Hydrogen Peroxide → 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-({5-[3-(2,2-difluoro-1-hydroxyethyl)phenyl]-6-methylpyridin-2-yl}amino)pyridine-2-carboxamide

Temperature

80 °C

To a solution of tert-butyl (1S,2R)-2-(5-(5-bromo-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate (PrepEx 1.6) (40 mg, 0.080 mmol) in degassed 1,4-dioxane (0.75 mL) was added 3-(2,2-difluoro-1-hydroxyethyl)phenylboronic acid (32 mg, 0.16 mmol), potassium phosphate tribasic (50 mg, 0.24 mmol), and 1,1′-bis(diphenylphosphino) ferrocene-palladium(II) dichloride dichloromethane complex (6 mg, 0.008 mmol), and the reaction vessel was flushed with argon. The reaction mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, and diluted with trifluoroacetic acid (0.5 mL). The reaction mixture was immediately concentrated under reduced pressure. The residue was dissolved in a 1:1 DCM/methanol solution (1 ml) and SiliaBond DMT resin (83 mg, 0.050 mmol) was then added at room temperature. After 16 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in NMP (0.5 mL). Sodium hydroxide (6.0 M aqueous solution, 0.10 mL, 0.60 mmol) and hydrogen peroxide (35% solution in water, 0.30 mL, 3.4 mmol) were added and the reaction mixture was stirred at room temperature for 3 hours. The reaction was diluted with DMSO (1.0 mL) and purified by reverse phase HPLC (acetonitrile/water with 0.1% ammonium hydroxide, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-({5-[3-(2,2-difluoro-1-hydroxyethyl)phenyl]-6-methylpyridin-2-yl}amino)pyridine-2-carboxamide. MS ESI calc'd. for C26H31F2N6O2 [M+H]+ 497 found 497. 1H NMR (600 MHz, DMSO) δ 10.10 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J=5.1 Hz, 1H), 7.12 (s, 1H), 6.58 (t, J=8.4 Hz, 1H), 3.65-3.43 (m, 1H), 3.35-3.24 (m, 2H), 3.22-3.12 (m, 2H), 2.50 (dd, J=7.2 Hz, 5.4 Hz, 3H), 2.31 (s, 3H), 2.24-2.17 (m, 4H), 1.95-1.81 (m, 4H), 1.69 (dt, J=14.5 Hz, 7.1 Hz, 2H).

1. customthe reaction vessel was flushed with argon
2. temperatureThe reaction mixture was cooled to room temperature
3. additiondiluted with trifluoroacetic acid (0.5 mL)
4. concentrationThe reaction mixture was immediately concentrated under reduced pressure
5. additionwas then added at room temperature
6. waitAfter 16 hours
7. filtrationthe reaction mixture was filtered
8. concentrationconcentrated under reduced pressure
9. dissolutionThe residue was dissolved in NMP (0.5 mL)
10. stirringthe reaction mixture was stirred at room temperature for 3 hours
11. custompurified by reverse phase HPLC (acetonitrile/water with 0.1% ammonium hydroxide, linear gradient)

ORD record

ord-5a302991c75543319e701efd03f5d17d

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216173B2