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.
We
report a practical and protecting-group-free synthesis amenable
to produce multikilogram amounts of PI3K/mTOR inhibitor GDC-0980. The route employed metalation/formylation and reductive amination
followed by a metal catalyzed Suzuki–Miyaura cross-coupling.
The metalation was performed via triarylmagnesiate intermediates allowing
formylation under noncryogenic conditions. 2-Picoline·BH3 was employed to replace Na(OAc)3BH in the reductive
amination and to eliminate the use of molecular sieves. A concise
one-step synthesis was developed for the selective monoamidation of
piperazine with (S)-lactate to produce the piperazine
lactamide starting material. The boronic acid was produced from 2-amino-5-bromopyrimidine
in a one-step and protecting-group-free approach. The final crystallization
in 1-propanol and water afforded the API in 59% overall yield in four
steps and >99% purity by HPLC.
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