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Preparation method for high-purity gliclazide intermediate namely p-toluenesulfonylurea

A technology for tosyl urea, crude tosyl urea, applied in the field of pharmaceutical chemical synthesis, can solve the problems of restricting the production and development of tosyl urea products, having a purity of only 98%, low product quality and the like, achieving mild conditions and easy Storage, high purity effect

Active Publication Date: 2019-10-25
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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  • Preparation method for high-purity gliclazide intermediate namely p-toluenesulfonylurea
  • Preparation method for high-purity gliclazide intermediate namely p-toluenesulfonylurea
  • Preparation method for high-purity gliclazide intermediate namely p-toluenesulfonylurea

Examples

Experimental program
Comparison scheme
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 acetonitrile / water (volume ratio: 1:1) 1940L, heat to 80±5°C, reflux for 1h, program cooling (10°C / h), Lowered to below 20°C, centrifuged and dried to ob...

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Abstract

The invention discloses a simple and convenient preparation method for p-toluenesulfonylurea. The preparation method comprises the following reaction steps: according to a reaction flow as shown in aformula 3 which is described in the specification, filling a reaction container with nitrogen gas to replace air in the reaction container, then adding an organic solvent and p-toluenesulfonyl isocyanate, then charging ammonia gas, carrying out a reaction at a low temperature under stirring so as to generate a crude p-toluenesulfonylurea product, then carrying out filtering, adding acetonitrile / water for refluxing, carrying out programmed cooling (10 DEG C / h), and carrying out centrifuging and drying so as to obtain a white crystal, namely, the p-toluenesulfonylurea. The preparation method provided by the invention prepares the p-toluenesulfonylurea by ammonolysis of the p-toluenesulfonyl isocyanate with the ammonia gas in toluene and can reach a yield up to 96.3%; and a product has a purity of 99.9% or more, is a white crystalline solid and is free of impurities. The preparation method provided by the invention has the following advantages: operation is simple and convenient; conditions are mild; post-treatment is easy; and a product has high purity and high yield, is a white crystal and facilitates storage.

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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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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