Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 15, Issue 3, Pages 503-514Publisher
AMER CHEMICAL SOC
DOI: 10.1021/op2000207
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A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative-Mannich addition Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10 was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27-31% overall yield with six isolated intermediates.
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