Hexane → (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide

Participants

Reaction Conditions

Reaction Steps

A 2M solution of trimethylaluminium in hexane (0.404 mL, 0.81 mmol) was added to 5-methylpyridin-2-amine (84 mg, 0.77 mmol) in toluene (22 mL) at 5° C. under nitrogen. The resulting solution was stirred at 5° C. for 20 minutes. (2S)-Methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (300 mg, 0.70 mmol) (Intermediate J5) in toluene (6 mL) was added dropwise at 5° C. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was concentrated, diluted with EtOAc (100 mL) and washed sequentially with 1M citric acid (50 mL), then saturated brine (50 mL). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with EtOAc to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (160 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 1.09-1.12 (6H, m), 2.23 (3H, s), 2.26 (3H, s), 3.62-3.68 (1H, m), 4.00-4.09 (2H, m), 5.97 (1H, t), 7.30-7.33 (1H, m), 7.56-7.59 (1H, d), 7.70-7.73 (1H, d), 8.01-8.01 (1H, s), 8.21 (1H, d), 8.44 (1H, s), 8.46 (1H, m) 8.53 (1H, s), 9.5 (1H, broad s); m/z (ESI+) (M+H)+=448; HPLC tR=1.98 min.

Provenance & Evidence