbacks of the prior art processes were addressed in US'855 patent by using

excess of thionyl Chloride and suitable measures to overcome them have been described therein.
U.S. Pat. No. 5,990,141 discloses process for preparation of Teriflunomide of formula (I) which involves reacting 4-trifluoromethyl aniline of formula (V) with cyanoacetic acid ethyl ester of formula (VI) to give cyanoacet-(4-trifluoromethyl)-anilide of formula (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetyl chloride in THF to give Teriflunomide of formula (I) as shown in scheme 4.
The above process mentioned in US'141, requires higher temperatures of 180°C and also makes use of chromatographic purification which pose operational difficulties during scale up.
U.S. Pat. No. 6,365,626 discloses process for preparation of Teriflunomide of formula (I) involves reacting 4-trifluoromethyl aniline of formula (V) with cyanoacetic acid of formula (VIII) to give compound of formula (VII). This compound is further reacted first with sodium hydride and then with acetyl chloride to give Teriflunomide of formula (I) as shown in scheme 5.

U.S. Pat. Appl. No.US 20110105795 Al provides a process for preparation of Teriflunomide by refluxing ethyl acetoacetate of formula (IX) and 4-trifluoromethyl aniline of formula (V) in aromatic hydrocarbon for about 48 hours and purified by column chromatography followed by bromination and then treated with alkali cyanide for overnight and acidified with 50% HCI solution to prepare Teriflunomide of formula (1) as shown in scheme 6.
The processes described in US'626 and US20110105795 require the use of potentially dangerous sodium hydride and sodium cyanide respectively, which

require specialized handling procedures. Additionally, both the processes require chromatographic purification at some or the other stage.
Those skilled in the art will appreciate a process which will avoid the use of large excess of the reagents more specifically the TFMA and the chlorinating agent thereby circumventing the need for distillation of the corrosive chlorinating agent and eliminating the drawbacks mentioned during the preparation of 5-methyl-isooxazole-4-carboxylic acid chloride of formula (IV) viz explosive nature of 5-methyl-isooxazole-4-carboxylic acid chloride of formula (IV) during distillation.
Although the prior art processes dealing with preparation of Leflunomide of formula (II) mention the formation of Teriflunomide of formula (I) as an impurity, no mention is made to generate Teriflunomide of formula (1) as an active product completely in-situ without the need for isolating the intermediate Leflunomide of formula (II), followed by subsequent purification, isolation and conversion to Teriflunomide.
Thus, there exists a need for an improved preparative route, which for example, involves reduced number of steps, is operationally simple with no special handling procedures and requirements, consume optimum amounts of reagents and substrates, provide a product free from impurities, have reduced and/or more eco-friendiy waste products, and/or provide a product in high yield & purity.

OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to provide an improved, simple and cost-effective one pot process for the preparation of Teriflunomide of formula (I) with good yield and high purity.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a one pot process for the preparation of Teriflunomide of formula (I), which comprises:
a) Combining 5-methyl-isooxazole-4-carboxylic acid of formula (III) with a chlorinating agent to form an acid chloride of formula (IV), optionally in presence of solvent;
b) Combining acid chloride of formula (IV) with 4-trifluoromethyI aniline of formula (V) in presence of a base to form Teriflunomide of formula (I), without isolating Leflunomide of formula (II);
c) Isolating Teriflunomide of formula (I).
BRIEF DESCRIPTION OF THE DRAWING:
Figure 1: Shows the X-ray powder diffraction pattern of Teriflunomide of formula (I) obtained according to present invention
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a convenient, industrially feasible and efficient one pot process for the preparation of Teriflunomide of formula (1).

Thus in accordance with the present invention one pot process for the preparation of Teriflunomide of formula (I) comprises:
a) Combining 5-methyl-isooxazo!e-4-carboxylic acid of formula (Til) with a chlorinating agent to form an acid chloride of formula (IV), optionally in presence of solvent;
b) Combining acid chloride of formula (IV) with 4-trifluoromethyI aniline of formula (V) in presence of a base to form Teriflunomide of formula (I), without isolating Leflunomide of formula (II);
c) Isolating Teriflunomide of formula (I).
Preparation of 5-methyI-isooxazoIe-4-carboxylic acid chloride of formula (IV), involves combining 5-methyl-isooxazole-4-carboxylic acid of formula (III) with a chlorinating agent. The preferred chlorinating agent is thionyl chloride, though other chlorinating agents may be used, such as PCI3, PCI5, POCI3, oxalyl chloride or benzoyl chloride or suitable combinations thereof. In the Examples that follow, thionyl chloride was used. The thionyl chloride employed was preferably used in LI to 2 molar excess, more preferably in 1.5 M excess. The said reaction is carried out at a temperature range of 50 C to 70°C, preferably at reflux temperature of thionyl chloride. The chlorination reaction can be carried out either in the absence of or in presence of an inert solvent. Preferred inert solvent is Toluene. The said inert solvent can optionally be distilled after the completion of chlorination reaction. Preferably the said reaction is carried out in absence of a solvent and without the need for distillation of the excess thionyl chloride used.

Inventive step and the novelty of the process of present invention resides in use of remarkably lesser amounts of Chlorinating agents as compared to prior art and thereby eliminates steps for the removal of excess of chlorinating agent. Above reaction mass containing 5-methyl-isooxazole-4-carboxylic acid chloride of formula (FV) is reacted with 4-trifluoromethyl aniline of formula (V) in presence of a base. 4-trifluoromethyl aniline of formula (V) can be used from 0.8 to 1.2 molar equivalents of MIA or 5-methyl-isooxazole-4-carboxylic acid chloride of formula (TV), but more preferably around 1.1 molar equivalents with respect to MTA or 5-methyl-isooxazole-4-carboxylic acid chloride (MIA-C1) of formula (IV). The reaction is typically carried out under the Schotten-Baumann conditions employing a mixed system of aqueous base and a water miscible organic solvent. The solvents used for the above reaction can be selected from a group of ketones, ethers, nitriles, hydrocarbons and the like, more preferably ethers like tetrahydrofuran.
The base employed for the acylation cum hydrolysis reaction is selected from the alkali metal hydroxide consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or alkaline earth metal hydroxide consisting of barium hydroxide, calcium hydroxide, magnesium hydroxide; more preferably sodium hydroxide or potassium hydroxide. The quantity of the base employed is so adjusted to scavenge the hydrochloride generated from the decomposition of the excess chlorinating agent and during the N-acylation step and also to in-situ hydrolyze the intermediate Leflunomide of formula (II) so formed. Typical

quantities of the base employed are in excess of 2.5 mole equivalents of MIA, more preferably about 3.0 mole equivalents.
The reaction can suitably be carried out from 0 to 50°C or even higher, however preferably between 20 to 40°C and more preferably between 25 to 35°C. The Teriflunomide of formula (I) is isolated after acidifying the reaction mass with an acid selected from hydrochloric acid, sulphuric acid, and the like which is capable of neutralizing the selected base. The isolated product if required can suitably be purified by any of the methods known in the art such as recrystallization, reslurrying / leaching, acid-base treatment etc. The solvent used for the purification of Teriflunomide can suitably be selected from a group of ketones, ethers, esters, hydrocarbons, nitriles or the like and suitable mixtures thereof. Preferable solvents used are acetone and methanol. XRPD pattern of the Teriflunomide of formula (I) obtained by the process of the present invention is as depicted in Figure-1.
A one pot process for preparation of Teriflunomide of formula (I) according to the present invention is shown in Scheme 7.
Inventive step of the invention resides in the fact that the product Teriflunomide is free from the impurities associated with Leflunomide which necessitate

purification of Leflunomide. Surprisingly it was found that even when
Leflunomide is not isolated and not purified, the final product i.e. Teriflunomide
of ICH quality and NLT 99.5% purity is obtained by the process disclosed in the
present invention.
Novelty and non obviousness of the process of the present one pot invention also
resides in the fact that duration required to produce Teriflunomide is substantially
less than the prior art processes used to produce Leflunomide and then to produce
Teriflunomide from Leflunomide.
The following examples are set forth to aid the understanding of the invention,
and are not intended and should not be construed to limit in any way the
invention set forth in the claims which follow thereafter.
EXAMPLES:
Example 1: Preparation of Teriflunomide of formula (I)
A mixture of 5-methyI-isooxazole-4-carboxyIic acid (50 gm) and thionylchloride (43 ITIL) was heated to 65 + 5°C for 2-3 hrs. The clear solution is gradually cooled to 25- 30 C. The so obtained clear solution is slowly added to a well stirred mixture of sodium hydroxide (48 gms) in 150 mL of water and 4-trifluoromethyl aniline (69.7 gm) in Tetrahydrofuran (150 mL) maintaining the reaction temperature between 25 to 35 C. The biphasic reaction mixture is stirred for 1-2 hrs till TLC indicates absence of Leflunomide. The reaction mass is diluted with water (600 mL) and treated with activated carbon. The clarified reaction mixture is acidified below pH 2.5 and the solid is filtered and washed with water.

The product so obtained is slurried with acetone, cooled to 10 + 5 C and filtered
under suction. The wet-cake is dried at 45-50 C to yield pharmaceutical^ pure
grade Teriflunomide of formula (I).
Dry Wt: 85 gms; HPLC purity: above 99.5%, 4-trifluoromethyl aniline < 0.01%,
other individual impurity NMT 0.10%
The typical XRPD pattern of the product is as depicted in Figure-1
Example 2: Preparation of Teriflunomide of formula (I)
A mixture of 5-methyl-isooxazole-4-carboxylic acid (50 gm) and thionylchloride (43 mL) was heated to 60 + 5 C for 4-5 hrs. The clear solution is gradually cooled to 25- 30 C. The so obtained clear solution is slowly added to a well stirred mixture of sodium hydroxide (48 gms) in 150 mL of water and 4-trifluoromethyl aniline (69.7 gm) in Tetrahydrofuran (150 mL) maintaining the reaction temperature between 25 to 35 C. The biphasic reaction mixture is stirred for 3-4 hrs till TLC indicates absence of Leflunomide of formula (II). The reaction mass is diluted with water (600 mL) and treated with activated carbon. The clarified reaction mixture is acidified below pH 2.5 and the solid is filtered and washed with water.
The product so obtained is refluxed with methanol, cooled to 25 + 5 °C and filtered under suction. The wet-cake is dried at 45-50 °C to yield pharmaceutically pure grade Teriflunomide of formula (1). Dry Wt: 85 gms; HPLC purity: above 99.5 %, 4-trifluoromethyl aniline < 0.01%, other individual impurity NMT 0.10 %

CLAIMS:
We Claim:
1. A one pot process for the preparation of Teriflunomide of formula (I)
comprising
a) Combining 5-methyl-isooxazole-4-carboxylic acid of formula (III) with a chlorinating agent to form an acid chloride of formula (IV), optionally in presence of solvent;
b) Combining acid chloride of formula (IV) with 4-trifluoromethyl aniline of formula (V) in presence of a base to form Teriflunomide of formula (I), without isolating Leflunomide of formula (II);
c) Isolating and optionally purifying Teriflunomide of formula (I).

2. The process as claimed in claim 1 a), wherein said chlorinating agent is selected from the group consisting of thionyl chloride, PCI3, PC15, POCb, oxalyl chloride and benzoyl chloride, preferably thionyl chloride.
3. The process as claimed in claim 1 a) wherein the chlorination step is conducted in absence of a solvent and the excess chlorinating agent is not removed from the reaction mass.
4. The process as claimed in claim 1 b), wherein the base is selected from alkali metal hydroxide selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or alkaline earth metal hydroxide selected the group consisting of barium hydroxide, calcium hydroxide, magnesium hydroxide, preferred being sodium hydroxide or potassium hydroxide.

5. The process as claimed in claim 2, wherein the thionyl chloride is used in 1.1 to 2 molar excess, more preferably in 1.5 M excess and chlorination reaction is carried out at a temperature range of 50 C to 70°C, preferably at reflux temperature of thionyl chloride.
6. The process as claimed in claim 1 b), wherein base employed is in excess of 2.5 mole equivalents of MIA, more preferably about 3.0 mole equivalents.
7. The process as claimed in claim 1 c), wherein isolating Teriflunomide of formula (I) comprises acidification of reaction mass with a suitable acid preferably hydrochloric acid.
8. The process as claimed in claim 1 c), wherein the purification of Teriflunomide of formula (1) is carried out with a suitable solvent selected from a group of ketones, ethers, esters, hydrocarbons, nitrites or the like and suitable mixtures thereof.
9. Teriflunomide obtained according to any of the above claims and having an XRPD pattern as disclosed in Figure-1.
10. Teriflunomide obtained according to any of the above claims having TFMA NMT 0.01% and any other individual impurity NMT 0.10%.