WO2014177978A2

WO2014177978A2 - An improved process for the preparation of teriflunomide

Info

Publication number: WO2014177978A2
Application number: PCT/IB2014/060966
Authority: WO
Inventors: Venkat Raman JAYARAMAN; Samir Patel; Snehal Dhol; Vishal Ray
Original assignee: Alembic Pharmaceuticals Limited
Priority date: 2013-05-02
Filing date: 2014-04-24
Publication date: 2014-11-06
Also published as: WO2014177978A3

Abstract

The present invention provides an improved process for preparation of Teriflunomide of formula (I).

Description

Title: An improved process for the preparation of Teriflunomide

FIELD OF INVENTION

The present invention provides an improved process for preparation of teriflunomide of formula I.

Formula i

BACKGROUND OF THE INVENTION

The drug compound having the adopted name teriflunomide is 2-cyano-3- hydroxy-N-[4-(trifluoromethyl) phenyl]-2-butenamide; and is represented by structural formula I

Formula i

Teriflunomide is an immunosuppressant, acting as a tyrosine kinase inhibitor. It is also evaluated in the treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis. An oral film coated tablet containing teriflunomide as the active ingredient is marked in the United States by Sanofi Aventis US using brand AUBAGIO™. AUBAGIO is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

U.S. Patent No. 5,679,709 appears to claim teriflunomide and its pharmaceutically acceptable salts, the same patent also further covers pharmaceutical composition and method of administering top a patients suffering from autoimmune disease.

U.S. Patent No. 5,494,91 I disclosesthe process for the preparation of teriflunomide by reacting 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline in the presence of acetonitrile to yield Leflunomide with on further hydrolysis with aqueous sodium hydroxide solution in methanol gives teriflunomide of formula I.

U.S. Patent No. 5,990,141 discloses the process for the preparation of teriflunomide by reacting 4-trifluoromethyl aniline with cyano acetic acid ethyl ester to yield cyanoaceto-(4-trifluromethyl)-aniline, with on further reacted with acetyl chloride in the presence of sodium hydride base and THF and acetonitrile solvent to give teriflunomide of formula I.

U.S. patent No. 6,365,626 discloses the process for the preparation of teriflunomide by reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetyl chloride in the presence of sodium hydride to give teriflunomide of formula I.

U.S. Patent No. 6,894,184 discloses the process for the preparation of teriflunomide involves reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetic anhydride in the presence of base to give teriflunomide of formula I.

International PCT application No. WO 2009/147624 discloses the process for the preparation of teriflunomide involves condensation of ethyl-2-cyano-3- hydroxybut-2-enoate and 4-(trifluoromethyl) aniline in presence of xylene solvent at reflux temperatures for 16 hours to give teriflunomide of formula I.

The above discussed prior art requires chromatographic purification, use of sodium hydride as base, very high temperature and expensive coupling agents for the preparation of teriflunomide of formula I.

Hence, there is a need for process for the preparation of teriflunomide that are simple, cost effective, and viable on commercial scale and further avoid use of hazardous reagents like sodium hydride, high temperature and expensive coupling agent. In addition to that the present invention provides improved processes which not only reduce the number of steps, but also provides a safe and easy to operate at large scale. SUMMARY OF THE INVENTION

Aspects of the present application provide safe and simpler process for the preparation of teriflunomide. Each step of the process disclosed herein are contemplated both in the context of the multi step sequences described, and individually.

In one aspect, the process for the preparation of teriflunomide (I) comprises steps of;

1 ) condensation of cyanoacetic acid of formula (II) with 4-trifluoromethyl aniline of formula (III) in the presence of chlorinating agent to give 2-cyano-N-[4- (trifluromethyl)phenyl]acetamide of formula (IV);

(II I) (IV)

2) acetylation of 2-cyano-N-[4-(trifluromethyl)phenyl] acetamide of

formula (IV) with an acetylating agent in the presence of base and suitable solvents to yield teriflunomide of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

All percentages and ratios used here in are expressed by weight of the total composition and all measurements made are at ambient temperature and atmospheric pressure, unless other wise designated. All temperatures are in degrees Celsius unless specified otherwise. The present invention can comprise (open ended) the components of the present invention as well as other ingredients or elements described herein.

As used herein, "comprising" means the elements recited, or there equivalents in structure or function, plus any other element or elements which are not recited. The terms having and including are also to be construed as open ended unless the context suggests otherwise.

All ranges recited here include the end points, including those that recite a range "between" two values.

Terms such as "about", "generally", "substantially" and the like are to be constructed as modifying a terms or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at the very least the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

When a molecule or material is identified herein as "pure", it generally means, unless specified otherwise, that the material has 99% purity or higher, as determined using method conventional in the art such as high performance liquid chromatography (HPLC), gas chromatography (GC), or spectroscopic methods. In general, this refers purity with regard to unwanted residual solvents, reaction, by-products, impurities and unreacted starting materials, "substantially pure" refers to the same as "pure", except that the lower limits is about 98% purity or higher and like wise "essential pure" means the same as "pure" except that the lower limit is about 97% purity.

2) acetylation of 2-cyano-N-[4-(trifluromethyl)phenyl] acetamide of

Step (1 ) involves condensation cyanoacetic acid of formula (II) with 4-

(trifluoromethyl aniline) of formula (III) in the presence of chlorinating agent and suitable reaction condition to give 2-cyano-N-[4-(trifluromethyl)phenyl]acetamide of formula (IV).

For the reaction of step (1 ); the suitable chlorinating agent may be used include but are not limited to thionyl chloride, phosphorous trichloride, phoshprous penta chloride, phosphorus oxychloride, oxalyl chloride and the like.

The quantities chlorinating agent preferably phosphorous pentachloride or oxalyl chloride may range from about 1 to about 10 molar equivalents, per mole of compound II.

Suitable solvents that used for chlorinating includes but are not limited to aromatic hydrocarbons such as toluene, xylene, n-hexane, n-heptane and cyclohexane and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform and the like; ether solvents such as 1 , 4- dioxane, tetrahydrofuran and methyl t-butyl ether; aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and dimethylacetamide (DMA) and any mixtures thereof. Optionally the reaction may be carried out without solvent.

Suitable temperatures for reaction may be less than about 100°C, less than about 100°C, less than about 60°C, less than about 25°C, less than bout 0°C or any other suitable temperatures.

The reaction may be carried out for time periods ranging from about 30 minutes to about 10 hours, or longer.

The product can be isolated from the reaction mass by quenching the reaction mixture in cold water and the separated solid was filtered and washed with cyclohexane and isopropanol to give pure 2-Cyano-N-[4- {trifluromethyl}phenyl]acetamide of formula (IV). Step (2) involves acetylation of 2-cyano-N-[4-(trifluoromethyl) phenyl] acetamide of formula (II) with suitable acetylating agent in the presence of base and suitable reaction condition to yield Teriflunomide of formula (I).

For the reaction of step (2), the suitable acetylating agents may be used includes but are not limited to sodium acetate, acetyl chloride, isopropenyl acetate and the like.

The quantities of acetylating agent preferably isopropenyl acetate may range from about 1 to about 10 molar equivalents, per mole of compound IV.

Bases that may be used in step (2) includes, but are not limited to organic bases, such as for example triethyl amine, diisopropylethylamine, pyridine, and the like; inorganic bases such as for example sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, caustic soda in solid form or in form of aqueous solution of differing concentration; and any mixtures thereof.

Optionally, the compound of formula I can be further be purified by a process involving acidifying and basifying steps, in any order, crystallization and combination thereof, to enhance the purity. The suitable crystallization techniques include, but are not limited to: concentrating, cooling, stirring, or shaking a solution containing the compound, combining a solution with an anti- solvent, adding seed crystals, evaporation, flash evaporation, and the like including any combination thereof. The solvent than be employed crystallization include, but are not limited to alcohol, such as methanol, ethanol, isopropyl alcohol, hexafluroisopropyl alcohol, phenol, and 2,2,2-trifluroethanol (TFE); esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; ketones such as acetone and methyl isobutyl ketone; hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as 1 ,4-dioxane and tertrahydrafuran; nitriles such as acetonitrile; water and any mixtures thereof. An antisolvent as used herein refers to a solvent in which a compound of formula I is insoluble, less soluble or poorly soluble.

Acids that can be employed for purification include, but are not limited to inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as acetic acid, methanesulfonic acid, oxalic acid formic acid and the like.

Bases that can be employed for purification include, but are not limited to inorganic bases such as alkali metal hydroxides and carbonates; and organic bases such as triethylamine, dicyclohexylamine, diisopropylethylamine, Imorpholine, ammonium hydroxide and the like.

A teriflunomide prepared in accordance with the process described in the present application are substantially free of process or structure related impurities. "Substantially free" as used herein refers to Teriflunomide free base or pharmaceutically acceptable salt having less than about 0.5% or less than about 0.3%, or less than about 0.2% or less than about 0.1 % or less than about 0.005% by weight of corresponding process or structural related impurity.

The compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, and the like or any other suitable techniques. The solids that are isolated may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the solids may be washed with a solvent to wash out the mother liquor and/or impurities and the resulting wet solids may optionally be suction dried. Evaporation, as used herein, refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent by using a technique including, but not limited to, tray drying, spray drying, fludized bed drying, and thin film drying, under reduced pressure or at atmospheric pressure. A wet cake obtained at any stage of the process may be optionally further dried. Drying may be carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 200°C, or about 20°C to about 80°C, or about 30°C to about 60°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure. The drying may be carried out for any desired times until the desired quality of product is achieved, such as about 30 minutes to about 20 hours, or about 1 to about 10 hours. Shorter or longer times also are useful.

The process of present invention are simple, cost effective, ecologically friendly, reproducible, useful on a commercial scale, and robust, to produce Teriflunomide with high chemical purity.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be constructed as limiting the scope of the application in any manner.

EXAMPLE 1 : Preparation of 2-cvano-N-f4-(trifluoromethyl> phenyl! acetamide (IV)

A round bottom flask is charged with cyanoacetic acid (100 g) and phosphorous pentachloride and tetrahydrofuran (300 ml) and the reaction mixture is stirred at room temperature for 4 hours. 4-trifluoromethyl aniline (161 g) dissolved in tetrahydrofuran (100 ml) is slowly added to the reaction mixture and stirred for completion of reaction. The resultant reaction mass is cooled and separated solid is filtered and washed with slurry of Isoproapnol and cyclohexane and dried under reduced pressure to afford the title compound. Weight: 196 gm.

Purity by HPLC: 98%

EXAMPLE 2: preparation of 2-cyano-3-hvdroxy-N-f4-( trifluoromethyl) phenyl] but-2-enamide (Teriflunomide crude) A round bottom flask is charged with 2-cyano-N-[4-{trifluromethyl} phenyl] acetamide (100g), sodium hydroxide (70 gm) and dimethyl formamide is added and the reaction mixture is stirred for 30 minutes. Isopropenyl acetate (60 ml) is added slowly and the resultant mixture is stirred for about 4-5 hours at room temperature. After completion of the reaction, the resulting reaction mixture is diluted with water and acidified with Cone. HCI solution and stirred for solid separation. The separated solid is filtered and washed with water and dried under reduced pressure to afford Teriflunomide.

The obtained teriflunomide is charged in round bottom flask and aqueous solution of sodium hydroxide solution (29.6 g in 300 ml water) is added slowly at 25-35°C and stirred for 1 to 2 hours. The mixture is brought to 5 to 10°C and dichloromethane is added, the mixture is stirred for 15 minutes. The organic and the aqueous layer are separated, and the resultant aqueous layer is acidified with aq. Hcl and stirred. The separated solid is filtered and washed with water and dried under vacuum at 65-70°C for 10-12 hours to afford teriflunomide.

Weight: 101 gm

Purity by HPLC: 95%

EXAMPLE 3; Purification of Teriflunomide:

Teriflunomide (5 g) is charged into a flask followed by addition of acetonitrile (125 ml) and heated to reflux and stirred for 2 hours. The resultant reaction solution is filtered through highflow bed to obtain a clear solution and cooled to room temperature and stirred for solid separation. The separated solid is filtered, washed with Isopropanol (50 ml) and dried under vacuum to afford pure teriflunomide.

Weight: 3.8 gm

Purity by HPLC: 99.7%

Claims

Claims:

1. The process for the preparation of teriflunomide of Formula I

Formula I

comprising the steps of;

i) condensation of cyanoacetic acid formula (II) with 4-trifluoromethyl aniline of formula (III) in the presence of chlorinating agent to give 2- cyano-N-[4-(trifluromethyl) phenyl] acetamide of formula (IV);

ii) acetylation of 2-cyano-N-[4-( trifluoromethyl)phenyl] acetamide of formula (IV) with an acetylating agent in the presence of base and suitable solvents to yield Teriflunomide of formula (I).

2. The process according to claim 1 ,wherein chlorinating agents are selected from thionyl chloride, phosphorous trichloride, phosphorous penta chloride, phosphorus oxychloride, oxalyl chloride and the like.

3. The process according to claim 1 , wherein aceylating agents are selected from sodium acetate, acetyl chloride, isopropenyl acetate and the like.

4. The process according to claim 1 , wherein solvents are selected from chlorinating includes but are not limited to aromatic hydrocarbons such as toluene, xylene, n-hexane, n-heptane and cyclohexane and the like;

halogenated hydrocarbons such as dichloromethane, ethylenedichloride and chloroform and the like; ether solvents such as 1 ,4-dioxane, tetrahydrofuran and methyl t-butyl ether; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and

dimethylacetamide (DMA) and any mixtures thereof.

5. The process according to claim 1 , wherein bases are selected from

organic bases, such as for example triethyl amine, diisopropylethylamine, pyridine, and the like; inorganic bases such as for example sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, caustic soda in solid form or in form of aqueous solution of differing concentration; and any mixtures thereof.

6. The process for the purification of teriflunomide comprising steps of :

i) Providing a solution of teriflunomide in base and solvent

ii) separating aqueous and organic layers

iii) acidifying aqueous layer with acid to obtain teiflunomide.

iv) Optionally recrystallising teiflunomide of step iii to afford pure

teriflunomide.

7. The process according to claim 6, wherein the said acid is selected from inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as acetic acid, methanesulfonic acid, oxalic acid formic acid and the like.

8. The process according to claim 6, wherein the said base is selected from inorganic bases such as alkali metal hydroxides and carbonates; and organic bases such as triethylamine, dicyclohexylamine,

diisopropylethylamine, Imorpholine, ammonium hydroxide and the like.

9. The process according to claim 6, wherein the solvent selected is acetonitrile.