Synthesis of D- and L-Thalidomide and Related Studies

Abstract

The optical isomers of thalidomide were synthesized by a route based on d- and L-isoglutamine. The thalidomide isomers were obtained in high yields by treating the optical isomers of N2-phthaloylisoglutamine at 0° with thionyl chloride in dimethylformamide. L-Thalidomide was also obtained by using N,N-carbonyldiimidazole to close the glutarimide ring. Application of these two methods, together with the active (cyanomethyl) ester method, to both N2-phthaloyl-L-isoglutamine and N2-phthaloyl-L-glutamine showed that L-thalidomide is formed more readily and with less risk of racemization from the isoglutamine derivative. DL-Thalidomide was also prepared under much milder conditions than those previously used. The optical isomers of thalidomide were synthesized by a route based on d- and L-isoglutamine. The thalidomide isomers were obtained in high yields by treating the optical isomers of N2-phthaloylisoglutamine at 0° with thionyl chloride in dimethylformamide. L-Thalidomide was also obtained by using N,N-carbonyldiimidazole to close the glutarimide ring. Application of these two methods, together with the active (cyanomethyl) ester method, to both N2-phthaloyl-L-isoglutamine and N2-phthaloyl-L-glutamine showed that L-thalidomide is formed more readily and with less risk of racemization from the isoglutamine derivative. DL-Thalidomide was also prepared under much milder conditions than those previously used.