A Practical,
Protecting-Group-Free Synthesis of a
PI3K/mTOR Inhibitor
Posted on 2015-03-20 - 00:00
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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Tian, Qingping; Hoffmann, Ursula; Humphries, Theresa; Cheng, Zhigang; Hidber, Pirmin; Yajima, Herbert; et al. (2016). A Practical,
Protecting-Group-Free Synthesis of a
PI3K/mTOR Inhibitor. ACS Publications. Collection. https://doi.org/10.1021/op500366s
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AUTHORS (12)
QT
Qingping Tian
UH
Ursula Hoffmann
TH
Theresa Humphries
ZC
Zhigang Cheng
PH
Pirmin Hidber
HY
Herbert Yajima
MG
Maud Guillemot-Plass
JL
Jane Li
UB
Ulrike Bromberger
SB
Srinivasan Babu
DA
David Askin
FG
Francis Gosselin