Acetic Acid → 6-[2-Methyl-4-[(3-phenyl-1-piperidinyl)methyl]phenoxy]-3-pyridinecarbonitrile

HRID 130784Notes

Reaction equation

HRID 130784 reaction equation
Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[C:18]([CH3:31])[CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO>[CH3:31][C:18]1[CH:17]=[C:16]([CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH:30]=[CH:29][C:19]=1[O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 173900083-Phenylpiperidine hydrochlorideHCID 597302456-(4-Formyl-2-methylphenoxy)nicotinonitrile

Product 1

HCID 597300426-[2-Methyl-4-[(3-phenyl-1-piperidinyl)methyl]phenoxy]-3-pyridinecarbonitrileYield 70%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

Convert 3-phenyl piperidine hydrochloride (0.652 g, 3.30 mmol) to the free base using ion exchange chromatography (methanol→2 M ammonia/methanol) and concentrate. Combine the free base with 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (from step 1 above) (0.748 g, 3.29 mmol), sodium triacetoxyborohydride (1.05 g, 4.95 mmol), and acetic acid (0.30 mL, 5.24 mmol) in 1,2-dichloroethane (33 mL) and stir at ambient temperature. After 17 h, wash reaction mixture with saturated sodium bicarbonate (aq) (2×50 mL), dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes→2:1 hexanes:ethyl acetate) to provide 0.878 g (70%) of the title compound as a white foam: 1H NMR (CDCl3): 8.46 (d, 1H, J=2.9 Hz), 7.91 (dd, 1H, J=2.9, 8.8 Hz), 7.34-7.19 (m, 7H), 6.99 (d, 2H, J=8.8 Hz), 3.52 (s, 2H), 3.06-2.94 (m, 2H), 2.86 (tt, 1H, J=3.9, 11.7 Hz), 2.13 (s, 3H), 2.10-1.91 (m, 3H), 1.84-1.68 (m, 2H), 1.48 (dq, 1H, J=4.9, 12.2 Hz).

Workup

  1. concentrationconcentrate
  2. washwash
  3. customreaction mixture with saturated sodium bicarbonate (aq) (2×50 mL)
  4. dry with materialdry over anhydrous magnesium sulfate
  5. filtrationfilter
  6. concentrationconcentrate
  7. customPurify the residue by silica gel chromatography (hexanes→2:1 hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-f76d390480af4c288e4ba40641dadda2
Source dataset
uspto-grants-2008_06
Patent number
US07381719B2

Reaction notes

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