反应详情

温度

-40 °C

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (730 mg, 1.92 mmol) (from example 92, step 1) was dissolved in MeOH (7 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (77 mg, 1.92 mmol) dissolved in water (0.700 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.118 mL, 1.92 mmol) was added. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (9.94 mL, 59.64 mmol) and the mixture was stirred at 80° C. for 20 min. DCM and water were added. The phases were separated, the aqueous phase extracted with DCM and the combined organic layers passed through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. DCM:MeOH:HCOOH=50:1:0.1 over 10 CV was used as mobile phase. Trans-methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (550 mg, 82%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.01-2.13 (m, 6H), 2.48-2.70 (m, 2H), 2.88-3.08 (m, 2H), 3.70 (s, 3H), 3.98-4.69 (m, 2H), 5.64 (s, 1H), 6.91-7.02 (m, 2H), 7.06-7.21 (m, 2H). MS m/z 349 (M+H)+

1. additionwas added
2. stirringThe resulting solution was stirred at −40° C. for 3 h
3. stirringthe mixture was stirred at 80° C. for 20 min
4. customThe phases were separated
5. extractionthe aqueous phase extracted with DCM
6. customevaporated
7. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column