DESCRIPTION

The present invention provides an industrially advantageous process for the preparation of entacapone Morph – D from entacapone.

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

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

US Patent 4,963,590. discloses a process for the preparation of entacapone (Formula I) by the condensation of 3,4-Dihydroxy-5- nitrobenzaldehyde and N-N-diethylcyanoacetamide in anhydrous ethanol.

US Patent 5,135,950 discloses crystallographically essentially pure and stable polymorphic form A of entacapone.

The processes of preparation of entacapone and different polymorphic forms are also disclosed in PCT patent application WO 2005063693; WO 2005063695; WO 2005063696; WO 200507088, WO 2005066117 and WO 2007135406.

The present inventors while developing the processes for the preparation of entacapone have developed process for the preparation of entacapone Morph –D from any polymorphic form or their mixture it has the advantage of (i) use of water as the solvent in the presence of readily available organic or inorganic bases (ii) commercially and industrially more economical and viable process without use of any organic solvent (iii) substantially pure entacapone Form-D prepared by the process of invention is free from the other polymorph.

In one of the aspect of the process for the preparation of substantially pure entacapone Morph -D includes dissolving entacapone in water in the presence of a base and contacting the resultant solution after filtration with acidified water comprising either an organic or inorganic acid to obtain entacapone Morph –D. The base used in to make water alkaline is 1 to 3 mole ratio of Entacapone. The acidified water containing acid is proportionate to mole base used.

The base may be an organic or an inorganic one. The organic bases may be one or more of pyridine, triethylamine, N-methylmorpholine, methylamine, imidazole, and benzimidazole. The inorganic bases may be one or more mixture of oxides, hydroxide or carbonates of sodum, potassium and ammonium.

The organic acid may be carboxylic acid. The carboxylic acid may be one or more of formic acid, acetic acid, lactic acid, citric acid and oxalic acid.

The inorganic acid comprises one or more of stronger acids, hydrochloric acid or sulfuric acid.

The process of invention may be used to make substantially pure Entacapone Form-D, which is free from the other polymorph. The term substantially pure include the meaning where any other polymorphic form is below the detection level or their presence is less than 1% when measured by the XRPD in the Form-D prepared by the process of invention. Other polymorph includes of Polymorph A and C.

The entacapone may be prepared by the process known to the person skilled in the art through US patent No. 5,135,950 and WO 2005066117.

In another aspect of the invention entacapone is dissolved in water comprising a base. The resultant solution is gradually added into acidified water at room temperature (20 -300C) or vice versa. For acidification an inorganic or organic acid may be used. The inorganic acid may be hydrochloric acid (HCl), sulphuric acid and the organic acid may be acetic acid and formic acid. The precipitated entacapone Morph-D, filtered and dried to get yellow colored entacapone polymorph-D. Drying may be performed by use of any conventional method at temperature 60 -900C.

Conventional method of drying may include of Vacuum tray drier, Fluid bed drier, rotary cone vacuum drier and air-drying.

The entacapone used here to make substantially pure Form-D of entacapone includes any polymorphic form of Entacapone including one or more Form A and C and their mixture with Form –D of entacapone in any percentage.

The present invention is further illustrated by the following examples which are 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

Entacapone (50 g, mixture of Entacapone Form A, C and D) is dissolved in water (500 ml) containing triethylamine (18.2 g). The solution is added slowly to water (1 L) containing concentrated HCl (25 g) at 25 – 300C. The precipitate is filtered and washed with water. The wet cake is dried in a fluid bed drier to yield entacapone Morph-D.
Yield: 48g
Polymorph A: 0.2% (XRPD)
Example: 2

Entacapone (50 g, Form A) is dissolved in water (500 ml) containing triethylamine (18.2 g). The solution is added slowly to water (1 L) containing acetic acid (20 g) at 25 – 300C. The precipitate is filtered and washed with water. The wet cake is dried in a fluid bed drier to yield entacapone Morph-D.
Yield: 47.5g
Polymorph A: 0.3% (XRPD)
Example: 3

Entacapone (25 g, Mixture of Entacapone Form A and D) is dissolved in water (250 ml) containing N-methylmorpholine (9.1 g). The solution is added slowly to water (500 mL) containing concentrated HCl at 25 – 300C (17 g). The precipitate is filtered and washed with water. The wet cake is dried in a fluid bed drier to yield entacapone Morph-D.
Yield: 24 g
Polymorph A: Not detected (XRPD)

Example 4

Entacapone (10 g, Polymorph A) is dissolved in 2.8% aqueous sodium bicarbonate solution (100 ml) containing triethylamine (1.66 g). The solution is added slowly to dilute HCl (8.5 g concentrated HCl in 200 ml water) solution at 25 -300C. The resulting suspension is stirred for 0.5 hours and filtered to collect the solids. The wet material is washed with water and air dried to yield entacapone Morph –D.
Yield: 9.6 g
Polymorph A: Not detected (XRPD)

We Claim:
1. A process for the preparation of substantially pure entacapone Morph-D comprising;
(a) dissolving entacapone in water in the presence of a base;
(b) contacting the solution with an acidified water;
(c) isolating the crystals of entacapone Morph –D
2. The process of claim 1, wherein the molar ratio of Entacapone to base is 1: 1to3.
3. The process of claim 1, wherein base is one or more mixture of organic base and inorganic base.
4. The process of claim 3, wherein the organic base comprises pyridine, triethylamine, N-methylmorpholine, methylamine, imidazole, and benzimidazole.
5. The process of claim 3 wherein, the inorganic base is oxides, hydroxide, carbonate of sodium, potassium or ammonium.
6. The process of claim 1, wherein the acidified water comprises an organic acid or an inorganic acid.
7. The process of clam 6, wherein the organic acid comprises carboxylic acids which comprises formic acid, acetic acid, lactic acid, citric acid and oxalic acid and inorganic acid comprises hydrochloric acid and sulfuric acid.
8. The process of claim 1, wherein entacapone used in step a) is comprises any polymorphic form or mixture of polymorphic form.
9. The process of claim 1, where in substantially pure Entacapone Form-D is free from other polymorphic form of entacapone.
10. The process of claim 9, wherein other polymorphic form is polymorph A present in Entacapone Form-D is less than 1% when measured by XRPD.