4 research outputs found
A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor
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 NaÂ(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
Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up
Herein,
the first-generation process to manufacture Akt inhibitor
Ipatasertib through a late-stage convergent coupling of two challenging
chiral components on multikilogram scale is described. The first of
the two key components is a <i>trans</i>-substituted cyclopentylpyrimidine
compound that contains both a methyl stereocenter, which is ultimately
derived from the enzymatic resolution of a simple triester starting
material, and an adjacent hydroxyl group, which is installed through
an asymmetric reduction of the corresponding cyclopentylpyrimidine
ketone substrate. A carbonylative esterification and subsequent Dieckmann
cyclization sequence was developed to forge the cyclopentane ring
in the target. The second key chiral component, a β<sup>2</sup>-amino acid, is produced using an asymmetric aminomethylation (Mannich)
reaction. The two chiral intermediates are then coupled in a three-stage
endgame process to complete the assembly of Ipatasertib, which is
isolated as a stable mono-HCl salt
Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up
Herein,
the first-generation process to manufacture Akt inhibitor
Ipatasertib through a late-stage convergent coupling of two challenging
chiral components on multikilogram scale is described. The first of
the two key components is a <i>trans</i>-substituted cyclopentylpyrimidine
compound that contains both a methyl stereocenter, which is ultimately
derived from the enzymatic resolution of a simple triester starting
material, and an adjacent hydroxyl group, which is installed through
an asymmetric reduction of the corresponding cyclopentylpyrimidine
ketone substrate. A carbonylative esterification and subsequent Dieckmann
cyclization sequence was developed to forge the cyclopentane ring
in the target. The second key chiral component, a β<sup>2</sup>-amino acid, is produced using an asymmetric aminomethylation (Mannich)
reaction. The two chiral intermediates are then coupled in a three-stage
endgame process to complete the assembly of Ipatasertib, which is
isolated as a stable mono-HCl salt
A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate
We report a practical synthesis of PI3K inhibitor <b>GDC-0941</b>. The synthesis was achieved using a convergent approach
starting
from a thienopyrimidine intermediate through a sequence of formylation
and reductive amination followed by Suzuki-Miyaura cross-coupling.
Metalation of the thienopyrimidine intermediate involving the intermediacy
of triarylmagnesiates allowed formylation under noncryogenic conditions
to produce the corresponding aldehyde. We also investigated aminoalkylation
via a benzotriazolyl-piperazine substrate as an alternative to the
reductive amination route. We evaluated both palladium and nickel
catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling.
Final deprotection and salt formation afforded the API