合成路线:The antibacterial activity of RBx-7644 is due to the 5(S)-acetamidomethyl configuration at the oxazolidinone ring,and thus,asymmetric synthesis of only the 5(S)-enantiomer was desirable:3,4-Difluoronitrobenzene (I) is condensed with piperazine in acetonitrile to give 4-(2-fluoro-4-nitrophenyl)-piperazine (II) as a light yellow compound.Compound (II) is dissolved in dichloromethane and triethylamine,followed by the addition of Boc-anhydride,to provide compound (III).4-(tert-Butoxycarbonyl)-1-(2-fluoro-4-nitrophenyl)piperazine (III),upon hydrogenation with H2 over Pd/C in methanol at 50 psi,yields 4-(tert-butoxycarbonyl)-1-(2-fluoro-4-aminophenyl)piperazine (IV) as a dark solid.Compound (IV) reacts with benzylchloroformate in dry THF in the presence of solid sodium bicarbonate to afford the desired compound (V).4-(tert-Butoxycarbonyl)-1-[2-fluoro-4-(benzyloxycarbonylamino)phenyl]piperazine (V),upon treatment with n-BuLi and (R)-glycidyl butyrate at -78 癈,gives the desired (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone (VI).The hydroxymethyl compound (VI) is treated with methanesulfonyl chloride in dichloromethane in the presence of triethylamine to give (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(methylsulfonyloxymethyl)-2-oxazolidinone (VII).The sulfonyl derivative (VII) is treated with sodium azide in dimethylformamide to provide the azide (VIII) as a white solid.(R)-(-)-3-[3-Fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl]-5-(azidomethyl)-2-oxazolidinone (VIII),upon hydrogenation with H2 over Pd/C at 45 psi,gives (S)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)-piperazin-1-yl]phenyl]-5-(aminomethyl)-2-oxazolidinone (IX).The aminomethyl compound (IX),upon treatment with acetic anhydride in dichloromethane in the presence of triethylamine,affords the acetamide derivative (X).The acetamidomethyl-oxazolidinone derivative (X),upon treatment with trifluoroacetic acid,gives (S)-(-)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-5-(acetamidomethyl)-2-oxazolidinone,which,without isolation,is treated with 5-nitro-2-furaldehyde in the presence of sodium triacetoxy borohydride to provide compound (XI).Compound (XI),upon treatment with ethanolic HCl,affords RBx-7644 as a light yellow crystalline solid.
参考文献标题:RBx-7644
文献作者:Rattan,A.
参考来源:Drugs Fut 2003,28(11),1070
产品链接: CAS No.392659-38-0››