Diisopropylethylamine → N-{(4aR,7aR)-7a-(5-Cyanothiophen-2-yl)-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}benzamide

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Reaction Steps

To a stirred clear and colorless solution of N-[(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.806 mmol) in 1,4-dioxane (16 mL) is added diisopropylethylamine (422 μL, 2.42 mmol) and 2-(2-chloro-5-fluoropyrimidin-4-yl)propan-2-ol (1.54 g, 8.06 mmol). The solution is heated to reflux for 14 hours. The pale yellow solution is allowed to cool, diluted with ethyl acetate (80 mL) and hexanes (20 mL), and washed with dilute aqueous sodium bicarbonate (30 mL, prepared from saturated aqueous sodium bicarbonate (15 mL) and water (15 mL), water (2×20 mL), and brine (20 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a hexanes/diethyl ether, gradient from 80:20 to 0:100, to give the title compound (374 mg, 89% over two steps) as a pale yellow glass. MS/ES (m/z) 523.2 (M+H).

Provenance & Evidence