噁唑烷酮类抗菌剂雷得唑来的合成

Improved synthesis of radezolid

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-氧代噁唑烷-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 Thera- peutics 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 （ 5S ） -N- {[-3-[4-（ 4-formylphenyl ） -3-fluorophenyl 1-2-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.