Sodium hydride → HCID 22222480, compound

Participants

Reaction Steps

3,4-Difluoroaniline (4.5 g) and 6 g of ethyl-2-methyl isovalerylacetate were refluxed in toluene (50 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation. The resultant intermediate was refluxed in diphenyl ether for 30 min. The reaction mixture was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 246 mg of a mixture of 2-isopropyl-3-methyl-4-hydroxy-6,7-difluoroquinoline with 2-isopropyl-3-methyl-4-hydroxy-5,6-difluoroquinoline. In 10 ml of dimethyl formamide was suspended 20 mg of 60% sodium hydride. Separately, 100 mg of the mixture of 2-isopropyl-3-methyl-4-hydroxy-6,7-difluoroquinoline with 2-isopropyl-3-methyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) was suspended in 20 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 100 mg of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 44.1 mg of 2-isopropyl-3-methyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (compound 34). 1H-NMR data are shown in Table 3.

Provenance & Evidence