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

HRID 1963360Notes

Reaction equation

HRID 1963360 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[F:8].Br>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

3

Reactant 2

HCID 260Hydrogen BromideHCID 68502596(2R,4S)-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

Product 1

HCID 469381615-((2R,4S)-2-(3,4-difluorophenyl)piperidin-4-yl)isoxazol-3(2H)-oneYield 65.5%

Procedure

(2R,4S)-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.7 g, 5.03 mmol) was dissolved in hydrobromic acid (33% in AcOH, 25 mL, 151.92 mmol) and stirred at room temperature for 20 h. The solvent was evaporated in vacuo. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. The compound was repurified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. 5-((2R,4S)-2-(3,4-difluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (0.923 g, 65.5%) was isolated as a white solid. 1H NMR (600 MHz, cd3od) δ 1.66-1.76 (m, 2H), 2.09 (d, 1H), 2.19 (d, 1H), 2.96-3.07 (m, 2H), 3.28-3.35 (omitted signals), 3.90-3.95 (m, 1H), 5.65 (s, 1H), 7.20-7.29 (m, 2H), 7.34-7.39 (m, 1H). HRMS Calcd for [C14H14F2N2O2+H]+: 281.1101. Found: 281.1106.

Workup

  1. customThe solvent was evaporated in vacuo
  2. customThe compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  3. custombuffer over 25 minutes
  4. customThe compound was repurified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  5. custombuffer over 25 minutes

Sources & evidence

ORD record
ord-2b07abd64d4847dbab1a3d12b0182d5e
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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