Indian Patents. 264147:A SINGLE STEP PROCESS FOR THE PREPARATION OF 2-CYANO-N,N-DIETHYL ACETAMIDE INTERMEDIATE USEFUL IN PREPARATION OF ENTACAPONE

Title of Invention	A SINGLE STEP PROCESS FOR THE PREPARATION OF 2-CYANO-N,N-DIETHYL ACETAMIDE INTERMEDIATE USEFUL IN PREPARATION OF ENTACAPONE
Abstract	The present invention provides a process for the preparation of 2-cyano-N,N-diethylacetamide intermediate useful in preparation of Entacapone, wherein the said process comprises of a) reacting N,N-diethyl amine with cyano acetic acid in presence of dicyclohexylcarbodiimide using organic solvent, b) isolating the 2-cyano-N,N-diethylacetamide from reaction mass thereof.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule13) 1. TITLE OF THE INVENTION: A SINGLE STEP PROCESS FOR THE PREPARATION OF 2-CYANO- N, N- DIETHYL ACETAMIDE INTERMEDIATE USEFUL IN PREPARATION OF ENTACAPONE. 2. APPLICANT (S) (a) NAME: WOCKHARDT LTD. (b) NATIONALITY: INDIAN (c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East), Mumbai- 400 051. 3. PREAMBLE TO THE DESCRIPTION The present invention provides a single step process for the preparation of 2- cyano-N,N-diethyl acetamide intermediate useful in preparation of entacapone The following specification particularly describes the invention and the manner in which it is to be performed. 1 4. DESCRIPTION The present invention provides a single step process for the preparation of 2-cyano-N,N-diethylacetamide, an intermediate useful in preparation of entacapone. Entacapone of formula I is chemically known as (E)-N, N-Diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide. rHM /CH2CH3 i ,C-N; C=C^ C H jC Hg CN Formula I 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 application WO 2005063693; WO 2005063695; WO 2005063696; WO 2005066117 and WO 2005070881. German patent DE 2538254 disclosed the process of preparation of 2-cyano-N, N-diethylacetamide by reacting halo-acetamide derivatives with alkali cyanide in the presence of water as a solvent. 2 Present invention provides an easy single step process for the preparation of 2-cyano-N,N-diethylacetamide intermediate useful in preparation of entacapone without use of toxic and lachrymatory alkali cyanide, chloroacetyl chloride reagents and haloacetamide. In the aspect of present invention there is provided a process for the preparation of 2-cyano-N,N-diethylacetamide intermediate useful in preparation of Entacapone, wherein the said process comprises of a) reacting N,N-diethyl amine with cyano acetic acid in presence of dicyclohexylcarbodiimide, b) isolating the 2-cyano-N,N-diethylacetamide from reaction mass thereof, The compound obtained from step b) is condensed with 3, 4-dihydroxy-5-nitrobenzaldehyde to get entacapone as method known in the art. The process involves reacting N,N-diethyl amine with cyano acetic acid using organic solvent in presence of dicyclohexylcarbodiimide at reflux temperature. After completion of reaction, the reaction mixture was concentrated and residue is treated with mixture of water and acetic acid. The dicyclohexyl urea was filtered and the product was extracted with organic solvent. The organic solvent was concentrated and 2-cyano-N,N-diethylacetamide isolated from the reaction mass thereof. The non-limiting examples of organic solvents include haloalkanes, ethers, and aromatic solvents. Haloalkanes such as methylene chloride, chloroform, carbon tetrachloride and the like or ethers such as diethyl ether, tetrahydrofuran, dioxane and the like or aromatic solvents such as toluene, xylene and the like. 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. 3 EXAMPLE Preparation of 2-Cyano-N, N-Diethyl acetamide Charged tetrahydrofuran (235 Litre) followed by dicyclohexylcarbodiimide (85 Kg), N,N-diethyl amine (34 Kg) and cyano acetic acid (36 Kg). Reflux the reaction mixture for 6-9 hour. After completion of reaction, reaction mixture was concentrated and residue treated with mixture of water (275 Litre) and acetic acid (12 Litre). Undissolved dicylohexylurea was removed through Alteration and filtrate was extracted with dichloromethane. Dichloromethane layer was concentrated to get the 2-Cyano-N,N-Diethyl acetamide as oil. Yield: 55.2 Kg. 4 WE CLAIM: 1. A process for the preparation of 2-cyano-N,N-diethylacetamide intermediate useful in preparation of Entacapone, wherein the said process comprises of a) reacting N,N-diethyl amine with cyano acetic acid in presence of dicyclohexylcarbodiimide using organic solvent, b) isolating the 2-cyano-N,N-diethylacetamide from reaction mass thereof. 2. A compound obtained according to claim 1 used in the synthesis of entacapone. 3. A process of claim 1 wherein the organic solvent is tetrahydrofuran. 4. Use of intermediate prepared according to process of claim 1 for the preparation of entacapone. Dated this 30th day of October, 2006 For Wockhardt Limited 5 (Mandar Kodgule) Authorized Signatory

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A SINGLE STEP PROCESS FOR THE PREPARATION OF 2-CYANO- N, N-
DIETHYL ACETAMIDE INTERMEDIATE USEFUL IN PREPARATION OF
ENTACAPONE.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai- 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a single step process for the preparation of 2-
cyano-N,N-diethyl acetamide intermediate useful in preparation of
entacapone
The following specification particularly describes the invention and the manner
in which it is to be performed.
1

4. DESCRIPTION
The present invention provides a single step process for the preparation of 2-cyano-N,N-diethylacetamide, an intermediate useful in preparation of entacapone.
Entacapone of formula I is chemically known as (E)-N, N-Diethyl-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide.

rHM /CH2CH3 i ,C-N;
C=C^ C H jC Hg CN

Formula I
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 application WO 2005063693; WO 2005063695; WO 2005063696; WO 2005066117 and WO 2005070881.
German patent DE 2538254 disclosed the process of preparation of 2-cyano-N, N-diethylacetamide by reacting halo-acetamide derivatives with alkali cyanide in the presence of water as a solvent.
2

Present invention provides an easy single step process for the preparation of 2-cyano-N,N-diethylacetamide intermediate useful in preparation of entacapone without use of toxic and lachrymatory alkali cyanide, chloroacetyl chloride reagents and haloacetamide.
In the aspect of present invention there is provided a process for the preparation of 2-cyano-N,N-diethylacetamide intermediate useful in preparation of Entacapone, wherein the said process comprises of
a) reacting N,N-diethyl amine with cyano acetic acid in presence of dicyclohexylcarbodiimide,
b) isolating the 2-cyano-N,N-diethylacetamide from reaction mass thereof,
The compound obtained from step b) is condensed with 3, 4-dihydroxy-5-nitrobenzaldehyde to get entacapone as method known in the art.
The process involves reacting N,N-diethyl amine with cyano acetic acid using organic solvent in presence of dicyclohexylcarbodiimide at reflux temperature. After completion of reaction, the reaction mixture was concentrated and residue is treated with mixture of water and acetic acid. The dicyclohexyl urea was filtered and the product was extracted with organic solvent. The organic solvent was concentrated and 2-cyano-N,N-diethylacetamide isolated from the reaction mass thereof.
The non-limiting examples of organic solvents include haloalkanes, ethers, and aromatic solvents. Haloalkanes such as methylene chloride, chloroform, carbon tetrachloride and the like or ethers such as diethyl ether, tetrahydrofuran, dioxane and the like or aromatic solvents such as toluene, xylene and the like. 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.
3

EXAMPLE
Preparation of 2-Cyano-N, N-Diethyl acetamide
Charged tetrahydrofuran (235 Litre) followed by dicyclohexylcarbodiimide (85 Kg), N,N-diethyl amine (34 Kg) and cyano acetic acid (36 Kg). Reflux the reaction mixture for 6-9 hour. After completion of reaction, reaction mixture was concentrated and residue treated with mixture of water (275 Litre) and acetic acid (12 Litre). Undissolved dicylohexylurea was removed through Alteration and filtrate was extracted with dichloromethane. Dichloromethane layer was concentrated to get the 2-Cyano-N,N-Diethyl acetamide as oil. Yield: 55.2 Kg.
4

WE CLAIM:
1. A process for the preparation of 2-cyano-N,N-diethylacetamide
intermediate useful in preparation of Entacapone, wherein the said
process comprises of
a) reacting N,N-diethyl amine with cyano acetic acid in presence of dicyclohexylcarbodiimide using organic solvent,
b) isolating the 2-cyano-N,N-diethylacetamide from reaction mass thereof.

2. A compound obtained according to claim 1 used in the synthesis of entacapone.
3. A process of claim 1 wherein the organic solvent is tetrahydrofuran.
4. Use of intermediate prepared according to process of claim 1 for the preparation of entacapone.

Dated this 30th day of October, 2006

For Wockhardt Limited

5

(Mandar Kodgule) Authorized Signatory

Documents:

1792-mum-2006-claim.pdf

1792-MUM-2006-CLAIMS(AMENDED)-(27-12-2013).pdf

1792-MUM-2006-CLAIMS(MARKED COPY)-(27-12-2013).pdf

1792-mum-2006-claims.doc

1792-mum-2006-correspondance-received.pdf

1792-mum-2006-description (complete).pdf

1792-MUM-2006-FORM 18(19-10-2010).pdf

1792-MUM-2006-FORM 2(TITLE PAGE)-(30-10-2006).pdf

1792-mum-2006-form-1.pdf

1792-mum-2006-form-2.doc

1792-mum-2006-form-2.pdf

1792-MUM-2006-REPLY TO EXAMINATION REPORT(27-12-2013).pdf

« Previous Patent

Next Patent »

Patent Number

264147

Indian Patent Application Number

1792/MUM/2006

PG Journal Number

50/2014

Publication Date

12-Dec-2014

Grant Date

09-Dec-2014

Date of Filing

30-Oct-2006

Name of Patentee

WOCKHARDT LTD

Applicant Address

WOCKHARDT TOWERS, BANDRA-KURLA COMPLEX, BANDRA(EAST), MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	YADAV RAM PRASAD	VILLAGE : LAKHANPUR, POST MAWAIYA, DIST. MIRZAPUR- 231001,
2	SHAIKH ZAKIR GAFOOR	Village & Post - Warigaon, Tehsil-Kopargaon, Dist.Ahmednagar- 413708
3	SIDDIQUI MOHAMMED JAWEED MUKARRAM	H.No. 4-8-65, Nawabpura, Near Nagina Masjid, Aurangabad -431 001

PCT International Classification Number

C07C255/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA