Title of Invention

A PROCESS FOR THE PREPARATION OF HIGHLY PURE (E) N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY- 5-NITRO PHENYL) ACRYLAMIDE (ENTACAPONE)

Abstract process for the preparation of highly pure (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide (Entacapone). It comprises condensing3,4-dihydroxy-5-nitro benzaldehyde with N,N-diethyl cyano acetamide in an organic solvent in the presence of an organic base and an acid under reflux conditions followed by distilling off the solvent under vacuum and treating the residue with a lower aliphatic carboxylic acid at 40 - 8O0C. The resulting residue is extracted with a chlorinated solvent and the solvent is distilled off under vacuum. The resulting residue is extracted with an organic solvent to obtain crude N,N-diethyl-2-cyano-3-3,4-dihydroxy-5-nitrophenyl)acrylamide. The crude product N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide formed is treated with a mixture of organic alcohol and organic acid in the molar ratio of the crude product to organic alcohol 1:5 to 15 and crude product to organic acid 1:1 to 3 under reflux conditions.
Full Text THE PATENTS ACT, 1970
(39 of 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
A process for the preparation of highly pure (E) N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide (Entacapone)
INVENTORS
Name : Tarur Venkatasubramanian Radhakrishnan
Address : A-301, Vaishali Towers, B R Road, Mulund (West), Mumbai 400080,
Maharashtra, India
Nationality : an Indian National
Name : Sathe Dhananjay Govind
Address : 202/A-l, Golden Park, LBS Marg, Panchpakhadi, Thane 400602
Maharashtra, India
Nationality : an Indian National
Name : Bhise Nandu Baban
Address : 402, Pearl Bldg, Nirmal Life Style, LBS Marg, Mulund (W)
Mumbai 400080, Maharashtra, India
Nationality : an Indian National
Name : Naidu Avinash Venkatraman
Address : C-3, Tirupati Balaji Aparments, M G Road, Vishnu Nagar
Dombivli, Thane 421 202, Maharashtra, India
Nationality : an Indian National
Name : Aher Umesh Parashram
Address : Flat No 3, B-Wing, Vanashri Shrushti, Khadakpada, Kalyan 421 301,
Maharashtra, India
Nationality : an Indian National
Name : Patil Sachin Shivaji
Address : Sakharam Niwas, Naik wadi, Kon, Kalyan - 427304, Maharashtra, India
Nationality : an Indian National
APPLICANTS
Name: USV LIMITED,
Address : BSD Marg, Govandi, Mumbai 400088, Maharashtra, India
Nationality : an Indian Company
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of this invention and the
manner in which it is to be performed:

Technical Field
The invention relates to a process for the preparation of highly pure (E) N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide (Entacapone) of the formula I:

N02
Formula I Background and Prior Art
US 4,963, 590 describes catechol derivatives including N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide as being useful in the treatment of diseases like central or peripheral nervous system disorders, Parkinson's disease or parkinsonian disorders. Process for the preparation of N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide comprises condensation of 3,4-dihydroxy-5-nitro benzaldehyde and N,N- hydrochloric diethyl cyanoacetamide in the presence of piperidine-acetate in dry ethanol (Example 100). The condensation reaction and yield are reported to be very long (overnight) and 73%, respectively. The process is not, therefore, commercially viable for industrial scale production of entacapone and economical.
US 5,135,950 reports that N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-
nitrophenyl)acrylamide is a mixture of two geometric isomers namely E- and Z-isomers (70 - 80% E-isomer and 30-20% Z-isomer) of the following formulae I and II, respectively :


Formula I


Formula II
This patent relates to a stable and crystallographically essentially pure polymorphic
form A of E- isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-
nitrophenyl)acrylamide obtained by purifying the crude product by recrystallisation from lower aliphatic carboxylic acid such as formic acid or acetic acid with catalytic amount of hydrochloric or hydrobromic acid. The purification procedure increases the process duration and renders it commercially unviable for industrial scale production.
WO 2005/063693 describes a process for the preparation of entacapone using 3-alkoxy-4-hydroxy-5-nitrobenzaldehyde.
WO 2005/070881 describes a process for the production of (E)-entacapone polymorphic form A. 3,4Dihydroxy-5-nitrobenzaldehyde is condensed with N,N-diethylcyanoacetamide in the presence of a base like piperidine in alcohol like isopropanol. The reaction mixture is poured into a mixture of aqueous ethyl acetate and water followed by pH adjustment with acetic acid. The product is separated from the organic layer to yield (E) isomer of entacapone having 99.7% purity. The condensation reaction itself is reported to be quite long (10 - 15 hours).


Novel polymorphic forms C and D of entacapone are disclosed in WO2005/066117. 3,4Dihydroxy-5-nitrobenzaldehyde is condensed with N,N-diethylcyanoacetamide in the presence of a base like piperidine in isopropanol followed by addition of acetic acid and crystallization with a mixture of alcohols to obtain polymorphic form C. Polymorphic form D is obtained from form C or form A by dissolution in solvents such as polar organic solvents aliphatic alcohols or sulfoxides.
WO 2005/063695 and WO 2005/063696 also disclose novel polymorphs C, D and E of Entacapone by crystallisation.
Objects of the Invention
An object of the invention is to provide a process for the preparation of (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide, which gives the product in high purity and good yield.
Another object of the invention is to provide a process for the preparation of (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide, which reduces the process duration and is simple, easy and convenient to carry out and is commercially viable and economical.
Another object of the invention is to provide (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide in very high purity and good yield.
Detailed Description of invention
According to the invention there is provided a process for the preparation of highly
pure (E)-N,N-diethyl-2-cyano-3 -(3,4-dihydroxy-5 -nitrophenyl) acrylamide
(Entacapone) of the formula I



Formula I
comprising
i) condensing 3,4-dihydroxy-5-nitro benzaldehyde with N,N-diethyl
cyano actinide in an organic solvent in the presence of an organic base and an acid under reflux conditions followed by distilling off the solvent under vacuum and treating the residue with a lower aliphatic carboxylic acid at 40 - 80°C;
ii) extracting the residue with a chlorinated solvent and distilling off the solvent under vacuum;
iii) extracting the residue with an organic solvent to obtain crude N,N-diethyl-2-cyano-3-3,4-dihydroxy-5-nitrophenyl)acrylamide; and
iv) treating the crude product N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide with a mixture of organic alcohol and organic acid in the molar ratio of the crude product to organic alcohol 1:5 to 15 and crude product to organic acid 1:1 to 3 under reflux conditions.
The organic solvent used in step (i) is selected from lower aliphatic alcohol like methanol, ethanol, n-propanol, isopropanol or mixtures thereof or is preferably ethanol. The organic base used in step (i) is selected from piperidine morpholine, N-methyl morpholine or pyrrolidine or is preferably piperidine. The acid used in step (i) is organic acid selected from lower aliphatic carboxylic acid or inorganic acid selected from sulfuric acid or hydrochloric acid. The lower aliphatic carboxylic acid used in step (i) is preferably acetic acid or formic acid. Preferably, the residue in step (i) is treated at 65°C.


The chlorinated solvent used in step (ii) is selected from methylene chloride or chloroform or is preferably methylene chloride.
The organic solvent used in step (iii) is selected from polar and non-polar solvents such as alcohols, ketones, esters or mixtures thereof. The organic solvent is preferably ester selected from methyl acetate, ethyl acetate, propyl acetate or mixtures thereof or is preferably ethyl acetate.
The mixture of organic alcohol and organic acid used in step (iv) is selected from aliphatic alcohol like methanol, ethanol, n-propanol or isopropanol and lower aliphatic carboxylic acid like acetic acid, formic acid, methane sulfonic acid or trifluoro acetic acid or is preferably, methanol and acetic acid.
Preferably, the molar ratio of the crude product to organic alcohol is 1:8 and the crude product to organic acid is 1:2.
The product namely N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide is recovered from the reaction mixture of step (iv) by filtering the reaction mixture, precipitating the product from the filtrate by gradually cooling the filtrate at 0-30°C preferably 10 - 50° C and drying the precipitate at 60 - 70° C preferably in an electric oven.
The process of the invention affords (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide in high purity ( > 99.8%) and in good yield (about 53.68%) with Z- isomer content The following experimental example is illustrative of the invention but not limitative of the scope thereof:
Example 1
A mixture of 3,4-dihydroxy-5-nitro benzaldehyde (500g), N,N-diethyl cyano acetamide (575ml), acetic acid (375ml) and piperidine (500ml) in ethanol (4.51) were refluxed for 6 hrs. Ethanol was distilled off under vacuum and 1.5 1 of formic acid


was added to the residue at 65 C and stirred for 30 mins at 65 C. The reaction mixture was cooled to R T and charged with methylene dichloride. The organic layer was separated and washed twice with 2 x 3.5 1 water. Methylene dichloride was distilled off under vacuum from the organic layer and the residue was treated with ethyl acetate 1.25 1. The yellow solid was filtered out from the solvent, washed with 1.25 1 ethyl acetate and dried in an electric oven at 60-70° C to obtain crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide.
Yield of crude entacapone 495g (59.63 %), Purity 99.2++ Z- isomer 0.5%
The crude product (495 g), methanol (3960ml) and acetic acid (990ml) were refluxed for lhr. The clear solution was filtered and the product was precipitated by gradually cooling the filtrate to 10-15° C. The solid was filtered out, washed twice with cold ethyl acetate (2 x 990 ml) at 15°C_and dried in an electric oven at 60-70° C.
Yield of entacapone based on the crude product 445.5g (90 %). Purity 99.8%. Z-isomer 0.02 %


We claim
1. A process for the preparation of highly pure (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide (Entacapone) of the formula I

N02
Formula I
comprising
i) condensing 3,4-dihydroxy-5-nitro benzaldehyde with N,N-diethyl
cyano acetamide in an organic solvent in the presence of an organic base and an acid under reflux conditions followed by distilling off the solvent under vacuum and treating the residue with a lower aliphatic carboxylic acid at 40 - 80°C;
ii) extracting the residue with a chlorinated solvent and distilling off the solvent under vacuum;
iii) extracting the residue with an organic solvent to obtain crude N,N-diethyl-2-cyano-3-3,4-dihydroxy-5-nitrophenyl)acrylamide; and
iv) treating the crude product N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide with a mixture of organic alcohol and organic acid in the molar ratio of the crude product to organic alcohol 1:5 to 15 and crude product to organic acid 1:1 to 3 under reflux conditions.
2. The process as claimed in claim 1, wherein the organic solvent used in step (i) is selected from lower aliphatic alcohol like methanol, ethanol, n-propanol, iso-propanol or mixtures thereof or is preferably ethanol.


3. The process as claimed in claim 1, wherein organic base used in step (i) is selected from piperidine, morpholine, N-methyl morpholine or pyrrolidine or is preferably piperidine and the acid used in step (i) is selected from lower aliphatic carboxylic acid like acetic acid or formic acid or inorganic acid selected from hydrochloric acid or sulphuric acid or is preferably acetic acid or formic acid.
4. The process as claimed in claim 1, wherein the residue in step (i) is treated 65° C.
5. The process as claimed in claim 1, wherein the chlorinated solvent used ins tep (ii) is selected from chlorofom or methylene dichloride or is preferably methylene dichloride.
6. The process as claimed in claim 1, wherein the organic solvent used in step (iii) is selected from polar and non-polar solvents such as alcohols, ketones or esters or mixtures thereof or is preferably ester, preferably ethyl acetate.
7. The process as claimed in claim 1 wherein the mixture of organic alcohol and organic acid used in step (iv) is selected from aliphatic alcohol like methanol, ethanol, n-propanol or iso-propanol and lower aliphatic carboxylic acid like acetic acid, formic acid or trifluoro acetic acid or is preferably methanol and acetic acid.
8. The process as claimed in claim 1, wherein molar ratio of the crude product to alcohol is 1:8 and the crude product to organic acid is 1:2.


9 N,N-diethyl-2-cyano-3-)3,4-dihydroxy-5-nitrophenyl) acrylamide of the
formula 1

N02
Formula I
in high purity (> 99.8%) and in good yield (53.68%) prepared by the process as claimed in claim 1.




ABSTRACT
A process for the preparation of highly pure (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide (Entacapone). It comprises condensing 3,4-dihydroxy-5-nitro benzaldehyde with N,N-diethyl cyano acetamide in an organic solvent in the presence of an organic base and an acid under reflux conditions followed by distilling off the solvent under vacuum and treating the residue with a lower aliphatic carboxylic acid at 40 - 80°C. The resulting residue is extracted with a chlorinated solvent and the solvent is distilled off under vacuum. The resulting residue is extracted with an organic solvent to obtain crude N,N-diethyl-2-cyano-3-3,4-dihydroxy-5-nitrophenyl)acrylamide. The crude product N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide formed is treated with a mixture of organic alcohol and organic acid in the molar ratio of the crude product to organic alcohol 1:5 to 15 and crude product to organic acid 1:1 to 3 under reflux conditions.

Documents:

456-mumnp-2008-abstract.doc

456-mumnp-2008-abstract.pdf

456-MUMNP-2008-CLAIMS(AMENDED)-(2-8-2011).pdf

456-MUMNP-2008-CLAIMS(AMENDED)-(26-11-2009).pdf

456-mumnp-2008-claims.doc

456-mumnp-2008-claims.pdf

456-mumnp-2008-correspondence(11-6-2008).pdf

456-MUMNP-2008-CORRESPONDENCE(26-11-2009).pdf

456-MUMNP-2008-CORRESPONDENCE(30-7-2008).pdf

456-mumnp-2008-correspondence-received.pdf

456-mumnp-2008-description (complete).pdf

456-mumnp-2008-form 1(11-6-2008).pdf

456-mumnp-2008-form 13(11-6-2008).pdf

456-MUMNP-2008-FORM 18(30-7-2008).pdf

456-MUMNP-2008-FORM 2(TITLE PAGE)-(2-8-2011).pdf

456-MUMNP-2008-FORM 3(26-11-2009).pdf

456-MUMNP-2008-FORM 3(4-3-2011).pdf

456-mumnp-2008-form-1.pdf

456-mumnp-2008-form-2.doc

456-mumnp-2008-form-2.pdf

456-mumnp-2008-form-3.pdf

456-mumnp-2008-form-5.pdf

456-MUMNP-2008-OTHER DOCUMENT(4-3-2011).pdf

456-MUMNP-2008-PETITION UNDER RULE 137(2-8-2011).pdf

456-MUMNP-2008-REPLY TO EXAMINATION REPORT(2-8-2011).pdf

456-MUMNP-2008-REPLY TO EXAMINATION REPORT(4-3-2011).pdf


Patent Number 249020
Indian Patent Application Number 456/MUMNP/2008
PG Journal Number 39/2011
Publication Date 30-Sep-2011
Grant Date 22-Sep-2011
Date of Filing 11-Mar-2008
Name of Patentee USV LIMITED
Applicant Address BSD MARG, GOVANDI MUMBAI-400088,
Inventors:
# Inventor's Name Inventor's Address
1 TARUR VENKATASUBRAMANIAN RADHAKRISHNAN A-301, VAISHALI TOWERS, B R ROAD MULUND(WEST), MUMBAI-400080.
2 SATHE DHANANJAY GOVIND 202/A-1, GOLDEN PARK, L B S MARG PANCHPAKHADI, THANE 400602.
3 BHISE NANDU BABAN 402, PEARL BLDG, NIRMAL LIFE STYLE L B S MARG, MULUND(W) MUMBAI-400080.
4 NAIDU AVINASH VENKATRAMAN C-3, TIRUPATI BALAJI APARMENTS M G ROAD, VISHNU NAGAR DOMBIVLI, THANE 421202.
5 AHER UMESH PARASHRAM FLAT NO 3, B-WING, VANASHRI SHRUSHTI KHADAKPADA, KALYAN 421301.
6 PATIL SACHIN SHIVAJI SAKHARAM NIVAS, NAIK WADI KON, KALYAN-427304.
PCT International Classification Number C07C253/30
PCT International Application Number PCT/IN05/00363
PCT International Filing date 2005-11-09
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA