Hydrogen Peroxide → 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridine-2-carboxamide TFA salt

Dioxane (1.06 mL), 6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (51 mg, 0.32 mmol) and cesium carbonate (311 mg, 0.955 mmol) were added to tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (94 mg, 0.32 mmol) in a scintillation vial. The vial was purged and flushed with argon three times before Pd2 dba3 (29 mg, 0.032 mmol) and Xantphos (28 mg, 0.048 mmol) were added. The vial was purged and flushed 3 times with argon before the vial was sealed and heated to 80° C. After 16 hours, the reaction mixture was cooled to room temperature, filtered through CELITE (washed with dichloromethane), and diluted with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-70% acetone in hexanes, linear gradient) to afford tert-butyl {(1S,2R)-2-[(6-cyano-5-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridin-3-yl)amino]cyclohexyl}carbamate. The isolated solids were dissolved in DCM (1 mL) and TFA (1 mL), and stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL). To this solution was added sodium hydroxide (4.0 M in water, 0.1 mL, 0.4 mmol) and hydrogen peroxide (30 wt % in water, 0.050 mL, 0.49 mmol). The reaction mixture was stirred at room temperature until complete conversion of the nitrile intermediate was observed by LCMS. The reaction mixture was diluted with DMSO and filtered. The filtrate was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C19H24N9O [M+H]+ 394. found 394. 1H NMR (500 MHz, CD3OD) δ 9.20 (s, 1H), 8.07 (s, 2H), 7.83 (t, J=8.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.38 (s, 1H), 3.75-3.67 (m, 1H), 2.01-1.66 (m, 6), 1.66-1.51 (m, 2H).

1. concentrationthe reaction mixture was concentrated under reduced pressure
2. dissolutionThe residue was dissolved in DMSO (1 mL)
3. filtrationfiltered
4. customThe filtrate was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient)

ORD record

ord-9768d58f32cb45eeb41a2ad2ba90ba91

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216173B2