Hydrochloric Acid → HCID 68505101, compound

Temperature

-40 °C

Cis-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.38 g, 4.49 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.180 g, 4.49 mmol) dissolved in water (2.000 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.275 mL, 4.49 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (23.20 mL, 139.22 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (650 mg, 52%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.77-1.88 (m, 1H), 2.03-2.24 (m, 3H), 2.93-3.03 (m, 1H), 3.22-3.33 (m, 1H), 3.75 (s, 3H), 3.92-4.02 (m, 1H), 4.21-4.34 (m, 1H), 5.73 (s, 1H), 5.92 (dt, 1H). MS m/z 275 (M−H)−

1. additionwas added
2. stirringThe resulting solution was stirred at −40° C. for 1 h
3. stirringthe mixture was stirred at 80° C. for 20 min
4. customthe phases separated
5. extractionThe aqueous phase was extracted with DCM
6. filtrationthe combined organic layers were filtered through a phase separator
7. customevaporated
8. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
9. custombuffer over 20 minutes

ORD record

ord-08a936ff44ca44cc923ab68da41ed93b

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08415378B2