Lithium Hexamethyldisilazide → (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide

Participants

Reaction Steps

A solution of lithium bis(trimethylsilyl)amide (3.26 mL, 3.26 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate G1) (730 mg, 3.26 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (866 mg, 3.26 mmol) in dry THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with EtOAc to afford (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (930 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t), 2.29 (3H, s), 3.59-3.67 (2H, m), 4.06-4.17 (2H, m), 6.06-6.08 (1H, m), 7.47 (1H, dd), 7.53 (1H, dd), 8.00 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.48 (1H, s), 8.62 (1H, dd), 8.63 (1H, s), 8.65 (1H, s); m/z (ESI+) (M+H)+=454.3; HPLC tR=1.97 min.

Provenance & Evidence