Process for the Preparation of Entacapone Form-A
A process to prepare (2E)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) eliminating corrosive acids in the purification, with more than 99.5% purity with a Z-isomer content of less than 0.1% comprising condensation of e,4-Dihydroxy{5-nitrobensaldehyde with N,N-diethyl cyanoacetamide in the presence of a base selected from cyclic and acyclic secondary amines and a mixture of solvents, to obtain a crude product, stirring the crude product in a halogenated solvent, filtering and finally crystallization of polymorph A of Entacapone in a solvent.
1 - 26 . (canceled)
27 . A process to prepare crystalline polymorph A (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone) with at least 99.5% purity with Z-isomer content of less than 0.1% comprising the steps and sequence:—
a. Condensation of 3,4-dihydroxy-5-nitro benzaldehyde with N,N-diethyl cyano acetamide in presence of a base and a mixture of solvents to obtain a crude product,
b. Stirring of crude product obtained, in halogenated solvent and filtering to eliminate impurities and to obtain polymorph A of Entacapone
c. Crystallation of polymorph A of Entacapone in a solvent,
28 . A process according to claim 27 wherein the base is selected from cyclic and acyclic secondary amines.
29 . A process according to claim 27 wherein the cyclic and acyclic secondary amines are selected from a group comprising piperidine, pyrrolidine, diisopropyl amine, 4-(dimethyl amino)pyridine, di-n-butylamine, di-t-butylamine, diisobutylamine, or mixture thereof.
30 . A process according to claim 27 wherein the mixture of solvents is selected from a group comprising ether solvents and from a group comprising hydrocarbon solvents.
31 . A process according to claim 30 wherein the ether solvents shall have a general formula R—OR′, wherein R&R′ are similar or dissimilar alkyl or alkoxyalkyl groups of up to 4-carbon atoms or together form a ring of 5-carbon atoms.
32 . A process according to claim 31 wherein the alkyl is selected from a group comprising of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec butyl, t-butyl.
33 . A process according to claim 31 wherein the alkoxy alkyl is selected from a group comprising of methoxy methyl, methoxy ethyl and methoxy propyl.
34 . A process according to claim 27 wherein the ether solvent is selected from a group comprising, diisopropyl ether, diglyme, dimethoxy ethane, di-isopropyl ether, methyl-t-butyl ether, tetrahydrofuran and methyl tetrahydrofuran.
35 . A process according to claim 27 wherein the hydrocarbon selected is selected from a group comprising of heptane, hexane, petroleum ether, toluene, xylene and mixture thereof.
36 . A process according to claim 27 wherein the halogenated solvent is selected from methylene dichloride, ethylene dichloride, chlorobenzene, bromobenzene and chloroform.
37 . A process according to claim 27 wherein the condensation is at room temperature to 120° C.
38 . A process according to claim 27 wherein the ether solvent is dimethoxy ethane and hydrocarbon solvent is heptane.
39 . A process according to claim 27 wherein the ether solvent is di-isopropyl ether and hydrocarbon solvent is heptane.
40 . A process according to claim 27 wherein the ether solvent is dimethoxy ethane and hydrocarbon solvent is hexane.
41 . A process according to claim 27 wherein the ether solvent is dimethoxy ethane and hydrocarbon solvent is toluene.
42 . A process according to claim 27 wherein the ether solvent is dimethoxy ethane and hydrocarbon solvent is toluene.
43 . A process according to claim 27 wherein the ether solvent is di-isopropyl ether and hydrocarbon solvent is toluene.
44 . A process according to claim 27 wherein the solvent for crystallization is selected from a group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol and acetonitrile or mixtures thereof.
45 . A process according to claim 27 wherein the solvent for crystallization is methanol.
46 . A process according to claim 27 wherein the solvent for crystallization is ethanol.
47 . A process according to claim 27 wherein the solvent for crystallization is acetonitrile.
48 . A process according to claim 27 wherein the reaction temperature is the boiling temperature of hydrocarbon solvent.