合成路线1

Treatment of 3-nitrophthalimide (I) with ethyl chloroformate in the presence of Et3N in DMF produces the N-(ethoxycarbonyl)phthalimide derivative (II), which is condensed with glutamine tert-butyl ester (III) by means of Et3N in refluxing THF to afford the phthaloylglutamine derivative (IV). Hydrolysis of the tert-butyl ester group of compound (IV) with HCl in CH2Cl2 yields the corresponding carboxylic acid (V), which is cyclized by means of SOCl2 in the presence of pyridine and Et3N in CH2Cl2, resulting in the corresponding glutarimide (VI) . Finally, the nitro group of glutarimide (VI) is reduced by catalytic hydrogenation over Pd/C in acetone or with Sn/HCl .
Pure enantiomers of pomalidomide can been prepared using the corresponding enantiomers of glutamine tert-butyl ester (III), as the cyclization of phthaloyl-glutamine (V) takes place without racemization, resulting in the corresponding enantiomeric glutarimides. The nitrophthalimide precursor (VI) can be alternatively obtained by cyclization of N-(benzyloxycarbonyl)glutamine (VII) by means of CDI in refluxing THF to afford the glutarimide derivative (VIII), which is then N-deprotected to 2-aminoglutarimide (IX) by either hydrogenolysis over Pd/C or by treatment with HBr in AcOH. Finally, aminoglutarimide (IX) is condensed with 3-nitrophthalic anhydride (X) using AcOH at reflux .
Cyclization of 3-aminophthalic acid hydrochloride (XI) with 2-aminoglutarimide (IX) using Et3N or imidazole, optionally in the presence of AcOH in acetonitrile .
Condensation of 3-nitrophthalic anhydride (X) with glutamine (XII) in DMF yields N-(3-nitrophthaloyl)glutamine (V), which is reduced with H2 over Pd/C to give the corresponding amine (XIII). Finally, this compound undergoes cyclization by means of CDI .