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Method for synthesizing mebendazole by means of methyl cyanocarbamate

A technology of methyl cyanocarbamate and mebendazole, which is applied in the field of drug synthesis, can solve the problems of difficult handling, long cyclization time and high cost of raw materials, and achieves the effects of short production cycle, short cyclization time and shortened production cycle.

Pending Publication Date: 2019-09-27
CHANGZHOU YABANG QH PHARMACHEM +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in this process, there are problems such as high cost of raw materials, cyclization wastewater containing organic acids such as formic acid and acetic acid, and formic acid transformation wastewater are difficult to handle, and the cyclization time is long (more than 10h).

Method used

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  • Method for synthesizing mebendazole by means of methyl cyanocarbamate
  • Method for synthesizing mebendazole by means of methyl cyanocarbamate
  • Method for synthesizing mebendazole by means of methyl cyanocarbamate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 42.6g of 3,4-diaminobenzophenone, 65ml of acetone, and 48g of hydrochloric acid into a 500ml four-neck flask, heat to dissolve, add 242g of 12.5% ​​methyl cyanocarbamate, and reflux for 10min. Distill acetone to 97°C, reflux for 5 hours, cool down to 60°C and filter with suction, wash with 200ml of water and 300ml of methanol, the filter cake is crude mebendazole, wet weight 89.0g, dry weight 54.73g, yield: 92.3%.

[0027] Add 25g of crude mebendazole (dried) and 125ml of methanol into a 500ml reaction bottle, stir, heat to 60°C, add 20.4g of 65% nitric acid, after dissolving, add 2.5g of activated carbon at 60°C, heat, reflux for 55min, and heat Suction filtration, the filtrate was cooled slowly and stirred to crystallize, kept at 20°C for 1h, and suction filtration to obtain mebendazole nitrate.

[0028] Return mebendazole nitrate to the bottle, add 100ml of methanol, heat to 60°C, add about 11.5g of 65% nitric acid, dissolve it, cool down to 54°C, add 0.5g of meb...

Embodiment 2

[0030] Add 42.6g of 3,4-diaminobenzophenone, 18ml of new acetone to a 500ml four-neck flask, recover 47ml of acetone, 49g of hydrochloric acid, heat to dissolve, add 242g of 12.5% ​​methyl cyanocarbamate, continue heating, and reflux for 10min . Distill acetone to 95°C, keep at 95°C for 5 hours, cool down to 60°C and filter with suction, wash with 200ml of water and 300ml of methanol. The filter cake is crude mebendazole, with a wet weight of 87.5g and a dry weight of 54.61g. Yield: 92.09%.

[0031] Add 25g of crude mebendazole (dried), 125ml of methanol into a 500ml reaction bottle, stir, add 25g of nitric acid, heat, add 2.5g of activated carbon at 60°C after dissolving, heat to reflux for 55min, suction filter while hot, and slowly cool down and stir the filtrate Crystallize, keep warm at 20°C for 1h, and filter with suction to obtain mebendazole nitrate.

[0032] Return mebendazole nitrate to the bottle, add 100ml of methanol, add 12g of nitric acid, heat to dissolve, coo...

Embodiment 3

[0034] In a 500ml four-necked flask, add 42.6g of 3,4-diaminobenzophenone, 20ml of new acetone, recover 51ml of acetone, 48.5g of hydrochloric acid, heat to dissolve, add 242g of 12.5% ​​methyl cyanocarbamate, continue heating, and reflux 10min. Distill acetone to 96°C, keep at 96°C for 5 hours, cool down to 60°C and filter with suction, wash with 200ml of water and 300ml of methanol. The filter cake is crude mebendazole, with a wet weight of 86.28g and a dry weight of 55.0g, with a yield of 92.75%.

[0035] Add 39.3g of the wet crude product of mebendazole (25g after drying), 120ml of methanol into a 500ml reaction flask, stir, add 25g of nitric acid, heat, after dissolving, add 2.5g of activated carbon at 60°C, heat, reflux for 55min, and suction filter while hot, the filtrate Slowly lower the temperature and stir to crystallize, keep warm at 20°C for 1 hour, and filter with suction to obtain mebendazole nitrate.

[0036] Return mebendazole nitrate to the bottle, add 100ml ...

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Abstract

The invention discloses a method for synthesizing mebendazole by means of methyl cyanocarbamate. The method comprises the steps that 3,4-diaminobenzophenone and methyl cyanocarbamate react in acetone and hydrochloric acid to prepare a crude mebendazole, the crude mebendazole forms salt in methyl alcohol-nitric acid to obtain mebendazole nitrate, and finally the mebendazole nitrate is subjected to crystal transformation in methyl alcohol-nitric acid to obtain C crystal type mebendazole. The cheap and easily-obtained 3,4-diaminobenzophenone and methyl cyanocarbamate are adopted as raw materials, a large quantity of waste salts generated in the O-methyl isourea methyl formate synthesis process are avoided, the cyclization time is short and only needs 4-6 h, the production period is remarkably shortened, high-salt wastewater by-products can be treated through simple distillation, and the good industrial prospect is achieved.

Description

technical field [0001] The invention relates to a method for synthesizing mebendazole with methyl cyanocarbamate, belonging to the technical field of drug synthesis. Background technique [0002] Methyl cyanocarbamate (molecular formula is C 3 h 4 N 2 o 2 ) is also known as cyclizing agent. Its calcium salt or sodium salt solution is often used in production. It is easy to decompose under acidic conditions and is an important intermediate for the production of carbendazim and albendazole. [0003] Mebendazole is also known as benzophenone guanidine methyl ester, benzophenone imidazolamide ester, benzamide imidazole ester, Anleshi, Quchongkang, Pianling, Weilezhi, etc., and its chemical name is 5-benzoyl-2-benzo Methyl imidazole carbamate, molecular formula C 16 h 13 N 3 o 3 , the structural formula is: [0004] [0005] Mebendazole was chemically synthesized by VanGelDev for the first time and obtained a US patent. Belgian company Janssen put it into clinical pr...

Claims

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Application Information

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IPC IPC(8): C07D235/32
CPCC07D235/32
Inventor 张建峰朱云兵刘永林何小伟黄金占李志陵章文涛
Owner CHANGZHOU YABANG QH PHARMACHEM
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