反应详情

温度

-40 °C

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (0.454 g, 1.24 mmol) (from example 97, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.050 g, 1.24 mmol) dissolved in water (1 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, 0.076 mL, 1.24 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (6 mL, 36.00 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 slightly yellow oil. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.268 g, 64.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.47-1.75 (m, 2H), 1.85-2.14 (m, 2H), 2.71-3.00 (m, 2H), 3.02-3.16 (m, 2H), 3.40-3.76 (m, 3H), 4.22 (d, br., 1H), 4.59 (d, br., 1H), 5.64 (s, 1H), 6.95-7.03 (m, 2H), 7.15 (s, br., 2H). MS m/z 335 (M+H)+

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