反应详情

温度

-40 °C

Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 3.08 mmol) (from example 134, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.123 g, 3.08 mmol) dissolved in water (1.7 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.2 mL, 3.26 mmol) was added over 1 min and stirring continued at −40° C. for 2 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 101%) was isolated as a pale orange foam. 1H NMR (500 MHz, cdcl3) δ 1.43-2.15 (m, 4H), 2.66-3.23 (m, 4H), 3.39-3.79 (m, 3H), 4.04-4.41 (m, 1H), 4.45-4.78 (m, 1H), 5.67 (s, 1H), 6.73-6.90 (m, 2H), 7.03-7.37 (m, 1H). MS m/z 353 (M+H)+

1. additionwas added over 1 min
2. stirringstirring
3. waitcontinued at −40° C. for 2 h
4. stirringto be stirred at 80° C. for 1 h
5. temperatureThen cooled to room temperature
6. customMethanol was evaporated
7. additionwater was added
8. extractionExtracted three times with DCM
9. dry with materialCombined organic layers dried over MgSO4
10. customevaporated