Manufacture of the PI3K β-Sparing Inhibitor Taselisib. Part 2: Development of a Highly Efficient and Regioselective Late-Stage Process

Abstract

A highly efficient and regioselective manufacturing route for the phosphoinositide 3-kinase β-sparing inhibitor taselisib was developed. Highlights of the synthesis include: (1) magnesium-mediated formation of a challenging cyclic amidine;(2) regioselective imidazole construction via alkylation/condensation with bromopyruvic acid; and (3) triazole formation with 2-isopropyl acetamidrazone to generate the key bromobenzoxazepine core intermediate. Subsequent highly efficient one-pot palladium-catalyzed Miyaura borylation/Suzuki cross-coupling/saponification, followed by a 1,1′-carbonyldiimidazole-mediated coupling with ammonia, led to the pentacyclic taselisib. This new synthetic approach provides a more efficient route to taselisib with a significant decrease in process mass intensity compared to the previous early development routes to the bromobenzoxazepine core. Finally, implementation of a controlled crystallization provided the active pharmaceutical ingredient with the desired polymorphic form.

QbD Approach to Process Characterization and Quantitative Criticality Assessment of Process Parameters

“…The process characterization methodology outlined in this publication is elaborated with an example in the manufacturing process for the taselisib drug substance . In this example, step product triazole 3 is formed by condensation of carboxylic acid 1 with hydrazonium chloride 2 .…”

Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry

“…The Suzuki-Miyaura coupling is one of the widely used reactions in pharmaceutical synthesis. For example, St-Jean and coworkers [7] from Genentech developed an efficient late-stage synthetic method for PI3K β-Sparing Inhibitor taselisib 6 [8], which has been demonstrated to have increased activity against PIK3CA mutant breast cancer. A one-pot Miyaura borylation, Suzuki-Miyaura coupling, and saponification to produce 5 from 1 were described.…”