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A kind of preparation method of high-purity gliclazide intermediate p-toluenesulfonylurea

A technology of toluenesulfonylurea and crystals, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of restricting the production and development of toluenesulfonylurea products, the purity is only 98%, and the product quality is low, achieving mild conditions, easy storage, and high purity Effect

Active Publication Date: 2022-01-04
山东海佑福瑞达制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] As far as the current industrial production of p-toluenesulfonylurea is concerned, its yield is always between 60-80%. Production and development of Lichite products
[0007] Simultaneously, the product quality that existing technology produces is lower, and purity only has 98%, and is white powder, and stability is poor

Method used

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  • A kind of preparation method of high-purity gliclazide intermediate p-toluenesulfonylurea
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  • A kind of preparation method of high-purity gliclazide intermediate p-toluenesulfonylurea

Examples

Experimental program
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Effect test

Embodiment 1

[0029] A kind of simple and convenient preparation method of p-toluenesulfonylurea, comprises the steps:

[0030] First fill the 3000L stainless steel reactor with nitrogen to replace the air in it, then add p-toluenesulfonyl isocyanate (Sinopharm Chemical Reagent Co., Ltd.) (197kg, 1000mol) and toluene (1000L), stir and cool down to -5~5℃ , slowly filled with ammonia gas (136kg, 8000mol, about 0.6MPa), white solid precipitated out after 4 hours of heat preservation reaction, slowly emptied (absorbed with 1% hydrochloric acid solution), replaced with nitrogen, stopped refrigeration, and slowly heated up to 25-30 ℃, keep warm for 4 hours, filter, wash with water until the pH is about 7, and obtain the crude product of p-toluenesulfonylurea.

[0031] Then add the crude product of p-toluenesulfonylurea into a 3000L reaction kettle, then add 2000L of acetonitrile / water (volume ratio: 1:1), heat to 80±5°C, reflux for 1h, program cooling (10°C / h), Lowered to below 20°C, centrifuged...

Embodiment 2

[0037] A kind of simple and convenient preparation method of p-toluenesulfonylurea, comprises the steps:

[0038] First fill the 3000L stainless steel reactor with nitrogen to replace the air in it, then add p-toluenesulfonyl isocyanate (Sinopharm Chemical Reagent Co., Ltd.) (200kg, 1015mol) and toluene (1015L), stir and cool down to -5~5℃ , slowly filled with ammonia gas (86.3kg, 5075mol, about 0.6MPa), white solid precipitated out after 4 hours of heat preservation reaction, slowly emptied (absorbed with 1% hydrochloric acid solution), replaced with nitrogen, stopped refrigeration, and slowly heated up to 25~ Keep warm at 30°C for 4 hours, filter, and wash with water until the pH is about 7 to obtain the crude product of p-toluenesulfonylurea.

[0039] Then add the crude p-toluenesulfonylurea into a 3000L reaction kettle, then add 2030L of acetonitrile / water (volume ratio: 1:1), heat to 80±5°C, reflux for 1h, program cooling (10°C / h), Lowered to below 20°C, centrifuged and ...

Embodiment 3

[0041] A kind of simple and convenient preparation method of p-toluenesulfonylurea, comprises the steps:

[0042] First fill the 3000L stainless steel reactor with nitrogen to replace the air in it, then add p-toluenesulfonyl isocyanate (Sinopharm Chemical Reagent Co., Ltd.) (191kg, 970mol) and toluene (970L), stir and cool down to -5~5℃ , slowly filled with ammonia gas (247kg, 14550mol, about 0.6MPa), white solid precipitated out after 4 hours of heat preservation reaction, slowly emptied (absorbed with 1% hydrochloric acid solution), replaced with nitrogen, stopped refrigeration, and slowly heated up to 25-30 ℃, keep warm for 4 hours, filter, wash with water until the pH is about 7, and obtain the crude product of p-toluenesulfonylurea.

[0043]Then add the crude p-toluenesulfonylurea into a 3000L reaction kettle, then add 1940L of acetonitrile / water (volume ratio: 1:1), heat to 80±5°C, reflux for 1h, program cooling (10°C / h), Lowered to below 20°C, centrifuged and dried to...

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Abstract

The invention discloses a simple and convenient preparation method of p-toluenesulfonylurea, which comprises the following reaction steps: according to the reaction process shown in Formula 3, firstly fill nitrogen into the reaction vessel to replace the air in the reaction vessel, and then add an organic solvent and P-toluenesulfonyl isocyanate, then fill it with ammonia gas, react at low temperature under stirring conditions to generate p-toluenesulfonylurea crude product, then filter and add acetonitrile / water to reflux, program cooling (10°C / h), centrifuge, and dry to obtain white crystal p-toluenesulfonyl isocyanate Toluenesulfonylurea. In the present invention, p-toluenesulfonyl isocyanate is ammonolyzed with ammonia gas in toluene to prepare p-toluenesulfonylurea, the yield can be as high as 96.3%, the product purity is over 99.9%, and it is a white crystalline solid without other impurities. The method is simple in operation, mild in conditions, easy in post-treatment, high in purity and high in yield, and is white crystal, easy to store.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a convenient preparation method of p-toluenesulfonylurea. Background technique [0002] P-toluenesulfonylurea can be used to synthesize hypoglycemic drug Gliclazide (Gliclazide) and so on. There are many reports on the synthesis methods of p-toluenesulfonylurea. Literature reports mainly use p-toluenesulfonamide and p-toluenesulfonyl chloride as starting materials. For example, Chinese patent CN201210012306.X discloses a preparation method of p-toluenesulfonylurea shown in formula 1, using p-toluenesulfonamide It is produced by condensation with urea. The post-treatment of this method is cumbersome, the required temperature is too high, and the product quality is poor, and the yield is only 75.2%. [0003] [0004] And the Mannich-like reaction research report of the sulfonylurea shown in formula 2 is obtained by reacting p-toluenesulfonyl chlorid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C303/40C07C303/44C07C311/58
CPCC07C303/40C07C303/44C07C311/58
Inventor 郑德强魏乐坤王洪臣李祥陈为波许跃雷
Owner 山东海佑福瑞达制药有限公司
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