合成路线1

The esterification of N-(tert-butoxycarbonyl)-D-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-D-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(R)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(R)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(R)-(phthalimido)piperidine-2,6-dione (IX). Finally, the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (R)-thalidomide.