Both of the amino analogs are prepared from the condensation of 3-aminopiperidine-2,6-dione hydrochloride (Compound 3) which is synthesized in a two step reaction from commercially available Cbz--glutamine. The Cbz--glutamine is treated with CDI in refluxing THF to yield Cbz-aminoglutarimide. To remove the Cbz protecting group hydrogenolysis, under 50–60 psi of hydrogen with 10% Pd/C mixed with ethyl acetate and HCl, was performed. The formulated hydrochloride (Compound 3 in Scheme 3) was then reacted with 3-nitrophthalic anhydride in refluxing acetic acid to yield the 4-nitro substituted thalidomide analog and the nitro group then reduced with hydrogenation to give pomalidomide.
Lenalidomide is synthesized in a similar way using compound 3 (3-aminopiperidine-2,6-dione) treated with a nitro-substituted methyl 2-(bromomethyl) benzoate, and hydrogenation of the nitro group.