利奈唑胺主要代谢物PNU-142300和PNU-142586的合成

Synthesis of the Major Linezolid Metabolites,PNU-142300 and PNU-142586

合成利奈唑胺主要代谢物PNU-142300(2)和PNU-142586(3)。以3,4-二氟硝基苯(5)为起始原料,经亲核取代、羟基保护、硝基还原、缩合和环化反应得共同中间体(S)-2-[[3-[4-[苄基-[2-[(叔丁基二甲基硅烷基)氧基]乙基]氨基]-3-氟苯基]-2-氧代噁唑烷-5-基]甲基]异吲哚啉-1,3-二酮(15)。15依次经叔丁基二甲基硅基(TBS)脱除、Williamson醚合成、氨解、酰化、脱苄基和脱叔丁基反应,得代谢物(S)-2-[2-[[4-[5-(乙酰氨基甲基)-2-氧代噁唑烷-3-基]-2-氟苯基]氨基]乙氧基]乙酸(即PNU-142300),总收率78%,纯度98.62%。15依次经氨解、酰化、脱苄基、氮烷基化、苄基和TBS脱除反应,得(S)-N-[4-[5-(乙酰氨基甲基)-2-氧代噁唑烷-3-基]-2-氟苯基]-N-(2-羟乙基)甘氨酸(即PNU-142586)四丁基铵盐,总收率65%,纯度92.35%。2和3经MS、1H NMR和13C NMR确证结构。

The main metabolites of linezolid,PNU-142300(2)and PNU-142586(3),were synthesized.Compound 3,4-difluoronitrobenzene(5)was used as the starting material to synthesize the key intermediate(S)-2-[[3-[4-[benzyl[2-[(tert-butyldimethylsilyl)oxy]ethyl]amino]-3-fluorophenyl]-2-oxooxazolidin-5-yl]methyl]isoindoline-1,3-dione(15)by nucleophilic substitution,hydroxyl protection,nitro-reduction reaction,condensation and cyclization.Metabolite(S)-2-[2-[[4-[5-(acetamidomethyl)-2-oxooxazolidin-3-yl]-2-fluorophenyl]amino]ethoxy]acetic acid(namely PNU-142300)was obtained from 15 by removal of tert-butyldimethylsilyl(TBS)group,Williamson etherification,amolysis,acylation,debenzylation and removal of tert-butyl group in sequence with total yield of 78%and the purity of 98.62%.Metabolite(S)-N-[4-[5-(acetamidomethyl)-2-oxooxazolidin-3-yl]-2-fluorophenyl]-N-(2-hydroxyethyl)glycinate(namely PNU-142586)tetrabutylammonium salt was obtained from 15 by amolysis,acylation,debenzylation,nitroalkylation,debenzylation and TBS removal in sequence with total yield of 65%and the purity of 92.35%.The structures of 2 and 3 were confirmed by MS,^(1)H NMR and ^(13)C NMR.