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Method for synthesizing cephalosporin

A technology of cephalosporin and synthesis method, which is applied in the field of medicine, can solve the problems of 7-ADCA dissolution difficulty, low yield and content of cephalosporin products, etc., and achieve the effect of shortening the dissolution time and improving the yield and purity

Pending Publication Date: 2019-04-12
NORTH CHINA PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is exactly to provide a kind of synthetic method of cephalosporin, to solve 7-ADCA dissolving difficulty in existing synthetic technology, the problem that the synthetic cephalosporin product yield and content are relatively low

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1) Put 50mL of dichloromethane and 10.0g of 7-ADCA superfine powder with d(0.5)=1.36μm into a 100mL reaction bottle in turn, and cool down to -25°C;

[0038] 2) Add 6.2 mL of TMG dropwise for 5 minutes at a temperature of -25±1°C;

[0039] 3) At a temperature of -25±1°C, heat and dissolve for 25 minutes to obtain a solution; then cool down to -40°C for use;

[0040] 4) Put 50mL of dichloromethane and 14.1g of Dunn's salt of dihydrophenylglycine into a 250mL three-necked flask in sequence, cool down to -40°C, then add 15mL of DMA, 0.1mL of tetramethylpyridine, and 6.5mL of pivaloyl chloride;

[0041] 5) React at a temperature of -15~-20°C for 30 minutes to obtain a mixed anhydride solution; cool down to -50°C for use;

[0042] 6) Pour the solution obtained in step 3) into the mixed anhydride solution, and stir and keep warm for 0.5-2.5 hours at -35±5°C;

[0043] 7) Add 1.2mL ethylenediamine and stir for 10 minutes;

[0044] 8) Add 50mL of purified water and 10mL of co...

Embodiment 2

[0065] 1) Put 50mL of dichloromethane and 10.0g of 7-ADCA superfine powder with d(0.5)=1.36μm into a 100mL reaction bottle in turn, and cool down to -25°C;

[0066] 2) At a temperature of -25±1°C, add 7.2 mL of DBU dropwise for 3 minutes;

[0067] 3) At a temperature of -15±1°C, heat and dissolve for 10 minutes to obtain a solution; then cool down to -40°C for use;

[0068] 4) Put 50mL of dichloromethane and 14.1g of Dunn's salt of dihydrophenylglycine into a 250mL three-necked flask in sequence, cool down to -40°C, then add 15mL of DMA, 0.1mL of tetramethylpyridine, and 6.5mL of pivaloyl chloride;

[0069] 5) React at a temperature of -15~-20°C for 30 minutes to obtain a mixed anhydride solution; cool down to -50°C for use;

[0070] 6) Pour the solution obtained in step 3) into the mixed anhydride solution, and stir and keep warm for 0.5-2.5 hours at -35±5°C;

[0071] 7) Add 1.2mL ethylenediamine and stir for 10 minutes;

[0072] 8) Add 50mL of purified water and 10mL of con...

Embodiment 3

[0079] 1) Put 50mL of dichloromethane and 10.0g of 7-ADCA superfine powder with d(0.5)=8.91μm into a 100mL reaction bottle in turn, and cool down to -25°C;

[0080] 2) At a temperature of -25±1°C, add 6.2 mL of TMG dropwise for 3 minutes;

[0081] 3) At a temperature of -10±1°C, heat and dissolve for 28 minutes to obtain a solution; then cool down to -40°C for use;

[0082] 4) Put 50mL of dichloromethane and 14.1g of Dunn's salt of dihydrophenylglycine into a 250mL three-necked flask in sequence, cool down to -40°C, then add 15mL of DMA, 0.1mL of tetramethylpyridine, and 6.5mL of pivaloyl chloride;

[0083] 5) React at a temperature of -15~-20°C for 30 minutes to obtain a mixed anhydride solution; cool down to -50°C for use;

[0084] 6) Pour the solution obtained in step 3) into the mixed anhydride solution, and stir and keep warm for 0.5-2.5 hours at -35±5°C;

[0085] 7) Add 1.2mL ethylenediamine and stir for 10 minutes;

[0086] 8) Add 50mL of purified water and 10mL of c...

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PUM

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Abstract

The invention provides a method for synthesizing cephalosporin. The method comprises the following steps that 1, 7-ADCA dissolving liquid is prepared, wherein a solution and 7-ADCA submicron powder are put in a reaction tank, cooling is carried out, at the temperature of 10 DEG C or below, a solvent is added, heat preservation and reacting are carried out, and the 7-ADCA dissolving liquid is obtained; b, N-Phenylglycine potassium salt and pivaloyl chloride react in advance to prepare a mixed anhydride solution; c, the 7-ADCA dissolving liquid prepared in step a is added to the mixed anhydridesolution, a condensation reaction is carried out at the temperature of -40 DEG C to -30 DEG C, and a condensed solution is obtained; d, the condensed solution obtained in step c is subjected to hydrolysis and crystallization, and cephalosporin is obtained. According to the method for synthesizing cephalosporin, the 7-ADCA submicron powder raw material is used, the specific dissolving temperature is adopted in cooperation, the yield of the final cephalosporin product is greatly increased, the purity of the final cephalosporin product is greatly improved, and the method is suitable for industrial popularization and application.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing cephalosporins. Background technique [0002] As one of the three major nuclei (7-ADCA, 6-APA, 7-ACA), 7-ADCA (7-aminodesacetoxycephalosporanic acid) is cephalexin, cephradine, cefadroxil and ceftazidime pivoxil Proactive substances of cephalosporins. Due to the special physical and chemical properties of 7-ADCA: heat sensitivity, instability in the case of acid and alkali, resulting in destruction and decomposition, and insoluble in organic solvents, when the above drugs are synthesized with 7-ADCA as the precursor active substance, a certain dissolution temperature is required. Organic strong bases such as DBU, TMG, TEA and other co-solvents are dissolved in dichloromethane, acetone and other solvents to solvate them and then undergo condensation reactions with other side chains to obtain different target products. In view of the thermos...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/06
CPCC07D501/06C07D501/36
Inventor 米振瑞段志钢王平刘明儒薛同山仝雪霞付忠心冯立峰敦海红于辉崔世勇
Owner NORTH CHINA PHARMA COMPANY
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