Title of Invention	IMPROVED AND SIMPLIFIED PROCEDURE FOR THE PREPARATION OF (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE
Abstract	ABSTRACT IMPROVED AND SIMPLIFIED PROCEDURE FOR THE PREPARATION OF (E)N,N-DlETHYL-2-CYANO-3(3.4-DIHYDROXY-5- NITROPHENYDACRYLAMIPE Process for the preparation of N'-N-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide having the structure of Formula -IV by condensing 3,4-dihydroxy5-nitrobenzaldchdyc with N,N-diethyl cyanoacetamide in toluene in the presence of a catalyst piperadine acetate at reflux temperature for a period of 5-6 hours; and isolating (E) isomer of N.N-diethyl-2-cyano-3-(3.4-dihydroxy-5-nitrophenyI) acrylamide after removing the solvent completely by distillation at temperature of between 60-90"C followed by acidification to pH 0.5 to 1.5 preferably 1.0. The isolated {E)-N,n-diethyl-2-cyano-3(3.4-dihydroxy-5-nitrophenyl) acrylamide is substansially free from Z-isomer, preferably NM T 0.20%. 14

Title of Invention

IMPROVED AND SIMPLIFIED PROCEDURE FOR THE PREPARATION OF (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE

Abstract

ABSTRACT IMPROVED AND SIMPLIFIED PROCEDURE FOR THE PREPARATION OF (E)N,N-DlETHYL-2-CYANO-3(3.4-DIHYDROXY-5- NITROPHENYDACRYLAMIPE Process for the preparation of N'-N-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide having the structure of Formula -IV by condensing 3,4-dihydroxy5-nitrobenzaldchdyc with N,N-diethyl cyanoacetamide in toluene in the presence of a catalyst piperadine acetate at reflux temperature for a period of 5-6 hours; and isolating (E) isomer of N.N-diethyl-2-cyano-3-(3.4-dihydroxy-5-nitrophenyI) acrylamide after removing the solvent completely by distillation at temperature of between 60-90"C followed by acidification to pH 0.5 to 1.5 preferably 1.0. The isolated {E)-N,n-diethyl-2-cyano-3(3.4-dihydroxy-5-nitrophenyl) acrylamide is substansially free from Z-isomer, preferably NM T 0.20%. 14

Full Text	c c c c AT c I I I ■ i { FIELD OF THE INVENTION: The present invention relates to an improved process for the prepanition of ihe compound {E) N.N-DIETHYL-2-CYANO-3(3.4-DIHYDROXY-5-NlTROPHCNYL) ACRYLAMIDE having the structure of Formula-IV. Particularly the invention relates to a process for the preparation of (C) N.N-DlETHYL-2-CYANO-3(3.4-DIHYDROXY-5-NlTR0PHENYL)ACRYLAMlDE which is efficient and Industrial advantageous. The said compound of the present invention is known as Hntacapone. BACKGROUND OF THE INVENTION: Catechol-0-methyltransferase (COMT) one of the important enzyme involved in metabolism of catecholamines, Highest activity was found in the liver, kidney and intestine even though it is present both in periphery and the central nervous system of most of the tissues. COMT a important enzyme in the extra neuronal inaclivation of drugs with catechol structure and catecholasmines, GB 8.727854 teaches (H) N.N-DIETHYL-2-CYANO-3(3.4-DIHYDROXY-5-NITROPHENYDACRYLAMIDE f ENf ACAPONE] for the treatment of Parkinson's disease as a potential inhibitor of catechol-0-methyl- transferase (COMT) enzyme. US patent number 4.963.590 (1990) and GB 2200109 (1987) describes the condensation of 3,4-dihydroxy-5-nitrobenzaldehyde with N,N-diethyl cyano acetamide using ethano! 2 media in presence of catahsl piperidine acetate [scheme 11 and isolation of mixture of E (70 to 80%) and Z( 30-20%) isomers of Hntacaponc, US patent number 5,131.950 (1992) reported the structure of E and Z isomer along with polymorphic forms A and B and claims the process for the isomerization of Z isomer also conversion of unstable polymorphic form B to form A [scheme 2] J Intemaiional publication number WO 2005/063693 claims the improved process for the preparation of Rntacaponc startiiiji from 3-alkoxy-4-hydroxy-5-nilro benzaldehyde condensation with other intermediate N,N-diethylaminocyanoacetatTiide in presence of mild acid catalyst followed by de- alkylation [scheme-j]. Another application WO/2005 070881 claimed for an efficient procedure for the preparation of (E) Entacapone stable polymorphic Form A by simple extracfion of E isomer from the mixture of E and Z isomer from aqueous acidic media at pH 3,5 to 4.0. 4 The process of innovator is disadvantageous in that it requires isolation of mixture of E and Z isomers and further treatment with formic acid or acetic acid in presence of hydrobromic acid to get pure H isomer. ■fhe above process requires longer reaction times and uses hazardous and corrosive acids as a solvent for purification. f'urther the innovators process involves the disadvantage of isolation of mixture of isomers and polymorphic forms and needs additional purification to get a stable polymorph A and desired 0 isomer (pure enough). Lengthy process (liming) and isolation of mixture isomers are the major disadvantages for this process. To overcome this 5 disadvantage other process were claimed with modifications involving more either starting from costl> /excess raw material or using additional solvents with lengthy reaction timings. Process starting from j-alkox\-4-hydroxy -5-nitro pyridine, starting from expensive 3-ethoxy compound is not economically feasible. This process also involves usage of hazardous chlorinated chemical like aluminium chloride and pyridine in final stage and also additional solvents like methylene chloride and Pyridine. It's not advisable to use solvents like pyridine is final stages and it's difficult to remove completeh from ihe product where residual solvents presence is critical for a high dosage drugs litce Entacapone. Reaction time also too longer like inventors process. Process claiming extraction of E isomer from the reaction mixture also involved excess quantities of one of the intermediate (cyano acetamide) almost double the mole ratio and longer reaction hours. it is therefore an object of the present invention to overcome the drawbacks of the processes of prior art and to provide a simple and efilcient process for producing stable polymorph A with pure R isomer substantially free from Z-isomer. SUMMARY OF INVENTION: Thus according to ihc present invention there is provided an improved process for the preparation of the compound (E) N.N-DIETHYL-2-CYANO-3(3,4-DlHYDROXY-5-NITROPHENYDACRYLAMiDE having the structure of Formula -!V comprising: effecting condensation ol' 3.4-dihydroxy-?-nitro benzaldehyde with N.N-diethyl cyanoacetaniide in presence of piperidine acetate in an organic solvent : and isoladng pure E isomer from acidic alcoholic solution pH around 1.0 with Z-isomcr NMT 0.2%. The product isolated from the present process is pure polymorphic Ibrm A and Z- isomer NMT0.2%by HPI.C. DETAILED DESCRIPTION OF THE INVENTION The process of the present invention for the preparation of the compound (E) N.N- DIHTHYL-2-CYANO-3(3.4-D[KYDROXY-5-NrrROPHKNYL)ACRYLAMlDE is shown below in Reaction Scheme IV below: The organic solvent used in the step of condensation is selected from toluene and x;!ene. For the purpose of the process, the preferred soUent is toluene. According lo a preferred aspect the step of condensation is carried out in presence of catalyst. The catalyst is selected from peperidine acetate, pyridine acetate. Para toluene sulphonic acid. Preferably, the catalyst is piperidine acetate. 7 The condensation reaction is preferably carried out at reflux temperature. Preferably, the reflux temperature is 100-120 "C. and most preferably between 108-112 "'C. The reaction period i^ between 4 to 8 hours, preferably between 5 to 6 hours. Also, in the step of isolation the reaction mass is acidified using hydrochloric acid or sulphuric acid although hydrochloric acid is preferred. Further, the reaction mass is refluxed in presence of aqueous hydrobromic acid at reflux temperature of between 108-112 "C for about 1-4 hours and preferably 1.5 to 2.0 hours. in the step of isolation, in the process of the invention the solvent is removed completely by distillation. Preferably, the solvent is distilled under vacuum and the distillation is caiTied out at temperatures between 60-90 '^C. preferably 70-80 ''C. Further, in the step of isolation a protic solvent is added, fhe said protic solvent is selected from methanol and ethanol, preferably methanol. In the said step of isolation the solvent is removed completely by distillation. Preferably the solvent is distilled under vacuum and at temperatures between 60-^0 C, preferably 70-80'C. "fhe solvent is concentrated to about 50% by vacuum distillation. The reaction mass is acidified to pH 0.5 to 1.5 preferably 1.0 by the use of hydrochloride acid or sulphuric acid preferably hydrochloric acid. In the step of isolation the (H)-N,n-diethyl-2-cyano-3(j,4-dihydroxy-5- nitrophenyl) acrylamide that is isolated is mixture of E and Z isomer, [he said isolated (Ej-N,n-diethyl-2-cyano-j(3.4-dihydroxy-5- nitrophenyl) acrylamide is rccryslaliscd in solvent selected from methanol. eth\ 1 acetate or a mixture of toluene and methanol. The finally recrystallizcd (E)-N.n-diethyl-2-cyano-3{3,4-dihydroxy-5-nitrophenyl) acrylamide is substantially free from Z-isomer. preferably NMT 0.20%. Example 1 : Preparation of (E) N.N-dietliy]-2-cyano-3-(3.4-dihydroxy-5-nitro) acrylamide [Entacapone] Charge 3.4-dihydroxy-5-nitro benzaldehdye 100 Kg. followed by N'.N-diethyl-2-eyano acetamide 92 Kg in to solvent Toluene, Charge piperidinc acetate prepared from 30 kg piperidine and 35 Kg acetic acid. Reaction mass was heated to reflux (108-112 "C), maintained at reflux with azeotropic distillation (108-112 "C) for 6 Hours and water was collected. Alter reaction completion Toluene was removed completely under vacuum below 80 " C, Mass was cooled to 50-55"C methanol (500 its) was charged in to the above mass under stirring. To this clear solution carbon was added maintained at 55-60"^ foe 1 hour. Mass was filtered through hyflow bed in hot condition. Filtrate was cooled to 10 "C. pM of the filtrate adjusted to 1.0 to 2,0 with Con HCI. Mass was cooled to 5-l0" C and product (E) -entacapone with Z-isomer content NMT 0.20% is isolated, dried at 70-80C was found to be stable polymorph A \\ith melting point 162-164"C. Example 2 : Preparation of {E) N.N-dieth>l-2-cyano-j-(3.4-dih\dyoxy-5-nitro) acvylnmide [EntacaponcJ Charge 3.4-dihydroxy-5-nitro benzaldehdye 100 gms, followed by N,N-diethyl-2-cyano acetantidc 95 gms in lo solvent Toluene. Charge piperidine acetate prepared from 30 gm piperidine and 35 gm acetic acid. Reaction mass was heated to reflux (108-112 C), maintained at rellux with azeotropic distillation (108--112"C) for 6 Hours and water was collected. After reaciion completion 10 ml aqueous HBr (48%) is added and maintained at reflux temperature, Fokiene was removed completely under vacuum below 80 C. Mass was cooled to 50-55"C methanol (500 Its) was charged in to the above mass under stirring, fo this clear solution carbon was added maintained at 55-60 C for I hour. Mass was nitcred through hyflow bed in hot condition. Filtrate was concentrated by vacuum distillation. Mass was cooled to 10 "C. Con UCl is added and further cooled to -5 *^C. Precipitated mass was maintained at 0 to -5C for 2 hours and 150 gms product mixture of (E) and Z-isomer is isolated, dried at 70 to 80"C . This mixture of E and Z isomer is re-crystallized in methanol or ethyl acetate resulting E -entacapone with Z-isomer NMT 0.20%. polymorph A. The advantages of the process of the present invention are the following: 1) Reduction of reaction time by increasing the temperature of the reaction mass and driving the reaction last by removing water formed in the reaction azeotropically. Reaction time was reduced to 6 hours from maximum of 100 hours and minimum of 20 hours of prior art. 2) Avoiding use of excess amount of one of the intermediate as also hazardous chemicals and number of solvents. 3) It employs simple modifications of pH and isolating from the solvent alcohol preferably from methanol. 4) It avoids additional step of converting the mixture of E and Z isomer to desired E i.somer using highly acidic medium. 10 CLAIMS 1. Process for the pieparalion of N.N-diet!wl-2-cyano-3(3.4-dihydroxy-S- nitrophenyl)acryianiide ha\ing the siructure of Formula -IV i) effecting condensation of j.4-dihydroxy -5-nitro benzaldehyde with N.N- diethyl cyanoacetamide in presence of catalyst in an organic solvent selected from toluene and Xylene ; ii) azeotropic distillation; and iii) isolating (Ii) isomer of N.N-diethyl-2-cyano-3-(3.4-dihydroxy-5- nitrophenyl) acrylamide from acidic alcoholic solution of pH around 0.5 to 2 with 2-isomer NMT 0.2%. 2. fhe process according to claim I wherein the solvent is preferably toluene. 3. The process according to claim 1. wherein the catalyst is selected from piperidine acetate, pyridine acetate, and Para toluene sulphonic acid. 4. The process according to claim 3. wherein the catalyst is preferably piperidine acetate, II 5. The process according to claim I. wherein in step (i) condensation is carried out al reflux temperalure. 6. The process according to claim 5 wherein the reflux temperature is 100-120 "C . and preferably between 108-112 "C. 7. The process according to claim 1, wherein the reaction lime in step (i) is preterably between 4 to 8 hours, and more preferably between 5 to 6 hours. 8. The process according to claim 5, wherein the reaction mass is further rctluxed in presence of aqueous mineral acid. 9. The process according to claim 8 wherein the aqueous mineral acid is hydrobromic acid or hydrochloric acid. 10. The process according to claim 8 wherein the reflux temperature is preferably 108-112 "C for a period of 1-4 hours and more preferably 1.5 to 2.0 hours. 11. The process according to claim 1. wherein in step (iii) the solvent is removed completely by distillation. 12. fhe process according to claim 1. wherein in step (iii) the solvent is distilled under vacuum. 13. Vhe process according to claim 1 wherein in step (iii) the soivenl is distilled at preferably temperature of hetw-een 60-90"C. and more preferably 70-80"C. 14. The process according to claim 1, wherein in step (iii) a protic solvent is added, 15. The process according to claim 13. wherein the protic solvent selected from methanol and ethanol and preferably methanol. 16. 'I'he process according to claim 14. wherein the sohent is eoncenlrated to 50% by vacuum distillation. 17. The process according to claim 1, wherein in step (iii) the reaction mass is acidified. 18. The process according to claim 17 wherein the acidification is effected with an acid selecved from hydrochloric acid and sulphuric acid, preferably hydrochloric acid. 19. The process according to claim I, wherein in step (iii) the reaction mass is acidified to pH 1.0, 20. The process according to claim 1. step (iii) wherein the isolated (K)-N,n-dielhyl-2-cyano-3(3.4-dihydroxy-5- nitrophenyl) acrylamide is mixture of E and Z isomer, 21. The process according to claim 20 wherein the isolated (E)-N,n-diethyl-2-cyano-3(3.4-dihydroxy-5- nitrophenyl) acrylamide is mixture of E and Z isomer is recrystalised in solvent. 22. The proces.4 according to claim 21 wherein the solvent for recrystallisalion is methanol or ethyl acetate or mixture of toluene and methanol. Dated this 5'" day of February 2009. 1

Full Text

c c c
c
AT
c
I I
I
■
i {

FIELD OF THE INVENTION:
The present invention relates to an improved process for the prepanition of ihe compound
{E) N.N-DIETHYL-2-CYANO-3(3.4-DIHYDROXY-5-NlTROPHCNYL)
ACRYLAMIDE having the structure of Formula-IV. Particularly the invention relates to a process for the preparation of (C) N.N-DlETHYL-2-CYANO-3(3.4-DIHYDROXY-5-NlTR0PHENYL)ACRYLAMlDE which is efficient and Industrial advantageous. The said compound of the present invention is known as Hntacapone.

BACKGROUND OF THE INVENTION:
Catechol-0-methyltransferase (COMT) one of the important enzyme involved in metabolism of catecholamines, Highest activity was found in the liver, kidney and intestine even though it is present both in periphery and the central nervous system of most of the tissues. COMT a important enzyme in the extra neuronal inaclivation of drugs with catechol structure and catecholasmines,
GB 8.727854 teaches (H) N.N-DIETHYL-2-CYANO-3(3.4-DIHYDROXY-5-NITROPHENYDACRYLAMIDE f ENf ACAPONE] for the treatment of Parkinson's disease as a potential inhibitor of catechol-0-methyl- transferase (COMT) enzyme.
US patent number 4.963.590 (1990) and GB 2200109 (1987) describes the condensation of 3,4-dihydroxy-5-nitrobenzaldehyde with N,N-diethyl cyano acetamide using ethano!
2

media in presence of catahsl piperidine acetate [scheme 11 and isolation of mixture of E (70 to 80%) and Z( 30-20%) isomers of Hntacaponc,

US patent number 5,131.950 (1992) reported the structure of E and Z isomer along with polymorphic forms A and B and claims the process for the isomerization of Z isomer also conversion of unstable polymorphic form B to form A [scheme 2]
J

Intemaiional publication number WO 2005/063693 claims the improved process for the preparation of Rntacaponc startiiiji from 3-alkoxy-4-hydroxy-5-nilro benzaldehyde condensation with other intermediate N,N-diethylaminocyanoacetatTiide in presence of mild acid catalyst followed by de- alkylation [scheme-j]. Another application WO/2005 070881 claimed for an efficient procedure for the preparation of (E) Entacapone stable polymorphic Form A by simple extracfion of E isomer from the mixture of E and Z isomer from aqueous acidic media at pH 3,5 to 4.0.
4

The process of innovator is disadvantageous in that it requires isolation of mixture of E and Z isomers and further treatment with formic acid or acetic acid in presence of hydrobromic acid to get pure H isomer.
■fhe above process requires longer reaction times and uses hazardous and corrosive acids as a solvent for purification.
f'urther the innovators process involves the disadvantage of isolation of mixture of isomers and polymorphic forms and needs additional purification to get a stable polymorph A and desired 0 isomer (pure enough). Lengthy process (liming) and isolation of mixture isomers are the major disadvantages for this process. To overcome this
5

disadvantage other process were claimed with modifications involving more either starting from costl> /excess raw material or using additional solvents with lengthy reaction timings.
Process starting from j-alkox\-4-hydroxy -5-nitro pyridine, starting from expensive 3-ethoxy compound is not economically feasible. This process also involves usage of hazardous chlorinated chemical like aluminium chloride and pyridine in final stage and also additional solvents like methylene chloride and Pyridine. It's not advisable to use solvents like pyridine is final stages and it's difficult to remove completeh from ihe product where residual solvents presence is critical for a high dosage drugs litce Entacapone. Reaction time also too longer like inventors process.
Process claiming extraction of E isomer from the reaction mixture also involved excess quantities of one of the intermediate (cyano acetamide) almost double the mole ratio and longer reaction hours.
it is therefore an object of the present invention to overcome the drawbacks of the processes of prior art and to provide a simple and efilcient process for producing stable polymorph A with pure R isomer substantially free from Z-isomer.
SUMMARY OF INVENTION:
Thus according to ihc present invention there is provided an improved process for the preparation of the compound (E) N.N-DIETHYL-2-CYANO-3(3,4-DlHYDROXY-5-NITROPHENYDACRYLAMiDE having the structure of Formula -!V comprising:
effecting condensation ol' 3.4-dihydroxy-?-nitro benzaldehyde with N.N-diethyl
cyanoacetaniide in presence of piperidine acetate in an organic solvent : and
isoladng pure E isomer from acidic alcoholic solution pH around 1.0 with Z-isomcr NMT
0.2%.

The product isolated from the present process is pure polymorphic Ibrm A and Z- isomer NMT0.2%by HPI.C.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention for the preparation of the compound (E) N.N-
DIHTHYL-2-CYANO-3(3.4-D[KYDROXY-5-NrrROPHKNYL)ACRYLAMlDE is
shown below in Reaction Scheme IV below:

The organic solvent used in the step of condensation is selected from toluene and x;!ene. For the purpose of the process, the preferred soUent is toluene.
According lo a preferred aspect the step of condensation is carried out in presence of catalyst. The catalyst is selected from peperidine acetate, pyridine acetate. Para toluene sulphonic acid. Preferably, the catalyst is piperidine acetate.
7

The condensation reaction is preferably carried out at reflux temperature. Preferably, the reflux temperature is 100-120 "C. and most preferably between 108-112 "'C. The reaction period i^ between 4 to 8 hours, preferably between 5 to 6 hours. Also, in the step of isolation the reaction mass is acidified using hydrochloric acid or sulphuric acid although hydrochloric acid is preferred. Further, the reaction mass is refluxed in presence of aqueous hydrobromic acid at reflux temperature of between 108-112 "C for about 1-4 hours and preferably 1.5 to 2.0 hours.
in the step of isolation, in the process of the invention the solvent is removed completely by distillation. Preferably, the solvent is distilled under vacuum and the distillation is caiTied out at temperatures between 60-90 '^C. preferably 70-80 ''C.
Further, in the step of isolation a protic solvent is added, fhe said protic solvent is selected from methanol and ethanol, preferably methanol.
In the said step of isolation the solvent is removed completely by distillation. Preferably the solvent is distilled under vacuum and at temperatures between 60-^0 C, preferably 70-80*'C. "fhe solvent is concentrated to about 50% by vacuum distillation.
The reaction mass is acidified to pH 0.5 to 1.5 preferably 1.0 by the use of hydrochloride acid or sulphuric acid preferably hydrochloric acid.
In the step of isolation the (H)-N,n-diethyl-2-cyano-3(j,4-dihydroxy-5- nitrophenyl) acrylamide that is isolated is mixture of E and Z isomer, [he said isolated (Ej-N,n-diethyl-2-cyano-j(3.4-dihydroxy-5- nitrophenyl) acrylamide is rccryslaliscd in solvent selected from methanol. eth\ 1 acetate or a mixture of toluene and methanol.
The finally recrystallizcd (E)-N.n-diethyl-2-cyano-3{3,4-dihydroxy-5-nitrophenyl) acrylamide is substantially free from Z-isomer. preferably NMT 0.20%.

Example 1 :
Preparation of (E) N.N-dietliy]-2-cyano-3-(3.4-dihydroxy-5-nitro) acrylamide [Entacapone]
Charge 3.4-dihydroxy-5-nitro benzaldehdye 100 Kg. followed by N'.N-diethyl-2-eyano acetamide 92 Kg in to solvent Toluene, Charge piperidinc acetate prepared from 30 kg piperidine and 35 Kg acetic acid. Reaction mass was heated to reflux (108-112 "C), maintained at reflux with azeotropic distillation (108-112 "C) for 6 Hours and water was collected. Alter reaction completion Toluene was removed completely under vacuum below 80 " C, Mass was cooled to 50-55"C methanol (500 its) was charged in to the above mass under stirring. To this clear solution carbon was added maintained at 55-60"*^ foe 1 hour. Mass was filtered through hyflow bed in hot condition. Filtrate was cooled to 10 "C. pM of the filtrate adjusted to 1.0 to 2,0 with Con HCI. Mass was cooled to 5-l0" C and product (E) -entacapone with Z-isomer content NMT 0.20% is isolated, dried at 70-80C was found to be stable polymorph A \\ith melting point 162-164"C.
Example 2 :
Preparation of {E) N.N-dieth>l-2-cyano-j-(3.4-dih\dyoxy-5-nitro) acvylnmide [EntacaponcJ
Charge 3.4-dihydroxy-5-nitro benzaldehdye 100 gms, followed by N,N-diethyl-2-cyano acetantidc 95 gms in lo solvent Toluene. Charge piperidine acetate prepared from 30 gm piperidine and 35 gm acetic acid. Reaction mass was heated to reflux (108-112 C), maintained at rellux with azeotropic distillation (108--112"C) for 6 Hours and water was collected. After reaciion completion 10 ml aqueous HBr (48%) is added and maintained at reflux temperature, Fokiene was removed completely under vacuum below 80 C. Mass was cooled to 50-55"C methanol (500 Its) was charged in to the above mass under stirring, fo this clear solution carbon was added maintained at 55-60 C for I hour. Mass was nitcred through hyflow bed in hot condition. Filtrate was concentrated by vacuum distillation. Mass was cooled to 10 "C. Con UCl is added and further cooled to -5 *^C. Precipitated mass was maintained at 0 to -5C for 2 hours and 150 gms product mixture of

(E) and Z-isomer is isolated, dried at 70 to 80"C . This mixture of E and Z isomer is re-crystallized in methanol or ethyl acetate resulting E -entacapone with Z-isomer NMT 0.20%. polymorph A.
The advantages of the process of the present invention are the following:
1) Reduction of reaction time by increasing the temperature of the reaction mass and driving the reaction last by removing water formed in the reaction azeotropically. Reaction time was reduced to 6 hours from maximum of 100 hours and minimum of 20 hours of prior art.
2) Avoiding use of excess amount of one of the intermediate as also hazardous chemicals and number of solvents.
3) It employs simple modifications of pH and isolating from the solvent alcohol preferably from methanol.
4) It avoids additional step of converting the mixture of E and Z isomer to desired E i.somer using highly acidic medium.
10

CLAIMS
1. Process for the pieparalion of N.N-diet!wl-2-cyano-3(3.4-dihydroxy-S-
nitrophenyl)acryianiide ha\ing the siructure of Formula -IV

i) effecting condensation of j.4-dihydroxy -5-nitro benzaldehyde with N.N-
diethyl cyanoacetamide in presence of catalyst in an organic solvent
selected from toluene and Xylene ; ii) azeotropic distillation; and iii) isolating (Ii) isomer of N.N-diethyl-2-cyano-3-(3.4-dihydroxy-5-
nitrophenyl) acrylamide from acidic alcoholic solution of pH around 0.5 to
2 with 2-isomer NMT 0.2%.
2. fhe process according to claim I wherein the solvent is preferably toluene.
3. The process according to claim 1. wherein the catalyst is selected from piperidine acetate, pyridine acetate, and Para toluene sulphonic acid.
4. The process according to claim 3. wherein the catalyst is preferably piperidine acetate,
II

5. The process according to claim I. wherein in step (i) condensation is carried out al reflux temperalure.
6. The process according to claim 5 wherein the reflux temperature is 100-120 "C . and preferably between 108-112 "C.
7. The process according to claim 1, wherein the reaction lime in step (i) is
preterably between 4 to 8 hours, and more preferably between 5 to 6 hours.
8. The process according to claim 5, wherein the reaction mass is further rctluxed in presence of aqueous mineral acid.
9. The process according to claim 8 wherein the aqueous mineral acid is hydrobromic acid or hydrochloric acid.
10. The process according to claim 8 wherein the reflux temperature is preferably 108-112 "C for a period of 1-4 hours and more preferably 1.5 to 2.0 hours.
11. The process according to claim 1. wherein in step (iii) the solvent is removed completely by distillation.
12. fhe process according to claim 1. wherein in step (iii) the solvent is distilled under vacuum.
13. Vhe process according to claim 1 wherein in step (iii) the soivenl is distilled at preferably temperature of hetw-een 60-90"C. and more preferably 70-80"C.
14. The process according to claim 1, wherein in step (iii) a protic solvent is added,
15. The process according to claim 13. wherein the protic solvent selected from methanol and ethanol and preferably methanol.

16. 'I'he process according to claim 14. wherein the sohent is eoncenlrated to 50% by
vacuum distillation.
17. The process according to claim 1, wherein in step (iii) the reaction mass is
acidified.
18. The process according to claim 17 wherein the acidification is effected with an
acid selecved from hydrochloric acid and sulphuric acid, preferably hydrochloric
acid.
19. The process according to claim I, wherein in step (iii) the reaction mass is
acidified to pH 1.0,
20. The process according to claim 1. step (iii) wherein the isolated (K)-N,n-dielhyl-2-cyano-3(3.4-dihydroxy-5- nitrophenyl) acrylamide is mixture of E and Z isomer,
21. The process according to claim 20 wherein the isolated (E)-N,n-diethyl-2-cyano-3(3.4-dihydroxy-5- nitrophenyl) acrylamide is mixture of E and Z isomer is recrystalised in solvent.
22. The proces.4 according to claim 21 wherein the solvent for recrystallisalion is
methanol or ethyl acetate or mixture of toluene and methanol.
Dated this 5'" day of February 2009.
1

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Patent Number

277903

Indian Patent Application Number

1315/CHENP/2009

PG Journal Number

51/2016

Publication Date

09-Dec-2016

Grant Date

05-Dec-2016

Date of Filing

09-Mar-2009

Name of Patentee

BATTULA, SRINIVASA, REDDY

Applicant Address

RA CHEM PHARMA LIMITED, 608 SAPTHAGIRI TOWERS, BEGUMPET, HYDERABAD 500 016,

Inventors:

#	Inventor's Name	Inventor's Address
1	BATTULA, SRINIVASA, REDDY	RA CHEM PHARMA LIMITED, 608 SAPTHAGIRI TOWERS, BEGUMPET, HYDERABAD 500 016,

PCT International Classification Number

C07C 253/30

PCT International Application Number

PCT/IN2006/000310

PCT International Filing date

2006-08-24

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	NA	2009-03-09	Argentina