Improvement Of The Synthetic Process Of Meropenem Side Chain

Meropenem is a carbapenem antibiotic with excellent efficacy and wide application.The meropenem side chain is one of the main raw materials for synthesis.In the synthetic process of meropenem side chain,the large-scale production is restricted by the disadvantages of high preparation cost,complicated reaction route,many side reactions,low yield and crude product purity.In the present study,the synthesis of thiolactone is facilitated by addition of phase transfer catalyst or surfactant via a ring closed one-pot method.The prepared thiolactone could be used to synthesize meropenem side chains with an improved high yield,which is of great significance for the industrial production of meropenem side chains.A simple one-pot method for the preparation of thiolactone was developed by activation of the carboxyl group of M1[（2S,4R）-2-carboxy-1-（4-nitrobenzyloxycarbonyl）pyrrolidine],hydroxyl group activation and a ring closed reaction,with assistance of phase transfer catalyst.Then meropenem side chain could be successfully prepared via a ring-opening reaction of thiolactone.Furthermore,the influence of molar ratio of isopropyl chloroformate,MsCl（methylsulfonyl chloride）,triethylamine（TEA）,Na₂S·9H₂O and three types of phase transfer catalysts（polyethylene glycols（PEG）,quaternary ammonium salts and crown ethers）and three types of surfactants on the yield and purity of the thiolactone were explored.The effects of reaction time and feed ratio on thiolactone were also investigated.The addition of a phase transfer catalyst during the preparation of the thiolactone can both speed up the reaction and increase the purity and yield of the product.In the optimal conditions,M1:isopropyl chloroformate:MsCl:Na₂S·9H₂O:CTEA（TEA added during carboxyl activation）:HTEA（TEA added during hydroxyl activation）:the molar ratio of catalyst loading is 1:1:1.3:1.3:1.3:1.2:（0.07-0.16）,carboxyl activation and hydroxyl activation temperature are-30～-17°C,carboxyl activation and hydroxyl activation reaction time are 15min,30min;vulcanization into the ring from（-30～-17）°C to 0°C,the temperature rise reaction time was 30min;the reflux temperature was40°C,and the reflux time was 165min,the thiolactone yield was up to 98.4%and the purity was 98.3%.Under the same conditions,PEG-600 was used to assist Na HS to synthesize thiolactone with a yield of 98.9%and purity was 97.4%.Under the same conditions,Span-85 was used to assist Na₂S·9H₂O to synthesize thiolactone with a yield of 96.5%and purity of 98.1%.The meropenem side chain can be directly prepared from the new synthesized non-purified thiolactone,the yield is still 92.3%,and the purity is 99.1%.The developed synthetic process of thiolactone could be uased for the synthesis of meropenem side chain with high yield,which solves the prominent problems of multiple steps and high cost in actual production.It is a simple method with short process route and high practical application value.