反应详情

温度

-40 °C

Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.404 g, 6.27 mmol) was dissolved in MeOH (21 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.251 g, 6.27 mmol) dissolved in water (2.100 mL) was added over 8 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.384 mL, 6.27 mmol) was added over 6 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (32.3 mL, 193.76 mmol) and the mixture continued to stir at 80° C. for 25 min. The solvent was evaporated and the crude mixture was redissolved in DCM/water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.232 g, 55.8%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.94-2.04 (m, 2H), 2.08-2.16 (m, 2H), 2.63-2.73 (m, 1H), 2.81-2.91 (m, 1H), 2.98-3.09 (m, 1H), 3.24-3.37 (m, 4H), 3.88-3.99 (m, 1H), 4.41-4.54 (m, 1H), 5.81 (s, 1H), 6.82-6.92 (m, 2H), 7.16-7.26 (m, 1H). MS m/z 353 (M+H)+

1. additionwas added over 8 min
2. stirringthe solution was stirred for 3.5 hours at −40° C
3. stirringto stir at 80° C. for 25 min
4. customThe solvent was evaporated
5. dissolutionthe crude mixture was redissolved in DCM/water
6. customThe organic phase was dried
7. concentrationconcentrated
8. customThe compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
9. custombuffer over 20 minutes