US 11,999,749 B2
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
Francis Gosselin, San Mateo, CA (US); Stefan G. Koenig, San Francisco, CA (US); Eduardo V. Mercado-Marin, Escondido, CA (US); Andreas Stumpf, Dublin, CA (US); Daniel Zell, Belmont, CA (US); Haiming Zhang, San Mateo, CA (US); Stephan Bachmann, Allschwil (CH); Diane E. Carrera, Redwood City, CA (US); Michael E. Dalziel, Chicago, IL (US); Yonghui Ge, Suzhou (CN); Jie Zhang, Changzhou (CN); Raphael Bigler, Aargau (CH); Laure Elizabeth Simone Finet, Buschwiller (FR); Regis Jean Georges Mondiere, Basel (CH); and Yuki Nakagawa, Toda (JP)
Assigned to Genentech, Inc., South San Francisco, CA (US); and Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed by Genentech, Inc., South San Francisco, CA (US); and Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed on Jun. 28, 2022, as Appl. No. 17/852,227.
Claims priority of application No. PCT/CN2021/103873 (WO), filed on Jun. 30, 2021.
Prior Publication US 2023/0028651 A1, Jan. 26, 2023
Int. Cl. C07D 495/04 (2006.01)
CPC C07D 495/04 (2013.01) 13 Claims
 
1. A method of synthesizing a compound of formula 1b, the method comprising:

OG Complex Work Unit Chemistry
reacting compound 4 with compound 5a to produce compound 6a;

OG Complex Work Unit Chemistry
reducing compound 6a with hydrogen over a platinum-vanadium catalyst, with aqueous ammonia, in 2-methyl tetrahydrofuran as a solvent, to form compound 7;

OG Complex Work Unit Chemistry
coupling compound 7 with compound 2 using N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate and 2,6-lutidine, in THF, to produce a THF adduct of compound 1; and

OG Complex Work Unit Chemistry
dissolving the THF adduct of compound 1 in an aqueous mixture of methanesulfonic acid in iso-propyl alcohol, to provide a pure form of compound 1b.