Method for synthesizing 7-phenylacetamide-3-chloromethyl-4-cephalosporanic acid p-methoxybenzyl ester

A technology of cephalosporanic acid and phenylacetamide, which is applied in the field of drug production, can solve problems such as poor quality, high cost, and difficult synthesis technology, and achieve the effects of convenient operation, short synthetic route, and convenient industrial production

Inactive Publication Date: 2008-09-10
HUNAN NANXIN PHARMA CO LTD
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  • Description
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  • Application Information

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Problems solved by technology

The synthesis technology of GCLE is relatively difficult. Although there has been some progress in domestic research on its synthesis technology, the cost is still high and the quality is not good.

Method used

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  • Method for synthesizing 7-phenylacetamide-3-chloromethyl-4-cephalosporanic acid p-methoxybenzyl ester
  • Method for synthesizing 7-phenylacetamide-3-chloromethyl-4-cephalosporanic acid p-methoxybenzyl ester
  • Method for synthesizing 7-phenylacetamide-3-chloromethyl-4-cephalosporanic acid p-methoxybenzyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0024] (1) Synthesis of penicillin p-methoxybenzyl ester (II)

[0025] Weigh 100g of penicillin industrial salt, add 200mL of DMF and 200mL of purified water to dissolve, add 60g of p-methoxybenzyl chloride and 4g of tetrabutyl bromide, heat to reflux, then react at this temperature for 4 hours, cool to room temperature, and use Extract with 3×150 mL of toluene, combine the extracts, add and dry for 2 hours, the obtained can be directly used in the oxidation reaction without separation, and the yield is 97%.

[0026] (2) Synthesis of penicillin G sulfoxide p-methoxybenzyl ester (III)

[0027] Pour the obtained esterification solution into a three-necked flask, add 100mL of anhydrous methanol, control the temperature at 10-15°C, add 150mL of 15% peracetic acid dropwise, and keep it warm for 20 hours. Wash twice with 200 mL of purified water, then wash twice with 200 mL of 10% sodium bisulfite solution, then dry with anhydrous magnesium sulfate for 2 hours, evaporate the solven...

Embodiment 2

[0033] (1) Synthesis of penicillin p-methoxybenzyl ester (II)

[0034] Weigh 150g of penicillin industrial salt, add 300mL of DMF and 300mL of purified water to dissolve, add 90g of p-methoxybenzyl chloride and 6g of tetrabutyl bromide, heat to reflux, then react at this temperature for 4 hours, cool to room temperature, and use Extract with 3×230 mL of toluene, combine the extracts, add and dry for 2 hours, and the yield is 96.5%.

[0035] (2) Synthesis of penicillin G sulfoxide p-methoxybenzyl ester (III)

[0036] Pour the obtained esterification solution into a three-necked flask, add 150mL of anhydrous methanol, control the temperature at 10-15°C, add 230mL of 15% peracetic acid dropwise, and keep it warm for 20 hours. Wash twice with 300 mL of purified water, then wash twice with 300 mL of 10% sodium bisulfite solution, then dry with anhydrous magnesium sulfate for 2 hours, evaporate the solvent under reduced pressure, add 150 mL of anhydrous methanol to the residue, and...

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Abstract

The invention discloses a synthesis method of 7- phenylacetamide-3-chloromethyl-4- cephalsporanic acid p- methoxybenzyl ester(GCLE). The invention takes the penicillin G kali salts mass made in China as starting materials; firstly, the penicillin G kali salts reacts with the p- methoxy benzyl chloride to obtain p- methoxybenzyl ester; secondly, the p- methoxybenzyl ester is oxidized by peroxy acetic acid to obtain penicillin sulfoxide ester; the penicillin sulfoxide ester firstly reacts with the 2- mercaptobenzothiazole, and then reacts with benzene sulfinic acid to obtain ring opening products; the ring opening products reacts with chlorine gases to obtain chlorination products; the chlorination products reacts with ammonia gases to obtain 7- phenylacetamide-3-chloromethyl-4- cephalsporanic acid p- methoxybenzyl ester(GCLE).

Description

technical field [0001] The invention relates to a synthesis method of cephalosporin antibiotic intermediate 7-phenylacetamide-3-chloromethyl-4-cephalosporanic acid p-methoxybenzyl ester (GCLE), belonging to the technical field of medicine production. Background technique [0002] The cephalosporin intermediate represented by the following formula is a known important compound for the synthesis of various cephalosporins, and is mainly used as a raw material for the preparation of cephalosporins with different side chains at the 7-position and different methyl groups at the 3-position . [0003] [0004] Use GCLE to produce semi-synthetic cephalosporins, such as: cefixime, cefazolin, cefamandole, ceftazidime, ceftinib, cefepime, cefpirome, etc., with high yield and simple process, Low cost and other advantages, so it has the potential to replace 7-ACA. [0005] The synthesis of GCLE is mainly based on penicillin, and is synthesized by two methods: (1) halogenation method ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/24C07D501/02
CPCC07D501/24C07D501/02
Inventor 张世喜莫章桦潘向东刘和平
Owner HUNAN NANXIN PHARMA CO LTD
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