反应详情

温度

-40 °C

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.062 g, 4.96 mmol) was dissolved in MeOH (16 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.199 g, 4.96 mmol) dissolved in water (1.600 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, 0.304 mL, 4.96 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-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 5-30% 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-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.30 g, 68%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.79-1.95 (m, 2H), 1.95-2.14 (m, 2H), 2.79-2.98 (m, 3H), 3.17-3.27 (m, 1H), 3.34 (s, 3H), 4.04 (dd, 1H), 4.30-4.41 (m, 1H), 5.68 (s, 1H), 7.14 (d, 1H), 7.19-7.28 (m, 1H), 7.39 (t, 1H), 7.57 (d, 1H). MS m/z 385 (M+H)+

1. additionwas added during 10 min
2. stirringThe resulting solution was stirred at −40° C. for 3.5 h
3. stirringto stir at 80° C. for 20 min
4. customThe phases were separated
5. customevaporated
6. customto yield a yellow semi-solid
7. customThe compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm)
8. custombuffer over 20 minutes