Sodium hydride → 6-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile

関与物質

反応手順

Sodium hydride (2.78 g, 69.46 mmol) was added portionwise to 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (3.06 g, 17.37 mmol), in THF (8 mL) under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 20 minutes and then 4,6-dichloropyridine-3-carbonitrile (3.00 g, 17.37 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (100 mL). The mixture was washed sequentially with water (100 mL), a saturated solution of NaHCO3 (100 mL), and finally with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was loaded onto an SCX column and the product was eluted using a mixture of MeOH in CH2Cl2. Fractions containing product were combined and evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 50-70% EtOAc in isohexane. Fractions containing the required product were combined and evaporated to afford 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.149 g, 21% yield). The mixed fractions were combined and repurified by silica chromatography, eluting with a gradient of 0-20% EtOAc in CH2Cl2. Fractions containing the required product were combined and evaporated to leave 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.287 g, 24% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.98 (2H, t), 3.06 (3H, s), 3.58 (2H, t), 7.07 (1H, dd), 7.36 (1H, s), 7.48-7.52 (2H, m), 8.63 (1H, s), 12.00 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=313.34 and 315.33.

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