Sodium hydride → 6-(Bis(4-methoxybenzyl)amino)-4-methylnicotinonitrile

HRID 874688

Reaction equation

HRID 874688 reaction equation
[NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:2]2[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:17][CH:16]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 699934-Methyloxybenzyl chlorideHCID 99641036-Amino-4-methylnicotinonitrile

Product 1

HCID 1176660526-(Bis(4-methoxybenzyl)amino)-4-methylnicotinonitrileYield 95%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred mixture of 6-amino-4-methylnicotinonitrile 4-2, which was prepared by using a similar method described in WO199618616 (669 mg, 5.02 mmol) and N,N-dimethylformamide (15.0 mL) at 0° C. under an atmosphere of nitrogen gas was added sodium hydride (60% dispersion in mineral oil; 605 mg, 15.1 mmol). To the mixture was added 4-methoxybenzyl chloride (1.70 mL, 12.5 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with methanol (5.0 mL) and concentrated under reduced pressure. To the resulting residue was added water (50 mL) and the resulting mixture was extracted with dichloromethane (60 mL, 30 mL×2). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 30 g, step gradient eluting with 10:1, 5:1, and 2:1 hexane/ethyl acetate) to give 1.78 g (95%) of 4-3 as a pale brown solid: 1H NMR (300 MHz, CDCl3) δ 8.39 (1H, s), 7.11 (4H, m), 6.85 (4H, m), 6.32 (1H, s), 4.71 (4H, br s), 3.79 (6H, s), 2.33 (3H, s); ESI-MS m/z 374 [C23H23N3O2+H]+.

Workup

  1. customwas prepared
  2. customThe reaction mixture was quenched with methanol (5.0 mL)
  3. concentrationconcentrated under reduced pressure
  4. additionTo the resulting residue was added water (50 mL)
  5. extractionthe resulting mixture was extracted with dichloromethane (60 mL, 30 mL×2)
  6. washThe combined organic extracts were washed with brine (30 mL)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe resulting residue was purified by column chromatography (silica gel 30 g, step gradient eluting with 10:1, 5:1, and 2:1 hexane/ethyl acetate)

Sources & evidence

ORD record
ord-33577ac376f74829aa55800dc4642f10
Source dataset
uspto-grants-2015_03
Patent number
US08980916B2

Linked notes

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