反应详情

温度

-40 °C

Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.46 g, 6.42 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.257 g, 6.42 mmol) dissolved in water (2 mL) was added over 5 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.4 mL, 6.53 mmol) was added over 1 min and stirring continued at −40° C. for 1 h 15 min. 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 35 min. 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. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-60% Acetonitrile in H2O/MeCN/Acetic Acid 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.62 g, 72%) was isolated as a colorless foam. 1H NMR (400 MHz, cd3od) δ 1.90-2.10 (m, 4H), 2.65-2.80 (m, 2H), 3.04 (p, 1H), 3.19-3.34 (m, 1H), 3.44 (s, 3H), 3.94 (ddd, 1H), 4.32-4.44 (m, 1H), 5.85 (s, 1H), 6.78-6.90 (m, 2H), 7.09-7.20 (m, 1H). MS m/z 353 (M+H)+

1. additionwas added over 5 min
2. stirringstirring
3. waitcontinued at −40° C. for 1 h 15 min
4. stirringto be stirred at 80° C. for 35 min
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
11. customThe residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
12. custombuffer over 30 minutes