Title of Invention

"A PROCESS FOR THE PREPARATION OF Z & E ISOMERS OF ENTACAPONE"

Abstract

The invention relates to Novel Z form of ENTACAPONE-( Z N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide) of the formula 1 from pure 3- O- alkylated Entacapone of the formula (7) by treating with aluminium chloride and pyridine with dichloromethane as solvent to get crude Entacapone of the formula ( 3) with no impurity of the formula (9). and dissolving the crude entacapone of the formula 3 in one or more solvents selected from soluble or partially soluble solvents or their mixtures, filtering and concentrating by distillation

Full Text

FORM 2 THEPATENTS ACT, 70 (Act 39 of 70) COMPLETE SPECIFICATION (See Section TO) AN IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE SUVEN LIFE SCIENCES LIMITED, a company registered under the Indian Company’s Act 1956, having its registered office located at Serene Chambers, Road No: 7, Banjara Hills, Hyderabad - 500034, AP, INDIA The following specification particularly describes the nature of the invention and the manner in which it is to be performed 2 FIELD OF THE INVENTION The present invention relates to Novel Z isomer of entacapone , a process for its preparation and an improved process for the preparation of highly pure entacapone. ENTACAPONE is (E)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide prepared by the process of the present invention has the formula 2 given below. The present invention, particularly relates to a process for the preparation of the (Z) isomer of N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitropenyl)-acrylamide. The (Z)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide prepared by the process of the present invention has the formula 1 which is geometrical isomer of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide having the formula 2. The invention also relates to an improved process for the preparation of (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5—nitrophenyl)-acrylamide having the formula 2 of polymorphic form A using the process of the present invention. ENTACAPONE and its E & Z isomers prepared by the process of the present invention has COMT- inhibiting properties and are therefore useful for treating Parkinson's disease, sometime referred to as shaking palsy. BACKGROUND OF THE PRESENT INVENTION (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyI)-acrylamide herein called ENTACAPONE means (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide having the formula 2 is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It is used in combination with levodopa/carbidopa to treat Parkinson's disease, sometime referred to as shaking palsy. Entacapone enhances the effect of levedopa/carbidopa by improving muscle control. Entacapone of the formula 2 is known from the US Patent No. 4,963,590. Entacapone is a novel drug used to improve the bioavailability of L-dopa in the treatment of parkinsonian diseases. When L-dopa is administered with peripheral dopa decarboxylase, inhibitor 3-O-methylation by COMT become important consideration as 3-O-methyldopa is potentially harmful and amy compete with L-dopa for transport in to brain. Entacapone is designed to inhibit COMT with high affinity and then reduce the formation of 3-O-methyldopa when co-administered under this treatment regime. The nitrogroup in position 5 and another strong electron withdrawing hydrophobic substituent in position 1 are essential for their pharmacological action as COMT inhibitor (lotta et al., J.Comput. Aided. Mol. Des 6,235-272 (1992)) US patent No 4,963,590 discloses a process for the preparation of crude N,N-Diethyl-2-cyano-3- (3,4-dihydroxy-5-nitrophenyi)-acryl amide (3). 4 The synthetic method disclosed in US patent no 4,963,590 comprises knoevenagel condesation of 3,4-dihydroxy-5-nitrobenzadehyde of the formula (5) and N,N-diethylaminocyanoacetamide of the formula (4) in the presence of piperidine acetate and dry ethanol as a solvent gave crude Entacapone of the formula (3) with melting point 153-56°Cwith 73% yield . This reaction is shown in the scheme-1. Subsequently in US Patent No 5135950 described the process for preparing essentially and crystallographically pure (E)- N,N-Diethyl-2-cyano-3- (3,4-dihydroxy-5-nitrophenyI)-acryl amide with melting point 162-163°C and polymorphism form-A from a crude Entacapone obtained using US PATENT 4,963,590 having melting point 153-156°C. In addition to the above, the Pat No WO 2005/063695 and WO 2005/063696 disclose a new crystalline (E)-Entacapone form C, D and E using different mixture of solvents for crystallization. In the patent No WO 2005/070881 an improved process for the manufacture of (E)- N, N-Diethyl-2-cyano-3- (3,4-dihydroxy-4-nitrophenyl)-acrylamide is disclosed in which use is made of the procedure of the original patent No 4,963,590 with a change in the 5 isolation procedure. The isolation procedure used in this patent is quenching in ethyl acetate and aqueous hydrochloric acid and extracting in to ethyl acetate at Ph 3.5-4 followed by concentration to get directly pure (E)- N, N-Diethyl-2-cyano-3- (3,4-dihydroxy-5 nitrophenyl)-acryl amide with 99.7% HPLC purity with All the above mentioned patents discloses the process for making the isomer (E)- N,N-Diethyl-2-cyano»3-(3/4-dihydroxy-5-nitrophenyl) acrylamide of polymorphic forms. A, and C,D and E. No patents or literature is currently available for the preparation of (Z)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide in pure form though there was a mentioning about its melting point and its ready conversion to E-isomer in US Patent 5,135,950 referred to above . In our co pending WO 2005/063693 application , we have disclosed an process for the preparation of (E)- N,N-Diethyl-2-cyano-3-(3,4~ dihydroxy-5-nitrophenyl)-acrylamide of polymorphic form A which comprises reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde of the formula (6) with N,N-diethyIaminocyanoactamide of the formula ( 4) in the presence of mild acid catalyst and a solvent to get the intermediates of the formula (7 ) wherein R is methyl,ethyl, , further treating the 3- O- alkylated Entacapone of the formula (7 ) with aluminium chloride and pyridine and methylene dichloride as solvent to get crude Entacapone of the formula ( 3) and purifying the crude entacapone to get pure (E)-ENTACAPONE of the formula 2 of polymorphic form A with 99.8% HPLC purity as depicted in scheme-2 R=Methyl or Ethyl Scheme-2 We observed, during our continued R & D for further development of the process that the use of piperidine and acetic acid as a catalyst for the knoevenogel reaction, the formation of piperidine derived impurity of the formula (9). This impurity of the formula (9) could be formed due to the exchange of reaction between the diethyamine moity present in the compound of the formula (4) with piperidine. This impurity of the formula (9) forming about 0.5-1.5% in the crude Entacapone produced which needs extensive purification for making the use of the end product as a drug. Therefore we thought to develop an improved process for the preparation of pure E-ENTACAPONE OF POLYMORPH FORM A which avoids the formation of the intermediate of the formula 8which leads to the impurity of the formula 9 Scheme-3) scheme-3 Therefore, the main objective of the present invention is to provide a process for the preparation of high purity E-ENTACAPONE of the formula 2 given above. 8 Another objective of the present invention is to provide an improved process for the preparation of ENTACAPONE without the formation of any intermediate which forms as an impurity. Still another objective of the present invention is to provide a process for the preparation of (Z)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide (Z-ENTACAPONE) of the formula 1 from the crude ENTACAPONE of the formula 3 useful for formulation and medicament, in place of E- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide, as the activity and toxicology studies are same. Yet another objective of the present invention is to provide a process for the preparation of (Z)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenylj-acrylamide of the formula 1 in >98 % Purity from the highly pure ENTACAPONE of the formula 2 Still another objective of the present invention is to provide a process for the preparation of Z-isomer of (Z)- N,N-Diethyl-2-yano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide of the formula 1 in a stable form Yet another objective of the present invention is to provide a process for the preparation of Z-isomer of (Z)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide of the formula 1 in pure form in98 % Purity , which is simple and economical as described in scheme-4 Further objective of the invention is to provide a novel stable form of Z-entacapone. Accordingly , the present invention provides an improved process for the preparation of highly pure ( >98% ) E-ENTACAPONE ( N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide ) of the formula 2 which comprises (I) reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde of the formula (6) Wherein R=Ethyl or methyl (ii) with N,N-diethylaminocyanoactamide of the formula (4) (iv) Dissolving the crude Entacapone of the formula 3 with acetic acid in presence of hydrobromic acid on heating and cooling to 20-25°C to get the technical grade E-entacapone which on further purification with methanol gives pure E-ENTACAPONE of the formula 2 According to another embodiment of the present invention there is provided a process for the preparation of (Z) -ENTACAPONE-( Z N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-S-nitrophenyl)-acrylamide) of the formula 1 which comprises (II) reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde of the formula (6) (ii) with KN-diethylaminocyanoactamide of the formula (4) 12 in the presence of mild acid catalyst and a solvent to produce the intermediates of the formula (7) wherein R is methyl or ethyl without the formation of impurity of the formula (8) (v) treating the 3- O- alkylated Entacapone of the formula (7) 13 with aluminium chloride and pyridine with dichloromethane as solvent to get crude Entacapone of the formula (3) with no impurity of the formula (9). (vi) dissolving the crude entacapone of the formula 3 in one or more solvents selected from soluble or partially soluble solvents or their mixtures, filtering the resulting fully or partially soluble solution , concentrating by distillation to get a residue and further purfying using polar solvets to get pure Z-ENTACAPONE with HPLC purity of >98% with <.5 of e-isomer.> To avoid the impurity formation and increase the yield of E-entacapone of polymorph-a in the knovenogel condensation reaction between the 3-hydroxy-4-methoxy-5-nitrobenzaldehyde of the formula 6 and N,N-diethylaminocyanoacetamide of the formula 4 in presence of bases like dimethylamine diethylamine, glycine, alanine and imidazole preferably imidazole and glycine most preferably glycine. The acid can be chosen from formic acid and acetic acid most preferably acetic acid. The solvents can be used for the step involving the preparation Z-entacapone of the formula 1, from the crude ENTACAPONE of the formula 3 is hydrocarbon solvents like toluene, xylene, hexane, heptane and octane and protic solvents like methanol ethanol, isopropanol and n-butanol and acids like acetic acid and formic acid. 14 Preferably toluene, xylene, acetic acid and methanol, most preferably toluene, acetic acid and methanol and the mixture thereof to obtain a partially soluble slurry which on filtration gives clear solution. The same can be repeated two to three times to get maximum yield. The polar solvents which may be used for the purification may be selected from methanol ethanol, isopropyl alcohol, tetrahydrofuran and ethyl acetate. In the drawings accompanying this specification Fig.1 Shows the IR (KBr) Spectrum of Z-ENTACAPONE prepared by a process according to the present invention is shown . Flg.2 Shows 1HNMR(δ,CD3OD, 400MHz): ( Spectrum of Z-ENTACAPONE prepared by a process according to the present invention. Fig.3 Shows 1HNMR (δ,CD3OD, 400MHz): Spectrum of Z-ENTACAPONE prepared by a process according to the present invention Fig.4 and TABLE-1 shows X-RAY DIFFRACTOGRAMof Z-ENTACAPONE prepared by a process according to the present invention The details of the present invention are given in the following Examples which are provided by way of illustration only and therefore cannot be construed to limit the scope of the invention 16 EXAMPLE-1 Preparation of N,N-DIETHYL-2 -CYANO-3-(3-METHOXY-4-HYDROXY-3-NITRO PHENYL)ACRYL AMIDE. STEP-1 3-Methoxy-4-hydroxy-5-nitrobenzaldehyde of the formula (6) 150.0 gm (0.761 mole), N,N-diethyl cyanoacetamide of the formula (4) 135.3 gm (0.96 mole), glycine 10.5 gm (0.13 mole) and acetic acid 25.12 gm (0.41 mole) were charged sequentially to 1500.0 ml toluene. The resulting reaction mixture was heated to reflux and maintained with removal of water by azeotropically for 12-15 hrs. After the completion of reaction the solvent is concentrated and quenched into a cooled solution of isopropyl alcohol aqueous hydrogen bromide and water (2400.0 ml) and stirred for 3 hrs. The precipitated solid is filtered and dried to get 229.0 gm (94.2%) of title product of the formula (7) as crystalline solid. This product is used for next stage without purification. STEP 2. Preparation of N,N-DIETHYL-2-CYANO-3-(3-4-DlHYDROXY-5-NITRO PHENYL)ACRYL AMIDE( CRUDE ENTACAPONE (3) The product N,N-Diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro phenyl)acryl amide of the formula (7) 160.0 gm (0.50 mole) obtained from step-1 and 960 ml of dichloromethane and 400 ml pyridine were cooled to 0-5°C and slowly charged 200.4gm (1.50 mole, 3.0 equiv.) of aluminium chloride in lot keeping the temperature below 5°C in 35-45 min. The resulting reaction mixture was stirred for 30 min. at 0-5°C and slowly heated to 45-50 degrees and maintained that temperature with stirring for 2-3 hrs. After completion of the reaction dichloromethane evaporated and resulting reaction mixture is added to ice water containing little hydrochloric acid and stirred for 2-3 hrs. The precipitated product was filtered and dried to get 140,0 gm (94.6%) of title product of the 17 formula (3) as crystalline solid with total HPLC purity 99.49% having 68.74% of E-isomer and 30.75% of Z-isomer. STEP 3 . Preparation of N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5-NITRO PHENYL)ACRYL AMIDE . (PURE E-ENTACAPONE). A mixture containing 140.0 gm of the crude product obtained according to step-2 in 420.0 ml of acetic acid was heated to 85-90°C and 9.8 ml hydrogen bromide is added and cooled to 20-25°C. The reaction mixture was stirred for 18-20 hrs at 20-25°C and for 5-6 hrs at 15-18°C. The precipitated product was filtered and washed with a mixture of toluene and acetic acid (14.0 ml each) and finally with toluene (28.0 ml) .The product was dried at 50-55°C. The dried weight is 104.0 gm with HPLC purity of 99.88%. It was further purified using methanol as solvent to get 95.0 gm of the E-Entacapone of polymorphic form A as a pure product having HPLC purity of 99.91% Melting 163.6-164.9° and matching in all repect with the reported E-Entacapone of polymorph form A. EXAMPLE-2 Preparation of N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl)acryl amide (PURE Z-ENTACAPONE). The crude Entacpone of the formula (3), 25.0 gm obtained according to step-2 of example-1 was treated with 550 mi toluene and heated to reflux for 4 hrs. and cooled to 5°C over the period of 3-5 hours and filtered to remove insoluble solid and filtrate. The filtrate is concentrated and co evaporated with n-hexane gives 6.0 gm of the crude of Z-Entacapone. The above operation can be repeated to maximise the yield of crde Z-Entacapone. The combined residue of crude Z-Entacapone on further purification using methanol as solvent to get the pure Z-Entacapone having HPLC purity of 99.87%. MR.148.8°C 18 PMR (δ,CD3OD, 400MHz): 1.1 (t,3H),1.21 (t.3H),3.38(d,2H),3.52(d,3H),7.22 (d,1H),7.45(S,1H),7.74(d,lH). CMR(δ,CD3OD,400MHz): 11.999(q), 13.79(q) ,106.73(t) ,117.12(t), 117.35(s),118.85(d),122.82(s) ,137.19(d),144.51(s),144.57(d),144.59(s),148.02(s),161.21(s) EXAMPLE-3 Preparation of N,N-Diethyl-2-cyano-3-(3-4-dihydroxy-5-nftro phenyl)acryl amide .(PURE Z-ENTACAPONE). The crude Entacpone of the formula (3), 25.0 gm obtained according to step-2 of example-1 was treated with 500 ml toluene , 50ml of acetic acid and heated to reflux for 4 hrs. After maintaining at reflux temperature the reaction mixture is cooled to 5° C over the period of 3-5 hours and filtered to separate insoluble solid and filtrate. The filtrate is concentrated and also co-evaporated with n-hexane gives 7.5g gm of the crude product of Z-Entacapone which on further purification using methanol as solvent to get the Z-Entacapone pure having HPLC purity of 99.87%. MR.148.80C While the present invention has been described in terms of specific embodiments, certain modifications and equivalent to those skilled in the art and are intented to be included with in the scope of the present invention. Advantages of the invention 1. The invention provides a novel highly pure Z isomer of N,N-Diethyl-2-cyano-3-(3-4dihydroxy-4-nitrophenyl)-acrylamide of the formula 1 19 ( >98%) which is stable against heat & light as it does not undergo any conversion from Z-isomer to E-isomer 2. The Z isomer is pharmacologically active as COMT-inhibitor and hasan similar to E isomer 3. The process for the preparation of Z-isomer of Z- is simple economical 4. The invention provides an improved process for the preparationof Highly pure (99.9%)Z-E ENTACAPONE 5. The invention provides an improved process for the preparation ofHighly pur (99%) E isomer of Z-ENTACAPONE

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