2H-Pyran-4-carbonitrile, tetrahydro-4-methoxy- synthesis

Yield:155650-56-9 78%

Reaction Conditions:

with titanium tetrachloride in dichloromethane at -78 - 20;Inert atmosphere;

Steps:

182.1

EXAMPLE 182 6-[2-tert-Butyl-1-(4-methoxytetrahydropyran-4-ylmethyl)-1H-imidazol-4-yl]-N-methyl-N-propylpyrazine-2-carboxamide (Compound 182) Step 1; Under an argon atmosphere, 4,4-dimethoxytetrahydropyran (4.39 g, 30.0 mmol) was dissolved in dichloromethane (60 mL), and tert-butyl isocyanide (3.73 mL, 33.0 mmol) and titanium tetrachloride (3.95 mL, 36.8 mmol) were added thereto at -78°C, and then, the mixture was stirred overnight at room temperature. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was filtered through Celite, and then, the filtrate was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 80/20) to give 4-methoxytetrahydropyran-4-carbonitrile (3.30 g, 23.4 mmol, yield: 78%). ¹H-NMR (dppm, CDCl₃): 3.98-3.89 (m, 2H), 3.72-3.62 (m, 2H), 3.47 (s, 3H), 2.18-2.08 (m, 2H), 1.92-1.81 (m, 2H).

References:

EP2090570,2009,A1 Location in patent:Page/Page column 95