反应详情

温度

60 °C

To a stirred suspension of zinc dust (0.75 wt, 3.5 eq) in isopropyl acetate (5 vols), add a solution of DME (0.5 vol) and water (0.5 eq). Heat the resulting solution from room temperature to 40° C. Treat the reaction mixture with a solution of ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate (1.0 wt, 1.0 eq) and dichlorodimethylsilane (0.32 wt, 0.75 eq) in isopropyl acetate (3 vols) over a period of 2 h as this addition is mildly exothermic. After the addition is complete, increase the process temperature to 60° C. Treat the suspension at 60° C. slowly with neat dichlorodimethylsilane (0.95 wt, 2.3 eq) over a period of 1 h. When the reduction of the sulfonylchloride is deemed complete (by HPLC), treat the reaction mixture with {5-Hydroxymethyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol (1.04 wt, 1.1 eq) in one portion at 60° C. After the addition is complete, increase the process temperature to 89° C. and stir the reaction mixture at this temperature for 3 to 5 h then cool to ambient temperature. Filter the reaction mixture to remove unreacted zinc residue, wash the filtrate with water (2×8 vols) and concentrate the organic layer to about 3.5 volumes via vacuum distillation at 40–45° C. Dissolve the resultant, somewhat syrupy, residue in ethanol (2 vols) and treat the resulting solution with iso-octane (2 vols). Cool the clear yellow-tinted solution to ambient temperature to induce crystallization of the product. Collect the solid via filtration. Wash the wet cake with iso-octane/EtOH (9:1, 1 vol) and dry under vacuum (˜21 Torr) at 60° C. for 12 h to afford the title compound as an off-white solid.

1. temperatureHeat the resulting solution from room temperature to 40° C
2. additionas this addition
3. additionAfter the addition
4. additionAfter the addition
5. temperatureincrease the process temperature to 89° C.
6. temperaturethen cool to ambient temperature
7. filtrationFilter the reaction mixture
8. customto remove unreacted zinc residue
9. washwash the filtrate with water (2×8 vols)
10. concentrationconcentrate the organic layer to about 3.5 volumes
11. distillationvia vacuum distillation at 40–45° C
12. dissolutionDissolve the resultant
13. additionsomewhat syrupy, residue in ethanol (2 vols) and treat the resulting solution with iso-octane (2 vols)
14. temperatureCool the clear yellow-tinted solution to ambient temperature
15. customcrystallization of the product
16. customCollect the solid
17. filtrationvia filtration
18. washWash the wet cake with iso-octane/EtOH (9:1, 1 vol)
19. customdry under vacuum (˜21 Torr) at 60° C. for 12 h