反应详情

温度

-40 °C

Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.278 g, 0.73 mmol) (from example 120, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.029 g, 0.73 mmol) dissolved in water (0.300 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.044 mL, 0.73 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4 mL, 24.00 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 semi-solid. The compound was purified by preparative HPLC 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. Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (83 mg, 34%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-2.14 (m, 4H), 2.71-3.14 (m, 4H), 3.43-3.75 (m, 3H), 4.01-4.78 (m, 2H), 5.65 (s, 1H), 6.78-7.14 (m, 3H). MS m/z 353 (M+H)+

1. additionwas added during 10 min
2. stirringThe resulting solution was stirred at −40° C. for 3 h 15 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 semi-solid
9. customThe compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
10. custombuffer over 20 minutes