Claims:WE CLAIM:

1. An improved process for the preparation of Teriflunomide (I), which comprising the steps of;
a) 5-methylisoxazole-4-carboxylic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 5-methylisoxazole-4-carboxylic acid chloride (II), which is reacted with 4-(trifluoromethyl) aniline (III) in presence of organic base and organic solvent to obtain Leflunomide (IV), and

b) The Leflunomide (IV) is hydrolysed in presence of NaOH/MeOH and water to obtain Teriflunomide (I).

2. The process as claimed in claim 1, wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, carbon tetrachloride and N-chlorosuccinimide.

3. The process as claimed in claim 1, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (MDC), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and water or mixtures thereof.

4. The process as claimed in claim 1, wherein the organic base is selected from1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), dimethylaminopyridine (DMAP), 5-diazabi cyclo [4.3.0] non-5-ene (DBN), pyridine, triethylamine (TEA), Diisopropylethylamine (DIPEA), trimethylamine, diethylamine, Tertiary butyl amine and N,N-dimethyl aniline.
, Description:“IMPROVED PROCESS FOR TERIFLUNOMIDE”

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Teriflunomide. The present invention is also relating to an improved and commercially viable process of Teriflunomide with high yield and high purity.

BACKGROUND OF THE INVENTION
Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions. Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system. It has been found that Teriflunomide blocks the transcription factor NF-?B. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.

Teriflunomide is chemically known as (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoro methylphenyl) amide and structurally represented as below.

Teriflunomide (I)

Teriflunomide is marketed under the, brand name AUBAGIO®, and it is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Teriflunomide was first disclosed in US 5,679,709 but this application does not mention the process of preparation.

U.S. Patent No. 5,494,911 describes a process for preparation of Teriflunomide, wherein the process comprises reacting 5-methylisoxozole-4-carbonyl chloride (II) with 4-trifluorlomethyl aniline (III) in presence of acetonitrile to obtain Leflunomide (IV), which is subsequent hydrolysis with aqueous sodium hydroxide in methanol to yield Teriflunomide (1).

The scheme representation is shown in Scheme-I.

U.S. Patent No. 5,990,141 describes a process for preparation of Teriflunomide, wherein the process involves reacting 4-trifluoromethyl aniline (III) with cyanoacetic acid ethyl ester (V) in presence of xylene to obtain cyanoaceto-(4-trifluoromethyl)-anilide (VI). The compound of formula (VI) is reacted with sodium hydride in presence of acetonitrile and followed by reacted with acetyl chloride in presence of tetrahydrofuran to obtain Teriflunomide (I).

The scheme representation is shown in scheme-II:

U.S. Patent No. 6,365,626 describes process for preparation of Teriflunomide (I), wherein the process involves reacting 4-trifluoromethyl aniline (III) with cyanoacetic acid (VII) to obtain cyanoaceto-(4-trifluoromethyl)-anilide (VI). The compound of formula (VI) is reacted with acetyl chloride in presence of NaH / HCl and H2O to obtain Teriflunomide (I).
The scheme representation is shown in scheme-III:

The main drawback of the prior art above mentioned processes requires chromatography for purification / isolation, which enhance the cost.

PCT publication WO 2015/029063 describes a process for preparation of Teriflunomide, wherein the process involves reacting 5-methyl isoxazole-4-carboxylic acid with (VIII) with thionyl chloride and mixed solvents (DMF and MDC) and followed by reacted with 4-(trifluoromethyl) aniline (III) in presence of acetonitrile to obtain Leflunomide (IV), which is hydrolysed in presence of NaOH /MeOH /water and conc. HCl to obtain Teriflunomide (I).

The scheme representation is shown in scheme-IV:

IN 356988 of Biocon describes a process for the preparation of Teriflunomide, which comprises 5-methyl isoxazole-4-carboxylic acid (VIII) is reacted with SOCl2 in presence of toluene to obtain 5-methylisoxazole-4-carbonyl chloride (II). The compound of formula (II) is reacted with 4-(trifluoromethyl) aniline (III) in presence of Cs2CO3 /MEK and water (biphasic medium) to obtain Leflunomide (IV), which is hydrolysed in presence of NaOH/MeOH and water to obtain Teriflunomide (I).

The scheme representation is shown in Scheme-V:

The main drawback of the prior art is process for the preparation of Teriflunomide with low yield and low purity and the reaction conversion is low and it is a time consuming process.

The advantage of the present invention is process for the preparation of Teriflunomide with high yield, high purity, less impurity, less time cycle and no aqueous effluent.

In view of the foregoing, the present inventors have result of extensive studies, process for the preparation of Leflunomide (IV) from 5-methylisoxazole-4-carbonyl chloride (II) reacted with 4-(trifluoromethyl)aniline (III) in presence of organic base, further converts into Teriflunomide (I).
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Teriflunomide. The present invention is also relating to an improved and commercially viable process of Teriflunomide with high yield and high purity.

In one aspect of the present invention provides an improved process for the preparation of Teriflunomide (I), comprising the steps of;
a) 5-methylisoxazole-4-carboxylic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 5-methylisoxazole-4-carboxylic acid chloride (II), which is reacted with 4-(trifluoromethyl) aniline (III) in presence of organic base and organic solvent to obtain Leflunomide (IV), and

b) The Leflunomide (IV) is hydrolysed in presence of NaOH/MeOH and water to obtain Teriflunomide (I).

In another aspect of the present invention provides, 5-methylisoxazole-4-carboxylic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 5-methylisoxazole-4-carboxylic acid chloride (II), which is reacted with 4-(trifluoromethyl) aniline (III) in presence of organic base / organic solvent to obtain Leflunomide (IV).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Teriflunomide. The present invention is also relating to an improved and commercially viable process of Teriflunomide with high yield and high purity.

In one embodiment of the present invention provides an improved process for the preparation of Teriflunomide (I), comprising the steps of;
a) 5-methylisoxazole-4-carboxylic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 5-methylisoxazole-4-carboxylic acid chloride (II), which is reacted with 4-(trifluoromethyl) aniline (III) in presence of organic base and organic solvent to obtain Leflunomide (IV), and

b) The Leflunomide (IV) is hydrolysed in presence of NaOH/MeOH and water to obtain Teriflunomide (I).

In another embodiment of the present invention provides, 5-methylisoxazole-4-carboxylic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 5-methylisoxazole-4-carboxylic acid chloride (II), which is reacted with 4-(trifluoromethyl) aniline (III) in presence of organic base / organic solvent to obtain Leflunomide (IV).

According to embodiment of the present invention, 5-methylisoxazole-4-carboxylic acid (VIII) is reacted with chlorinating agent in presence of organic solvent and the reaction is carried out at 30-50°C for 4-8 hours to obtain in-situ 5-methylisoxazole-4-carboxylic acid chloride (II), which is reacted with 4-(trifluoromethyl) aniline (III) in presence of organic base and organic solvent and the reaction is carried out at 50-75°C for 1-4 hours to obtain Leflunomide (IV). The compound of formula (IV) is subsequently hydrolysed in presence of NaOH/MeOH and water and the reaction mass pH adjusted 1-2 with hydrochloric acid to obtain Teriflunomide (I).

According to an embodiment of the present invention, wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, carbon tetrachloride and N-chlorosuccinimide.

According to an embodiment of the present invention, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (MDC), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and water or mixtures thereof.

According to an embodiment of the present invention, wherein the organic base is selected from 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), Dimethylaminopyridine (DMAP), 5-diazabi cyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine (TEA), Diisopropylethylamine (DIPEA), trimethylamine, diethylamine, Tertiary butyl amine, and N,N-dimethylaniline.

In yet another embodiment of the present invention provides pure Teriflunomide (I) having 99.96% having HPLC purity.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example -1:
Preparation of Leflunomide:
Charge 5-methyl-isoxazole-4-carboxylic acid (100 gm), dimethylformamide (5 ml), methylene dichloride (500 ml) and thionyl chloride (200 gm) into RB flask. The resultant reaction mas was heated to 40-45°C and stir for 5-6 hours at same temperature. After completion of the reaction distill out the solvent completely from the reaction mixture to get 5-methyl-isoxazole-4-carbonyl chloride. Charge ethyl acetate (500 ml), 4-(trifluoromethyl) aniline (127 gm) and triethyl amine (20 gm) in another RB flask at 25-30°C and its allow to cool at 0-5°C. Add 5-methyl-isoxazole-4-carbonyl chloride into the reaction mixture and heat the reaction mixture to 50-55°C and stir for 1-2 hours. After completion of the reaction, add purified water (500 ml) to the reaction mixture and then separate two layers. Distil out the ethyl acetate layer under reduced pressure at below 60°C. The resultant product treated with n-heptane (400 ml) and stir for 30 min at 50-55°C, then cool to 25-30°C. The resultant material washed with n-Heptane (50 ml) and dried to get title compound (Purity by HPLC: 98.11%).
Yield: 80.2% (170 gm)

Example-2:
Preparation of Leflunomide:
Charge 5-methyl-isoxazole-4-carboxylic acid (100 gm), dimethyl formamide (5 ml), methylene dichloride (500 ml) and oxalyl chloride (149.7 gm) in to RB flask. The resultant reaction mass heated to 40-45°C and stir for 2-3 hours at same temperature. After completion of the reaction distil out the solvent completely from the reaction mixture to get 5-Methyl-isoxazole-4-carbonyl chloride. Charge ethyl acetate (500 ml), 4-(trifluoromethyl) aniline (127 gm) and triethyl amine (20gm) in another RB flask at 25-30°C and then allow to cool at 0-5°C. Add 5-Methyl-isoxazole-4-carbonyl chloride to the reaction mixture and heat the reaction mixture at 50-55°C, stir for 1-2 hours. After completion of the reaction, add purified water (500 ml) to the reaction mixture and then separate two layers. Take aqueous layer and wash with 10% sodium chloride solution (100ml) and again separate two layers. Distil out the ethyl acetate layer under reduced pressure at below 60°C. The resultant product treated with n-Heptane (400 ml) and stir for 30 min at 60-65°C and allow to cool at 25-30°C. The obtained reaction mixture again stir for 60 min and filter the material at 25-30°C. The resultant material washed with n-Heptane (50 ml) and dried to get title compound.
Yield: 81.1% (172gm)

Example-3:
Preparation of Leflunomide:
Charge 5-methyl-isoxazole-4-carboxylic acid (100 gm), dimethylformamide (5ml), methylene dichloride (500 ml) and phosphorus pentachloride (245.7gm,) in to RB flask. The obtained reaction mass heated to 40-45°C and stir for 5-6 hours at same temperature. After completion of the reaction distil out the solvent completely from the reaction mixture to get 5-methyl-isoxazole-4-carbonyl chloride. Charge ethyl acetate (500ml), 4-(trifluoromethyl) aniline (127gm and triethyl amine (20gm) into another RB flask at 25-30°C and then cool to 0-5°C. Add 5-methyl-isoxazole-4-carbonyl chloride to the reaction mixture. Heat the obtained mixture to 50-55°C and stir for 1-2 hours. After completion of the reaction, add purified water (500 ml) to the reaction mixture and then separate two layers. Take aqueous layer and wash with 10% sodium chloride solution (100 ml) and again separate two layers. Distil out the ethyl acetate under reduced pressure at below 60°C. The obatained product washed with n-Heptane (400 ml) and stir for 30 min at 60-65°C and then allow to cool at 25-30°C. The resultant product washed with n-heptane (50 ml) and dried to get title compound.
Yield: 80.2% (170 gm)

Example-4:
Preparation of Leflunomide:
Charge 5-methyl-isoxazole-4-carboxylic acid (100 gm), dimethylformamide (5 ml), methylene dichloride (500 ml) and thionyl chloride (200 gm) into RB flask. The obtained reaction mass heated to 40-45°C and stir for 5-6 hours at same temperature and after completion of the reaction distil out the solvent completely from the reaction mixture to get 5-methyl-isoxazole-4-carbonyl chloride to the mixture. Charge toluene (500 ml), 4-(trifluoromethyl) aniline (127 gm) and diethylamine (25 gm) into another RB flask at 25-30°C and then allow to cool at 0-5°C. Add 5-methyl-isoxazole-4-carbonyl chloride to the mixture and heat the obtained mixture at 50-55°C, stir for 1-2 hours. After completion of the reaction, add purified water (500 ml) to the reaction mixture and then separate two layers. Take aqueous layer wash with 10% sodium chloride solution (100ml) and again separate the two layers. Distil out the toluene under reduced pressure at below 60°C. The resultant product with n-heptane (400 ml) and stir for 15 min at 60-65°C, allow to cool at 25-30°C. The obtained product washed with n-Heptane (50 ml) and dried to get title compound.
Yield: 77.8% (165 gm)

Example-5:
Preparation of Leflunomide:
Charge 5-methyl-isoxazole-4-carboxylic acid (100 gm), dimethylformamide (5 ml), methylene dichloride (500 ml) and thionyl chloride (200 gm,) in to RB flask. The obtained reaction mass heated to 40-45°C and stir for 5-6 hours at same temperature and after completion of the reaction distil out the solvent completely from the reaction mixture to get 5-methyl-isoxazole-4-carbonyl chloride. Charge methylene dichloride (500 ml), 4-(trifluoromethyl) aniline (127gm) and tertiary butyl amine (30gm) in another RB flask at 25-30°C and then allow to cool at 0-5°C. Add 5-methyl-isoxazole-4-carbonyl chloride to the mixture and heat the obtained mixture at 35-40°C, stir for 1-2 hours. After completion of the reaction, add purified water (500 ml) to the reaction mixture and then separate two layers. Take organic layer and wash with 10% sodium chloride solution (100ml), again separate two layers. Distil out the methylene dichloride under reduced pressure at below 40°C. The obtained product washed with n-heptane (400 ml) and stir for 30 min at 60-65°C and then allow to cool at 25-30°C. The resultant product was washed with n-heptane (50 ml) and dried to get title compound.
Yield: 78.3% (166 gm)

Example-6:
Preparation of Leflunomide:
Charge 5-methyl-isoxazole-4-carboxylic acid (100 gm), dimethylformamide (5ml), methylene dichloride (500 ml) and thionyl chloride (200 gm,) in to RB flask. The obtained reaction mass heated to 40-45°C and stir for 5-6 hours at same temperature. After completion of the reaction, distil out the solvent completely from the reaction mixture to get 5-methyl-isoxazole-4-carbonyl chloride. Charge acetone (500 ml), 4-(trifluoromethyl) aniline (127 gm) and methyl amine (22gm) in another RB flask at 25-30°Cand then cool to 0-5°C. Add 5-methyl-isoxazole-4-carbonyl chloride to the reaction mixture and heat the obtained mixture at 50-55°C, stir for 1-2 hours. Distil out the solvent completely and add ethyl acetate (500 ml), purified water (500 ml) to the reaction mixture and then separate two layers. Take aqueous layer and wash with 10% sodium chloride solution (100 ml) again separate the two layers. Distil out the ethyl acetate layer under reduced pressure at below 60°C.The obtained reaction mixture wash with n-Heptane (50 ml) and dried to get title compound.
Yield: 79.2% (168 gm)

Example-7:
Preparation of Teriflunomide:
Charge Leflunomide (100 gm), methanol (400 ml), sodium hydroxide (50 gm) and water (200 ml) in to RB flask at 25-30°C.The obtained reaction mass heated to 60-65°C and stir for 1-2 hours at same temperature. After completion of the reaction, distil out the methanol and charge water (600 ml) and then allow to cool at 0-5°C. The reaction mass adjusted pH 1-2 with 5N hydrochloric acid (100 ml) and stir for 60 min. The obtain material was filtered, washed with water (200 ml), followed by addition of acetone (1000 ml) and stir for 30 min at 50-55°C, and then cool to 25-30°C. The resultant material was filtered, washed with acetone (100 ml) and dried to get title compound

Yield: 90% (90 gm)
Purity: 99.98%