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
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 carbonylatio...
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Main Authors | , , , , , , , , , , , , , , |
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Format | Patent |
Language | English |
Published |
04.01.2024
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Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | Application Number: AU20220303488 |