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Method for preparing cephalosporin propylene

A technology of cefprozil and acetone, which is applied in the field of preparation of antibiotic drugs, can solve problems such as unstable quality, hard to find raw materials, and low yield, and achieve the effects of high yield, low cost, and reduced loss

Inactive Publication Date: 2013-05-08
南通康鑫药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of this invention is to provide a new method for preparing cefprozil, which overcomes the problems of low yield, unstable quality and difficult raw materials in the existing method for preparing cefprozil, significantly improves the yield and reduces the cost. The process route is simple and fully meets the requirements of industrial production.

Method used

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  • Method for preparing cephalosporin propylene
  • Method for preparing cephalosporin propylene
  • Method for preparing cephalosporin propylene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 7-Trimethylsilylamino-3-triphenylphosphomethylene-4-cephalosporanic acid trimethylsilyl ester

[0036] Add 100 mL of ether to a clean 250 mL reaction flask, add 12 g of 7-ACA, 12.6 g of BSA, and 0.15 g of imidazole under stirring to 37° C. and maintain reflux for 7 hours. At the end of reflux, the material was cooled to 5°C, 13.5g of triphenylphosphorus was added, and then 8.8g of trimethylsilyl iodide was added, and the temperature was always maintained at 4°C. React at this temperature for about 6 hours. The disappearance of the raw material 7-ACA as detected by liquid chromatography is the end of the reaction, and the compound 7-trimethylsilylamino-3-triphenylphosphomethylene-4-cephalosporanic acid is obtained. A mixed solution of trimethylsilyl ester (II).

Embodiment 2

[0037] Example 2 Trimethylsilyl 7-trimethylsilylamino-3-(prop-1-enyl)-4-cephalosporanic acid

[0038] Keep the temperature of the mixed solution in step 1 between 4±1°C, add 5g of dry phenyllithium to it, stir for 20 minutes, then add 10.5mL of anhydrous acetaldehyde, control the temperature at -3±1°C for 15 hours Until the disappearance of compound (II) is the end of the reaction, a mixed solution of compound 7-trimethylsilylamino-3-(prop-1-enyl)-4-cephalosporanic acid trimethylsilyl ester (III) is obtained , Cool to -15℃ for later use.

Embodiment 3

[0040] Add 50mL of dichloromethane to a clean 100mL reaction flask, and then add 5.2g of D-p-hydroxyphenylglycine dun potassium salt in one go, stir for 10 minutes, cool to -50℃, add 10mL of DMF, and methylsulfonic acid 0.05g, 0.01g N-methylmorpholine, continue to cool to -60°C, add 1.8g ethyl chloroformate, keep the reaction at -40°C for 2 hours, and then immediately add the mixture in the 100mL reaction flask to the step In the mixed solution of 2, slowly increase the temperature to -5°C, react for 30 minutes, and then slowly increase to room temperature to obtain the mixed solution of compound (IV).

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Abstract

The invention discloses a preparation method of cefprozil, which comprises: 7-amin cethalosporanic acid (7-ACA) reacts with triphenyl phosphine to get 7- trimethylsilyl amino-3-triphenyl phosphate methylene-4-cethalosporanic acid trimethylsilyl ester through silanization protection and iodination reagent replacing under the condition of catalyst existing; WITTIG reaction is made for the product and acetaldehyde to get 7-trimethylsilyl amino -3-(propenyl-1-alkenyl)-4-cethalosporanic acidtrimethylsilyl ester; then the compound reacts with D-para hydroxybenzene glycine dane potassium salt to geta compound (6R, 7R)-7-[(2R)-2- ethoxycarbonyl-1-methyl - ethylene amino (4-trimethylsilyl oxyphenyl) acetamido group(amide)]-8-oxo-3- (1- propenyl)-5-thio-1- heterobicycle [4.2.0] octylene-2-ene-2-carboxylic acid trimethylsilyl ester; hydrolytic treatment is then used to get the cefprozil. The invent adopts the method of one pot and can participate in next reaction without separating intermediateproducts. The preparation method of cefprozil has the advantages of low cost, convenient operation and high overall yield, adapting to demands of industrial production.

Description

Technical field [0001] The invention relates to a preparation method of an antibiotic drug, in particular to a process for synthesizing the antibiotic drug cefprozil with 7-ACA (7-aminocephalosporanic acid) as a starting material. [0002] Background technique [0003] Cefprozil (cefprozil), chemical name (6R, 7R)-7-[(2R)-amino(4-hydroxyphenyl)acetamido]-8-oxo-3-(1-propenyl)-5 -Thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, as a monohydrate for medicinal purposes, is a broad-spectrum cephalosporin antibiotic developed by Bristol-Myers Squibb , For G + , G - The antibacterial activity of bacteria and anaerobic bacteria is very strong, and the G + Bacterial activity is particularly outstanding. [0004] At present, the reported methods for synthesizing cefprozil basically adopt GCLE and GCLH routes, such as US Patent US4694079, Chinese Patent Publication No. CN101024649, "Synthesis of Cefprozil"-Chinese Journal of Pharmaceutical Industry. 2004, 35(7): 388, etc. . The main ro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/22C07D501/04
Inventor 唐子安
Owner 南通康鑫药业有限公司
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