A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor

Abstract

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.

Development of an Efficient Synthesis of (2-Aminopyrimidin-5-yl) Boronic Acid

“…Initial efforts on the formation of the target boronic acid following a literature procedure, using 2-amino-5-bromopyrimidine and B­(O i -Pr) 3 with n -BuLi/THF/–78 °C gave inconsistent or poor yields (11–40%). It is known that boronic acid 1b can be prepared from 2-amino-5-bromopyrimidine via an amine protection/metal–halogen exchange process, followed by trapping with trialkylborate . The amine protecting groups that were utilized in the literature methods included the BOC group, ,,,, imines derived from benzophenone, , and a benzyl protecting group; however, those methods suffered from modest yields and required two or three isolation steps as well as a deprotection step.…”

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

“…Esters have been converted to amides by direct treatment with the corresponding amine. Reports employing methyl esters, ,,,, ethyl esters, ,,, tert -butyl esters, isobutyl esters, benzyl esters, lactones, thioesters, pentafluorophenyl esters, , and N -hydroxysuccinimido esters ,, have been published.…”