A Practical,
Protecting-Group-Free Synthesis of a
PI3K/mTOR Inhibitor
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Abstract
We
report a practical and protecting-group-free synthesis amenable
to produce multikilogram amounts of PI3K/mTOR inhibitor <b>GDC-0980</b>. 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·BH<sub>3</sub> was employed to replace Na(OAc)<sub>3</sub>BH 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 (<i>S</i>)-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