WO2005063693A1 - Improved process for the preparation of entacapone - Google Patents
Improved process for the preparation of entacapone Download PDFInfo
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- WO2005063693A1 WO2005063693A1 PCT/IN2003/000401 IN0300401W WO2005063693A1 WO 2005063693 A1 WO2005063693 A1 WO 2005063693A1 IN 0300401 W IN0300401 W IN 0300401W WO 2005063693 A1 WO2005063693 A1 WO 2005063693A1
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- WIPO (PCT)
- Prior art keywords
- formula
- improved process
- ethyl
- entacapone
- toluene
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 37
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 title claims abstract description 36
- 229960003337 entacapone Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 19
- 239000003377 acid catalyst Substances 0.000 claims abstract description 6
- 150000007530 organic bases Chemical class 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 239000000543 intermediate Substances 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 claims description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 3
- QPFYXYFORQJZEC-FOCLMDBBSA-N Phenazopyridine Chemical compound NC1=NC(N)=CC=C1\N=N\C1=CC=CC=C1 QPFYXYFORQJZEC-FOCLMDBBSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- QHDUBNMGSDGCKZ-UHFFFAOYSA-N piperidin-1-ium;propanoate Chemical compound CCC(O)=O.C1CCNCC1 QHDUBNMGSDGCKZ-UHFFFAOYSA-N 0.000 claims 2
- GAPYKZAARZMMGP-UHFFFAOYSA-N pyridin-1-ium;acetate Chemical compound CC(O)=O.C1=CC=NC=C1 GAPYKZAARZMMGP-UHFFFAOYSA-N 0.000 claims 2
- 229940070891 pyridium Drugs 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 1
- 239000003586 protic polar solvent Substances 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- BBFJODMCHICIAA-UHFFFAOYSA-N 3,4-dihydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC(C=O)=CC([N+]([O-])=O)=C1O BBFJODMCHICIAA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- RYSHIRFTLKZVIH-UHFFFAOYSA-N N,N-diethylcyanoacetamide Chemical compound CCN(CC)C(=O)CC#N RYSHIRFTLKZVIH-UHFFFAOYSA-N 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 description 2
- JRURYQJSLYLRLN-UHFFFAOYSA-N 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide Chemical compound CCN(CC)C(=O)C(C#N)=CC1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-UHFFFAOYSA-N 0.000 description 2
- MAZRYCCTAIVEQP-UHFFFAOYSA-N 2-cyano-n,n-diethyl-3-(4-hydroxy-3-methoxy-5-nitrophenyl)prop-2-enamide Chemical compound CCN(CC)C(=O)C(C#N)=CC1=CC(OC)=C(O)C([N+]([O-])=O)=C1 MAZRYCCTAIVEQP-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 2
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000020335 dealkylation Effects 0.000 description 2
- 238000006900 dealkylation reaction Methods 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- -1 peperidinium acetate Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 description 1
- MDWLNBVKBMKTKN-UHFFFAOYSA-N 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde Chemical compound CCOC1=CC(C=O)=CC([N+]([O-])=O)=C1O MDWLNBVKBMKTKN-UHFFFAOYSA-N 0.000 description 1
- ZEHYRTJBFMZHCY-UHFFFAOYSA-N 5-nitrovanillin Chemical compound COC1=CC(C=O)=CC([N+]([O-])=O)=C1O ZEHYRTJBFMZHCY-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 0 C*C(C(C#N)=C[C@](CC([N+]([O-])=O)=C1O)C=C1O)=O Chemical compound C*C(C(C#N)=C[C@](CC([N+]([O-])=O)=C1O)C=C1O)=O 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- STMDHJPGTOYRJQ-UHFFFAOYSA-N acetic acid;ethanol;piperidine Chemical compound CCO.CC(O)=O.C1CCNCC1 STMDHJPGTOYRJQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000004059 quinone derivatives Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Abstract
The invention disclosed in this application relates to an improved process for the preparation of the Entacapone which comprises. (i)reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde with N,N-diethylaminocyanoactamide in the presence of mild acid catalyst and a solvent at a temperature in the range of 50-115 °C, to get the 3-O-alkylated (methyl or ethyl) Entacapone and treating with acid catalysts in the presence of organic base and solvents at temperature in the range of 20-60 °C to get Entacapone.
Description
IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE .
The present invention relates to an improved process for the preparation of ENTACAPONE. ENTACAPONE having the formula 1 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.
The invention also relates to a novel intermediate of the formula 4 where R =ethyl and a process for its preparation
The preparation of Entacapone of the formula (1) has been reported in GB 2200109 and US Patent No 4963590 (1987, 1990,Orion-Yhtymaeoy (FI)) from two critical intermediates viz; 3,4-dihydroxy-5-nitrobenzadehyde of the formula (5) and N,N- diethylaminocyanoacetamide of the formula (3). The compound of the formula 5 is condensed with the compound of the formula(3) in the presence of piperidine acetate and dry ethanoll as a solvent gave Entacapone of the formula (1). The 3,4-dihydroxy- 5-nitrobenzaldehyde of the formula (5) in turn was prepared from 3-methoxy- 4,hydroxy-5-nitrobenzaldehyde(6) using acetic acid and hydrobromic acid as described in scheme- 1.
ACETICACID/HYDROBROMIC ACID
PIPERIDINE ACETATE Ethanol
Scheme 1
The above patent has described the preparation of the entacapone of the formula (I) without describing the stereochemistry or the polymorphism.
Subsequently it was described in the US Patent No 5135950(1992, Orion Orion- Yhtymaeoy (FI)) about preparing E-isomer and polymorphism-A from the mixture abtained from the reaction reported in the GB patent No 2200109.
The main disadvantage of this method , according tour findings , is that the reaction times are very long ranging about 84-100 hours and the reaction never goes to completion .
Further the preparation of intermediate of the formula 5 from 3-hydroxy-4-methoxy- 5-nitrobenzadehyde of the formula 6 as described in the scheme -1 has to be purified repeatedly and yield of the intermediate is only about 55% . Consequently the yield of the final product is also very low ,.
The critical raw material 3,4-dihydroxy-5-nitrobenzaldehyde of the formula 5 a catechol derivative, changes its colour from light yellow to dark colour on storage at room temperature in short period of time due to which the final product entacapone yield and quality is varies between the batches and there is no consistency in yield and quality. Hence storing of this compound required special conditions such as below 15°C under dark room.
In addition it was known in the literature that the catechol derivatives are known to under goes the aerial oxidation and gives quinone derivatives which contributes the colour changes over the storage.
Hence it is of paramount important to find out the stable penultimate stage intermediate which can be stable enough at room temperature for longer period and it can be stored and used as and when it is required and it was our target to improve the overall yield of the final product Entacapone which in the present route is about 58%.
Therefore the main objective of the present invention is to provide an improved process for the preparation of ENTACAPONE of the formula (1).
Another objective of the present invention is to provide an improved process for the preparation of ENTACAPONE of the formula (1) using 3-alkoxy-4-hydroxy-5- nitrobenzadehyde of the formula (2) which is a guaiacol derivative and the product of the formula (4) wherer R = methyl 'or ethyl , which is also a guaiacol derivative is stable at room temperature. It is not found to change the color for two months storage.
Yet another objective of the present invention is to provide an improved process for the preparation ENTACAPONE of the formula (Y) by reducing the reaction time and making the reaction going to completion thereby making the process economical.
Still another objective of the present invention is to provide an improved process for the preparation of ENTACAPONE of the formula (1) by avoiding the use of 3,4- dihydroxy-5-nitrobenzaldehyde of the formula (5)
Yet another objective of the present- invention is to provide an improved process for the preparation of ENTACAPONE of the formula (1) employing intermediates of the formula 4 where R + methyl or ethyl
Another objective of the present invention is to provide a novel intermediate of the formula 4 where R = ethyl
Still another objective of the present invention is to provide a process for the preparation of novel intermediate of the formula 4 where R = methyl or ethyl
The compound of the formula 4 wherein R= methyl is known as metabolite in Entacapone viz ;Drug Metabolism and Disposition (1993),2J_ , 81-92 but has hitherto been prepared by any chemical method . Further the compounds of the formula 4 where R =methyl or ethyl have not been hitherto known as an intermediate for the preparation of Entacapone.
To achieve the above objectives , we devised an entirely different strategy for the preparation of the.Entacapone of the formula (I).
Accordingly the process envisaged and developed by us involves the reaction shown in the scheme 2
R= Methyl or ethyl. Scheme -2
Accordingly , the present invention provides an improved process for the preparation of Entacapone of the formula (I) which comprises.
(i)reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde of the formula (2 ) with N,N- diethylaminocyanoactamide of the formula ( 3_) in the presence of mild acid catalyst and a solvent at a temperature in the range of 50-115° c,to get the intermediates of the formula (4 ) wherein R is methyl, ethyl
(ii)Treating the 3- O- alkylated ( methyl Or ethyl) Entacapone of the formula (4 ) with acid catalysts in the presence of organic base and solvents at a temperature in the range of 20-60° to get crude Entacapone of the formula ( 1}
(iii) purifying the crude entacapone obtained using solvent or a mixture thereof.
In a preferred embodiment of the invention the Step (i) may be carried out using solvents such as alcohols with carbon ( Cl to C5) and toluene in presence of pyridine and piperidine salts such as peperidinium acetate, piperidiniumpropionate and pyridinium para toluene sulfonate etc. The reaction temperature used in this step can be preferably between 70-115° c and more preferably between 110 to 115°C. The solvent which can be employed is selected from isopropyl alcohol, ethanol, n- butanol, and toluene etc.
We have observed hat the intermediate of the formula 4 where R =methyl or ethyl exist in two isomeric forms . Though we could separate the isomer in respect of the compound where R =m ethyl, we could not , in spite of our repeated and best efforts separate the isomers of the compound where R =ethyl However it si to be noted that the non separation of the isomers does not afefcet the conversion of the compound of the formual 4 where R =is methylor ethyl for its conversion to Entacapone of the formula (I)
Another significant aspect of this invention is that intermediate of the formula (4 ) where R =methyl or ethyl having a cyano group is very susceptible for hydrolysis even at mild acidic and basic condition it can convert to corresponding amide or acid and subsequently we may get the starting material of the formula (2) but by careful designing and execution of the dealkylation to get ENTACAPONE in good yield by doing the reaction at room temperature between 25-50°C.
Another aspect of this invention is that the reaction time for condensation of the formula (2) and formula (3 ) is only 17 hours and the reaction goes. to completion thereby increasing the yield to 86% . The overall yield from compound of the formula (2) over two stages is 80%.
Yet another importance of this invention is that the intermediate of the formula (4) where R =methyl or ethyl is stable and there is no colour change occurred during the normal storage condition.
The another aspect of this invention is that the step (ii) is that the dealkylation which normally required higher temperature is presently carried out at of about 25-50°. The solvents which can be employed is selected from chloroform, methylene dichloride and ethylene dichloride and tetahydrofuran etc:
The solvents which can be employed purification of the crude entacapone may be selected from like toluene, isopropylalchlol ,methanol and acetone or their mixtures thereof .
The details of the process of this invention are described in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention.
EXAMPLE-1
STEP- 1 : PREPARATION OF N.N-DIETHYL -2- CYANO- 3- (-3-ETHOXY - 4-HYDROXY-5 NITROPHENYL) ACRYLAMIDEOF THE FORMULA 4 WHERE R = ETHYL :
Charge 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde 20g (0.0947mole) of the formula 2 where R= ethyl and N,N-diethylamino cyanoacetamide of the formula (3 ) 14.6g, (0.1042),acetic acid 3.13g and piperidine 4.45g along with toluene 200ml and heated to reflux temperature of about 100-115 C with continuous removal of water azeotrophically 15 hours. After the reaction is over the reaction mixture is concentrated to a volume of 20-30ml quenched in to dilute hydrochloric acid and chilled water 200ml and stirred for 60 minutes. The precipitated solid was filtered and dried to get 30g (95%),the HPLC purity is 94% (including isomer) of N.N-DIETHYL -2- CYANO- 3- (-3-ETHOXY -4-HYDROXY-5 NITROPHENYL)
ACRYLAMIDE. The product is used as such directly to the.next stage. MR = 110.1- 117.2°C.
STEP-2: PREPARATION OF N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5- NITROPHENYL)ACRYLAMIDE( ENTACAPONE
EXAMPLE-2 STEP-1 : PREPARATION OF N,N-DIETHYL -2-CYANO -3-( -3- ETHOXY -4- HYDROXY-5-NITROPHENYL) ACRYLAMIDEOF THE FORMULA 4 WHERE R = METHYL :
Charged 3-methoxy4-hydroxy-5-nitrobenzaldehyde 25g (0.126 mole) of the formula 2, where R= methyl ) and N,N-diethylamino cyanoacetamide of the formula (3) ) 22.2g,( 0.158 mole) acetic acid 4.18g and piperidine 5.94g along with toluene 250ml and heated to reflux temperature of about 105-110° and remove the water azeotrophically for 15 hours. The reaction mixture is concentrated and quenched in to dilute hydrochloric acid and chilled water 375ml and stirred for 3 hours. The precipitated solid was filtered and dried to get 36g (88.95%) with HPLC purity is 94.2% ( including isomer) and the N,N-DIETHYL -2-CYANO -3-( -3- METHOXY -4-HYDROXY-5-NITROPHENYL) ACRYLAMIDE which is used as such for the next stage.
Small sample was purified to get the pure single isomer (HPLC) by crystallising form methanol. The pure product is having the following properties.
HPLC PURITY : 99.63% MR ; 130-132° C
IR: ( Cm"1): 2204 ( -CN), 1637 ( -C=0),
PMR( 200MHz), δ value; 1.28(m, .6H), 3.49 (q, 4H), 4.02(s, 3H), 7.608(s, 1H,), 8.02(d, 1H, J=0.01), 7.98( s, 1H, J=0.01), MS= M/Z= 320.2 ( M+1)
STEP-2 PREPARATION OF N,N- DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5- NITROPHENYL) ACRYLAMIDE (ENTACAPONE):
N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl) acrylamide (20g) (0.062mole) of the formula 4 where , R=methyl obtained by the process described in step(i) of Example -2 is charged with pyridine 50ml along with dichloromethane 120 ml and stirred and cooled to 0-5 degrees and slowly charged the aluminium chloride 32g (0.239 mole) keeping the temperature below 5°and stirred at 0-5° C for 30 minutes . After maintaining for 30 minutes the reaction mixture was slowly raised to room temperature to 40-45°C and stirred for 2 hours. The reaction mixture quenched in dilute hydrochloric acid and ice water (50ml) after removing the methylene chloride and stirred for 60 minutes. The formed product was filtered and dried. The dried weight is 18g (94.1 %) with HPLC purity of about 94.42%.
It was purified using methanol and toluene as a solvent to get the ENTACAPONE as a pure product having HPLC purity of 99.5%. it is matching with in all respect with the product obtained from the Example- 1 (step-2).
Advantages of the invention
The process is simple and economical as the reaction time reduced and the reaction goes to completion.
The process avoids the use of 3,4-dihydroxy-5-nitrobenzaldehyde of the formula (5_
The process results in a new intermediate of the formula 4 Wherein R= ethyl
Claims
We Claim 1. An improved process for the preparation of Entacapone of the formula (1)
(i)reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde of the formula (2 ) with N,N- diethylaminocyanoactamide of the formula ( 3_) in the presence of mild acid catalyst and a solvent at a temperature in the range of 50-115°,to get the intermediates of the formula (4 ) wherein R is methyl or ethyl.
(ii)Treating the 3- 0- alkylated ( methyl Or ethyl) entacapone of the formula (4 ) where R =methyl or ethyl with acid catalysts in the presence of organic base and solvents at a temperature in the range of 20-60° to get crude entacapone of the formula ( 1) and if desired ,
(iii) purifying the crude entacapone obtained using solvent or a mixture thereof.
2. An improved process as claimed in claim 1 wherein the solvent used in Step (1) is selected from solvents such as alcohol with carbon ( Cl to C5) and toluene.
3. An improved process as claimed in claims 1 & 2 wherein the step (1) is carried out in the presence of pyridine and piperidine salt such as piperidine acetate and piperidine propionate, pyridinium acetate and pyridium propionate and pyridinium para toluene sulfonate etc.
4.An improved process as claimed in claims 1 to 3 wherein the reaction temperature used in the step (1) ranges between 60-115degrees and more preferably between 75 to 110 degrees C .
5. An improved process as claimed in claims 1 to 4 wherein the solvent used in step(l) is selected from isopropyl alcohol, ethanol, n-butanol and toluene etc.
6. An improved process s claimed in claims 1 to 5 wherein the reaction time for the condensation of the formula (2J and formula (3 ) ranges between 15 to 25 hours
7. An improved process as claimed in claims 1 to 6 wherein the reaction temperature for step (2) is ranges from about 25-50 degrees C .
8 An improved process as claimed in claims 1 to 7 wherein the chlorinated solvent used in step(2) is selected from chloroform, methylene dichloride and ethylene dichloride and tetrahydrofuran etc.
9. An improved process as claimed in claims 1 to 8 wherein the solvent used for purification in step (2) is selected from toluene, isopropylalchlol and methanol and toluene or their mixtures
10 A novel intermediate of the formula (4 ) wherein R is ethyl.
11.A process for the preparation of intermediates of the formula (4 ) wherein R is methyl or ethyl which comprises reacting a compound of the formula (2 ) where R =methylor ethyl with N,N-diethylaminocyanoactamide of the formula ( 3_) in the presence of mild catalyst and a solvent at a temperature in the range of 50-115 degrees C ,to get the intermediates of the formula (4 ) wherein R is methyl or ethyl.
12 A process as claimed in claim 11 wherein the solvent used in Step (i) is selected from solvents such as alcohol with carbon ( Cl to C5) and toluene.
13 A process as claimed in claims 11& 12wherein the step (1) is carried out in the presence of pyridine and piperidine salt such as acetate and propionate and para toluene sulfonate etc. 14A process as claimed in claims 11 to 13 wherein the reaction temperature used in the step (1) ranges between 60-115 degrees and more preferably between 100 to 110 degrees C .
15 An improved process as claimed in claiml l to 14 the solvent used in Step (1) is selected from protic solvents such as alcohol with carbon ( Cl to C5) and toluene.
16 An improved process as claimed in claims 11 & 14 wherein the step (1) is carried out in the presence of pyridine and piperidine salt such as piperidine acetate and piperidine propionate, pyridinium acetate and pyridium propionate and pyridinium para toluene sulfonate etc.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03780615.5A EP1699753B1 (en) | 2003-12-29 | 2003-12-29 | Improved process for the preparation of entacapone |
| JP2005512713A JP4550740B6 (en) | 2003-12-29 | Entacapone improved manufacturing method | |
| PCT/IN2003/000401 WO2005063693A1 (en) | 2003-12-29 | 2003-12-29 | Improved process for the preparation of entacapone |
| CNB2003801110441A CN100519517C (en) | 2003-12-29 | 2003-12-29 | Improved method for preparing entacapone |
| CA2552099A CA2552099C (en) | 2003-12-29 | 2003-12-29 | Improved process for the preparation of entacapone |
| AU2003288712A AU2003288712B2 (en) | 2003-12-29 | 2003-12-29 | Alternative process for the preparation of entacapone |
| US11/478,552 US7385072B2 (en) | 2003-12-29 | 2006-06-29 | Methods for the preparation of Entacapone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000401 WO2005063693A1 (en) | 2003-12-29 | 2003-12-29 | Improved process for the preparation of entacapone |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US11/478,552 Continuation US7385072B2 (en) | 2003-12-29 | 2006-06-29 | Methods for the preparation of Entacapone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005063693A1 true WO2005063693A1 (en) | 2005-07-14 |
Family
ID=34717535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2003/000401 WO2005063693A1 (en) | 2003-12-29 | 2003-12-29 | Improved process for the preparation of entacapone |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US7385072B2 (en) |
| EP (1) | EP1699753B1 (en) |
| CN (1) | CN100519517C (en) |
| AU (1) | AU2003288712B2 (en) |
| CA (1) | CA2552099C (en) |
| WO (1) | WO2005063693A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006064296A1 (en) * | 2004-12-15 | 2006-06-22 | Alkaloida Kutato Es Fejlesztö Kft | Process for the preparation of (e)-n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitro-phenyl)-acrylamide in stable polymorphic form and intermediates of the process |
| WO2007094007A1 (en) * | 2006-02-13 | 2007-08-23 | Suven Life Sciences Ltd., | An improved process for the preparation of entacapone |
| WO2007113845A1 (en) * | 2006-04-03 | 2007-10-11 | Alembic Limited | A process for the preparation of (e)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-n, n-diethyl-2-propenamide (entacapone) |
| EP1935873A1 (en) | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | A process for the preparation of entacapone |
| EP1978014A1 (en) * | 2007-04-02 | 2008-10-08 | Esteve Quimica, S.A. | Process for the preparation of entacapone and intermediates thereof |
| JP2009525971A (en) * | 2006-02-06 | 2009-07-16 | オリオン コーポレーション | Entacapone manufacturing method |
| EP2251323A1 (en) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
| WO2011008675A2 (en) * | 2009-07-15 | 2011-01-20 | Chadeayne Andrew R | Catecholamine compounds, compositions, and formulations, and methods of using the same |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1945607B1 (en) * | 2005-11-09 | 2009-10-14 | USV Limited | A process for the preparation of highly pure (e) n,n-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitro phenyl) acrylamide (entacapone) |
| WO2008053304A2 (en) * | 2006-10-30 | 2008-05-08 | Wockhardt Research Centre | Processes for the preparation of a stable polymorphic form of entacapone |
| CN104402764A (en) * | 2014-11-26 | 2015-03-11 | 千辉药业（安徽）有限责任公司 | Preparation method for entacapone |
| CN112624941A (en) * | 2020-12-30 | 2021-04-09 | 海南通用康力制药有限公司 | Method for producing entacapone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4963590A (en) * | 1986-11-28 | 1990-10-16 | Orion-Yhtyma Oy | Pharmacologically active compounds, methods for the preparation thereof and compositions containing the same |
| US5981569A (en) * | 1992-11-13 | 1999-11-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease |
-
2003
- 2003-12-29 CN CNB2003801110441A patent/CN100519517C/en not_active Expired - Fee Related
- 2003-12-29 AU AU2003288712A patent/AU2003288712B2/en not_active Ceased
- 2003-12-29 CA CA2552099A patent/CA2552099C/en not_active Expired - Fee Related
- 2003-12-29 EP EP03780615.5A patent/EP1699753B1/en not_active Expired - Lifetime
- 2003-12-29 WO PCT/IN2003/000401 patent/WO2005063693A1/en active Application Filing
-
2006
- 2006-06-29 US US11/478,552 patent/US7385072B2/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4963590A (en) * | 1986-11-28 | 1990-10-16 | Orion-Yhtyma Oy | Pharmacologically active compounds, methods for the preparation thereof and compositions containing the same |
| US5981569A (en) * | 1992-11-13 | 1999-11-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP1699753A4 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006064296A1 (en) * | 2004-12-15 | 2006-06-22 | Alkaloida Kutato Es Fejlesztö Kft | Process for the preparation of (e)-n,n-diethyl-2-cyano-3(3,4-dihydroxy-5-nitro-phenyl)-acrylamide in stable polymorphic form and intermediates of the process |
| JP2009525971A (en) * | 2006-02-06 | 2009-07-16 | オリオン コーポレーション | Entacapone manufacturing method |
| WO2007094007A1 (en) * | 2006-02-13 | 2007-08-23 | Suven Life Sciences Ltd., | An improved process for the preparation of entacapone |
| WO2007113845A1 (en) * | 2006-04-03 | 2007-10-11 | Alembic Limited | A process for the preparation of (e)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-n, n-diethyl-2-propenamide (entacapone) |
| EP1935873A1 (en) | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | A process for the preparation of entacapone |
| US7750177B2 (en) | 2006-12-19 | 2010-07-06 | Dipharma Francis S.R.L. | Process for the preparation of entacapone |
| EP1978014A1 (en) * | 2007-04-02 | 2008-10-08 | Esteve Quimica, S.A. | Process for the preparation of entacapone and intermediates thereof |
| WO2008119793A1 (en) * | 2007-04-02 | 2008-10-09 | Esteve Química, S.A. | Process for the preparation of entacapone and intermediates thereof |
| EP2251323A1 (en) | 2009-05-14 | 2010-11-17 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Method for the purification of entacapone |
| WO2011008675A2 (en) * | 2009-07-15 | 2011-01-20 | Chadeayne Andrew R | Catecholamine compounds, compositions, and formulations, and methods of using the same |
| WO2011008675A3 (en) * | 2009-07-15 | 2011-04-28 | Chadeayne Andrew R | Catecholamine compounds, compositions, and formulations, and methods of using the same |
Also Published As
| Publication number | Publication date |
|---|---|
| US7385072B2 (en) | 2008-06-10 |
| AU2003288712A1 (en) | 2005-07-21 |
| EP1699753B1 (en) | 2014-11-26 |
| EP1699753A4 (en) | 2008-12-31 |
| US20070060767A1 (en) | 2007-03-15 |
| CA2552099A1 (en) | 2005-07-14 |
| CA2552099C (en) | 2011-10-04 |
| AU2003288712B2 (en) | 2010-11-04 |
| JP2007527847A (en) | 2007-10-04 |
| JP4550740B2 (en) | 2010-09-22 |
| EP1699753A1 (en) | 2006-09-13 |
| CN1926095A (en) | 2007-03-07 |
| CN100519517C (en) | 2009-07-29 |
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