反应详情

温度

-40 °C

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.145 g, 3.13 mmol) (from example 101, step 1) was dissolved in methanol (10 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.000 mL) was added dropwise and continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.192 mL, 3.13 mmol) was added dropwise. 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 (15 mL, 90.00 mmol) and the mixture continued to stir at 80° C. for 55 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to a yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (468 mg, 45%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.46-1.77 (m, 2H), 1.80-2.13 (m, 2H), 2.28-3.23 (m, 4H), 3.38-3.80 (m, 3H), 4.04-4.34 (m, 1H), 4.50-4.80 (m, 1H), 5.65 (s, 1H), 6.99-7.12 (m, 2H), 7.12-7.30 (m, 2H). MS m/z 335 (M+H)+

1. additionwas added dropwise
2. stirringThe resulting solution was stirred at −40° C. for 2 h
3. stirringto stir at 80° C. for 55 min
4. customThe solvent was evaporated
5. additionMTBE/water added
6. customThe phases were separated
7. dry with materialthe organic phase dried over Na2SO4
8. customevaporated to a yellow foam
9. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min