DESC:Field of the invention:
The present invention relates to a novel process for the preparation of Leflunomide. More particularly, the invention relates to an improved process for preparation of intermediates, 4-(trifluoromethyl)anilne and 5-methylisoxazole-4-carboxylic acid, useful for the preparation of Leflunomide.



Background of Invention:
Leflunomide, chemically known as N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, is an inhibitor of pyrimidine biosynthesis with antiproliferative activity and is approved in the United States for treatment of rheumatoid arthritis. It helps to improve rheumatoid arthritis symptoms such as joint swelling and tenderness.

There is ample literature available on the synthesis of Leflunomide and its key intermediate, 4-trifluoromethylaniline as discussed herein below.
Leflunomide was first reported in US patent 4,284,786. According to the teachings of US’786 patent Leflunomide was prepared by reacting a 4-trifluoromethylaniline with 5-methylisoxazole-4-carboxylic acid derivatives such as 5-methylisoxazole-4-carboxylic acid chloride or 5-methylisoxazole-4-carboxylic acid, anhydride in acetonitrile solvent to obtain Leflunomide. However, this patent did not disclose the preparation of the starting compound, 4-trifluoromethylaniline.
Another patent publication, WO2001060363, reported preparation of Leflunomide using 5-methylisoxazole-4-carboxylic acid chloride with 4-trifluoromethylaniline in alkaline-earth metal bicarbonate. However, WO’363 also did not disclose the preparation of the starting compound, 4-trifluoromethylaniline.
It was found that during preparation of Leflunomide, two impurities viz., Des –trifluoromethyl leflunomide nitrile and Leflunomide impurity – E, formed substantially in higher levels.


Formation of the Des-Trifluoromethyl Leflunomide nitrile impurity is possible when 4-amino benzonitrile reacts with 5-methylisoxazole-4-carbonyl chloride.

Commercially available 4-trifluoromethylaniline intermediate for making Leflunomide found to contain 4-amino benzonitrile impurity which is leading to formation of the Des-Trifluoromethyl Leflunomide nitrile impurity in the final product.
Various routes are reported for preparation of 4-trifluoromethylaniline in literature. Organic Letters, 14(4), 1114-1117; 2012 reports reduction of 4-(Trifluoromethyl)-1-nitrobenzene with Na2S/NaHCO3 in water. However this process leads to formation of impurities such as 4-methylaniline.
Another patent application, US20010047013, reported preparation of 4-trifluoromethylaniline from 1-bromo-4-trifluoromethylbenzene by reacting with ammonia in ethylene glycol using Cu2O catalyst with 72% yield. Other patent application, IN2013CH03883, also reported preparation of Leflunomide. But these applications did not discuss about formation of these impurities.
Another US patent, US4096185, reported preparation of 4-trifluoromethylaniline from para-chlorobenzotrifluoride by reacting with ammonia in presence of combination of catalysts -cuprous chloride and potassium fluoride at 200° C for 5 hrs.
Another granted patent, CN103408436B, reported preparation of 4-trifluoromethylaniline from para-chlorobenzotrifluoride by reacting with ammonia in presence of copper powder, sodium hydroxide, in methanol solvent in autoclave at 210°C. These processes are also having a major drawback of involving high temperature reactions. Commercially, operating reactions at higher temperature involves safety/explosion hazards and requires higher costs to operate.
Des-trifluoromethyl Leflunomide nitrile is a potential genotoxic impurity (PGI) based on in Silico (Q)SAR system. In accordance with ICH M-7 guidelines, this should be controlled at TTC level based on maximum daily dose (15 ppm considering a maximum daily dose of 100 mg).
Formation of the other impurity, Leflunomide impurity-E, is possible when 3-methylisoxazole-4-carbonyl chloride reacts with 4-trifluoromethylaniline.

Whereas, formation of the 3-methylisoxazole-4-carbonyl chloride (regio isomer) is possible during the reaction of ethyl ethoxymethylene acetoacetic ester with hydroxylamine.HCl followed by hydrolysis and conversion to its chloride derivative.

Reduction of the impurity, 3-Methylisoxazole-4-carboxylic acid (regio isomer), was taught in another patent application, WO03042193, by reacting ethyl ethoxymethylene acetoacetic ester with hydroxylamine sulfate in presence of sodium acetate or a salt of trifluoroacetic acid at lower temperature.
Problem with this process is twofold. This process recommends usage of costly reagents e.g. salt of trifluoroacetic acid / acetic acid, however the same results in higher level of the Regio isomeric impurity ~ 1.5%, which requires additional purification to reduce the content to the level of 0.1%. This will increase the cost of production of Leflunomide.
Therefore, the object of the present invention is to overcome the above stated drawbacks of the prior art processes by providing an economical and industrially scalable process for preparing highly pure intermediate, 5-Methylisoxazole-4-carboxylic acid (Isoxazole acid) with control of 3-Methylisoxazole-4-carboxylic acid (Regio isomer) well below 0.1% without any additional purification; process for preparing 4-(Trifluoromethyl)aniline by totally controlling the formation of 4-Amino benzonitrile and a process for preparation of substantially pure Leflunomide with level of Des-Trifluoromethyl Leflunomide nitrile impurity less than 1 ppm.

Summary of invention:
The present inventors have, surprisingly, found a novel process to prepare highly pure 4-(trifluoromethyl)anilne, 5-Methylisoxazole-4-carboxylic acid and Leflunomide with level of Des-Trifluoromethyl Leflunomide nitrile impurity less than 1 ppm and Leflunomide impurity-E not detected.
According to one aspect, the present invention provides a process for preparation of 4-(trifluoromethyl)aniline which comprises ; reacting 4-chlorobenzotrifluoride with ammonia in presence of copper catalyst and amino acid ligand to obtain 4-(trifluoromethyl)aniline.
Copper catalysts include copper halides such as cuprous or cupric halides selected from the group consisting of cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, cuprous chloride and cupric chloride; cuprous or cupric oxide, cuprous or cupric cyanide, and the like. However, in one preferred embodiment, the copper catalyst is copper halide.
Accordingly, in a preferred embodiment, 4-chlorobenzotrifluoride is reacted with ammonia in presence of copper halide catalyst and amino acid ligand to obtain 4-(trifluoromethyl)aniline.
According to another aspect, the present invention provides a process for preparation of Leflunomide comprising;
a) reacting 4-chlorobenzotrifluoride with ammonia in presence of copper halide catalyst and amino acid ligand to obtain 4-(trifluoromethyl)aniline; and
b) reacting 4-(trifluoromethyl)aniline with 5-methylisoxazole-4-carbonylchloride to obtain Leflunomide.

In another preferred embodiment, the present invention provides a process for preparation of 5-methylisoxazole-4-carbonylchloride comprising;
a) reacting ethyl ethyoxymethylene acetoacetic ester with hydroxylamine HCl by concurrent addition of ethyl ethoxymethylene acetoacetic ester and aqueous sodium hydroxide solution to the mixture of Hydroxylamine.HCl and sodium hydroxide in water to obtain ethyl-5-methylisoaxazole-4-carboxylate (isoxazole ester);
b) hydrolysing the ethyl-5-methylisoaxazole-4-carboxylate with hydrochloric acid to obtain 5-Methylisolzazole-4-caboxylic acid (isoxazole acid); and
c) reacting the 5-Methylisolzazole-4-caboxylic acid with thionyl chloride in presence of suitable solvent, methylene dichloride to obtain 5-methylisoxazole-4-carbonylchloride.

Description of Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

The invention is directed to a novel process for the preparation of Leflunomide. According to one aspect, the present invention provides a process for preparation of 4-(trifluoromethyl)anilne which process comprises; reacting 4-chlorobenzotrifluoride with ammonia in presence of copper halide catalyst and amino acid ligand to obtain 4-(trifluoromethyl)aniline.
Ammonia may be used in gaseous form or liquid (aqueous ammonia) form. However, ammonia gas is preferred over liquid ammonia.
Copper catalysts include cuprous or cupric halides selected from the group consisting of cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, cuprous chloride and cupric chloride; cuprous or cupric oxide, cuprous or cupric cyanide, and the like. However, in one preferred embodiment, the copper catalyst is cuprous chloride or Curprous bromide.
Amino acid ligands are selected from the group consisting of L-Proline, Glycine, Alanine, Valine, Phenyl alanine and Tyrosine. However, the preferred ligands are L-Proline and Glycine. Most preferred ligand is L-Proline. These ligands facilitates the reaction at lower temperature and thus convenient to operate at industrial scale.
The reaction is conducted in polar protic or aprotic solvents. Polar protic solvents include aliphatic alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert- butyl alcohol, 1-pentanol, 2 - pentanol, 3-pentanol and 2-methyl-1-butanol. The polar aprotic solvents include dimethylsulfoxide, dimethylacetamide and dimethyl formamide or the like. However, preferred solvent from polar protic solvent is methanol.

Usually, the reaction is conducted in autoclave at a pressure ranging from 15 to 35 bars. Preferably, the reaction is conducted between 20 to 25 bars. Usually the reaction is conducted at 80 to 140°C. However, preferably, the reaction is conducted at 100 to 120°C. Usually reaction time is about 36 hours.
After completion of reaction, the reaction mixture is cooled to ambient temperature and filtered the catalyst. Distilled organic layer to remove solvent and the obtained residue is extracted with suitable solvent. The extract is subjected for distillation to remove the solvent followed by distillation of the product 4-(Trifluoromethyl)aniline under high vacuum.

With this novel procedure, 4-(Trifluoromethyl)aniline with more than 99.5% purity and less than 20 ppm of 4-amino benzonitrile impurity is obtained.
According to another aspect, the present invention provides a process for preparation of Leflunomide comprising;
a) reacting 4-chlorobenzotrifluoride with ammonia in presence of copper halide catalyst and amino acid ligands to obtain 4-(trifluoromethyl)aniline; and
b) reacting the 4-(trifluoromethyl)aniline with 5-methylisoxazole-4-carbonylchloride to obtain Leflunomide.
In another preferred embodiment of the present invention, 5-methylisoxazole-4-carbonylchloride is prepared by reacting ethyl ethyoxymethylene acetoacetic ester with hydroxylamine HCl in presence of sodium hydroxide in water at 60-70°C to obtain ethyl-5-methylisoaxazole-4-carboxylate (isoxazole ester). After completion of the reaction, without isolation of the product from the reaction mixture, the formed isoxazole ester is hydrolysed with dilute hydrochloric acid to obtain 5-Methylisoxazole-4-caboxylic acid (isoxazole acid). The hydrolysis reaction is carried out at reflux temperature. After completion of hydrolysis, reaction mixture is cooled to 0-10°C and filtered the product, 5-Methylisoxazole-4-caboxylic acid. With this method of the invention, the formation of the isomeric impurity, 3-Methylisoxazole-4-caboxylic acid (regio isomer) found to be less than 0.1%.

Further, the obtained 5-Methylisoxazole-4-caboxylic acid is converted into 5-Methylisoxazole-4-cabonyl chloride by reacting with thionyl chloride in presence of suitable solvent such as methylene dichloride using dimethyl formamide as a catalyst. After completion of reaction, solvent and excess thionyl chloride is distilled to get 5-Methylisoxazole-4-cabonyl chloride as oil.

The 5-Methylisoxazole-4-cabonyl chloride is further reacted with 4-(Trifluoromethyl)aniline in suitable solvent such as ethyl acetate in presence of a base such as sodium carbonate. Reaction is conducted at 60-70°C for about 4-5 hours. After completion of reaction, the reaction mixture is filtered. The filtrate is washed with water followed by dilute sodium carbonate. Then the organic layer is concentrated to obtain crude Leflunomide. The crude is further purified with Heptane/Ethyl acetate mixture. The invention is mentioned in scheme-1.

Scheme-1

Accordingly, in a further aspect, the present invention provides an improved process for preparation of Leflunomide which process comprises;
a) reacting 4-chlorobenzotrifluoride with ammonia in presence of copper halide catalyst and amino acid ligands to obtain 4-(trifluoromethyl)aniline;
b) reacting ethyl ethyoxymethylene acetoacetic ester with hydroxylamine HCl by concurrent addition of ethyl ethoxymethylene acetoacetic ester and aqueous sodium hydroxide solution to the mixture of Hydroxylamine.HCl and sodium hydroxide in water to obtain ethyl-5-methylisoaxazole-4-carboxylate (isoxazole ester);
c) hydrolysing the ethyl-5-methylisoaxazole-4-carboxylate with hydrochloric acid to obtain 5-Methylisolzazole-4-caboxylic acid (isoxazole acid);
d) reacting the 5-Methylisolzazole-4-caboxylic acid with thionyl chloride in methylene dichloride solvent to obtain 5-methylisoxazole-4-carbonylchloride; and
e) reacting the 4-(trifluoromethyl)aniline obtained in step a) with 5-methylisoxazole-4-carbonylchloride obtained in step d) to obtain Leflunomide.
The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

Example 1:
Example-1 : Preparation of 4-(Trifluoro)methyl aniline (4-TFMA)
4-Chlorobenzotrifluoride (50 g), Cuprous chloride (21.9 g), L-Proline (38.3 g) and Methanol (150 ml) were charged into a 500 ml Autoclave reactor. Agitation started and 4.5 bar pressure was applied with Ammonia gas. The Autoclave was heated to 105-110°C and pressure of the reaction was maintained between 20-25 bar for 35 hours. Progress of the reaction was monitored by GC. After 35 hours the reaction mass was cooled to room temperature. After venting out ammonia gas from autoclave, the reaction mass was unloaded and filtered. Filtrate was subjected to vacuum distillation to remove methanol and un-reacted 4-chloro benzotrifluoride. Residual mass was treated with water and extracted with Diisopropylether. Organic layer was concentrated and subjected to high vacuum distillation (temp 90-100°C, pressure 10-15 mbar) to get 4-(Trifluoromethyl)aniline.
Weight of 4-TFMA : 23.4 g
Yield : 52.6% (isolated)
82.5 % (based on %conversion)
Purity : 99.77%.
4-Amino benzonitrile : Not detected

Example-2: Preparation of Ethyl Ethoxymethylene acetoacetic ester ( EEAE)
A four neck round bottom flask was fitted with stirrer, thermometer pocket, condenser and dawn ward distillation set-up. Ethyl acetoacetate (100 g), Triethyl orthoformate (136.6 g) and Acetic anhydride (149.7 g) were charged to the RBF and the mixture was heated at 100-110°C for one hour. Temperature of the reaction mixture was increased to 120-130°C and maintained for 2 hour with simultaneous distillation of low boiling bi-product generated during reaction. The progress of the reaction was monitored by GC (Ethyl acetoacetate NMT: 5%). Reaction mass was cooled to 50-60°C and residual low boiler were distilled under vacuum. Further reaction mass was heated to 130-150°C and distillation continued under vacuum to get Ethyl ethoxymethylene acetoacetic ester ( EEAE) as an reddish yellow color liquid.
Weight of Oil : 99.2 g
Yield : 69.5%
GC Purity : 97.84%

Example-3: Preparation of 5-Methylisoxazole-4-carboxylic acid (Isoxazole Acid)
A four neck round bottom flask fitted with stirrer, thermometer pocket and condenser was charged with Water (36 ml) and Hydroxylamine hydrochloride (16.1 g). To this solution 12.9% (w/v) aqueous solution of Sodium hydroxide (37 ml) was added slowly at 10-15°C. After stirring for 15 min, Ethyl Ethoxymethylene Acetoacetic Ester (36 g) and 12.9% (w/v) aqueous solution of Sodium hydroxide (37 ml) were added simultaneously to the reaction mass at 10-15°C over a period of 20-30 minutes. Reaction mass was heated to 60-65°C and maintained for one hour. Progress of the reaction was monitored by HPLC. After completion of the cyclization reaction (EEAE; NMT 0.5%), conc HCl (144ml) was added to the reaction mixture and heated to 95-100°C. Subsequent to completion of the hydrolysis reaction (Isoxazole ester NMT 7%), reaction mass was cooled to RT followed by to 0-5°C and maintained for 2 hours. Solid was filtered and washed with Water to get the title compound 5-Methylisoxazole-4-carboxylic acid (Isoxazole Acid) having less than 0.1% of Regio-isomer (3-Methylisoxazole-4-caboxylic acid).
Weight of Solid : 17.5 g
Yield : 71.3%
HPLC Purity : 99.51%
Isomeric Impurity : 0.09%

Example-4 : Preparation of 5-Methylisoxazole-4-carbonyl chloride
A four neck round bottom flask fitted with stirrer, thermometer pocket and condenser was charged with Dichloromethane (400 ml), 5-Methylisoxazole-4-carboxylic acid (80 g) and catalytic amount of Dimethyl formamide. Thionyl chloride (149.7 g) was added to the above mixture and heated to 40-45°C. The progress of the reaction was monitored by HPLC. After completion of the reaction (5-Methylisoxazole-4-carboxylic acid; NMT : 3 %), excess of Thionyl chloride and Dichloromethane were distilled out under vacuum below 45°C to get the title compound 5-Methylisoxazole -4-carbonyl chloride as a reddish brown oil.
Weight of oily product: 91.6 gm

Example-5 : Preparation of 5-Methyl-N-(4-(trifluoromethyl)phenyl)isoxazole-4-carboxamide (Leflunomide).
A four neck round bottom flask fitted with stirrer, thermometer pocket and condenser was charged with Ethyl acetate (1200 ml), Sodium carbonate (133.4 g) and 4-(Trifluoromethyl) aniline (111.6 g). Heterogeneous mixture was cooled to 5-10°C. To this mixture 5-Methylisoxazole-4-Carbonyl Chloride (91.6 g, from example 4) was added slowly at 5-10°C. Reaction mixture was heated to 60-65°C and maintained for 4 hr. After completion of the reaction (5-Methylisoxazole-4-carbonyl chloride; NMT: 3 %), reaction mixture was cooled and solid was filtered off. Ethyl acetate layer was washed with Water (560 ml), 5% Sodium bicarbonate solution (560 ml) followed by carbon treatment (8 gm). Ethyl acetate layer was concentrated under vacuum below 55°C to get the solid residue which was treated with Toluene /Ethylacetate mixture (7: 1.5 vol) to get crude Leflunomide. Isolated solid was purified in Heptane/Ethyl acetate mixture (7: 2.5 vol) and dried under vacuum at 60-70°C for 10 hours to get the Leflunomide (White crystalline powder).
Weight of Leflunomide : 120 g
Yield : 63.6%
HPLC Purity : 99.99%

Des-Trifluoromethyl Leflunomide Nitrile 0.4 ppm
Impurity E (3-Methyl-N-[4-(trifluoromethyl)phenyl]isoxazole-4-carboxamide): Not detected
Impurity A (4-(Trifluoromethyl)aniline) Not detected
Impurity B ((Z)-N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide) Not detected
,CLAIMS:1. A process for preparation of Leflunomide comprising;
a) reacting 4-chlorobenzotrifluoride with ammonia in presence of copper halide catalyst and amino acid ligand to obtain 4-(trifluoromethyl)aniline; and
b) reacting the 4-(trifluoromethyl)aniline with 5-methylisoxazole-4-carbonylchloride to obtain Leflunomide.

2. The process as claimed in claim-1, wherein the copper catalyst is selected from a group consisting of cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride, cuprous oxide, cupric oxide, cuprous cyanide and cupric cyanide.

3. The process as claimed in claim-2, wherein copper catalyst is cuprous chloride or Cuprous bromide.

4. The process as claimed in claim-1, wherein the amino acid ligand is selected from a group consisting of L-Proline, Glycine, Alanine, Valine, Phenyl alanine and Tyrosine.

5. The process as claimed in claim-4, wherein the amino acid ligand is L-Proline.

6. The process as claimed in claim-1, wherein the step a) reaction is conducted in polar protic or aprotic solvents.

7. The process as claimed in claim-6 , wherein the polar protic solvents are selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert- butyl alcohol, 1-pentanol, 2 - pentanol, 3-pentanol and 2-methyl-1-butanol; and aprotic solvents are selected from the group consisting of dimethylsulfoxide, dimethylacetamide and dimethyl formamide.

8. The process as claimed in claim-7, wherein the reaction is conducted in methanol solvent.

9. A process for preparation of 4-(trifluoromethyl)aniline which comprises; reacting 4-chlorobenzotrifluoride with ammonia in presence of copper catalyst and amino acid ligand to obtain 4-(trifluoromethyl)aniline.

10. The process as claimed in claim-1, wherein, the process for preparation of 5-methylisoxazole-4-carbonylchloride comprises;
a) reacting ethyl ethyoxymethylene acetoacetic ester with hydroxylamine HCl by concurrent addition of ethyl ethoxymethylene acetoacetic ester and aqueous sodium hydroxide solution to the mixture of Hydroxylamine.HCl and sodium hydroxide in water to obtain ethyl-5-methylisoaxazole-4-carboxylate (isoxazole ester);
b) hydrolysing the ethyl-5-methylisoaxazole-4-carboxylate with hydrochloric acid to obtain 5-Methylisolzazole-4-caboxylic acid (isoxazole acid); and
c) reacting the 5-Methylisolzazole-4-caboxylic acid with thionyl chloride in methylene dichloride solvent to obtain 5-methylisoxazole-4-carbonylchloride.

11. A process for preparation of Leflunomide as claimed in any one of the preceding
claims 1 to 10, which process comprises;
a) reacting 4-chlorobenzotrifluoride with ammonia in presence of copper halide catalyst and amino acid ligands to obtain 4-(trifluoromethyl)aniline;
b) reacting ethyl ethyoxymethylene acetoacetic ester with hydroxylamine HCl by concurrent addition of ethyl ethoxymethylene acetoacetic ester and aqueous sodium hydroxide solution to the mixture of Hydroxylamine.HCl and sodium hydroxide in water to obtain ethyl-5-methylisoaxazole-4-carboxylate (isoxazole ester);
c) hydrolysing the ethyl-5-methylisoaxazole-4-carboxylate with hydrochloric acid to obtain 5-Methylisolzazole-4-caboxylic acid (isoxazole acid);
d) reacting the 5-Methylisolzazole-4-caboxylic acid with thionyl chloride in methylene dichloride solvent to obtain 5-methylisoxazole-4-carbonylchloride; and
e) reacting the 4-(trifluoromethyl)aniline obtained in step a) with 5-methylisoxazole-4-carbonylchloride obtained in step d) to obtain Leflunomide.