Methanol → methyl 3-fluoro-5-(3-((1S,2S)-2-fluorocyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpicolinate

Temperature

100 °C

A flask charged with (1S,2S)-N-(7-(6-chloro-5-fluoro-4-methylpyridin-3-yl)-isoquinolin-3-yl)-2-fluoro-cyclopropanecarboxamide (261 mg; 0.5237 mmol), palladium(II) acetate (13.7 mg; 0.0610 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (66.8 mg; 0.106 mmol), potassium carbonate (136.1 mg; 0.9749 mmol), N,N-dimethylformamide (3.0 mL; 38 mmol) and methanol (0.75 mL; 18 mmol) was evacuated and backfilled with CO gas 3 times, and then stirred under a balloon of CO gas at 100° C. for 20 hours. To the reaction mixture was then added triethylamine (0.20 mL; 1.4 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (64.9 mg; 0.0795 mmol). The reaction vessel was re-purged with CO gas and stirred at 100° C. for an additional 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 134.9 mg (70% pure, 45% yield) of the title compound. LCMS (ESI): M+H=398.2.

1. customwas evacuated
2. customThe reaction vessel was re-purged with CO gas
3. stirringstirred at 100° C. for an additional 3 hours
4. additionThe reaction mixture was diluted with ethyl acetate
5. washwashed with water and brine
6. dry with materialdried over magnesium sulfate
7. filtrationfiltered
8. customevaporated in vacuo
9. customThe crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-10% methanol in dichloromethane)

ORD record

ord-410123abf0eb43d88f7d709dda947293

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206175B2