反应详情

温度

-40 °C

Trans-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (502 mg, 1.36 mmol) (from example 23, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.358 mL, 1.36 mmol) dissolved in water (0.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (0.083 mL, 1.36 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (7.02 mL, 42.13 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (50 mL). The combined organic phase were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (242 mg, 52.6%) was isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 1.60-1.72 (m, 1H), 1.94 (d, 1H), 1.98-2.07 (m, 1H), 2.60 (d, 1H), 2.78-2.94 (m, 2H), 3.77 (s, 3H), 4.25 (s, 1H), 5.51-5.71 (m, 2H), 6.94-6.99 (m, 1H), 7.02-7.09 (m, 1H), 7.17 (dd, 1H). MS m/z 337 (M−H)−.

1. additionwas added
2. stirringstirring
3. waitcontinued for 3.5 h at −40° C
4. stirringstirred for 20 min
5. customThe solvent was evaporated in vacuo
6. additionDCM (50 mL) and water (50 mL) were added
7. stirringshaken
8. customthe phases separated
9. extractionThe aqueous phase was extracted with DCM (50 mL)
10. customThe combined organic phase were dried with a phase separator
11. customevaporated in vacuo
12. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
13. custombuffer over 25 minutes