Method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester

A technology of chloromethyl cephalenic acid and p-methoxybenzyl ester, which is applied in the field of cephalosporin antibiotic drug synthesis, can solve the problems of difficult control of reaction conditions, high technical difficulty, influence on yield and the like, and achieves outstanding substantive characteristics , The effect of reducing production cost and easy operation

Inactive Publication Date: 2011-05-18
SHANDONG FANGXING SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this method is technically difficult, and the reaction conditions are difficult to control. If the reaction conditions are not properly controlled, the reaction will be difficult to proceed smoothly, which will cause more side reactions and affect the yield.

Method used

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  • Method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester
  • Method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0014] Add 40kg of penicillin sulfoxide ester, 18kg of ammonium benzenesulfinate, and 13kg of 2-mercaptobenzothiazole into the reaction tank, then add 120kg of dichloromethane, stir and heat up to react at 38°C for 4 hours, and under normal pressure at 39°C The solvent was distilled off to generate the azetidinone thiosulfinate intermediate; the temperature of the reaction tank was cooled with tap water for 1 hour, and then 150 kg of dichloromethane was pumped in, and the saturated ice brine was cooled to -15°C with stirring, and then added 30kg of trichloroisocyanic acid was stirred and reacted at -15°C for 1 hour to generate azetidinone thiosulfinate allylic chlorination product; after the reaction solution was evaporated to dryness under reduced pressure at 0.06MPa, di Methylformamide 150kg, start stirring and let saturated ice brine cool down to -15°C, add 15kg of 16% ammonia water, stir and react at -15°C for 2.5 hours, add water 200kg and dichloromethane 150kg to the reac...

Embodiment 2

[0016] Add 40kg of penicillin sulfoxide ester, 18kg of ammonium benzenesulfinate, and 13kg of 2-mercaptobenzothiazole into the reaction tank, then add 120kg of dichloromethane, start stirring and heat up at 40°C for 4.5 hours, and under normal pressure at 42°C The solvent was distilled off to generate the azetidinone thiosulfinate intermediate; the temperature of the reaction tank was cooled with tap water for 1.5 hours, and then 150 kg of dichloromethane was sucked in, and the saturated ice brine was cooled to -20°C with stirring, and added 30kg of trichloroisocyanic acid was stirred and reacted at -20°C for 1.2 hours to generate azetidinone thiosulfinate allylic chlorination product; after the reaction solution was evaporated to dryness under reduced pressure at 0.08MPa, di Methylformamide 150kg, start stirring and let saturated ice brine cool down to -20°C, add 15kg of 18% ammonia water, stir and react at -20°C for 3 hours, add water 200kg and methylene chloride 150kg to the...

Embodiment 3

[0018] Add 40kg of penicillin sulfoxide ester, 18kg of ammonium benzenesulfinate, and 13kg of 2-mercaptophenprothiazole into the reaction tank, then add 120kg of dichloromethane, start stirring and heat up at 39°C for 4.2 hours, and under normal pressure at 40°C The solvent was distilled off to generate the azetidinone thiosulfinate intermediate; the temperature of the reaction tank was cooled by tap water for 1.2 hours, and then 150 kg of dichloromethane was pumped in, and the saturated ice brine was cooled to -18°C with stirring, and added 30kg of trichloroisocyanic acid was stirred and reacted at -18°C for 1.1 hours to generate azetidinone thiosulfinate allylic chlorination product; after the reaction solution was evaporated to dryness under reduced pressure at 0.07MPa, di Methylformamide 150kg, start stirring and let saturated ice brine cool down to -18°C, add 15kg of 17% ammonia water, stir and react at -18°C for 2.8 hours, add water 200kg and dichloromethane 150kg to the ...

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Abstract

The invention belongs to the field of cephalosporin antibiotic medicaments, and in particular relates to a method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester (GCLE). The technical proposal is that the method comprises the following steps: reacting penicillin sulfoxide ester with ammonium benzene sulfinate and 2-mercaptobenzothiazole in dichloromethane, and steaming out a solvent at normal pressure to generate aza-cyclobutanone thiosulfinate intermediate; adding dichloromethane to the intermediate after cooling, stirring and introducing saturated brine ice for cooling, adding trichloro isocyanic acid for reaction so as to generate an allylic chlorination product of the aza-cyclobutanone thiosulfinate; and reducing the pressure and drying the allylic chlorination product by distillation, adding dimethyl formamide to the product, stirring and introducing saturated brine ice for cooling, adding ammonia for reaction, adding water and dichloromethane to the mixture, mixing and stirring the mixture, standing for layering, transferring a dichloromethane layer at the bottom layer to another reactor, and steaming out the solvent at the normal pressure to obtain a dry product which is the GCLE. The method has the advantages of mild reaction condition, few reaction steps, simple operation, short production cycle, and improved production efficiency.

Description

technical field [0001] The invention belongs to the field of synthesis of cephalosporin antibiotics, in particular to a synthesis method of p-methoxybenzyl 7-phenylacetamido-3-chloromethyl cephalosporanenoic acid. Background technique [0002] Cephalosporin antibiotics are a powerful new force in anti-infection drugs, which have the characteristics of high curative effect, small side effects, and strong antibacterial activity. Cephalosporins are a class of semi-synthetic antibiotics. The three major nuclei of traditional synthetic cephalosporins are 6-APA, 7-ACA and 7-ADCA, while 7-phenylacetamido-3-chloromethyl cephalosporin p-methoxybenzyl ester (GCLE for short) is another new type of cephalosporin nucleus intermediate raw material for the synthesis of cephalosporin drugs after 7-ACA and 7-ADCA, and is an important nucleus for the synthesis of cephalosporin antibiotics One, its structural formula is: [0003] [0004] The synthesis of GCLE mainly uses penicillin potas...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/24
Inventor 孙涛李秀兵叶红
Owner SHANDONG FANGXING SCI & TECH DEV
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