Genentech, Inc.

Hoffmann-la Roche Inc.

Andreas Stumpf

Alan G Olivero

Chudi Obioma Ndubaku

Andrew McClory

Herbert Yajima

Remy Angelaud

Francis Gosselin

Haiming Zhang

Stephan Bachmann

Stefan Koenig

Michael Dalziel

Yonghui Ge

Laure Elizabeth Simone Finet

Regis Jean Georges Mondiere

Yuki Nakagawa

Jie Zhang

Eduardo V Mercado-marin

Daniel Zell

Diane E Carrera

Raphael Bigler

Andrew Mcclory

A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N',N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.

Synthesis of a bis-mesylate salt of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide and intermediates thereto

The present disclosure provides for methods for preparing tricyclic PI3K inhibitor compounds in high yield and purity in aqueous solvent systems.

Process for the preparation of tricyclic PI3K inhibitor compounds and methods for using the same for the treatment of cancer

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South San Francisco, CA, United States of America

Andreas Stumpf