Synthesis of the Major Linezolid Metabolites,PNU-142300 and PNU-142586
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,1H NMR and 13C NMR.
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