反应详情

温度

-40 °C

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (1.826 g, 5.00 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.200 g, 5.00 mmol) dissolved in water (2.000 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.306 mL, 5.00 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then rapidly poured 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. 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 brown semi-solid. The compound was purified by preparative HPLC in 2 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 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.141 g, 68%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.83-2.15 (m, 4H), 2.58-2.67 (m, 1H), 2.77-2.86 (m, 1H), 2.93-3.03 (m, 1H), 3.10-3.21 (m, 1H), 3.63 (s, 3H), 3.96-4.05 (m, 1H), 4.22-4.32 (m, 1H), 5.73 (s, 1H), 6.81-6.95 (m, 3H), 7.18-7.27 (m, 1H). MS m/z 335 (M+H)+

1. additionwas added during 20 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 solvent was evaporated
5. additionDCM/water added
6. customThe phases were separated
7. customevaporated
8. customto yield a brown semi-solid
9. customThe compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm)
10. custombuffer over 20 minutes