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Method for preparing lamotrigine

The technology of lamotrigine and dichlorobenzoyl cyanide is applied in the field of preparation of epilepsy drug lamotrigine, can solve the problems of difficulty in realizing industrialized production, long reaction steps, unfriendly environment, etc. The effect of fewer steps and lower production costs

Inactive Publication Date: 2011-05-25
蒋勇
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The patent literature reports of preparing lamotrigine in the early stage have BP 759014 (1956), EP 247892, WO 2000 / 35888, US 633198, US 6329521, US 6639072, WO 96 / 20934, WO 96 / 20935, BP 2395483, these methods have Many deficiencies, such as too long reaction time, low yield, long reaction steps, uneconomical, difficult to realize defects such as industrialized production
Related patent documents in recent years include WO 03 / 078407, WO 2004 / 026845, WO 2004 / 039767, WO 2007 / 069265 and CN 101506178. In these literature reports, there are harmful dehydrating agents and environmentally unfriendly substances, which are not Defects that are good for the environment

Method used

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  • Method for preparing lamotrigine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Slowly mix concentrated sulfuric acid (114g, 1.015mol) with 50ml of water, then add 2 drops of methanesulfonic acid, add aminoguanidine bicarbonate (10.2g, 0.075mol) under stirring at 0°C, and then add dropwise 2,3- Dichlorobenzoyl cyanide (10g, 0.05mol) in 20ml of acetonitrile solution, stirred at 28°C for 0.5h, heated to 50°C for 2h, cooled, filtered, washed with water, and drained, the resulting solid was added to 10g of silica gel, and added 2.5 g powdered NaOH, stir well, then heat in microwave for 1 minute, the maximum temperature is 110°C, the solid mixture is cooled, extracted (residual silica gel is recovered and used repeatedly), most of the solvent is evaporated, crystallized, and finally dried to obtain 10.8 g of white solid, the total yield is 78% based on 2,3-dichlorobenzoyl cyanide. Melting point: 216-217°C, HPLC: >99.9%.

Embodiment 2

[0018] Slowly mix concentrated sulfuric acid (57g, 0.501mol) with 50ml of water, add 2 drops of methanesulfonic acid, add aminoguanidine bicarbonate (10.2g, 0.075mol) under stirring at 0°C, and then add dropwise 2,3- Dichlorobenzoyl cyanide (10g, 0.05mol) in 20ml of acetonitrile solution, stirred at 28°C for 0.5h, heated to 50°C for 2h, cooled, filtered, washed with water, and drained, the resulting solid was added to 10g of silica gel, and added 2.5 g powdered NaOH, stir well, then heat in microwave for 1 minute, the maximum temperature is 110°C, the solid mixture is cooled, extracted (residual silica gel is recovered and used repeatedly), most of the solvent is evaporated, crystallized, and finally dried to obtain 8.0 g of white solid, the total yield is 58% based on 2,3-dichlorobenzoyl cyanide.

Embodiment 3

[0020] Slowly mix concentrated sulfuric acid (114g, 1.015mol) with 50ml of water, add aminoguanidine bicarbonate (10.2g, 0.075mol) and 2 drops of methanesulfonic acid under stirring at 0°C, and then add 2,3-dichloro Benzoyl cyanide (10g, 0.05mol) in 20ml of acetonitrile solution, stirred at 25-28°C for 0.5h, heated to 50°C for 2h, cooled, filtered, washed with water, and drained, the obtained solid was added to 10g of aluminum oxide, And add 2.5g of powdered NaOH, stir well, then heat in microwave for 1 minute, the maximum temperature is 110°C, the solid mixture is cooled, extracted, solvent evaporated, washed with water, recrystallized, and finally dried to obtain 9.7g of white solid , The total yield is 70% based on 2,3-dichlorobenzoyl cyanide.

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Abstract

The invention discloses a method for preparing lamotrigine. Under the acid condition, aminoguanidine bicarbonate reacts with 2,3-dichlorobenzoylcyanide to generate an intermediate compound Schiff base. The method is characterized in that the intermediate compound Schiff base is directly heated in an alkaline carrier through microwaves to carry out cyclization reaction to obtain a lamotrigine product. The method disclosed by the invention has the advantages of high yield, few steps and high utilization rate of raw materials, and is simple and convenient in operation; by adopting a microwave-promoted solid-phase reaction to carry out cyclization, materials which are not environment-friendly are prevented from being used widely, thereby being more beneficial to environment protection, obviously lowering the production cost, and improving the production efficiency; and the invention has obvious social and economic benefits.

Description

technical field [0001] The invention belongs to the field of chemical synthesis and pharmacy, and in particular relates to a preparation method of lamotrigine, a drug for treating epilepsy. Background technique [0002] Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine), used in the treatment of epilepsy. The patent literature reports of preparing lamotrigine in the early stage have BP 759014 (1956), EP 247892, WO 2000 / 35888, US 633198, US 6329521, US 6639072, WO 96 / 20934, WO 96 / 20935, BP 2395483, these methods have Many deficiencies, such as too long reaction time, low yield, long reaction steps, uneconomical, difficult to realize defects such as industrialized production. Related patent documents in recent years include WO 03 / 078407, WO 2004 / 026845, WO 2004 / 039767, WO 2007 / 069265 and CN 101506178. In these literature reports, there are harmful dehydrating agents and environmentally unfriendly substances, which are not Conducive to environmental defects. Co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D253/075
Inventor 蒋勇
Owner 蒋勇
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