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

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PATENT NO 11999749
SERIAL NO

17852227

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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.

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HOFFMANN-LA ROCHE INC340 KINGSLAND STREET NUTLEY NJ 07110

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Inventor(s)

Inventor Name Address # of filed Patents Total Citations
Bachmann, Stephan Allschwil, CH 32 55
Bigler, Raphael Aargau, CH 7 1
Carrera, Diane E Redwood City, US 3 8
Dalziel, Michael E Chicago, US 2 0
Finet, Laure Elizabeth Simone Buschwiller, FR 2 0
Ge, Yonghui Suzhou, CN 4 4
Gosselin, Francis San Mateo, US 59 271
Koenig, Stefan G San Francisco, US 11 40
Mercado-Marin, Eduardo V Escondido, US 4 0
Mondiere, Regis Jean Georges Basel, CH 14 13
Nakagawa, Yuki Toda, JP 36 85
Stumpf, Andreas Dublin, US 23 78
Zell, Daniel Belmont, US 3 4
Zhang, Haiming San Mateo, US 57 133
Zhang, Jie Changzhou, CN 1052 8750

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