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A kind of preparation method of cefotiam dihydrochloride

A technology of dihydrochloride and cephalosporin, which is applied in the field of preparation of cephalosporin drugs, can solve the problems of low product yield, inapplicability to industrialized large-scale production, and difficult control of the production process, and achieve high yield, easy control, The effect of uniform product quality

Active Publication Date: 2017-08-25
NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to provide a kind of preparation method of cefotiam dihydrochloride, to solve the problems that the product yield in the prior art is low, the production process is not easy to control and is not suitable for industrialized large-scale production

Method used

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  • A kind of preparation method of cefotiam dihydrochloride
  • A kind of preparation method of cefotiam dihydrochloride
  • A kind of preparation method of cefotiam dihydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0037] a. Add 26.8g of AFTA into a mixed solvent prepared by 22ml of DMA and 90ml of dichloromethane, cool down to -15~-5°C, slowly add 15.0g of triethylamine, stir, and react for 15~30min. It fully forms a salt; cool the reaction liquid to -50~-45°C, add an appropriate amount of 4-picoline, quickly add 18.1g of pivaloyl chloride, control the temperature at -16~-12°C, and react for 1 hour to obtain a mixture of AFTA Anhydride reaction solution.

[0038] b. Add 50g of 7-AMT into 200ml of acetonitrile, lower the temperature to -5°C, slowly add 22.8g of triethylamine, then raise the temperature to 3°C~10°C, stir and dissolve for 10~20min to obtain a solution of 7-AMT .

[0039] c. Add the solution of 7-AMT to the mixed acid anhydride reaction solution of AFTA at -40~-35°C within 15~45min, and then control the temperature at -20~-15°C to carry out the acylation condensation reaction 3~8h, take a sample to detect that the residual amount of 7-AMT is ≤3.8mg / ml to end the reaction,...

Embodiment 2

[0042]a. Add 26.8g of AFTA into a mixed solvent prepared by 35ml of DMF and 110ml of dichloromethane, cool down to -15~-5°C, slowly add 15.0g of triethylamine, stir, and react for 15~30min to make It fully forms a salt; cool the reaction solution to -50~-45°C, add an appropriate amount of 3-picoline, quickly add 18.1g of pivaloyl chloride, control the temperature at -16~-12°C, and react for 1 hour to obtain a mixture of AFTA Anhydride reaction solution.

[0043] b. Add 50g of 7-AMT into 300ml of dichloromethane, cool down to -5°C, slowly add 25.16g of tetramethylguanidine, slowly raise the temperature to 0°C~5°C, stir and react for 5~15min to obtain 7-AMT solution.

[0044] c. Add the solution of 7-AMT to the mixed acid anhydride reaction solution of AFTA at -40~-35°C within 10~15min, then raise the temperature to -25~-20°C to carry out the acylation condensation reaction 3 ~8h, take a sample to detect that the residual amount of 7-AMT is ≤3.8mg / ml to end the reaction, add 1...

Embodiment 3

[0048] a. Add 26.8g of AFTA into a mixed solvent prepared by 35ml of DMF and 110ml of dichloromethane, cool down to -10~0°C, slowly add 10.9g of diethylamine, stir, and react for 5~20min to make it Fully salt; cool the reaction solution to -50~-45°C, add an appropriate amount of 3-picoline, quickly add 18.1g of pivaloyl chloride, control the temperature at -30~-22°C, and react for 2 hours to obtain the mixed anhydride of AFTA The reaction solution.

[0049] b. Add 50g of 7-AMT into 300ml of dichloromethane, cool down to -5°C, slowly add 16.5g of diethylamine, raise the temperature to 6°C~10°C, stir and dissolve for 30~40min to obtain the dissolution of 7-AMT liquid.

[0050] c. Add the solution of 7-AMT to the mixed acid anhydride reaction solution of AFTA at -40~-35°C within 10~15min, then raise the temperature to -25~-20°C to carry out the acylation condensation reaction 3 After ~8h, the residual amount of 7-AMT was detected to be ≤3.8mg / ml by sampling to end the reaction....

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Abstract

The invention provides a preparation method of cefotiam dihydrochloride. The preparation method of cefotiam dihydrochloride comprises the following steps: salifying AFTA and organic alkali and subsequently reacting with an acylation reagent to prepare a mixed anhydride reaction solution of AFTA; protecting carboxyl of 7-AMT in an organic solvent to prepare a dissolving solution of 7-AMT; then adding the dissolving solution of 7-AMT into the mixed anhydride reaction solution of AFTA to carry out acylation condensation reaction; after the reaction is ended, adding water and hydrochloric acid for hydrolyzing and separating water phase to prepare an acid solution of formyl cefotiam; further hydrolyzing formyl cefotiam under the acid condition to prepare cefotiam, then salifying the cefotiam prepared by hydrolyzing with hydrochloric acid, crystallizing, filtering, washing and drying to prepare cefotiam dihydrochloride. The preparation method of cefotiam dihydrochloride is simple in process and high in efficiency, the production process is mild and easily controlled, and the prepared cefotiam dihydrochloride is uniform and stable in quality; therefore the preparation method of cefotiam dihydrochloride is applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of cephalosporin medicine, in particular to a preparation method of cefotiam dihydrochloride. Background technique [0002] Cefotiam dihydrochloride is a second-generation cephalosporin antibiotic for injection. Its effect on Gram-positive bacteria is similar to that of Cefazolin. It also has antibacterial effects on Enterobacter, Citrobacter, and indole-positive Proteus. Its mechanism of action is to bind to penicillin-binding proteins (PBPs) on the bacterial cell membrane, acylate transpeptidase, inhibit the synthesis of bacterial septum and cell wall, and affect the cross-linking of mucin components in the cell wall, thereby inhibiting cell division and growth , the bacterial morphology becomes elongated, and finally dissolves and dies. [0003] The synthetic route of cefotiam dihydrochloride usually uses 7-aminocephalosporanic acid (7-ACA) as a raw material, and first introduces the corresponding side...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36C07D501/04
CPCC07D501/04C07D501/36
Inventor 胡国刚魏青杰蒋晓声孙燕许永红陈建军王亚其刘亚林彭贺涛
Owner NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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