WO2008023380A1

WO2008023380A1 - Improved and simplified procedure for the preparation of (e) n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)acrylamide

Info

Publication number: WO2008023380A1
Application number: PCT/IN2006/000310
Authority: WO
Inventors: Srinivasa Reddy Battula
Original assignee: Srinivasa Reddy Battula
Priority date: 2006-08-24
Filing date: 2006-08-24
Publication date: 2008-02-28

Abstract

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-dihydroxy-5-nitrobenzaldehdye 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-nitrophenyl) 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 NMT 0.20%.

Description

IMPROVED AND SIMPLIFIED PROCEDURE FOR THE PREPARATION OF (E) RN-DIETHYL-Z-CYANO-SfS^-DIHYDROXY-S-NITROPHENYUACRYLAMIDE

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of the compound (E) N,N-DffiTHYI_^2-CYANOO(3,4-DIHYDROXY-5-NrrROPHENYL) ACRYLAMIDE having the structure of Formula -IV. Particularly the invention relates to a process for the preparation of (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY- 5-NITROPHENYL)ACRYLAMIDE which is efficient and Industrial advantageous. The said compound of the present invention is known as Entacapone.

Formula -IV

BACKGROUND OF THE INVENTION:

Catechol-O-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 inactivation of drugs with catechol structure and catecholasmines.

GB 8.727854 teaches (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5- NITROPHENYL)ACRYLAMIDE [ ENTACAPONE] for the treatment of Parkinson's disease as a potential inhibitor of catechol-O-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 ethanol media in presence of catalyst piperidine acetate [scheme 1] and isolation of mixture of E (70 to 80%) and Z ( 30-20%) isomers of Entacapone.

Formula-I Formula-II

Formula-Ill (E) and (Z) isomers of Entacapone

Scheme- 1

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]

HCOOH OR CH3COOH

HCl ORHBr

Formula-Ill (E ) and (Z) isomers of Entacaopne

Formula-IV (E ) Entacaopne

Scheme-2

International publication number WO 2005/063693 claims the improved process for the preparation of Entacapone starting from^' 3-alkoxy-4-hydroxy-5-nitro benzaldehyde condensation with other intermediate N,N-diethylaminocyanoacetamide in presence of mild acid catalyst followed by de- alkylation [scheme-3]. Another application WO/2005 070881 claimed for an efficient procedure for the preparation of (E) Entacapone stable polymorphic Form A by simple extraction of E isomer from the mixture of E and Z isomer from aqueous acidic media at pH 3.5 to 4.0.

Formula-V Formula-II

Formula- VI R = ETHYL OR METHYL

Formula- VI Formula-Ill R = ETHYL OR METHYL (E ) and (Z) isomers of Entacaopne

Scheme-3

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 E isomer.

The above process requires longer reaction times and uses hazardous and corrosive acids as a solvent for purification.

Further 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 E isomer ( pure enough). Lengthy process ( timing) and isolation of mixture isomers are the major disadvantages for this process. To overcome this disadvantage other process were claimed with modifications involving more either starting from costly /excess raw material or using additional solvents with lengthy reaction timings.

Process starting from 3-alkoxy-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 completely from the product where residual solvents presence is critical for a high dosage drugs like 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 efficient process for producing stable polymorph A with pure E isomer substantially free from Z-isomer.

SUMMARY OF INVENTION:

Thus according to the present invention there is provided an improved process for the preparation of the compound (E) N,N-DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5- NITROPHENYL)ACRYLAMIDE having the structure of Formula -IV comprising:

effecting condensation of 3,4-dihydroxy -5-nitro benzaldehyde with N,N-diethyl cyanoacetamide in presence of piperidine acetate in an organic solvent ; and isolating pure E isomer from acidic alcoholic solution pH around 1.0 with Z-isomer NMT 0.2%. The product isolated from the present process is pure polymorphic form A and Z- isomer NMT 0.2% by HPLC. DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention for the preparation of the compound (E) N₅N- DIETHYL-2-CYANO-3(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE is shown below in Reaction Scheme IV below:

(E)-Entacapone

Scheme -4

The organic solvent used in the step of condensation is selected from toluene and xylene. For the purpose of the process, the preferred solvent is toluene.

According to 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.

The condensation reaction is preferably carried out at reflux temperature. Preferably, the reflux temperature is 100-120 ⁰C, and most preferably between 108-112 ⁰C. The reaction period is 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 ⁰C 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 carried out at temperatures between 60-90 ⁰C, preferably 70-80 ⁰C.

Further, in the step of isolation a protic solvent is added. The 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 60-90 ⁰C, preferably 70-80 ⁰C. The 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 (E)-N,n-diethyl-2-cyano-3(3,4-dihydroxy-5- nitrophenyl) acrylamide that is isolated is mixture of E and Z isomer. The said isolated (E)-N,n- diethyl-2-cyano-3(3,4-dihydroxy-5- nitrophenyl) acrylamide is recrystalised in solvent selected from methanol, ethyl acetate or a mixture of toluene and methanol.

The finally recrystallized (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-diethyl-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-cyano acetamide 92 Kg in to solvent Toluene. Charge piperidine acetate prepared from 30 kg piperidine and 35 Kg acetic acid . Reaction mass was heated to reflux ( 108-112 ⁰C), maintained at reflux with azeotropic distillation ( 108-112 ⁰C) for 6 Hours and water was collected. After reaction completion Toluene was removed completely under vacuum below 80 ° C. Mass was cooled to 50-55 ⁰C methanol ( 500 Its) was charged in to the above mass under stirring. To this clear solution carbon was added maintained at 55-60 ° ^c for 1 hour. Mass was filtered through hyflow bed in hot condition. Filtrate was cooled to 10 ⁰C, pH of the filtrate adjusted to 1.0 to 2.0 with Con HCl. Mass was cooled to 5-10 ° 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 with melting point 162-164 ⁰ C.

Example 2 :

Charge 3,4-dihydroxy-5-nitro benzaldehdye 100 gms, followed by N.N-diethyl-2-cyano acetamide 95 gms in to solvent Toluene. Charge piperidine acetate prepared from 30 gm piperidine and 35 gm acetic acid . Reaction mass was heated to reflux ( 108-112⁰C), maintained at reflux with azeotropic distillation ( 108-112 ⁰C) for 6 Hours and water was collected. After reaction completion 10 ml aqueous HBr ( 48%) is added and maintained at reflux temperature. Toluene was removed completely under vacuum below 80 ⁰C. Mass was cooled to 50-55 ⁰C methanol (500 Its) was charged in to the above mass under stirring. To this clear solution carbon was added maintained at 55-60 ⁰C for 1 hour. Mass was filtered through hyflow bed in hot condition. Filtrate was concentrated by vacuum distillation . Mass was cooled to 10 ⁰C, Con HCl is added and further cooled to -5 ⁰C. Precipitated mass was maintained at 0 to -5 C for 2 hours and 150 gms product mixture of (E) and Z-isomer is isolated, dried at 70 to 80 ⁰C . 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 fast 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 ' isomer using highly acidic medium.

Claims

1. Process for the preparation of N,N-diethyI-2-cyano-3(3,4-dihydroxy-5- nitrophenyl)acrylamide having the structure of Formula -IV

Formula- IV

the process comprising

i) effecting condensation of 3,4-dihydroxy-5-nitrobenzaldehdye with N₉N- diethyl cyanoacetamide; and ii) isolating (E) isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl) acrylamide.

2. The process according to claim 1, wherein step( i) is carried out in an organic solvent.

3. The process according to claim 2 wherein the solvent is selected from toluene and xylene.

4. The process according to claim 3 wherein the solvent is toluene.

5. The process according to claim 1 wherein step (i) is carried out in presence of a catalyst.

6. The process according to claim 5, wherein the catalyst is selected from peperidine acetate, pyridine acetate, and Para toluene sulphonic acid.

7. The process according to claim 6, wherein the catalyst is piperadine acetate.

8. The process according to claim 1, wherein in step (i) condensation is carried out at reflux temperature.

9. The process according to claim 8 wherein the reflux temperature is 100-120 ⁰C , and preferably between 108-112⁰C.

10. The process according to claim 1, wherein the reaction time in step (i) is between 4 to 8 hours, and preferably between 5 to 6 hours.

11. The process according to claim 8, wherein the reaction mass is further refluxed in presence of aqueous mineral acid.

12. The process according to claim 11 wherein the aqueous mineral acid is hydrobromic acid or hydrochloric acid.

13. The process according to claim 11 wherein the reflux temperature is 108-112 ⁰C for a period of 1-4 hours and preferably 1.5 to 2.0 hours.

14. The process according to claim 1, wherein in step (ii) the solvent is removed completely by distillation.

15. The process according to claim 1, wherein in step (ii) the solvent is distilled under vacuum.

16. The process according to claim 1 wherein in step (ii) the solvent is distilled at temperature of between 60-90 ⁰C, and preferably 70-80 ⁰C.

17. The process according to claim 1, wherein in step (ii) a protic solvent is added.

18. The process according to claim 16, wherein the protic solvent selected from methanol and ethanol and preferably methanol.

19. The process according to claim 17, wherein the solvent is concentrated to 50% by vacuum distillation.

20. The process according to claim 1, wherein in step (ii) the reaction mass is acidified.

21. The process according to claim 19 wherein the acidification is effected with an acid selected from hydrochloric acid and sulphuric acid, preferably hydrochloric acid.

22. The process according to claim 1, wherein in step (ii) the reaction mass is acidified to pH 0.5 to 1.5 preferably 1.0.

23. The process according to claim 1, step (ii) wherein the isolated (E)-N,n-diethyl-2- cyano-3(3,4-dihydroxy-5- nitrophenyl) acrylamide is mixture of E and Z isomer.

24. The process according to claim 22 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.

25. The process according to claim 23 wherein the solvent for recrystallisation is methanol or ethyl acetate or mixture of toluene and methanol.

26. The process according to claim 1 wherein isolated (E)-N,n-diethyl-2-cyano-3(3,4- dihydroxy-5 -nitrophenyl) acrylamide is substansially free from Z-isomer , preferably NMT 0.20%.