反应详情

To a stirred mixture of 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbaldehyde (which may be prepared as described in Description 141) (2980 mg, 10.904 mmol) and 3-amino-1-methyl-pyrrolidin-2-one (508.12 mg, 4.4514 mmol) in anhydrous DCM (10 mL) at room temperature, was added magnesium sulfate (3937.5 mg, 32.711 mmol). The resulting mixture was left to stir at room temperature for 3 h. The reaction mixture was filtered through a plug of cotton wool and the filtrate was washed with brine. The organic layer was collected by means of a PhaseSep cartridge. Evaporation of solvent under reduced pressure gave yellow oil, 3-[(E)-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]methyleneamino]-1-methyl-pyrrolidin-2-one (3.97 g, 10.746 mmol, 98.6% yield). To a portion of this material (3920 mg, 10.611 mmol) in anhydrous THF (35 mL) under nitrogen at room temperature, was added phenyl vinyl sulfone (2141.9 mg, 12.733 mmol) and silver acetate (1771.1 mg, 10.611 mmol). The resulting mixture was left to stir in the dark for 10 min. DBU (0.7932 mL, 5.3055 mmol) was added. The resulting mixture was left to stir in the dark for 2 h. The dark filtrate was evaporated and further dried under house vac. It was purified by silica gel chromatography (100 g SiO2) eluting with ethyl acetate in iso-hexane (30-100%) followed by methanol in ethyl acetate (0-15%). Evaporation of desired fractions gave 3-(benzenesulfonyl)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (3880 mg, 7.2166 mmol, 68.0% yield) as brown solid. To a stirred solution of this material in anhydrous THF (30 mL) under nitrogen at 0° C., was added potassium tert-butoxide (4048.9 mg, 36.083 mmol). The resulting mixture was left to stir for 2 h and acetic acid (2.07 mL, 36.08 mmol) was added. Stirring was continued for 15 min at room temperature. Evaporation of solvent under reduced pressure gave a dark oily residue. It was purified by silica gel chromatography (50 g SiO2) eluting with ethyl acetate in iso-hexane (30-100%). Evaporation of desired fractions gave brown oil, 2-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D142) (543 mg, 1.373 mmol, 19.0% yield);

1. waitThe resulting mixture was left
2. filtrationThe reaction mixture was filtered through a plug of cotton wool
3. washthe filtrate was washed with brine
4. customThe organic layer was collected by means of a PhaseSep cartridge
5. customEvaporation of solvent under reduced pressure