Synthesis of thalidomide has usually been performed as seen in scheme 1. This synthesis is a reasonably simplistic three step process. The downside of this process however is that the last step requires a high-temperature melt reaction which demands multiple recrystallizations and is not compliant with standard equipment.
Scheme 2 is the newer synthesis route which was designed to make the reaction more direct and to produce better yields. This route uses -glutamine rather than -glutamic acid as a starting material and by letting it react with N-carbethoxyphthalimide gives N-phthaloyl--glutamine (4), with 50–70% yield. The substance 4 is then stirred in a mixture with carbonyldiimidazole (CDI) with enough 4-dimethylaminopyridine (DMAP) in tetrahydrofuran (THF) to catalyze the reaction and heated to reflux for 15–18 hours. During the reflux thalidomide crystallizes out of the mixture. The final step gives 85–93% yield of thalidomide, bringing the total yield to 43–63%.