Synthesis of racemic cis-5-hydroxy-3-phthalimidoglutarimide. A metabolite of thalidomide isolated from human plasma.
[reaction: see text] A synthesis of the glutarimide-derived metabolite of thalidomide, 5'-hydroxythalidomide (2), is described. The synthesis employed the lactone derivative of N-benzyloxycarbonyl (CBZ)-protected 4-hydroxyglutamic acid 12, which is prepared by a de novo route from diethyl acetamidomalonate. The reaction of 12 with 4-methoxybenzylamine gave the corresponding isoglutamine, which then provided the key CBZ-protected N-PMB-glutarimide 14 after dehydration. Deprotection of both the CBZ and PMB groups followed by phthalimidation and deacetylation of the 3-amino-5-acetoxyglutarimide 16 afforded 2.
Luzzio
Frederick A
FA
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, USA. faluzz01@gwise.louisville.edu
Duveau
Damien Y
DY
Lepper
Erin R
ER
Figg
William D
WD
D006801:Humans; D015394:Molecular Structure; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification*; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification*; D013237:Stereoisomerism; D013792:Thalidomide / Q000737:chemistry* / Q000378:metabolism
D010797:Phthalimides; D010881:Piperidones; C511505:cis-5-hydroxy-3-phthalimidoglutarimide; D013792:Thalidomide