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A process for the preparation of entacapone form-A

A technology of cyano group and dihydroxy group, applied in the field of A-type crystallization, can solve the problems such as the type of polytype is not disclosed

Inactive Publication Date: 2009-06-17
ACTAVIS GRP PTC EHF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Patent Application Publication WO2005 / 063693 A1 describes an improved process for the preparation of entacapone, but does not disclose the type of polytype

Method used

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  • A process for the preparation of entacapone form-A
  • A process for the preparation of entacapone form-A
  • A process for the preparation of entacapone form-A

Examples

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Embodiment 1

[0030] Preparation of (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-acrylamide (entacapone).

[0031]3,4-dihydroxy-5-nitrobenzaldehyde (50g), N,N-diethylcyanoacetamide (76.5g), piperidine (19.2g) were loaded into a mixture containing dimethoxyethane (200ml ) and heptane (200ml) in a reaction vessel. The reaction mixture was refluxed for 15-25 hours until the disappearance of starting material (monitored by HPLC). The solvent was distilled off under high vacuum at 70-80°C. Then cool to 25-35°C. To the intermediate product in the flask was added dichloromethane (1.0 L) at 25-35°C. The mixture was stirred at this temperature for 24 hours. It was then filtered, dried and charged to a reaction flask containing methanol. The mixture was treated with activated carbon, filtered and concentrated to obtain the target compound (HPLC 99.78%, Z-isomer content <0.1%) with a yield of 75%.

Embodiment 2

[0033] 3,4-dihydroxy-5-nitrobenzaldehyde (25g), N,N-diethyl cyanoacetamide (38.25g), dibutylamine (10g) were charged into dimethoxyethane (100ml ) and heptane (100ml) in a reaction vessel. The reaction mixture was refluxed for 15-25 hours until the disappearance of starting material (monitored by HPLC). Under high vacuum at 70-80°C, the solvent was distilled off. Then cool to 25-35°C. To the intermediate product in the flask was added dichloromethane (500ml) at 25-35°C. The mixture was stirred at this temperature for 24 hours. Then, it was filtered, washed with water, dried and charged to a reaction flask containing acetonitrile. The mixture was treated with charcoal, filtered and concentrated to give the title compound (HPLC 99.7%, Z-isomer content <0.1%).

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Abstract

A process to prepare (2E) -2-cyano-3- (3 , 4-dihydroxy-5-nitrophenyl) -N, N-diethyl-2- propenamide (Entacapone) eliminating corrosive acids in the purification, with more than 99.5 % purity with a Z-isomer content of less than 0.1% comprising condensation of 3, 4-Dihydroxy{5-nitrobenzaldehyde with N,N-diethyl cyanoacetamide in the presence of a base selected from cyclic and acyclic secondary amines and a mixture of solvents, to obtain a crude product, stirring the crude product in a halogenated solvent, filtering and finally crystallization of polymorph A of Entacapone in a solvent.

Description

technical field [0001] The present invention relates to having figure 1 (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrobenzene)-N,N-diethyl-2-acrylamide (INN name is Entacar A new preparation method for stable type A crystals of Entacapone. The method is simple, efficient and suitable for large-scale production. Entacapone is an inhibitor of catechol-O-methyltransferase. Background technique [0002] US Patent No. 4963590 (UK Patent No. 8727854) first disclosed entacapone (molecular formula 1) and its application in inhibiting catechol-O-methyltransferase. The chemical name of entacapone is (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-acrylamide. It is used as an adjuvant to levodopa / carbidopa therapy in the treatment of Parkinson's disease. Parkinson's disease belongs to a class of disorders called motor disorders, which result from a loss of dopamine, which makes brain cells. Catechol-O-methyltransferase (COMT) inhibitors allow large amounts of levodopa to reach ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30
CPCC07C279/22C07C2101/02C07C255/54C07C2601/02
Inventor 格泰姆布·塞瑟莱姆·奇图尔拉觉莱姆·巴帕特·尤德尔加雅玛尼·穆努沙米纳格·维恩卡他·撒特雅·普拉撒纳·恩杰内雅·莱德哈·克里士纳·穆思·穆皮德
Owner ACTAVIS GRP PTC EHF
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