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

HRID 1963441Notes

Reaction equation

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

Participants

Reactant 2

HCID 260Hydrogen Bromide

HCID 68501466HCID 68501466, compound

Product 1

HCID 469374755-((2R,4S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidin-4-yl)isoxazol-3(2H)-oneYield 63%

Procedure

(2R,4S)-Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (458 mg, 1.13 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 8.93 mL, 50.98 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo 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-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (246 mg, 63%). 1H NMR (600 MHz, dmso) δ 1.37 (q, 1H), 1.47 (dq, 1H), 1.84-1.90 (m, 1H), 1.93-1.99 (m, 1H), 2.74 (dt, 1H), 2.87-2.94 (m, 1H), 3.07-3.13 (m, 1H), 3.94 (dd, 1H), 5.74 (s, 1H), 7.18-7.22 (m, 1H), 7.28-7.33 (m, 1H), 7.66 (t, 1H); HRMS Calculated for [C15H14F4N2O3+H]+: 347.1019. Found: 347.0995

Workup

customThe solvent was removed in vacuo
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-a0d7e8946cab44f0877cfcad11a73063
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08415378B2

Reaction notes

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