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Development of a Scalable Synthesis of a Bruton’s Tyrosine Kinase Inhibitor via C–N and C–C Bond Couplings as an End Game Strategy

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Technical Sciences—Chemical Synthesis, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, United States
Cite this: Org. Process Res. Dev. 2014, 18, 1, 228–238
Publication Date (Web):August 27, 2013
https://doi.org/10.1021/op4001077
Copyright © 2013 American Chemical Society

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    Abstract

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    A scalable and convergent synthesis of a BTK (Bruton’s tyrosine kinase) inhibitor has been developed. Synthetic routes to key intermediates were explored for the scale-up campaign, especially the process for 6-dimethylaminodihydroisoquinolinone, which was prepared via a regioselective cyclization of an isocyanate, mediated by AlCl3. Improved routes to key building blocks were demonstrated by expedient multikilogram productions. The target compound was assembled through a Pd-catalyzed amidation reaction followed by a Suzuki–Miyaura cross-coupling reaction.

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    Reaction conditions of the Suzuki–Miyaura coupling of aryl chloride 38 with boronate 33; and 1H and 13C NMR spectra for compounds 5, 21, 22, 24, 25, 32b, 33, 36, 37, and 1. This material is available free of charge via the Internet at http://pubs.acs.org.

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