反应详情

To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+.

1. customrose to 35° C
2. concentrationthe mixture was concentrated in high vacuo at 45° C
3. extractionThe residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L)
4. washOrganic phases were washed with water (2×1.5 L)
5. dry with materialdried with MgSO4
6. concentrationconcentrated in vacuo to ˜800-900ml volume
7. customThe product precipitated
8. stirringthe mixture was stirred at 0° C. for about 30 min
9. filtrationFiltration
10. washwashing with ethyl acetate/n-heptane 1:1 (4×50 mL)
11. customdrying in vacuo at 40° C. for 18 h