反应详情

To a yellow, homogeneous mixture of N-hydroxypicolinimidoyl chloride (4.67 g, 29.8 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (4.50 g, 27.1 mmol) in dichloromethane (90 mL) at room temperature was added triethylamine (7.93 mL, 56.9 mmol) slowly over 30 min. During the addition, the reaction mixture slowly became dark in color. The reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was diluted with ether (100 mL) and washed with water (100 mL). The organic layer was collected, and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By HPLC, the product mixture contained a ˜15:85 mixture of the desired isomer and its regioisomer. The mixture was purified by preparative HPLC, and the desired fractions were concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with a saturated aqueous solution of sodium bicarbonate (100 mL), washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (0.518 g, 1.81 mmol, 6.7% yield) as a pale yellow, viscous oil. The compound had an HPLC ret. time=2.18 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=286.9. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (t, J=7.15 Hz, 3H), 4.54 (q, J=7.03 Hz, 2H), 7.46 (ddd, J=7.53, 4.77, 1.25 Hz, 1H), 7.76-7.81 (m, 1H), 7.83-7.89 (m, 1H), and 8.78 (d, J=4.77 Hz, 1H).

1. additionDuring the addition
2. customThe solvent was removed under reduced pressure
3. additionthe residue was diluted with ether (100 mL)
4. washwashed with water (100 mL)
5. customThe organic layer was collected
6. extractionthe aqueous layer was extracted with ether (2×100 mL)
7. dry with materialThe combined organic layers were dried over anhydrous magnesium sulfate
8. concentrationconcentrated under reduced pressure
9. additiona ˜15:85 mixture of the desired isomer and its regioisomer
10. customThe mixture was purified by preparative HPLC
11. concentrationthe desired fractions were concentrated under reduced pressure
12. additionThe residue was diluted with ethyl acetate (100 mL)
13. washwashed with a saturated aqueous solution of sodium bicarbonate (100 mL)
14. washwashed with brine (50 mL)
15. dry with materialdried over anhydrous magnesium sulfate
16. concentrationConcentration under reduced pressure