A review of reactions scaled in the GMP facilities at the Pfizer-Groton site was undertaken. Reactions were categorized into
one of seven categories: carbon−carbon bond formation,
carboxylic acid derivative interconversion, carbon−nitrogen
bond formation, carbon−oxygen bond formation, red-ox, salt
formation/resolution, and other. Reactions scaled from 1997 to
2002 were compared to chemistry scaled from 1985 to 1996 to
look for changes in the nature of chemistry being scaled between
the two time periods. Reactions were further subcategorized
within those categories, and some interesting trends were noted.
Previously our group reported synthetic efforts used to synthesize kilogram quantities of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, 1, via a mid-stage resolution. This account describes research conducted to develop an asymmetric route to this clinical candidate suitable for longterm manufacturing. The first asymmetric center is established via coupling of (R)-3-aminopentanenitrile to a trifluoromethylarene. After elaboration of the nitrile to a suitable precursor, a key step in the synthesis is diastereoselective cyclization of immonium ion 7 to provide the tetrahydroquinoline core. This approach also permitted a streamlined sequence to complete the synthesis of 1. Development of the process and synthetic rationale are described.
A practical, efficient synthesis of (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1), a cholesteryl ester transfer protein (CETP) inhibitor, is described. The key reaction in the synthesis, addition of an N-vinylcarbamate to an iminium ion rapidly followed by an iminium ion cyclization onto the aryl ring, sets up the cis relationship of the two subsituents of the tetrahydoquinoline ring of 6. The origin of the high cis stereoselectivity in the cyclization was explored using high-level quantum chemistry calculations.
Synthesis
of (S)-5-fluoro-3-methylisobenzofuran-1(3H)-one (6), a key intermediate to lorlatinib,
is described. A few synthetic methodologies, that is, boron reduction,
enzymatic reduction, asymmetric hydrogenation, and asymmetric transfer
hydrogenation, were evaluated for the chiral reduction of the substituted
acetophenone intermediate (8). A manufacturing process,
on the basis of the asymmetric transfer hydrogenation, was developed.
This process was successfully scaled up to prepare 400 kg of 6.
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