2-Amino-5-fluoropyridine → HCID 57504539, compound

Participants

Reaction Conditions

Reaction Steps

Trimethylaluminium (2M in hexane)(0.474 mL, 0.95 mmol) was added to 5-fluoropyridin-2-amine (102 mg, 0.91 mmol) in toluene (7 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AN2) (430 mg, 0.82 mmol) in toluene (7 mL) was added and the reaction was allowed to warm to room temperature and then heated to 100° C. for 5 hours in the microwave reactor. The reaction was allowed to cool to room temperature before adding EtOAc (30 mL) and 20% sodium potassium tartrate solution (30 mL), which was stirred vigorously for 16 hours. The phases were separated and the organic layer was washed with sat. brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to give (2S)-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (303 mg, 61.1%). 1H NMR (400 MHz, DMSO) δ-0.01 (d, 6H), 0.80 (s, 9H), 1.09 (d, 3H), 3.46-3.63 (m, 2H), 3.67-3.77 (m, 1H), 4.07-4.20 (m, 2H), 5.90-5.95 (m, 1H), 7.71-7.80 (m, 2H), 8.02-8.08 (m, 1H), 8.33-8.39 (m, 2H), 8.58 (s, 1H), 8.63 (s, 1H), 8.67-8.71 (m, 1H), 11.09 (s, 1H); m/z (ES+), (M+H)+=602.48; HPLC tR=3.33 min

Provenance & Evidence