Potassium Sodium Tartrate → (2S)-3-[2-(tert-butyl-diphenylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-cyanopyridin-2-yl)propanamide

Participants

Reaction Conditions

Reaction Steps

A solution of 2M Trimethyl aluminium in toluene (1.790 mL, 3.58 mmol) in toluene (15 mL) was added dropwise to a stirred suspension of 6-aminonicotinonitrile (0.426 g, 3.58 mmol) in toluene (15 mL) cooled to 0° C., over a period of 2 minutes under nitrogen and the resulting suspension stirred for 20 minutes at 0° C. A solution of (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AE2) (1.05 g, 1.63 mmol) in toluene (10 mL) was added dropwise over 2 minutes, the mixture allowed to warm to ambient temperature and then heated to 60° C. for 20hrs. Cooled to ˜5° C. and a 10% solution of Rochelle's salt (25 mL) added followed by ethyl acetate (30 mL) and stirred at ambient temperature for 30 minutes. The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated to a yellow gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (1.1 g, 92%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, s), 2.03 (3H, s), 3.71-3.78 (4H, m), 4.05-4.10 (1H, m), 4.14-4.19 (1H, m), 6.00-6.02 (1H, m), 7.34-7.45 (8H, m), 7.59-7.61 (4H, m), 7.67-7.69 (1H, m), 8.11-8.14 (1H, m), 8.20-8.23 (1H, m), 8.51 (1H, s), 8.84 (1H, s), 8.80-8.82 (1H, m), 11.55 (1H, s); m/z (ESI+) (M+H)+=732; HPLC tR=3.48 min.

Provenance & Evidence