Hydrochloric Acid → HCID 131730501, compound

Temperature

-40 °C

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (309 mg, 0.77 mmol) (from example 143, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.203 mL, 0.77 mmol) in water (0.500 mL) was added and the mixture was stirred at −40° C. for 20 min. Hydroxylamine (50% in water, 0.047 mL, 0.77 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (3.98 mL, 23.87 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)-piperidine-1-carboxylate (111 mg, 38.9%) was isolated. MS m/z 371 (M+H)+

1. stirringstirring
2. waitcontinued at −40° C. for 3 h
3. customwas then transferred to a preheated 80° C.
4. temperatureheating
5. waitwas continued for 20 min
6. customThe solvent was then evaporated
7. additionDCM (50 mL) and water (50 mL) were added
8. stirringshaken
9. customthe phases separated
10. customThe organic phase was dried with a phase separator
11. customevaporated in vacuo
12. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm)
13. waitover 30 minutes with a flow of 19 mL/min

ORD record

ord-75a094d9e9644743a4e20bb3f7fb0b42

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08415378B2