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Method for preparing cephalosporin propylene

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

Inactive Publication Date: 2008-07-23
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-triphenylphosphonomethylene-4-cephalosporanic acid trimethylsilyl ester

[0036] Add 100 mL of diethyl ether into a clean 250 mL reaction flask, add 12 g of 7-ACA, 12.6 g of BSA, and 0.15 g of imidazole with stirring, and heat to 37°C under the protection of an inert gas, and maintain reflux for 7 hours. After the reflux was completed, the material was cooled to 5°C, and 13.5 g of triphenylphosphine was added, followed by 8.8 g of iodotrimethylsilane, and the temperature was maintained at 4°C. React at this temperature for about 6 hours at a constant temperature. 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-triphenylphosphonomethylene-4-cephalosporanic acid is obtained A mixed solution of trimethylsilyl ester (II).

Embodiment 2

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

[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 point of the reaction to obtain a mixed solution of compound 7-trimethylsilyl amino-3-(prop-1-enyl)-4-cephalosporanic acid trimethylsilyl ester (III) , cooled to -15°C for later use.

Embodiment 3

[0040] Add 50mL of dichloromethane into a clean 100mL reaction bottle, then add 5.2g of D-p-hydroxyphenylosysine Deng potassium salt at one time, stir for 10 minutes, cool down to -50°C, add DMF 10mL, methanesulfonic acid 0.05g, N-methylmorpholine 0.01g, continue to cool to -60°C, add 1.8g of ethyl chloroformate, keep the reaction at -40°C for 2 hours, then immediately add the mixed solution in the 100mL reaction bottle to the step In the mixed solution of 2, the temperature was slowly raised to -5°C, reacted for 30 minutes, and then slowly raised to room temperature to obtain a 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 antibiotic medicine, in particular to a process for synthesizing antibiotic medicine cefprozil by using 7-ACA (7-aminocephalosporanic acid) as a starting material. [0002] Background technique [0003] Cefprozil (cefprozil), the chemical name is (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, medicinal as a monohydrate, is a broad-spectrum cephalosporin antibacterial drug developed by Bristol-Myers Squibb , for G + , G - Bacteria and anaerobic bacteria have strong antibacterial activity, against G + Bacterial activity is particularly prominent. [0004] At present, the reported method for synthesizing cefprozil basically adopts GCLE and GCLH routes, such as U.S. Patent US4694079, Chinese Patent Publication No. CN101024649, "Synthesis of Cefprozil" - Chinese Journal of Pharmaceutical Industry. 2004, 35 (7): 388, etc. ...

Claims

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Application Information

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Patent Type & Authority Applications(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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