Hydrogen Peroxide → (+/-)-6-[2-Methyl-4-(3-phenyl-piperidin-1ylmethyl)-phenoxy]-nicotinamide methanesulfonate

HRID 228246Notes

Reaction equation

HRID 228246 reaction equation
[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:31].[K+].[K+].OO.[CH3:38][S:39]([OH:42])(=[O:41])=[O:40]>CS(C)=O.O.O1CCCC1>[CH3:38][S:39]([OH:42])(=[O:41])=[O:40].[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:31])=[CH:7][N:6]=1

Participants

8

Reactant 4

HCID 784Hydrogen PeroxideHCID 6395Methanesulfonic AcidHCID 11430Potassium CarbonateHCID 597300426-[2-Methyl-4-[(3-phenyl-1-piperidinyl)methyl]phenoxy]-3-pyridinecarbonitrile2×

Product 1

HCID 86623805(+/-)-6-[2-Methyl-4-(3-phenyl-piperidin-1ylmethyl)-phenoxy]-nicotinamide methanesulfonateYield 16.4%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Combine (±)-6-[2-methyl-4-(3-phenyl-piperidinylmethyl)-phenoxy]-nicotinonitrile (compound of example 365, step 2) (0.878 g, 2.29 mmol) and potassium carbonate (0.159 g, 1.15 mmol) in dimethylsulfoxide (11.0 mL,). Treat the mixture with 30% hydrogen peroxide solution (aq) (0.77 mL, 6.79 mmol), and stir at ambient temperature. After 4 h, dilute the reaction mixture with water (25 mL) and extract with ethyl acetate (3×30 mL). Wash combined ethyl acetate extracts with brine, dry over anhydrous magnesium sulfate, filter, and concentrate. Crude product is pure by 1H NMR and reverse-phase HPLC. Dissolve product in tetrahydrofuran (12 mL) and treat with methanesulfonic acid (0.148 mL, 2.28 mmol). White precipitate forms and turns oily within 3 minutes. Dissolve residue in tetrahydrofuran and concentrate. Product purity is 82% by reverse-phase HPLC. Purify residue by reverse-phase HPLC. Concentrate fractions containing pure product, recrystallize from methanol:diethyl ether (2:5, 16 mL), and isolate product by vacuum filtration to provide 0.0941 g (10%) of the title compound as white/tan crystals: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2172; 1H NMR (methanol-d4): 8.62 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.57-7.54 (m, 1H), 7.48 (dd, 1H, J=1.5, 7.8 Hz), 7.43-7.38 (m, 2H), 7.37-7.30 (m, 3H), 7.23 (d, 1H, J=8.3 Hz), 7.16 (d, 1H, J=8.8 Hz), 4.45-4.36 (m, 2H), 3.63 (t, 2H, J=14.6 Hz), 3.22 (t, 1H, J=12.2 Hz), 3.17-3.07 (m, 2H), 2.23 (s, 3H), 2.20-2.13 (m, 1H), 2.12-2.92 (m, 2H), 1.86 (dq, 1H, J=3.9, 12.2 Hz).

Workup

  1. extractionextract with ethyl acetate (3×30 mL)
  2. washWash
  3. dry with materialdry over anhydrous magnesium sulfate
  4. filtrationfilter
  5. concentrationconcentrate
  6. waitWhite precipitate forms and turns oily within 3 minutes
  7. concentrationDissolve residue in tetrahydrofuran and concentrate
  8. additionConcentrate fractions containing pure product
  9. customrecrystallize from methanol:diethyl ether (2:5, 16 mL)
  10. customisolate product
  11. filtrationby vacuum filtration

Sources & evidence

ORD record
ord-48a39ab4a70e40f6ab52d02ad694a611
Source dataset
uspto-grants-2009_07
Patent number
US07560463B2

Reaction notes

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