Trifluoroacetic acid → 3-(aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinone

HRID 1522516Notes

Reaction equation

HRID 1522516 reaction equation
[CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]#[N:11])=[C:5]([CH3:12])[CH:4]=1)[CH3:2].[BH4-].[Na+].NCCNCCN.C(O)(C(F)(F)F)=O>CO.[Ni](Cl)Cl>[NH2:11][CH2:10][C:6]1[C:7](=[O:9])[NH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[CH3:12]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8111DiethylenetriamineHCID 4311764Sodium borohydride2×HCID 106308306-Ethyl-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

Product 1

HCID 671243233-(aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinoneYield 91.5%

Reagents, catalysts & solvents 2

HCID 24385Nickel DichlorideCatalystHCID 887MethanolSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred solution of 6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.462 g, 9.01 mmol) in Methanol (50 mL), cooled to 0° C. were added di-tertbutoxycarbonyl anhydride (4.19 mL, 18.03 mmol) and nickel(II) chloride.hexahydrate (0.214 g, 0.901 mmol). Sodium borohydride (2.387 g, 63.1 mmol) was added portionwise over 30 min, then the mixture was allowed to warm to room termperature and stirred overnight. Additional sodium borohydride (2.387 g, 63.1 mmol) was added and the reaction stirred overnight again. Diethylenetriamine (0.979 mL, 9.01 mmol) was added, and the reaction mixture was stirred for 30 min. at room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate (20 mL) and extracted with sodium bicarbonate (2×10 mL). The organics were dried over sodium sulfate, and concentrated. The residue was dissolved in chloroform (25 mL) and TFA (3.47 mL, 45.1 mmol) was added. The reaction was heated to 50° C. for 3 h, then cooled to room temperature and concentrated. The reaction mixture was concentrated in vacuo and the crude product was purified by reverse phase HPLC (eluent; 0-30% gradient ACN in H2O, 0.1% TFA) to afford the title compound (TFA salt, 1.37 g, 54.1% yield) as a white solid. LC-MS (ES) m/z=167 [M+H]+. 1H NMR (400 MHz, DMSO-d) δ ppm 1.12 (t, J=7.58 Hz, 3H), 2.20 (s, 3H), 2.44 (q, J=7.58 Hz, 2H), 3.78-3.83 (m, 2H), 6.01 (s, 1H), 7.75-7.9 (br s, 3H), 11.86 (s, 1H).

Workup

  1. temperatureto warm to room termperature
  2. stirringthe reaction stirred overnight again
  3. stirringthe reaction mixture was stirred for 30 min. at room temperature
  4. customThe solvent was evaporated
  5. dissolutionthe residue was dissolved in ethyl acetate (20 mL)
  6. extractionextracted with sodium bicarbonate (2×10 mL)
  7. dry with materialThe organics were dried over sodium sulfate
  8. concentrationconcentrated
  9. dissolutionThe residue was dissolved in chloroform (25 mL)
  10. temperaturecooled to room temperature
  11. concentrationconcentrated
  12. concentrationThe reaction mixture was concentrated in vacuo
  13. customthe crude product was purified by reverse phase HPLC (eluent; 0-30% gradient ACN in H2O, 0.1% TFA)

Sources & evidence

ORD record
ord-43de6aae69cd40cda938490e549c512a
Source dataset
uspto-grants-2015_07
Patent number
US09073924B2

Reaction notes

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