WO2007086076A2

WO2007086076A2 - An improved process for preparation of leflunomide

Info

Publication number: WO2007086076A2
Application number: PCT/IN2006/000359
Authority: WO
Inventors: Arul Ramakrishnan; Kapkoti Gobind; Kumar Neeraj; Shingare Dnyaneshwar
Original assignee: Unichem Laboratories Limited
Priority date: 2006-01-24
Filing date: 2006-09-12
Publication date: 2007-08-02
Also published as: WO2007086076A3

Abstract

This invention describes a process for the preparation of N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide commonly known as leflunomide comprising : (a) reacting ethylaceto acetate, triethylorthoformate, and acetic anhydride with simultaneous distillation to form ethyl ethoxymethyleneacetoacetic ester; (b) reacting the ethyl ethoxymethyleneacetoacetic ester with aqueous hydroxylamine without using any external base and without any distillation to form ethyl-5-methylisoxazole-4-carboxylate; (c) reacting the ethyl-5-methylisoxazole-4-carboxylate with strong acid to form -5-methylisoxazole-4-carboxylic acid; (d) 5-methylisoxazole-4-carboxylic acid is reacted with thionyl chloride in presence of N, N-Dimethylformamide and equimolar of 4-trifluoromethylaniline without any external base to obtain highly pure Leflunomide.

Description

TTEyE-AN IMPROVED PROCESS FOR PREPARATION OF LEFLUNOMIDE

FIELD OF THE INVENTION

The present invention relates to the antiproliferative compound N-(4-trifluoromethyl)-5- methylisoxazole-4-carboxamide commonly known as leflunomide and a process for synthesizing it.

* BACKGROUND OF THE INVENTION

Leflunomide, N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide having formula (I) is one of the disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of arthritis. DMARDs reduce inflammation and slow the progression of joint damage caused by rheumatoid arthritis. It helps to improve rheumatoid arthritis symptoms such as joint swelling 1 o and tenderness.

(I)

Anti-rheumatic property of leflunomide was first reported in US patent 4,284,786. This patent also reported that leflunomide can be prepared by reacting a 4-trifluoromethylaniline with a 5-methylisoxazole-4-carboxylic acid derivative. In example (al), 5-methylisoxazole-4- carboxylic acid chloride is reacted with two molar equivalents of 4-trifluoromethylaniline in 1 5 acetonitrile. Excess of 4-trifluoromethylaniline is used as a scavenger for HCl formed as a byproduct in the reaction of example (al). It is too expensive to be used in this manner in a commercial process in addition this process is uneconomical at industrial scale due to the use of acetonitrile as a solvent.

German patent 634,286 describes a process for preparing N-(4-trifluoromethyl)-5-

⁹^ methylisoxazole-4-carboxamide by the reaction of acid chloride of 5-methyl-isoxazole-4- carboxylic acid with 4-trifluoromethyl aniline in the presence of a strong base like potassium hydroxide or drop wise addition of acid chloride to 4-trifluoromethylaniline in basic environment. This basic medium leads to an undesirable side reaction to generate the acid as well as a byproduct, 2-cyanoacetoacetic-ϊ-(4'-trifluoromethyl)anilide (CATA) which is very difficult remove even after repeated crystallization.

^*> WO 01/60363 describes a process for preparing N-(4-trifluoromethyl)-5-methylisoxazole-4- carboxamide by conversion of 5-methylisoxazole-4-carboxylic acid to an acid chloride, followed by the reaction with 4-trifluoromethylaniline in the presence of strong base. The process described in WO 01/60363 is similar to the DE 634,286 process except that in the last step a biphasic solution of organic solvent and water under hot condition is utilized, instead i o of one solvent system. In hot condition under aqueous and basic environment, there is always a possibility of hydrolysis of acid chloride and amide bond as well as the formation of the byproduct CATA by abstraction of the base sensitive proton at 3-position of the isoxazole ring.

US patent 4,892,963 teaches the preparation of 5-methylisoxazole-4-carbonyl chloride. 5- methylisoxazole-4-carbonyl chloride is prepared in four steps. In first step ethyl acetoacetate, ¹ ^ triethylorthoformate and acetic anhydride are heated under reflux for 90 minutes. The obtained dark red oil, after the evaporation of more volatile by-product, is distilled under reduced pressure (1 mm) to obtain ethyl ethoxymethyleneacetoacetate. The distillation is carried out at a very low pressure (1 mm) after 90 minutes of reflux. Such a low pressure is difficult to achieve at Industrial scale.

?0 In second step ethyl ethoxymethyleneacetoacetate is dissolved in absolute alcohol and added to hydroxylamine solution, which is prepared by dissolving hydroxylamine hydrochloride in water and stirring with sodium hydroxide and absolute ethanol. After removal of the solvent the obtained oil is distilled to get ethyl-5-methylisoxazole-4-yl-carboxylate. In this step hydroxylamine hydrochloride as well as base are used. It also involves distillation of product,

25 which finally increases cost of production and reduces the yield.

In third step ethyl-5-methylisoxazole-4-yl-carboxylate is heated under reflux in HCl for 3 hours and cooled to obtain crystalline 5-methylisooxazole-4-yl carboxylic acid. In fourth step, thionyl chloride is added to 5-methylisooxazole-4-yl carboxylic acid and stirred at room temperature. N, N-Dimethylformamide is added to it and refluxed to obtain 5-methylisoxazole-4-yl carbonyl chloride as an oil after distillation.

Thus the condensation /cyclisation and subsequent reaction conditions employed according to

<_> the patent US 4892963 and DE 634,286 processes produce byproducts and impurities necessitating an additional chemical step, distillation, to restore the purity of the cyclized ester thereby and the end product. Thus these processes suffers in two aspects (i) lowering the yield and (ii) generates an isomeric impurity of etliyl-5-methylisoxazole-4-yl-carboxylate to a level of 10.4% which is very difficult to purify from the drug substances even after

10 distillation in the second step of reaction or repeated crystalisation of the acid in the third step of the reaction

WO 03/042193 describes a process for the preparation of N-(4-trifluoromethyl)-5- methylisoxazole-4-carboxamide in five steps more or less similar to DE634,286. In the first step the distillation is done after the completion of reaction, in second step for the preparation l 5 of Ethyl-5-methylisoxazole-4-carboxylate, hydroxylamine sulphate and sodium acetate have been used. In the third step the obtained 5-methylisoxazole-4-carboxylic acid is subjected to crystalisation to reduce the isomeric impurity of 5-methylisooxazole-4-yl carboxylic acid, which hampers yield of the product. In fourth step acid chloride has been formed and isolated which in the next step is reacted with 4-trifluoromethylaniline to get the final compound.

^Cl US patent 6,723,855 discloses a process for preparation leflunomide from 5- methylisooxazole-4-yl carboxylic acid. 5-methylisooxazole-4-yl carboxylic acid, thionyl chloride and toluene are heated. The excess thionyl chloride and toluene are evaporated to obtain 5-methylisooxazole-4-yl carboxylic acid chloride. This acid chloride is added to a warm suspension of 4-trifluoromethylaniline and sodium bicarbonate in water. Leflunomide -₅ is precipitated by filtration.

^

US patent 4,284,786 and 6,723,855 prepare leflunomide from 5-methylisoxazole-4-yl carboxylic acid in two steps using base which causes significant decomposition of leflunomide to N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide of formula (II).

(H)

Although it is the active metabolite of leflunomide that forms in a patient's body. Its presence in pharmaceutical composition is problematic for accurate dosing and also affects other aspects of pharmaceutical processing.

Thus there is a need to have such a process for preparation of leflunomide, which can solve 5 all the above problems.

Surprisingly, we developed a process by which leflunomide can be prepared economically and easily at industrial scale with high yield and high purily.

SUMMARY OF THE INVENTION

The present invention¹¹ provides an improved process for the preparation of lefunomide, which n is economical and easy to carry out at industrial scale.

Another embodiment of this invention is to provide a process for the preparation of leflunomide involving less number of reaction steps.

DETAIL DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of antiproliferative compound s leflunomide, N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide having formula (I).

In the present invention leflunomide is prepared in four steps where as most of the prior art teaches a five or more steps process. Thus the present invention reduces the process by one step.

In the first step, a mixture of ethylacetoacetate, acetic anhydride and triethylorthoformate is 0 heated to 100-150° C, preferably 120-140° C. The byproducts formed, is distilled off simultaneously. The reaction mixture is stirred for 1 hr and again the leftover byproducts are distilled out by applying vacuum (50 mm). The reaction mixture is cooled to 20-30° C to get ethyl ethoxymethyleneacetoacetate as blakish thick oil, mixture of E and Z isomers with more than 95% purity by GC. Here the distillation of byproducts is done simultaneously by applying vacuum (50-200 mm), which facilitate the reaction in forward direction. Whereas in prior art the product is distilled out at a very low pressure (1 mm) which is difficult to achieve at industrial scale.

In second step, ethyl ethoxymethyleneacetoacetate obtained in step I is taken in methanol and cooled to -10 to +10 ⁰C. Aqueous hydroxylamine is added drop wise to it over a period of 1 to 2 hrs at -10 to +10 ⁰C and stirred at the same temperature for 30 minutes. The reaction mixture is allowed to attain room temperature and then refluxed for 1 hour. Solvent is removed under reduced pressure and cooled to room temperature. The product is extracted using n-hexane. Hexane layer is washed with aqueous sodium bicarbonate solution to minimise the impurities. Aqueous layer is re-extracted with n-hexane. All organic layers are mixed and washed with water twice to obtain ethyl-5-methylisoxazole-4-carboxylate as yellowish thick oil with more than 75% yield and more than 98.0 % HPLC purity, having isomeric purity less than 0.5 %.

In prior art hydroxylamine sulphate or hydroxylamine hydrochloride has been used and the product has been distilled whereas in the present invention no base has been used in reaction only hydroxylamine has been used. The distillation has been avoided. These modifications help in the formation of regioselective desired product with more than 98% purity and high yield.

In third step, Ethyl-5-methylisoxazole-4-carboxylate obtained in step 2 is taken in 20% v/v aqueous sulphuric acid and refluxed for 12-18 hours and cooled to 90 ⁰C. Toluene is added for in-situ purificatioii and further cooled to 25 to 35 °C and stirred for 4 hours. The obtained solid product is filtered and washed with toluene followed by water. It is dried to obtain 5-methylisoxazole-4-carboxylic acid with more than 99.0 % HPLC purity having isomeric impurity less than 0.5 % which facilitates to obtain pure final product.

In fourth step, 5-methylisoxazole-4-carboxylic acid is taken in toluene and heated to reflux. After partial distillation of toluene the mixture is cooled to 20-30 ⁰C and catalytic amount of N, N-Dimethylformamide was added followed by thionyl chloride (lto 1.1 molar equivalents) at 20-30 ⁰C. The mixture is heated to 60 to 70°C for 5-10 hours. Then the reaction mass is cooled to O⁰C without distillation. Equimolar amount of 4-trifluoromethylaniline is added drop wise to it at 0 to 10 ⁰C. The resulting reaction mixture is stirred at the same temperature for 2 hours and stirred for 4 hours after reaching the temperature 25 to 30 ⁰C. Water is added and stirred for 2 hours. The solid is separated out, which is filtered and washed with water and dried well to obtain off-white solid, which is purified with toluene to give white purified leflunomide (60-70 %) with HPLC purity more than 99.8% having any individual impurity less than 0.1%.

^ In all the process described in the prior art, during the reaction between 5-methylisoxazole-4- carboxylic acid chloride with 4-trifluoromethylaniline either external base or excess of 4- trifluoromethylaniline is used as a scavenger for the HCl. Whereas in our experiment we found that without any external base or without excess of 4-trifluoromethylaniline the product Leflunomide is formed in high yield with high purity without the CATA impurity. 0 The invention can be illustrated by the following non-limiting examples.

Example

(i) Ethyl ethoxymethyleneacetoacetatp:

A mixture of 100.00 g (0.768 mol) ethylacetoacetate, acetic anhydride 156.89 g (1.536 mol) and triethylorthoformate 138.93 g (0.937 mole) were heated to 135 ⁰C. The byproducts 5 formed were distilled off simultaneously. After attaining a temperature of 135 ⁰C, the reaction mixture was stirred for 1 hr. The left over byproducts was distilled out by applying 50 mm vacuum and was cooled to 20-30 ⁰C to obtain 114.00 g of Ethyl ethoxymethyleneacetoiacetate as a blackish thick oil (as a mixture of E and Z isomers) with more than 95% purity by GC The oily material is used as such for the next step.

0 (ϋ) Ethyl-5-methylisoxazole-4-carboxylate:

Ethyl ethoxymethyleneacetoacetate, 110.00 g (0.59 mol) was taken in methanol (330 ml) and cooled to -5 ⁰C and 50% aqueous hydroxyl amine 39.03 g (0.59 mol on anhydrous basis) was added drop wise over a period of 1 hour at -5 to O⁰C. It was stirred for 30 minutes. The reaction mixture was allowed to attain temperature of 20 to 30 ⁰C and then refluxed for 1 S hour. Solvent was removed under reduced pressure and the reaction mass was cooled to room temperature. n-Hexane (500 ml) was added and stirred for 30 minutes. Saturated sodium bicarbonate solution (100 ml) was added followed by water (400 ml) and stirred well. The organic layer was separated. The aqueous layer was re-extracted with n-hexane (2x200 ml). The combined organic layer was washed with water (2x250 ml). After removal of the solvent 72.5 g (79%) of Ethyl-5-methylisoxazole-4-carboxylate was obtained as yellowish thick oil with 98.7 % HPLC purity and having isomeric impurity less than 0.5 %.

(iii) S-MethyIisoxazole-4-carboxyiic acid:

Ethyl-5-methylisoxazole-4-carboxylate 72.58 g (0.47 mol) was taken in 20% v/v aqueous sulphuric acid (193.5 ml) and refluxed for 16 hours. Toluene (73 ml) was added at 90 ⁰C, cooled to 25 to 35 ⁰C and stirred for 4 hours. The crystallized solid product was filtered and washed with toluene (2x36 ml) followed by water (2x72.5 ml). The product was dried under vacuum to get 27.2 g of 5-Methylisoxazole-4-carboxylic acid as an off white solid with 99.5 % HPLC purity having isomeric impurity 0.27 %.

(iv) N-(4'-trifluoromethyIp)-5-methylisoxazole-4-carboxamide:

5-Methylisoxazole~4-carboxylic acid 25.0 g (0.197 mol) was taken in toluene (312.5 ml), heated to reflux arid 62.5 ml toluene was distilled off. The solution was cooled to 25-30 ⁰C. To this solution N, N-Dimethylformamide (0.16 ml) and thionyl chloride 25.68 g (0.216 mol) was added at 25-30 C and heated to 65 to 70 ⁰C for 6 hours. Then the reaction mass was cooled to 0 ⁰C and 4-trifluoromethylaniline 30.07 g (0.199 mol) was added drop wise at this temperature. The resulted reaction mixture was stirred at the same temperature for 2 hours, allowed to come to 25-30 ⁰C and stirred for 4 hours. Water (125 ml) was added to the ' reaction mixture and stirred for 2 hours. The solid was separated out, which was filtered and washed with water (250 ml), dried under vacuum at 80 ⁰C to obtain 40.25 g off white solid which was purified with toluene to give 33.15 g (62.34 %) leflunomide with 99.9% HPLC purity and any individual impurity less than 0.1%.

Claims

We claim:

1. A process for the preparation of leflunomide comprising: a) heating a mixture of ethylacetoacetate, acetic anhydride and triethyforthoformate with simultaneous distillation of byproducts to form ethyl ς, ethoxymethyleneacetoacetate b) reaction of ethyl ethoxymethyleneacetoacetate and hydroxylamine in the presence of an organic solvent to form ethyl-5-methylisoxazole-4-carboxylate without using any external base c) heating ethyl-5-methylisoxazole-4-carboxylate at reflux temperature in T O presence of strong acid and purifying in-situ using toluene to obtain 5- methylisoxazole-4-carboxylic acid d) reaction of 5-methylisoxazole-4-carboxylic acid and equimolar thionyl chloride in presence of catalytic amount of N,N-dimethylformamide to obtain a reaction mass

1 s e) contacting the above obtained reaction mass without distillation or isolation with equimolar amount of 4-trifluoromethylaniline to form a solid mass in absence of any external base f) Purification of the solid mass with toluene to obtain purified leflunomide.

2. The process as claimed in claim 1, wherein the heating in (a) is done in the range of ? 0 100 to 150° C preferably in the range of 120 to 140° C.

3. The process as claimed in claim 1, wherein the organic solvent used in (b) is alcohol preferably methanol.

4. The process as claimed in claim 1, wherein the strong acid used in (c) is a mineral acid preferably aqueous sulphuric acid.

₇^ 5. The process as claimed in claim 1, where the reaction in (d) is carried out at 60-70 ⁰C.