2-Amino-5-methylpyridine → (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)-4-(methylsulfonamido)butanamide

Participants

Reaction Conditions

Reaction Steps

Trimethylaluminium (2M in hexane) (0.164 mL, 0.33 mmol) was added to 5-methylpyridin-2-amine (33.8 mg, 0.31 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (3S)-3-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-1-(methylsulfonyl)pyrrolidin-2-one (Intermediate AC1) (116 mg, 0.28 mmol) in toluene (1 mL) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was then heated to reflux for 2.5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid and sodium potassium tartrate solution (sat.) and stirred vigorously for 45 mins. The mixture was separated and the aqueous re-extracted with ethyl acetate, the organic layer was dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (52.0 mg, 35.4%). 1H NMR (400 MHz, CDCl3) δ 2.30 (3H, s), 2.37-2.55 (2H, m), 2.98 (3H, s), 3.35-3.55 (2H, m), 4.95-5.10 (1H, m), 6.04 (1H, t), 7.44-7.58 (4H, m), 7.60-7.65 (1H, m), 8.07-8.15 (2H, m), 8.44 (1H, s), 8.61 (1H, s), 8.69 (1H, s); m/z (ES+) (M+H)+=516.28; HPLC tR=1.84 min.

Provenance & Evidence