Hydrogen Bromide → 5-((2R,4S)-2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one

HRID 1963470Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:23][NH:22][C:21](=[O:24])[CH:20]=3)[CH2:16][CH2:15][N:14]2C(OC)=O)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].Br>>[F:12][C:6]1[CH:5]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:23][NH:22][C:21](=[O:24])[CH:20]=3)[CH2:16][CH2:15][NH:14]2)[CH:3]=[C:2]([F:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]

Participants

Reactant 2

HCID 260Hydrogen Bromide

HCID 66732123HCID 66732123, compound

Product 1

HCID 469375275-((2R,4S)-2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-oneYield 68.2%

Procedure

(2R,4S)-Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (226 mg, 0.56 mmol) was dissolved in hydrobromic acid (33% in AcOH, 5 mL, 30.38 mmol) and stirred at room temperature for 20 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (133 mg, 68%). 1H NMR (600 MHz, dmso) δ 1.30 (q, 1H), 1.43 (dq, 1H), 1.84-1.89 (m, 1H), 2.02-2.07 (m, 1H), 2.70 (dt, 1H), 2.86 (tt, 1H), 3.07-3.13 (m, 1H), 3.75 (dd, 1H), 5.73 (s, 1H), 7.37 (d, 2H). HRMS Calcd for [C15H13F5N2O2+H]+: 349.0975. Found: 349.0972.

Workup

customThe solvent was evaporated
customthe residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm)

Sources & evidence

ORD record: ord-f7db5a0ed85d4c2689fcd8ab591b5d9f
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08415378B2

Reaction notes

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