FIELD OF THE INVENTION
The present invention relates to a process for the preparation of teriflunomide having desired purity. Specifically, the invention relates to a process for preparing 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide (1) comprising acid-catalyzed reaction of 4-trifluoromethyl aniline (2) with cyanoacetic acid (3) to give 2-cyano-N-(trifLuoromethylphenyl) acetamide (4), which on further treatment with base and further reaction with acetic acid in presence of a carbonyl coupling agent yields teriflunomide.
BACKGROUND OF THE INVENTION
Teriflunomide of formula (1) was approved by USFDA on September 12, 2012, under the trade name AUBAGIO, for the treatment of patients with relapsing forms of multiple sclerosis. The active ingredient, chemically known as 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl] but-2-enamide, is an immunomodulatory drug, which acts by inhibiting pyrimidine de novo synthesis through blocking of the enzyme dihydroorotate dehydrogenase.
Teriflunomide (1) first disclosed genetically in US 5,494,911 and specifically in US 5,679,709 was synthesized by reaction of 5-methylisoxazole-4-carbonyl chloride with 4-trifluoromethyl aniline to yield leflunomide, which was subjected to hydrolysis using sodium hydroxide to give teriflunomide.
Since then various synthetic methods for teriflunomide have been disclosed in the prior art. US 5,990,141 discloses reaction of 4-trifluoromethyl aniline with ethyl cyanoacetate and further reaction of the resulting cyanoaceto aniline derivative with acetyl chloride using sodium hydride as base. Factors such as low yield, use of pyrophoric bases like sodium hydride and environmentally hazardous reagents like acetyl chloride render this process unviable on industrial scale.

A similar process is disclosed in US 6,894,184 wherein the cyanoaceto aniline derivative is reacted with acetic anhydride in presence of bases such as alkali metal hydroxides, alkoxides, or hydrides. Use of hydride bases and stringent regulatory norms for acetic anhydride due to its potential use in narcotics hampers the commercial application of this process.
In general, the processes disclosed in the prior art pose serious limitations such as use of hazardous and strictly regulated reagents, requirement of chromatographic purifications at different stages in the synthesis, and subsequent low yields; making them unviable for industrial scale.
Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of teriflunomide (1), which avoids use of pyrophoric bases like sodium hydride, environmentally hazardous chlorinating reagents like thiony] chloride, or acerylating agents such as acetyl chloride and affords teriflunomide having desired purity in good yield.
The present inventors have developed a practical process for synthesis of teriflunomide (1) comprising acid catalyzed amidation of cyanoacetic acid using 4-trifluoromethyl aniline to give the cyanoaceto derivative, which, on treatment with a base, followed by acetylation in presence of a carbonyl coupling agent provides teriflunomide (1) having desired purity and in high yield as compared to prior art.
OBJECT OF THE INVENTION
An objective of the present invention is to provide teriflunomide (1) having desired purity by a simple and industrially viable process which does not involve hazardous hydride reagents or cumbersome chromatographic separation procedures.
Another object of the present invention is to provide an efficient process for preparation of teriflunomide (1), wherein the reaction of cyanoacetic acid with 4-trifluoromethyl aniline is catalyzed by a mild acid and the resulting acetamide on further reaction with acetic acid in presence of a carbonyl coupling agent yields teriflunomide (1) conforming to regulatory specifications.

Yet another object of the present invention is to provide teriflunomide of desired purity by isolating in presence of solvents belonging to the class of ketones, esters, alcohols, amides etc.
SUMMARY OF THE INVENTION
The present invention relates to a novel method for synthesis of 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide (1) having desired purity.
An aspect of the invention relates to a process for preparation of teriflunomide (1) having desired purity comprising the reaction of cyanoacetic acid (2) with 4-trifluoromethyl aniline (3) in presence of boric acid to give 2-eyano-N-(lrifluoromethylphenyl)acetamide (4), further reaction with sodium tertiary butoxide followed by treatment with acetic acid and carbonyldiimidazole to yield teriflunomide.
The objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Teriflunomide, which structurally belongs to the class of substituted crotonamides, is an important immunomodulatory drug which has been evaluated for autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
The present inventors, while designing an industrially applicable process for teriflunomide, aimed at a robust process which would afford the final compound having desired purity in good yield, yet avoiding hazardous reagents like hydride bases, acetyl chloride and cumbersome chromatographic separation procedures.
While carrying out experimental work aimed at synthesis of teriflunomide, the present inventors surprisingly found that the amidation of cyanoacetic acid (2) with 4-trifluoromethyl aniline (3) was very facile when the reaction was carried out in presence of catalytic amount of boric acid. The catalyst eliminated the need for chemical activation of cyanoacetic acid, or its conversion to acid chloride, thus avoiding use of hazardous reagents such as thionyl chloride or carbonyl activating agents like 1-hydroxybenzotriazole (HOBt) and N,N'-

dicyclohexylcarbodiimide (DCC). Elimination of thionyl chloride avoided the associated environmental hazards. Similarly, avoiding use of DCC ensured that problems of side product like dicyclohexyl urea, which is sparingly soluble in most of the solvents were not encountered.
It was also observed that use of boric acid substantially reduced the undesired reactions, thus consequently minimizing the side products and impurities. Further, a commercially available, inexpensive reagent like boric acid, which could be easily separated from the reaction mass, was a catalyst of choice due to its non-toxic nature and environment-friendly properties.
The inventors also observed that 2-cyano-N-(trifluoromethylphenyl) acetamide (4), after treatment with a base, could be conveniently acetylated using acetic acid in presence of a carbonyl coupling agent like carbonyldiimidazole (CDI).
While prior art methods resort to use of reagents such as acetic anhydride or acetyl chloride for acetylation, however, due to the regulatory and environment related problems associated with their use, it was not a viable option for industrial scale production of teriflunomide. The use of CDI for activation of acetic acid not only resulted in efficient acetylation due to the reactive acetic acid-imidazolide intermediate, but also obviated the formation of toxic by-products. Imidazole was generated as a side product, and since imidazole is soluble in various solvents including water and organic solvents such as alcohol, ether, chloroform etc., its removal from the reaction mixture was facile. Further, the other side product, carbon dioxide was effectively neutralized with a suitable scavenging agent before being released into the atmosphere. Thus, in the present synthetic strategy, in the first stage of amidation, moisture sensitive, hazardous reagents such as thionyl chloride, sodium hydride are avoided due to use of catalytic amounts of boric acid. In the subsequent stage, acetylating agents like acetic anhydride having stringent regulatory requirements are eliminated. Thus, the strategy results in an industrially feasible, convenient process for teriflunomide wherein the final product having desired purity is obtained in good yield.

Scheme 1: Method embodied in the present invention for the preparation of Teriflunomide (1)
In an embodiment, cyanoacetic acid of formula (2) was treated with 4-trifluoromethyl aniline (3) in presence of catalytic quantity of boric acid and an organic solvent to give 2-cyano-N-[4-(trifluoromethylphenyl) acetamide] of formula (4).
The organic solvent was selected from the group comprising aromatic hydrocarbons such as toluene, ortho-, meta- and para- xylenes etc.
Boric acid was used in catalytic amounts in the range of 0.1 to 0.4 molar equivalents of the reactants. The reaction was carried out in the temperature range of 90-120°C.
After completion of reaction, as monitored by HPLC, the reaction mixture was concentrated, followed by addition of water, stirring and filtration. Optionally, the solid was added to aqueous ammonia solution, stirred and filtered to give compound (4).
In another embodiment, 2-cyano-N-[4-(trifluoromethylphenyl) acetamide] of formula (4) prepared as described above, was treated with a base, followed by reaction with acetic acid in presence of carbonyldiimidazole (CDI) in an organic solvent.
Optionally, the reaction mass containing Compound (4) was concentrated, subjected in-situ to treatment with a base, followed by reaction with acetic acid in presence of carbonyldiimidazole (CDI) in an organic solvent.

1 The base was selected from alkoxides of alkali metals such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium tertiary butoxide, isopropoxides of sodium, potassium, lithium etc.
The organic solvent was selected from the group comprising alcohols, aromatic hydrocarbons, amides, ethers etc.
The organic solvent was selected from the group comprising dimethyl formamide, 2-Methyl tetrahydrofuran, ethyl acetate, methyl alcohol, isopropyl alcohol, tetrahydrofuran, toluene, ortho, meta, para xylenes etc.
The reaction was carried out in the temperature range of-10 to 20°C.
After completion of reaction as monitored by HPLC, the reaction mass was quenched with water followed by acidification with hydrochloric acid, stirring and filtration to give crude teriflunomide. Recrystallizations of the obtained residue from acetone yielded Teriflunomide
(i).
Alternatively, the solid was treated with aqueous ammonium hydroxide solution, followed by washing with dichloromethane. Acidification of the aqueous layer, stirring and filtration gave a solid which was washed with cyclohexane.
The solid thus obtained was treated with charcoal using ethyl acetate, followed by isolation from a mixture of isopropyl alcohol and dimethylformamide. Optionally, teriflunomide was further recrystallized from a mixture of isopropyl alcohol and acetone.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of 2-cyano-N-[4-(trifluoromethylphenyl) acetamide (4)
Cyanoacetic acid (Compound 2, 180 g) was added to a mixture of 4-trifluoromethyl-aniline (Compound 3, 250 g) and toluene (2250 ml) at 25 to 30°C, followed by addition of boric acid (26.0 g). The reaction mass was heated to 110 to 115°C with azeotropic removal of water till completion of the reaction as monitored by HPLC. The resultant mass was concentrated, water was added to the residue, and filtered. The isolated solid was added to ammonium hydroxide solution, stirred and filtered to give 2-cyano-N-[4-(trifluoromethylphenyl)acetamide (4). Yield: 352.3 g (85%)
Example 2: Preparation of Teriflunomide (1)
A stirred mixture of acetic acid (250-g), tetrahydrofuran (2500 ml) and carbonyldiimidazole (81.1g) was heated at 50°C. The resulting mass was cooled to room temperature and added to the mixture prepared by gradual addition of sodium tertiary butoxide (62.5 g) to 2-cyano-N-[4-(trifluoromethylphenyl) acetamide (compound 4, 92.5g) in tetrahydrofuran (2500 ml) which was stirred at -10 to 20°C till completion of reaction as monitored by HPLC. The reaction mixture was quenched with water, neutralized with hydrochloric acid, stirred and filtered. The solid was added to aqueous ammonium hydroxide solution and resulting mixture was washed with dichloromethane. The aqueous layer was separated, neutralized with hydrochloric acid, stirred and filtered to give solid which was washed with cyclohexane to give crude teriflunomide.
The solid thus obtained was added to ethyl acetate for charcoal treatment; the mixture was heated to 70-75°C and filtered. Concentration of ethyl acetate gave a residue which was treated with a mixture of isopropyl alcohol and dimethylformamide. The resultant mixture was heated to 65-70 C, cooled and filtered to give a solid, which, after treatment with isopropyl alcohol followed by treatment with acetone and filtration yielded pure teriflunomide. Yield: 74.8 g (69%).

Claims
1. A process for preparation of Teriflunomide (1) comprising reaction of cyanoacetic acid of formula (2) with 4-trifluoromethyl aniline of formula (3) in presence of boric acid and in an organic solvent to give 2-cyano-N-[4-(trifluoromethylphenyl) acetamide of formula (4), further reaction with a base, followed by reaction with acetic acid in presence of carbonyl diimidazole to give Teriflunomide (1).
2. A process as claimed in claim 1, wherein the organic solvent is selected from toluene, ortho xylene, meta xylene, and para xylene
3. A process as claimed in claim 1, wherein the reaction with 4-trifluoromethyl aniline is carried out in the temperature range of 90 to 120°C.
4. A process as claimed in claim 1, wherein the base is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tertiary butoxide and sodium isopropoxide.
5. A process as claimed in claim 1, wherein the reaction with acetic acid is carried out in the temperature range of -10°C to 20°C.