Hydrochloric Acid → trans-Methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

HRID 1963615Notes

Reaction equation

[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]

Participants

Conditions

Temperature: -40 °C

Procedure

Trans-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.399 g, 1.04 mmol) (from example 127, step 1) was dissolved in MeOH (3.5 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.306 mL, 1.04 mmol) was added over 5 min. After 45 min with stirring, hydroxylamine (50% by weight in water, 0.064 mL, 1.04 mmol) was added over one minute and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5.36 mL, 32.16 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with water. The organic phase was dried and concentrated to give crude trans-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.331 g, 90%). MS m/z 353 (M+H)+

Workup

stirringthe solution was stirred for 3.5 hours at −40° C
stirringto stir at 80° C. for 20 min
customThe solvent was evaporated
dissolutionthe crude mixture redissolved in DCM
washwashed with water
customThe organic phase was dried
concentrationconcentrated

Sources & evidence

ORD record: ord-782be93204944542a92e3b577e03e813
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08415378B2

Reaction notes

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