Bibliographic Details
| Title: |
PROCESS FOR THE PREPARATION OF ENTACAPONE |
| Document Number: |
20080146829 |
| Publication Date: |
June 19, 2008 |
| Appl. No: |
11/958778 |
| Application Filed: |
December 18, 2007 |
| Abstract: |
A process for the preparation of entacapone, in particular as the polymorphic form A, comprising the preparation of a compound of formula (V), as herein defined, by condensation of N,N-diethyl-cyano-acetamide with a compound of formula (IV), as herein defined, in the presence of a strong basic agent; the dealkylation of said compound of formula (V) to obtain entacapone and the crystallization thereof to the polymorphic form A. |
| Inventors: |
MANTEGAZZA, Simone (Milano, IT); ALLEGRINI, Pietro (Milanese, IT); RAZZETTI, Gabriele (Sesto San Giovanni, IT) |
| Assignees: |
DIPHARMA FRANCIS s.r.l. (Baranzate, IT) |
| Claim: |
1. A process for the preparation of N,N-diethyl-2-cyano-3-(-3-alkoxy-4-hydroxy-5-nitrophenyl-)-acrylamide, of formula (V) [chemical expression included] wherein R is C1-C6 alkyl, wherein the process comprises reaction of a compound of formula (III), namely N,N-diethyl-cyano-acetamide, [chemical expression included] with a compound of formula (IV) [chemical expression included] wherein R is C1-C6 alkyl, in the presence of a strong basic agent. |
| Claim: |
2. A process according to claim 1, wherein the strong basic agent is selected from the group consisting of an alkali or alkaline-earth metal hydroxide, an alkali or alkaline-earth metal alkoxide and aluminium isopropoxide. |
| Claim: |
3. A process according to claim 2, wherein the alkali or alkaline-earth metal hydroxide is selected from sodium hydroxide and potassium hydroxide. |
| Claim: |
4. A process according to claim 1, wherein the reaction is carried out at a temperature approximately ranging from −10 to 70° C. |
| Claim: |
5. A process according to claim 1, wherein the reaction is carried out in a solvent selected from a C1-C6 alkanol, a dipolar aprotic solvent, an ether, a glycol a glycol that is partially alkylated, a glycol that is completely alkylated, a chlorinated solvent, a nitrile or mixtures of said solvents or mixtures thereof with water. |
| Claim: |
6. A process according to claim 5, wherein the solvent is selected from methanol, ethanol, isopropanol and mixtures thereof with water. |
| Claim: |
7. A process according to claim 1, wherein the molar ratio of basic agent to compound of formula (IV) approximately ranges from 1 to 10. |
| Claim: |
8. A process according to claim 1, further comprising the dealkylation of a compound of formula (V) to obtain entacapone. |
| Claim: |
9. A process according to claim 8, wherein the dealkylation is carried out by reaction with aluminium trichloride and triethylamine. |
| Claim: |
10. A process according to claim 9, wherein the molar ratio of triethylamine to compound of formula (V) approximately ranges from 1 to 5. |
| Claim: |
11. A process for isolating entacapone in the substantially pure crystallographic form of polymorph A, comprising the crystallization of entacapone from methyl-ethyl-ketone (2-butanone). |
| Claim: |
12. A process according to claim 11, comprising: dissolution of entacapone in 2-butanone, and either a) rapid cooling to about 30-40° C. to obtain a precipitate, subsequent heating to about 60° C.; stirring at about 60° C. for about an hour; subsequent slow cooling and recovery of the resulting solid; or b) cooling to about 60° C. and seeding with crystalline germs, stirring at about 60° C. for about an hour and subsequent slow cooling and recovery of the resulting solid. |
| Claim: |
13. A process according to claim 8, further comprising the crystallization of entacapone from methyl-ethyl-ketone (2-butanone) to obtain entacapone in the substantially pure crystallographic form of polymorph A. |
| Claim: |
14. (canceled) |
| Claim: |
15. A process for isolating entacapone in the substantially pure crystallographic form of polymorph A, comprising: (a) crystallization of entacapone from methyl-ethyl-ketone (2-butanone); and (b) dissolution of entacapone in 2-butanone, and either i. rapid cooling to about 30-40° C. to obtain a precipitate, subsequent heating to about 60° C.; stirring at about 60° C. for about an hour; subsequent slow cooling and recovery of the resulting solid; or ii. cooling to about 60° C. and seeding with crystalline germs, stirring at about 60° C. for about an hour and subsequent slow cooling and recovery of the resulting solid, wherein the entacopone is prepared by a process for the preparation of N,N-diethyl-2-cyano-3-(-3-alkoxy-4-hydroxy-5-nitrophenyl-)-acrylamide, of formula (V) [chemical expression included] wherein R is C1-C6 alkyl, wherein the process comprises reaction of a compound of formula (III), namely N,N-diethyl-cyano-acetamide, [chemical expression included] with a compound of formula (IV) [chemical expression included] wherein R is C1-C6 alkyl, in the presence of a strong basic agent; and obtaining entacapone by dealkylation of the compound of formula (V), wherein crystallization of entacapone from methyl-ethyl-ketone (2-butanone) obtains entacapone in the substantially pure crystallographic form of polymorph A. |
| Current U.S. Class: |
558/410 |
| Current International Class: |
07 |
| Accession Number: |
edspap.20080146829 |
| Database: |
USPTO Patent Applications |
