We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.
A highly efficient asymmetric synthesis
of the IDO inhibitor navoximod,
featuring the stereoselective installation of two relative and two
absolute stereocenters from an advanced racemic intermediate, is described.
The stereocenters were set via a crystallization-induced dynamic resolution
along with two selective ketone reductions: one via a biocatalytic
ketoreductase transformation and one via substrate-controlled hydride
delivery from LiAlH(Ot-Bu)3. Following
this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde
and isolated in 23% overall yield with 99.7% ee and high purity.
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 trans-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 β2-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.
This study uses infrared (IR) spectroscopy to achieve process understanding during the synthesis of a tetrasubstituted acyclic olefin via ketone enolization and tosylation. ReactIR, an inline Fourier transform IR immersion probe, was used to monitor ketone enolate formation and tosylation in a two-step, one-pot reaction. A quantitative univariate model was constructed from the ketone carbonyl IR peak height of the starting material. This model was used to determine the rate of consumption of the starting material and to establish end points for various reaction conditions. For the second step of the reaction, the vinyl sulfonate formation, the entire IR spectrum was analyzed and offline HPLC data were collected to measure the ratio of E versus Z tetrasubstituted vinyl tosylate products. Principal component analysis and partial least-squares regression were employed to build a multivariate model that was then used to quantify and predict the relative amount of E and Z stereoisomers in situ. Sensitivity and applicability of the models were then validated using reaction data acquired across a variety of experimental conditions.
An array of tetrasubstituted saturated fused pyrimidines has been synthesized through two-sequential, simple, and efficient one-pot operations. The strategic utilization of the N-PMB group proved critical in the ability to construct a broad range of N-vinyl tertiary enamide starting materials. This stands as a flexible approach to functionalized pyrimidines with the capability of manipulating either ketone, acid chloride, or nitrile reaction partners.
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