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A clear colorless solution of 5-bromo-N-methyl-imidazole (47.7 g, 296 mmol) in THF (500 mL) was placed in an ice bath and ethylmagnesium bromide in diethyl ether (3.0 M, 98.7 mL, 296 mmol) was added via syringe fairly rapidly, over 17 min. The thick suspension was stirred at room temperature for 20 min. The mixture was again cooled in an ice water bath before addition of neat <strong>[116332-54-8]4-fluoro-N-methoxy-N-methylbenzamide</strong> (45.2 g, 247 mmol, Intermediate 49, step a). The resulting suspension was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous NH4Cl (100 mL) followed by water (200 mL). The pH was adjusted to 7 by addition of 1 N aqueous HCl, the mixture was partially concentrated to remove THF, and was extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was triturated with EtOAc:heptane(1:1, 150 mL) to afford the title compound as a white crystalline solid.
(1-methyl-1H-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A clear colorless solution of 5-bromo-1-methyl-1H-imidazole (1.12 g, 6.93 mmol) in THF (10 mL) was placed in an ice bath and ethylmagnesium bromide (3.0 M in Et2O, 2.31 mL, 6.93 mmol) was added via syringe. The reaction mixture was stirred for 20 minutes at room temperature. N-Methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (1.0 g, 5.8 mmol, Intermediate 1: step a, Procedure A) was added neat by syringe (using 1 mL THF rinse to quantitate transfer), and the resulting white suspension was stirred at room temperature for 2 days. The mixture was diluted with saturated aqueous NH4Cl followed by water, then was extracted with EtOAc (3*). The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography two times (1-4% MeOH-DCM first column; 40-60% CH3CN-DCM second column) to provide the title compound as a white crystalline solid.
lntermediate 1: step b (1-Methyl-lH-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone A clear colorless solution of 5-bromo-l-methyl-lH-imidazole (1.12 g, 6.93 mmol) in THF (10 mL) was placed in an ice bath and ethylmagnesium bromide (3.0 M in Et20, 2.31 mL, 6.93 mmol) was added via syringe. The reaction mixture was stirred for 20 minutes at room temperature. N-Methoxy~N-methyltetrahydro-2H~pyran-4~ca.rboxamide (1.0 g, 5.8 mmol. Intermediate 1 : step a. Procedure A) was added neat by syringe (using 1 mL THF rinse to quantitate transfer), and the resulting white suspension was stirred at room temperature for 2 days. The mixture was diluted with saturated aqueous NH4C1 followed by water, then was extracted with EtOAc (3 x). The organic phase was dried (Na2S04), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography two times (1 -4% MeOH-DCM first column; 40-60% CH CN-DCM second column) to provide the title compound as a white crystalline solid.
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