反应详情

温度

100 °C

A 3 L flask was charged with 200.0 g (1.60 mol) of N-(1H-pyrazol-3-yl)-acetamide and 1 L of anhydrous DMF. To the agitated suspension was added 173.8 g (1.75 mol) of sodium tert-butoxide in one portion. To the mixture was added 82.0 g (1.91 mol) of lithium chloride in one portion. To the mixture was added 267 g (1.75 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane in one portion. The mixture was agitated at 100° C. for 5 h. To the resulted mixture was added additional 31.6 g (0.32 mol) of sodium tert-butoxide and followed by 48.5 g (0.32 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane. The mixture was agitated at 100° C. for additional 5 h. To the resulted mixture was added additional 31.6 g (0.32 mol) of sodium tert-butoxide and followed by 48.5 g (0.32 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane. The mixture was agitated at 100° C. for 16 h. Then the mixture was cooled to 60° C. and concentrated under reduced pressure (60-25 mbar, 60° C.) to remove 720 g of the solvents. To the residue was added 1.6 L of water. The resulting solution was extracted with 3.2 L of dichloromethane (DCM). The combined organic phases were washed with 1.6 L of 20 wt % sodium chloride solution, and concentrated by distillation in vacuo (30-40° C. (batch)/P<−100 mbar), giving 585 g (316 g after corrected with wt %, 82.8% yield) of N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-acetamide as a red-brown oil which was used in the subsequent step directly without further processing. 1H-NMR (400 MHz, d6-DMSO): δ 10.37 (s, 1H), 7.57 (s, 1H), 6.44 (s, 1H), 4.33-4.36 (m, 1H), 4.08-4.11 (m, 2H), 3.98-4.02 (m, 1H), 3.71-3.75 (m, 1H), 1.98 (s, 3H), 1.31 (s, 3H), 1.26 (s, 3H).

1. stirringThe mixture was agitated at 100° C. for additional 5 h
2. stirringThe mixture was agitated at 100° C. for 16 h
3. temperatureThen the mixture was cooled to 60° C.
4. concentrationconcentrated under reduced pressure (60-25 mbar, 60° C.)
5. customto remove 720 g of the solvents
6. additionTo the residue was added 1.6 L of water
7. extractionThe resulting solution was extracted with 3.2 L of dichloromethane (DCM)
8. washThe combined organic phases were washed with 1.6 L of 20 wt % sodium chloride solution
9. concentrationconcentrated by distillation in vacuo (30-40° C. (batch)/P<−100 mbar)