Hydrochloric Acid → 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one

HRID 885074Notes

Reaction equation

HRID 885074 reaction equation
[C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>C(#N)C>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10]2[C:1](=[O:11])[NH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 7498Benzyl BromideHCID 8177432,6-Naphthyridin-1-olHCID 4311764Sodium borohydride

Product 1

HCID 223351906-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-oneYield 76.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a suspension of 2,6-naphthyridin-1(2H)-one (2.04 g, 13.96 mmol) in acetonitrile (35 mL) was added benzylbromide (1.992 mL, 16.75 mmol). The mixture was heated to reflux. After 2 h the mixture was cooled to rt. The solvent was removed under reduced pressure and the residue was dissolved in EtOH (30 mL) and cooled to 0° C. Sodium borohydride (2.64 g, 69.8 mmol) was added portionwise over 30 min and the mixture was warmed to rt as the ice bath melted. After stirring the reaction mixture overnight at rt, the mixture was carefully acidified to pH=3 with 1N HCl and was stirred for 30 minutes at rt. The solution was concentrated under reduced pressure. The residue was neutralized with sat. aq. NaHCO3 and was extracted with dichloromethane (3×150 mL). The organic solution was concentrated under reduced pressure, and the residue was purified by BIOTAGE® flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (2.56 g, 10.65 mmol, 76% yield) as a light-yellow solid. LC/MS: m/z 241.08 (M+H)+, 1.362 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.29 (br. s., 1H) 7.31-7.37 (m, 4H) 7.24-7.30 (m, 1H) 7.12 (d, J=6.41 Hz, 1H) 5.89 (d, J=6.71 Hz, 1H) 3.63 (s, 2H) 3.32 (br. s., 2H) 2.62 (t, J=5.80 Hz, 2H) 2.40 (t, J=5.04 Hz, 2H).

Workup

  1. temperatureThe mixture was heated to reflux
  2. customThe solvent was removed under reduced pressure
  3. dissolutionthe residue was dissolved in EtOH (30 mL)
  4. temperaturecooled to 0° C
  5. stirringwas stirred for 30 minutes at rt
  6. concentrationThe solution was concentrated under reduced pressure
  7. extractionwas extracted with dichloromethane (3×150 mL)
  8. concentrationThe organic solution was concentrated under reduced pressure
  9. customthe residue was purified by BIOTAGE® flash chromatography
  10. additionThe fractions containing the expected product
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-07efa72ff03040f890a0ab354de7c9b0
Source dataset
uspto-grants-2012_08
Patent number
US08242124B2

Reaction notes

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