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

US11999749B2 · kind B2 · utility

Assignees

• Genentech, Inc. · US
• Hoffmann-La Roche Inc. · US

Inventors

• Francis Gosselin · South San Francisco, US
• Stefan G. Koenig · Shrewsbury, US
• Eduardo V. MERCADO-MARIN · Escondido, US
• Andreas Stumpf · Leverkusen, DE
• Daniel ZELL · Belmont, US
• Haiming Zhang · Pennington, US
• Stephan Bachmann · Allschwil, CH
• Diane E. Carrera · Redwood City, US
• Michael E. DALZIEL · South San Francisco, US
• Yonghui GE · Suzhou, CN
• Jie Zhang · Beijing, CN
• Raphael BIGLER · Basel, CH
• Laure Elizabeth Simone FINET · Buschwiller, FR
• Regis Jean Georges Mondiere · Chur, CH
• Yuki Nakagawa · Toda, JP

Key dates

• Filing date: Jun 28, 2022
• Grant date: Jun 4, 2024
• Expiry date: Jun 28, 2042

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D495/04
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

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.