Synthesis of 5-substituted 5-hydroxy-2-pyrrolidones, metabolites of the antipsychotic benzamide remoxipride.
This paper describes the synthesis of 5-[(3-bromo-2,6-dimethoxybenzamido)-methyl]-5-hydroxy-2-pyrrolidon e (3) and its 1-ethyl analogue 2, two urinary metabolites of the dopamine D-2 antagonist remoxipride [1, (S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2, 6-dimethoxybenzamide]. Two synthetic schemes leading to a common intermediate, 5-benzamido-4-oxopentanoic acid 4, were developed. This key intermediate permits conversion into either metabolite. Reaction of 4 with isobutyl chloroformate furnished a mixed carbonic anhydride, which upon treatment with ethylamine or ammonia gave the 4-oxopentanamides 5 and 6, respectively. Ring-closure afforded the corresponding 5-hydroxy-2-pyrrolidones 2 and 3.
Gawell
L
L
Department of Medicinal Chemistry, CNS 2, Södertälje, Sweden.
Hagberg
C E
CE
Högberg
T
T
Widman
M
M
D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000652:urine; D012015:Reference Standards; D017330:Remoxipride / Q000031:analogs & derivatives
D014150:Antipsychotic Agents; D001549:Benzamides; D011760:Pyrrolidinones; D017330:Remoxipride; C067544:5-((3-bromo-2,6-dimethoxybenzamide)methyl)-5-hydroxy-1-ethyl-2-pyrrolidone; C067543:5-((3-bromo-2,6-dimethoxybenzamido)methyl)-5-hydroxy-2-pyrrolidone