Preparation method of sulfamic acid methyl ester

The technology of methyl sulfamate and sulfamate chloride is applied in the field of impurity analysis in drug synthesis, which can solve problems such as affecting drug efficacy, toxic and side effects, and achieve the effects of clinical safety use guarantee, simple steps and high yield.

Inactive Publication Date: 2019-09-17
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The content of the active ingredient of a drug is an important indicator of the purity of the drug, and the impurities in the drug directly affect the efficacy of the drug and may cause toxic and side effects

Method used

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  • Preparation method of sulfamic acid methyl ester
  • Preparation method of sulfamic acid methyl ester
  • Preparation method of sulfamic acid methyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The preparation method of methyl sulfamate

[0029] 1, the preparation of aminosulfonyl chloride

[0030]

[0031] Add 141.5g (1.0mol) of chlorosulfonic acid isocyanate into a 500ml three-necked flask, protect it under nitrogen, stir, cool down to -15~-10°C, and add 49g (1.05mol) of formic acid dropwise at a temperature controlled below -10°C. The temperature was raised to room temperature and the stirring reaction was continued. After the reaction, add 200ml of dichloromethane, stir to dissolve, concentrate under reduced pressure and distill off the solvent, add 100ml of dichloromethane again, continue to concentrate under reduced pressure and distill off the residual solvent. The residue was suspended in petroleum ether (boiling point 60-90°C), stirred at room temperature under nitrogen protection, filtered under nitrogen protection, washed with petroleum ether, and the wet product was dried under reduced pressure below 35°C to obtain 107g of product with a yield ...

Embodiment 2

[0036] The preparation method of methyl sulfamate

[0037] 1, the preparation of aminosulfonyl chloride

[0038]

[0039] Add 141.5g (1.0mol) of chlorosulfonic acid isocyanate into a 500ml three-necked flask, protect with nitrogen, stir, cool down to -15~-10°C, control the temperature below -10°C and add 37.6g (0.8mol) formic acid dropwise. , warming up to room temperature and continuing to stir the reaction. After the reaction, add 200ml of chloroform, stir to dissolve, concentrate under reduced pressure and evaporate the solvent, add 100ml of chloroform again, continue to concentrate under reduced pressure and evaporate the residual solvent. The residue was suspended in methyl tert-butyl ether, stirred at room temperature under the protection of nitrogen, filtered under the protection of nitrogen, washed with methyl tert-butyl ether, and the wet product was dried under reduced pressure below 35°C to obtain 96.3g of the product, with a yield of 83.7% .

[0040] 2, the p...

Embodiment 3

[0044] The preparation method of methyl sulfamate

[0045] 1, the preparation of aminosulfonyl chloride

[0046]

[0047]Add 141.5g (1.0mol) of chlorosulfonic acid isocyanate into a 500ml three-necked flask, protect it under nitrogen, stir mechanically, cool down to -15~-10°C, and add 47g (1.0mol) of formic acid dropwise at a temperature below -10°C. , warming up to room temperature and continuing to stir the reaction. After the reaction, add 200ml of dichloroethane, stir to dissolve, concentrate under reduced pressure and evaporate the solvent, add 100ml of dichloroethane again, continue to concentrate under reduced pressure and evaporate the residual solvent. The residue was suspended in isopropyl ether, stirred at room temperature under the protection of nitrogen, filtered under the protection of nitrogen, washed with isopropyl ether, and the wet product was dried under reduced pressure below 35°C to obtain 109 g of the product, with a yield of 94.7%.

[0048] 2, the p...

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Abstract

The invention discloses a preparation method of sulfamic acid methyl ester. The preparation method comprises following steps: 1, chlorosulfonyl isocyanate is introduced into a reaction container, nitrogen gas protection is adopted, stirring is carried out, the temperature is reduced through cooling to -15 to -10 DEG C, formic acid is added drop by drop so as to obtain chlorosulfonamide; 2, chlorosulfonamide, a reaction solvent, and 4-dimethylaminopyridine are introduced into another reaction container, nitrogen gas protection is adopted, cooling is carried out, the temperature is reduced through cooling to -5 to 0 DEG C, methanol and an organic base are added drop by drop, after adding, stirring reaction is carried out, and a silica gel column is adopted for chromatography purification so as to obtain a finished product. The preparation method are simple in steps, and low in cost, and are suitable for large scale preparation. The content of prepared sulfamic acid methyl ester is 97.0% or higher, yield is 70% or higher, theory base is provided for medicine safe using, effective data support is provided for quality standards of medicines such as cefoxitin, and effective guarantee is provided for medicine safe clinical using.

Description

technical field [0001] The invention relates to a preparation method of methyl sulfamate, belonging to the field of impurity analysis in drug synthesis. Background technique [0002] Cefoxitin, the chemical name is (6R,7S)-3-carbamoyloxymethyl-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido] -5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is a semi-synthetic cephamycin antibiotic developed by Merck Company of the United States. [0003] The synthetic method of cefoxitin is as follows: [0004] [0005] During the synthesis process, chlorosulfonyl isocyanate (CSI) will be used, and there may be a by-product sulfamate, which is a genotoxic impurity, and its content needs to be checked in the finished product. [0006] Not limited to cefoxitin, in the pharmaceutical process, all reagents that use sulfamic acid derivatives in the reaction process may produce sulfamate by-products, and their content needs to be checked. [0007] In the process of new drug research and deve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/34C07C307/02
CPCC07C303/34C07C307/02
Inventor 邵倩何东贤杨治国李艳
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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