反应详情

温度

-40 °C

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.307 g, 5.75 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.230 g, 5.75 mmol) dissolved in water (2 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.75 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.682 g, 79%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.83-1.94 (m, 1H), 2.16-2.29 (m, 2H), 2.34-2.43 (m, 1H), 3.06-3.18 (m, 1H), 3.51 (ddd, 1H), 3.64 (s, 3H), 4.12 (ddd, 1H), 5.10-5.22 (m, 1H), 5.57 (s, 1H), 7.40 (d, 2H), 7.58 (d, 2H). MS m/z 371 (M+H)+

1. additionwas added during 10 min
2. stirringThe resulting solution was stirred at −40° C. for 3 h 20 min
3. stirringto stir at 80° C. for 20 min
4. customThe solvent was evaporated
5. additionDCM/water added
6. customThe phases were separated
7. customevaporated
8. customto yield a yellow solid
9. customThe compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm)
10. custombuffer over 20 minutes