Method for synthesizing antibiotic cefepime hydrochloride

A technology of cefepime hydrochloride and a synthetic method, which is applied in antibacterial drugs, organic chemistry, etc., can solve problems such as harsh reaction conditions, high raw material costs, and long reaction time, and achieve simple process conditions, stable product quality, and product yield. high rate effect

Active Publication Date: 2011-01-26
国药集团致君(苏州)制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In these known synthetic methods, there are the disadvantages of high raw material cost and difficult availability, harsh reaction conditions and long reaction time, which are unfavorable for continuous and large-scale industrial production
The synthesis technology of cefepime hydrochloride is relatively difficult. Although there has been some progress in the research of its synthesis technology in China, the cost is still high and the quality is not good.

Method used

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  • Method for synthesizing antibiotic cefepime hydrochloride
  • Method for synthesizing antibiotic cefepime hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The synthesis of embodiment 1 7-MPCA

[0025] In the flask, add 40g (0.14mol) 7-aminocephalosporanic acid (7-ACA), 27.4g (0.17mol) hexamethyldisilane, 240mL dichloromethane, and stir at 30-35°C for 6-7 hours . Then the temperature was lowered to -10°C, 27 mL of N,N-diethylaniline was added, 61.2 g (0.3 mol) of iodotrimethylsilane was added dropwise, and the reaction was stirred for 1-2 hours.

[0026] Then, 20.4 g (0.24 mol) of N-methylpyrrolidine was added dropwise. After the dropwise addition was completed, the mixture was incubated for 1 hour, and then naturally raised to room temperature for overnight reaction.

[0027] After the reaction, add 50mL of isopropanol + 160mL of concentrated hydrochloric acid + 300mL of deionized water mixture dropwise. During the dropwise addition, control the temperature of the feed liquid to not exceed 15°C, and stir at this temperature for 10 minutes until the solid is completely dissolved. Then the liquids were separated, the orga...

Embodiment 2

[0029] The preparation of embodiment 2 cefepime hydrochloride

[0030] In the flask, add 550mL of deionized water, 250mL of DMF, 39g of 7-MPCA and 80g of AE active ester, then cool to -5°C, and add 37mL of triethylamine dropwise. During the dropping process, the temperature does not exceed 0°C. After the dropwise addition was complete, stirring was continued for 1 hour. Then the temperature was raised to 15-20° C. for 6 hours, and the reaction solution was extracted three times with 600 mL of dichloromethane. The organic phase was back-extracted with 300 mL deionized water, and the aqueous phase was combined, and the aqueous phase was decolorized with activated carbon.

[0031] The aqueous phase was quickly filtered through an aluminum oxide column, then added 40.6mL of 6mol / L hydrochloric acid, stirred at room temperature for 1 hour, then added 2.5L of acetone, stirred for 4 hours, filtered, the filter cake was washed with acetone, and dried 52.6 g of cefepime hydrochloride...

Embodiment 3

[0035] 7-ACA is placed in the organic solvent N, N-dimethylformamide (DMF) or N, N-dimethylacetamide (DMAC), and 1 times of hexamethyldisilazane is added to the amount of 7-ACA and 0.1% iodotrimethylsilane in the amount of 7-ACA, and reflux for 2 hours to obtain an orange-yellow reaction solution, cool to room temperature, add trimethyliodosilane dropwise, then add N-methylpyrrolidine dropwise, and then Solution to obtain 7-MPCA; The weight ratio of 7-ACA and organic solvent is 1:1.

[0036] The obtained 7-MPCA and AE active ester are mixed and placed in a mixed solvent with a volume ratio of 1:5 of an organic solvent and water, and in a mixed solvent of an organic solvent and water, adjust the pH with alkali sodium hydroxide or potassium hydroxide When the value reaches 7.0, it dissolves and undergoes an acylation reaction to obtain a cefepime solution, and the temperature of the acylation reaction is -10°C. The weight ratio of the 7-MPCA and AE active ester is 1:1.5, and the ...

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Abstract

The invention relates to a synthesis method of cefepime dihydrochloride that is a bacteriophage. 7-amin cethalosporanic acid (7-ACA) is used as starting material and reacts with hexamethyldisilane amine (HMDS) and iodotrimethylsilane (TMSI) first to obtain 7-ACA for protecting amino and carboxyl; then 7-ACA, amino and carboxyl of which are protected, reacts with iodotrimethylsilane and N-methylpyrrolidine to synthesize (6R, 7R)-7-amino-3-((1-methyl-1-pyrrolidine) methyl) cephalosporin-3-alkene-4-carboxylic acid hydrochloride (7-MPCA) through a one-pot method; 7-MPCA reacts with AE active ester to obtain a product of cefepime dihydrochloride through acidylation reaction and salifying reaction. Compared with the existing technical route, the synthesis method has the advantages that the process conditions are simple, the operation is convenient, the product yield is high, the product quality is stable, the method is suitable for the large-scale industrialized production, etc.

Description

technical field [0001] The invention relates to a synthesis method of cefepime hydrochloride, a fourth-generation cephalosporin antibiotic, and belongs to the field of medicines. Background technique [0002] Cefepime was first developed by Bristol-Myers Squibb and first launched in Sweden in 1993. As the fourth-generation cephalosporin for injection, cefepime shows broad-spectrum antibacterial activity against Gram-positive bacteria, negative bacteria and anaerobic bacteria, and has enhanced resistance to Gram-positive bacteria compared with previous third-generation varieties The activity of bacteria, especially the activity of Streptococcus and Streptococcus pneumoniae is greatly enhanced. It is currently used clinically to prevent and treat a variety of bacterial infectious diseases. [0003] When cefepime is separated from the solution, it is in an amorphous state, has poor stability and is difficult to store. Making cefepime into the corresponding hydrochloride can ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/46A61P31/04
Inventor 史利军孙元强陈德华
Owner 国药集团致君(苏州)制药有限公司
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