Sodium cyanoborohydride → 6-[4-(3-Propyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamide

HRID 228495Notes

Reaction equation

HRID 228495 reaction equation
[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)=[CH:5][CH:4]=1.[H][H].C(C1C=CC(OC2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=2)=CC=1)=O.[BH3-]C#N.[Na+].CC(O)=[O:44].CO>[OH-].[OH-].[Pd+2].C(O)C>[CH2:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][C:1]3[CH:35]=[CH:34][C:31]([C:32]([NH2:33])=[O:44])=[CH:30][N:29]=3)=[CH:18][CH:17]=2)[CH2:9]1)[CH2:15][CH3:16]

Participants

8

Reactant 5

HCID 5003444Sodium cyanoborohydrideHCID 10129899Acetic acid methanolHCID 471502166-(4-Formylphenoxy)nicotinonitrile2×HCID 597300471-(4-Methoxy-benzyl)-3-propyl-piperidineHCID 178418361HCID 178418361, compound

Product 1

HCID 597301556-[4-(3-Propyl-piperidin-1-ylmethyl)-phenoxy]-nicotinamideYield 18%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 702EthanolSolvent

Procedure

Combine 1-(4-Methoxy-benzyl)-3-propyl-piperidine (105.2 mg, 0.43 mmol), Ethanol (50 mL), 20% Pd(OH)2/C (75.0 mg), and a Hydrogen at 30° C. under 50-60 psi for 12 hours on a Parr shaker. Filter the reaction mixture and then add 5% AcOH/MeOH (3 mL), 6-(4-Formyl-phenoxy)-nicotinonitrile (Intermediate 51) (40.0 mg, 0.31 mmol), and NaCNBH3 (83.7 mg, 0.34 mmol). Stir the reaction at room temperature for 72 hours and then concentrate the reaction mixture under reduced pressure. Add the reaction mixture to an SCX Column (2 g), wash with methanol, and elute with 1N NH3 MeOH. Concentrate under reduced pressure and flash chromatograph using 3% 1N NH3 MeOH in CH2Cl2 to give 19.8 mg (18% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.8-0.9 (4H, m), 1.0-1.4 (5H, m), 1.5-1.8 (4H, m), 1.9-2.1 (1H, br s), 2.8-3.0 (2H, br s), 3.4-3.7 (2H, br d), 6.9 (1H, d), 7.1 (2H, d), 7.3-7.5 (2H, m), 8.1 (1H, d), 8.6 (1H, s); MS m/z 354 (M+1).

Workup

  1. filtrationFilter the reaction mixture
  2. customthe reaction at room temperature for 72 hours
  3. concentrationconcentrate the reaction mixture under reduced pressure
  4. additionAdd the reaction mixture to an SCX Column (2 g)
  5. washwash with methanol
  6. washelute with 1N NH3 MeOH
  7. concentrationConcentrate under reduced pressure and flash chromatograph

Sources & evidence

ORD record
ord-2c6909afdcbc4859b12ef01c1baa8e05
Source dataset
uspto-grants-2009_07
Patent number
US07560463B2

Reaction notes

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