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Preparation method of cefprozil

A technology of cefprozil and its compounds, which is applied in the field of preparation of cefprozil, can solve the problems of high production cost and achieve the effects of low cost, improved yield and purity

Active Publication Date: 2019-01-18
湖北凌晟药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this kind of reaction mostly uses toxic reagents such as triphenylphosphine, and requires wittig reaction, the production cost is high, and there is still room for improvement in yield and purity.

Method used

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  • Preparation method of cefprozil
  • Preparation method of cefprozil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] A kind of preparation method of cefprozil, concrete steps are as follows:

[0025] Add 48.7g of the compound of formula Ⅰ and 16.8g of urotropine into acetic anhydride, stir and react at room temperature for 8 hours, and discharge the compound of formula Ⅱ; add the compound of formula Ⅱ into tetrahydrofuran, stir and dissolve, and then add 20g of ethylmagnesium bromide , reacted under stirring at 40°C for 2 hours, and discharged to obtain the compound of formula III; added the compound of formula III to toluene, then added 5.1 g of p-toluenesulfonic acid, refluxed for 5 hours, and obtained the compound of formula IV; added the compound of formula IV to tetrahydrofuran , then add 50ml of dilute hydrochloric acid with a mass concentration of 5%, react at room temperature for 1h, extract the reaction solution with ethyl acetate, and spin dry to obtain the compound of formula V; dissolve 17.3g of p-hydroxyphenylglycine in dichloromethane, add 16g of methyl chloride Methyl e...

Embodiment 2

[0027] A kind of preparation method of cefprozil, concrete steps are as follows:

[0028] Add 48.7g of the compound of formula I and 18g of urotropine into acetic anhydride, stir and react at room temperature for 6h, and discharge to obtain the compound of formula II; add the compound of formula II into tetrahydrofuran, stir and dissolve, then add 25g of ethylmagnesium bromide, Stir at 10°C for 4 hours, discharge to obtain the compound of formula III; add the compound of formula III to toluene, then add 4.5 g of p-toluenesulfonic acid, reflux for 5 hours, discharge to obtain the compound of formula IV; add the compound of formula IV to tetrahydrofuran, Then add 50ml of dilute hydrochloric acid with a mass concentration of 5%, react at room temperature for 1h, extract the reaction solution with ethyl acetate, and spin dry to obtain a compound of formula V; dissolve 17.3g of p-hydroxyphenylglycine in dichloromethane, add 16g of chloromethyl Methyl ether was reacted at 30°C for 1...

Embodiment 3

[0030] A kind of preparation method of cefprozil, concrete steps are as follows:

[0031] Add 48.7g of the compound of formula Ⅰ and 21g of urotropine into acetic anhydride, stir and react at room temperature for 5 hours, and discharge the compound of formula Ⅱ; add the compound of formula Ⅱ into tetrahydrofuran, stir and dissolve, and then add 26.7g of ethylmagnesium bromide , reacted under stirring at 20°C for 4 hours, and discharged to obtain the compound of formula III; added the compound of formula III to toluene, then added 7.5g p-toluenesulfonic acid, refluxed for 3 hours, and obtained the compound of formula IV; added the compound of formula IV to tetrahydrofuran , then add 50ml of dilute hydrochloric acid with a mass concentration of 5%, react at room temperature for 1h, extract the reaction solution with ethyl acetate, and spin dry to obtain a compound of formula V; dissolve 17.3g of p-hydroxyphenylglycine in dichloromethane, add 18g of methyl chloride Methyl ether, ...

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Abstract

The invention relates to the technical field of preparation of antibiotics, and specifically discloses a preparation method of cefprozil. The preparation method is characterized by taking GCLE (7-phenylacetyl amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester) as a starting material, and carrying out hydroformylation, ethylation and dewatering, thus obtaining GPRE; then hydrolyzing, thus obtaining APRA; firstly protecting hydroxyl groups and amino groups of p-hydroxyl phenylglycine, then carrying out condensation reaction with the APRA, and then deprotecting, thus obtainingthe cefprozil. According to the preparation method disclosed by the invention, toxic triphenyl phosphine is not used for preparing phosphine salt, so that the method is more environment-friendly; a reaction route requires no wittig reaction, so that the cost is lower; the hydroxyl groups and the amino groups of the p-hydroxyl phenylglycine are protected by adopting chloromethyl methyl ether and then are in reacting with a compound as shown in a formula VI, the cost is low, a deprotection reaction system is neutral, and the yield and the purity of a product are favorably increased.

Description

technical field [0001] The invention relates to the technical field of antibiotic preparation, in particular to a preparation method of cefprozil. Background technique [0002] Cefprozil is a second-generation cephalosporin antibiotic with a broad-spectrum antibacterial effect. Blood bacteria etc. also have inhibitory effect. The bactericidal mechanism is to hinder the synthesis of bacterial cell walls, which is safe and has extremely low adverse reactions. [0003] At present, the synthetic method of cefprozil mostly adopts 7-phenylacetamido-3-chloromethyl cesprenenoic acid p-methoxybenzyl ester (GCLE) as raw material, which has great advantages compared with 7-ACA as raw material method, such as The product yield is higher, the production process is simpler, and the production conditions are milder. However, this kind of reaction mostly uses toxic reagents such as triphenylphosphine, and requires wittig reaction, the production cost is high, and there is still room for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/04
CPCC07D501/04C07D501/22
Inventor 金联明何健门万辉邹菁
Owner 湖北凌晟药业股份有限公司