WO2008053304A2

WO2008053304A2 - Processes for the preparation of a stable polymorphic form of entacapone

Info

Publication number: WO2008053304A2
Application number: PCT/IB2007/003233
Authority: WO
Inventors: Ram Prasad Yadav; Zakir Gafoor Shaikh; Siddiqui Mohammed Jaweed Mukarram
Original assignee: Wockhardt Research Centre
Current assignee: Wockhardt Research Centre
Priority date: 2006-10-30
Filing date: 2007-10-26
Publication date: 2008-05-08
Anticipated expiration: 2009-04-30
Also published as: WO2008053304A3

Abstract

The invention relates to processes for the preparation of a stable polymorphic form of entacapone. More particularly, it relates to the preparation of stable polymorphic form designated as Form D. The invention also relates to an improved process for the preparation of 2-cyano-N,N-diethylacetamide, and to the use of this compound as an intermediate for the preparation of entacapone.

Description

PROCESSES FOR THE PREPARATION OF A STABLE POLYMORPHIC

FORM OF ENTACAPONE

Field of the Invention

The invention relates to processes for the preparation of a stable polymorphic form of entacapone. More particularly, it relates to the preparation of stable polymorphic foπn designated as Form D. The invention also relates to an improved process for the preparation of 2-cyano-N,N-diethylacetamide, and to the use of this compound as an intermediate for the preparation of entacapone.

Background of the Invention

Entacapone of Formula I is chemically known as (E)-N, N-Diethyl-2- cyano-3-(3,4- dihydroxy-5-nitrophenyl)acrylamide.

Formula I

British Patent No. 8,727,854 discloses entacapone as a potent inhibitor of catechol-O- methyl- transferase (COMT) enzyme. The product is indicated for the treatment of Parkinson's disease.

U.S. Patent No. 4,963,590 discloses a process for the preparation of entacapone of Formula I by condensing 3,4-Dihydroxy-5- nitrobenzaldehyde with N,N- diethylcyanoacetamide in anhydrous ethanol.

U.S. Patent No. 5,135,950 discloses crystallographically essentially pure and stable polymorphic Form A of entacapone. Several processes have been reported for the preparation of entacapone and different polymorphic forms for example, in International (PCT) Publication Nos. WO 2005063693; 2005063695; 2005063696; 20050661 17 and 2005070881.

Geπnan Patent DE 2538254 discloses a process for the preparation of 2-cyano-N, N- diethylacetamide by reacting halo-acetamide derivatives with alkali cyanide in the presence of water as a solvent.

Summary of the Invention

The present inventors have developed a process for the preparation of a stable polymorphic Foπn D of entacapone. The Form D of entacapone can be directly isolated by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N, N-diethyl acetamide in an alcoholic solvent in the presence of a base and contacting the resultant product with an aqueous acid. Further, the present invention have developed a single step process for the preparation of 2-cyano-N,N-diethylacetamide without the use of toxic and lachrymatory alkali cyanide, chloroacetyl chloride reagents and haloacetamide.

Accordingly, in one general aspect there is provided a process for the preparation of stable polymorphic Form D of entacapone. The process includes: a) reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N, N-diethyl acetamide in one or more alcoholic solvents in the presence of a base; b) contacting the product of step a) with an aqueous acid; and c) isolating the stable polymorphic Form D of entacapone by the removal of the solvents.

The Form D of entacapone may have the X-ray diffraction pattern as depicted in Figure 1 and may have the infrared spectrum as depicted in Figure 2.

Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

The process may include further drying of the product obtained. In another aspect there is provided a process for the preparation of 2-cyano-N,N- diethylacetamide. The process includes: a) reacting N,N-diethyI amine with cyanoacetic acid in the presence of dicyclohexylcarbodiimide; and b) isolating the 2-cyano-N, N-diethylacetamide from reaction mass thereof.

In another aspect, the 2-cyano-N, N-diethylacetamide prepared by the process of the present invention may be condensed with 3,4-dihydroxy-5-nitrobenzaldehyde according to any of the known processes to give entacapone, for example, process as disclosed in International (PCT) Publication No. WO 20050661 17.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

^'" Description of the Drawings

Figure 1 is an X-ray powder diffraction pattern of Form D of entacapone. Figure 2 is an infrared spectrum of Form D of entacapone.

Detailed Description of the Invention

The inventors have developed a process for the preparation of a stable polymorphic Form D of entacapone by reacting 3, 4-dihydroxy-5-nitrobenzaldehyde with 2-cyano- N,N-diethyl acetamide in one or more alcoholic solvents in the presence of acetic acid and a base; contacting with an aqueous acid; and isolating the stable polymorphic Form D of entacapone by the removal of the solvents.

Examples of bases include piperidine, pyridine, N-methyl morpholine, morpholine, piperazine, methylamine, diethylamine, triethylamine, and the like.

The reaction of 3, 4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N,N-diethyl acetamide may be carried out at a reflux temperature of the solvent used. In particular, the reaction may be carried out at a temperature from about 30° C to about 100° C. After completion of the reaction, the reaction mixture may be concentrated and the residue obtained may be treated with a mixture of alcohol and acid. The precipitated product may be then re-suspended in a mixture of water and an acid and polymorphic Form D of entacapone may be isolated from the reaction mass thereof.

The product obtained may be further or additionally dried. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

The acids which may be used include organic and inorganic acids. Examples of organic acids include acetic acid, formic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid.

A suitable alcoholic solvent includes one or more of straight chain and branched chain Ci-C₆ alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, and the like.

The inventors also have developed a process for the preparation of 2-cyano-N,N- diethylacetamide, by reacting N,N-diethyl amine with cyanoacetic acid in one or more solvents in the presence of dicyclohexylcarbodiimide.

The reaction of N,N-diethyl amine with cyanoacetic acid may be carried out at a reflux temperature of the solvent used. In particular, the reaction may be carried out at a temperature from about 3O⁰ C to about 100⁰ C. After completion of the reaction, the reaction mixture may be concentrated and the residue so obtained may be treated with a mixture of water and acetic acid. The mixture so obtained may be filtered to remove solid impurities such as dicyclohexyl urea and the filtrate containing the product may be extracted in an organic solvent. The organic solvent may be concentrated and 2- cyano-N,N-diethylacetamide isolated from the reaction mass thereof. Examples of organic solvents include haloalkanes, ethers, and aromatic solvents. Examples of haloalkanes include methylene chloride, chloroform, carbon tetrachloride, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, dioxane, and the like. Examples of aromatic solvents include solvents such as toluene, xylene, and the like.

The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 : Preparation of 2-cyano-N, N-diethyl acetamide

Dicyclohexylcarbodiimide (85 Kg) was added to a mixture of N,N-diethylamine (34 Kg) and cyanoacetic acid (36 Kg) in tetrahydrofuran (235 L) and stirred. The reaction mixture refluxed for about 6-9 hours. After completion of the reaction, the reaction mixture was concentrated and the residue so obtained was treated with a mixture of water (275 L) and acetic acid (12 L). The undissolved dicylohexylurea was removed through filtration and the filtrate was extracted with dichloromethane. The dichloromethane layer was concentrated to get the 2-cyano-N, N-diethyl acetamide as an oil.

Yield: 55.2 Kg.

Example 2: Preparation of Form D of entacapone

3, 4-dihydroxy-5-nitrobenzaIdehyde (500 gm) was added to a mixture of 2-cyano- N,N-diethylacetamide (640 gm), piperidine (620 gm) and acetic acid (400 gm) in isopropyl alcohol (5 L) and stirred. The reaction mixture was refluxed for about 15-24 hours. After completion of the reaction, the reaction mixture was concentrated and the concentrated mass treated with a mixture of isopropyl alcohol (700 mL) and acetic acid (640 mL). The reaction mixture was further stirred for about 22-25 hours. The product so precipitated was filtered and washed with a mixture of water (90%) -acetic acid (10%). The product was dried to get the Form D of entacapone. Yield: 449 gm. Purity (by HPLC): 99.31%. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim:

1. A process for the preparation of a stable polymorphic Foπn D of (E)-Entacapone, the process comprising: a) reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N,N-diethyl acetamide in one or more alcoholic solvents in the presence of a base; b) contacting the product of step a) with an aqueous acid; and c) isolating the stable polymorphic Form D of entacapone by the removal of the solvents.

2. The process of claim 1 , wherein the alcoholic solvent comprises one or more of a straight chain and branched chain Ci-C₆ alcohols.

3. The process of claim 2, wherein the alcoholic solvent comprises one or more of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and isobutyl alcohol.

4. The process of claim 1 , wherein the base comprises piperidine, pyridine, N-methyl morpholine, morpholine, piperazine, methylamine, diethylamine and triethylamine.

5. The process of claim 1 , wherein the aqueous acid is a mixture of water and acid.

6. The process of claim 5, wherein the acid comprises one or both of organic and inorganic acids.

7. The process of claim 6, wherein the organic acid comprises one or more of acetic acid, formic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid.

8. The process of claim 6, wherein the inorganic acid comprises one or more of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid.

9. The process of claim 1 , wherein removing the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

iθ. The process of claim 1, further comprising additional drying of the product obtained.

1 1. The process of claim 1, wherein the Form D of entacapone has the X-ray diffraction pattern of Figure 1.

12. The process of claim 1, wherein the Form D of entacapone has the infrared spectrum of Figure 2.

13. A process for the preparation of 2-cyano-N,N-diethylacetamide, the process ' comprising: a) reacting N,N-diethylamine with cyanoacetic acid in one or more organic solvents in the presence of dicyclohexylcarbodiimide; and b) isolating the 2-cyano-N,N-diethylacetamide from reaction mass thereof.

14. The process of claim 13, wherein the organic solvent comprises one or more of haloalkanes, ethers, and aromatic solvents.

15. The process of claim 14, wherein the haloalkanes comprise one or more of methylene chloride, chloroform, and carbon tetrachloride.

16. The process of claim 14, wherein the ethers comprise one or more of diethyl ether, tetrahydrofuran, and dioxane.

17. The process of claim 14, wherein the aromatic solvent comprise one or both of toluene and xylene.

18. A process for the preparation of entacapone, the process comprising: a) reacting N,N-diethylamine with cyanoacetic acid in one or more organic solvents in the presence of dicyclohexylcarbodiimide; b) isolating the 2-cyano-N,N-diethylacetamide; c) condensing the 2-cyano-N,N-diethylacetamide with 3,4-dihydroxy-5- nitrobenzaldehyde; and d) isolating the entacapone from reaction mass thereof.

19. The process of claim 18, wherein the organic solvent comprises one or more of haloalkanes, ethers, and aromatic solvents.