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Preparation method of 3-methylol cefazolin

A technology of hydroxymethyl cefazolin and methyl morpholine, applied in the field of chemical drug synthesis, can solve the problems of unfavorable impurity research, low content of 3-hydroxymethyl cefazolin, inconvenient separation, etc., to reduce solvent residue, Improve product conversion rate and ensure the effect of activity

Active Publication Date: 2020-05-08
HARBIN HEJIA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The content of 3-hydroxymethyl cefazolin produced during the synthesis of cefazolin sodium is relatively low, which is inconvenient for separation; and there is no synthesis and preparation method for 3-hydroxymethyl cefazolin at present, which is not conducive to the related research on impurities

Method used

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  • Preparation method of 3-methylol cefazolin
  • Preparation method of 3-methylol cefazolin
  • Preparation method of 3-methylol cefazolin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] a. Preparation of 7-ACA solution: Add 250ml chloroform and 35.4g 7-ACA (molecular weight 272.3, 0.13mol) to a 500ml four-necked flask under the condition of -20~-40℃, and then drop after temperature control at -15~20℃ Add 23.0g of tetramethylguanidine (molecular weight: 115.18, 0.20mol) until the 7-ACA solution is obtained after the solution is clear, and then the temperature is lowered to -25°C for use;

[0028] b. Preparation of tetrazolium acetic acid mixed anhydride solution: under the condition of -20~-60℃, add 280ml chloroform, 17.5g tetrazolium acetic acid (molecular weight 128.09, 0.14mol) and 19.3gN in another 1L four-necked flask. , After N-dimethylacetamide (molecular weight 87.12, 0.22mol), control the temperature at -20~-25℃, stir for 10min, and add 14.0g triethylamine (molecular weight 101, 0.14mol) dropwise in about 15min. After the tetrazolium acetic acid is dissolved, add 0.4g pyridine and 19.5g pivaloyl chloride (molecular weight 155.0, 0.13mol) successiv...

Embodiment 2

[0035] a. Preparation of 7-ACA solution: Add 400ml of dichloromethane and 35.4g of 7-ACA to a 500ml four-necked flask at -20~-40℃, add tetramethylguanidine dropwise after controlling the temperature at -15~20℃ 20.0g, until the 7-ACA solution is obtained after the solution is clarified, then the temperature is lowered to -25°C for use

[0036] b. Preparation of tetrazolium acetic acid mixed anhydride solution: under the condition of -20~-60℃, add 350ml dichloromethane, 21.78g tetrazolium acetic acid (0.17mol) and 26.5gN in another 1L four-neck flask. After N-dimethylacetamide (0.30mol), control the temperature at -20~-25℃ and stir for 10min, then add 21.5g triethylamine (0.20mol) dropwise for about 15min. When the tetrazolium acetic acid is dissolved, Then add 1.74g 2,6-lutidine and 21.7g pivaloyl chloride (0.14mol) successively, control the temperature at -20~-28℃ and stir for 1.5h to obtain the tetrazolium acetic acid mixed anhydride solution;

[0037] c. Preparation of 3-hydroxy...

Embodiment 3

[0043] a. Preparation of 7-ACA solution: Add 320ml of dichloromethane and 35.4g of 7-ACA in a 500ml four-necked flask at -20~-40℃, add tetramethylguanidine dropwise after controlling the temperature at -15~20℃ 18.1g, until the 7-ACA solution is obtained after the solution is clarified, then the temperature is lowered to -25°C for use;

[0044] b. Preparation of tetrazolium acetic acid mixed anhydride solution: Add 450ml dichloromethane, 25.0g tetrazolium acetic acid and 28g N,N-dimethyl ethyl into another 1L four-neck flask at -20~-60℃ After amide, after stirring at -20~-25℃ for 10min, 22.5g triethylamine was added dropwise in about 15min. When the tetrazolium acetic acid is dissolved, then 2.0g N-methylmorpholine and 23.25g special Valeryl chloride, temperature-controlled -20~-28℃, stirred for 1.5h to obtain tetrazolium acetic acid mixed anhydride solution;

[0045] c. Preparation of 3-hydroxymethyl cefazolin:

[0046] 1. Transfer the 7-ACA solution to the tetrazolium acetic acid ...

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Abstract

The invention discloses a preparation method of 3-methylol cefazolin. The preparation method comprises the following steps of dropwise adding a 7-ACA solution to a 1H-tetrazole-1-acetic acid anhydridemixing solution, performing a condensation reaction, after the reaction, adjusting pH phase splitting, then adding purified water, performing phase splitting, combining water phases, then adding an organic solvent for phase splitting, and performing concentration to obtain a primary purified water phase and a secondary purified water phase; and after adjusting pH of the secondary purified water phase, adding cephalosporin-C deacetylase, then adding a dispersing agent to the filtered water phase, then reducing the temperature, performing filtration after crystal formation, performing washing,and performing drying until the moisture is smaller than 1.0%. According to the preparation method disclosed by the invention, a traditional strong basic hydrolysis technology is substituted, waste water discharge can be reduced by 80%, the cephalosporin-C deacetylase after enzymolysis can be in cyclic utilization, solvent remains are smaller than 5%, the concentration weight reduction ratio is 2%-5%, the influence of various solvents on the enzymatic activity of the cephalosporin-C deacetylase is thoroughly eliminated, the consumption of enzymes and the activity of the enzymes being utilizedonce again are guaranteed, the cost is reduced, the reaction condition is mild, the conversion rate of products is as high as 90% or above, the purity of the products is not less than 98%, and subsequent structure elucidation and pharmacological research are facilitated.

Description

Technical field [0001] The invention belongs to the field of chemical drug synthesis, and specifically relates to a preparation method of 3-hydroxymethyl cefazolin, a key known impurity in the quality research of cefazolin sodium. Background technique [0002] Cefazolin Sodium (the English generic name is Cefazolin Sodium) was first developed by Fujisawa Pharmaceutical Co., Ltd., and was first marketed in Japan in 1971. It is the first-generation cephalosporin with a broad antibacterial spectrum and is an international and domestic clinical medicine treatment. The leading antibiotic of Langerhans-positive bacteria is clinically applied to infections of the respiratory tract, urogenital system, skin and soft tissues, bones and joints, and biliary tract caused by sensitive bacteria. It can also be used for endocarditis, sepsis, pharynx and ear infections. It can also be used as a preventive medication before surgery. [0003] Most of the synthetic routes of cefazolin sodium at home ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/06C12P35/00C07D501/34C07D501/06C07D501/12
CPCC07D501/34C07D501/06C07D501/12C12P35/06C12P35/00
Inventor 祁振海金石程广业周玲玲李秀珠孙收杰赵飞
Owner HARBIN HEJIA PHARMA CO LTD
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