2-Amino-5-fluoropyridine → (2S)-3-((S)-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

Participants

Reaction Conditions

Reaction Steps

Trimethylaluminium (2M in hexanes)(0.608 mL, 1.22 mmol) was added to 5-fluoropyridin-2-amine (130 mg, 1.16 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AO2) (552 mg, 1.06 mmol) in toluene (8 mL) was added and the reaction was 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 to afford the product (638 mg, 100%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.05 (d, 6H), 0.87 (s, 9H), 1.17 (d, 3H), 3.51-3.58 (m, 1H), 3.60-3.69 (m, 2H), 4.18-4.22 (m, 2H), 6.00 (t, 1H), 7.40-7.49 (m, 2H), 7.98-8.03 (m, 1H), 8.13 (d, 1H), 8.22-8.28 (m, 1H), 8.44 (s, 1H), 8.60-8.64 (m, 2H), 8.94 (s, 1H); m/z (ES+), (M+H)+=602.55; HPLC tR=3.35 min

Provenance & Evidence