(噁)唑烷酮类抗菌剂雷得唑来的合成

摘要

目的 研究(噁)唑烷酮类抗菌剂雷得唑来的合成.方法 以间氟苯胺为起始原料,依次经取代、碘代、环合、Suzuki偶联反应得到中间体(5S)-N-{[3-[4-(4-甲酰基苯基)-3-氟苯基]-2-氧代噁唑烷-5-基]甲基}乙酰胺(5);以对甲氧基氯苄为原料,经取代、Husigen-Click环加成反应得到中间体[1-(4-甲氧基苄基)-1H-1,2,3-三氮唑-4-基]甲胺(8);中间体5和8经还原胺化反应得到中间体(5S)-N-{[3-[2-氟-4'-({[1-(4-甲氧基苄基)-1H-1,2,3-三氮唑-4-基甲基]氨基}甲基)联苯-4-基]-2-氧代Ⅱ恶唑烷-5-基]甲基}乙酰胺(10),再经脱保护得到雷得唑来.结果与结论 雷得唑来的结构经MS、IR、1H-NMR和13 C-NMR确证,纯度经HPLC测定.其收率为40.7％(以间氟苯胺计).该路线未见文献报道,所用原料价廉易得,反应条件温和可控,后处理简便,为其工业化生产奠定了基础.%Radezolid,a novel biaryloxazolidinone antibacterial agent,is developed by the Melinta Therapeutics company.Based on the analysis and investigation of several synthetic routes of radezolid reported in the literatures,a novel synthetic route to radezolid was designed.Using 3-fluoro-phenylamine as the starting material,the key intermediate (5 S)-N-{ [-3-[4-(4-formylphenyl)-3-fluorophenyl]-2-oxooxazolidin-5-yl] methyl} acetamide (5) was synthesized via substitution reaction,nucleophilic iodination,oxazolidinone cyclization,and Suzuki-Miyaura cross-coupling.Another key intermediate [1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl] methanamine (8) was prepared starting from 4-methoxybenzyl chloride,followed by substitution reaction and Husigen-Click cycloaddition reaction.Then intermediate 5 was condensated with 8 through Borch reduction indirectly,followed by de-protection to give radezolid.This process technology has been investigated and optimized thoroughly.The final product radezolid was obtained in a yield of 40.7％ (calculated by 3-fluoro-phenylamine),and the purity was 99.9％.The structure of the final product was confirmed by MS,IR,1H-NMR,13C-NMR and the structures of some key intermediates were confirmed by MS and 1H-NMR.