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A kind of preparation method of cefsulapix

A technology of fesulfonic acid and sulfophenylacetic acid, which is applied in the field of preparation of cefsulofenac acid, can solve the problems of unstable intermediate, unstable acid chloride, equipment corrosiveness, etc., and achieves high product yield and stable process , easy to operate effect

Active Publication Date: 2019-02-12
CHENGDU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because sulfophenylacetyl chloride is difficult to prepare, or the acid chloride is unstable, or the intermediate is unstable in the subsequent reaction, and the equipment is corrosive, there are many deficiencies in the current process

Method used

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  • A kind of preparation method of cefsulapix
  • A kind of preparation method of cefsulapix
  • A kind of preparation method of cefsulapix

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preparation example Construction

[0026] A kind of preparation method of cefsulapixin of the present invention comprises the following steps: intermediate D-sulfophenylacetic acid or its salt (I) reacts with acylating agent to make mixed acid anhydride; key intermediate 7-PACA (II) is Dissolve in a solvent at a certain temperature under the action of a base to obtain a 7-PACA solution; add the mixed acid anhydride solution dropwise into the 7-PACA solution, fully react and post-process to obtain ceftriaxone;

[0027]

[0028] Among them, R 1 is H, Li, Na, K, Mg or Ca; R 2 Is trimethylamine, triethylamine, diisopropylethylamine or N-methylmorpholine; R 3 -Cl is: methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, butyl chloroformate, pivaloyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride.

[0029] Further, the preparation method of the cefsulapix is ​​specifically:

[0030] Step 1, the preparation of D-sulfophenylacetic acid mixed anhydride

[00...

Embodiment 1

[0048] Step 1, the preparation of D-sulfophenylacetic acid mixed anhydride

[0049] Add 165.2 grams (0.6937mol) of D-sulfophenylacetic acid sodium salt into 800mL dichloromethane and 80mL DMF, cool down to -15°C, add dropwise 19.2mL (0.1338mol) of triethylamine, control the temperature below -10°C, drop Add 76.8mL of pivaloyl chloride (0.6243mol), keep stirring for 3h to obtain a mixed anhydride solution of D-sulfophenylacetic acid;

[0050] Step 2, preparation of 7-PACA solution

[0051] Add 310.8 g (0.6937 mol) of 7-PACA into a mixed solvent of 1500 mL of purified water and 1500 mL of acetone, cool down to below 0°C, add 175.5 g (1.734 mol) of triethylamine, control the temperature below 0°C, and dissolve 7-PACA to obtain 7-PACA solution;

[0052] Step 3, the preparation of cefsulapix

[0053] Add the mixed anhydride solution of D-sulfophenylacetic acid into the 7-PACA solution, and react for 60 minutes. During the process, use triethylamine to maintain the pH6-7, fully r...

Embodiment 2

[0055] Step 1, the preparation of D-sulfophenylacetic acid mixed anhydride

[0056] Add 177.2 grams (0.6937mol) of D-sulfophenylacetic acid potassium salt into 800mL dichloromethane / 80mL N, N-dimethylacetamide, cool down to -15°C, add dropwise 82.3 grams (1.04mol) of pyridine, and control the temperature to Below -10°C, add 181.1 g (1.3874 mol) of methanesulfonyl chloride dropwise, and keep stirring for 1 hour to obtain a mixed anhydride solution of D-sulfophenylacetic acid;

[0057] Step 2, preparation of 7-PACA solution

[0058] Add 103.5 grams (0.2312mol) of 7-PACA to 300 milliliters of N,N-dimethylacetamide, cool down to -20°C, add 144.7 milliliters (1.156mol) of tetramethylguanidine, and control the temperature below -10°C, 7- PACA is dissolved to obtain 7-PACA solution;

[0059] Step 3, the preparation of cefsulapix

[0060] Add the mixed anhydride solution of D-sulfophenylacetic acid into the 7-PACA solution, and react for 60 minutes. During the process, use tetramet...

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Abstract

The present invention discloses a Preparing method of Cefsulodin, comprising the steps of Intermediate D-alpha-Sulfophenylacetic acid or its salt with acylating agent to form mixed acid anhydride; Key intermediate 7-PACA dissolved in the solvent in the organic base or inorganic base under the a certain temperature to get 7-PACA solution; dropping mixed acid anhydride solution into 7- PACA solution, and to obtain the Cefsulodin after full reaction and treatment. The method adopts the new synthetic method to carry out the 7-position condensation reaction with the mixed acid anhydride method. The new method has mild condition, stable process and easy operation, which is helpful in solving unstable process problems caused by hard production of Sulfophenylacetyl chloride, unstable Acyl chloride, or the instability of the intermediate in the subsequent reaction.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of cefsulapix. Background technique [0002] In 1964, the first cephalosporin, cephalosporin, was launched on the market. Since then, cephalosporin drugs have developed vigorously, and more than 60 types have been produced and sold globally. Cefsulodin belongs to the third-generation cephalosporin antibiotics. The English name is cefsulodine, also known as cephalosporin sulfapyridone, daxshulin, cefsuloprazone, etc. It was developed by Takeda Pharmaceutical Company of Japan and is the first anti-Pyosulodine Bacillus cephalosporin antibiotics for injection. Clinically, it is mainly used for various secondary infections of sepsis, pneumonia, bronchitis, bronchiectasis complications, pyelonephritis, cystitis, peritonitis, trauma or burn caused by Pseudomonas aeruginosa. The medicinal form is the sodium salt, namely cefsulprome sodium, th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/06C07D501/54
CPCC07D501/06C07D501/54
Inventor 陈林李江红石克金苟小军黄啸任凤英杨晨王炜刘嵬张淋淋
Owner CHENGDU UNIV
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