3,5-Dimethoxyaniline → 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide

HRID 626367Notes

Reaction equation

HRID 626367 reaction equation
Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[NH2:19]>C(O)CO>[CH3:24][O:23][C:21]1[CH:20]=[C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[CH:17]=[C:16]([O:15][CH3:14])[CH:22]=1

Participants

4

Reactant 2

HCID 663013,5-DimethoxyanilineHCID 246950472-Chloro-N-(prop-2-yn-1-yl)pyridine-3-carboxamide

Product 1

HCID 1181260802-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide

Reagents, catalysts & solvents 1

HCID 174Ethylene GlycolSolvent

Conditions

Temperature
140 °C

Procedure

Compound 8 (194 mg, 1 mmol) and 3,5-dimethoxyaniline (91,153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10i as pure product. To a solution of 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (101,150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1i (201 mg, 78%); mp: 123-125° C.; 1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 8.27 (dd, J=2.2, 1.5 Hz, 1H), 7.82 (dd, J=2.2, 1.5 Hz, 1H), 7.72 (t, J=6.0 Hz, 1H), 7.58 (s, 1H), 7.33-7.28 (m, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.97-6.90 (m, 7H), 6.62-6.58 (m, 1H), 6.08 (t, J=2.2 Hz 1H), 5.46 (s, 2H), 4.61 (d, J=5.2 Hz, 2H), 3.80 ppm (s, 6H); MS (ESI m/z): 537 [M+H]+ Yield: 78%

Workup

  1. temperatureThen the reaction mixture was cooled
  2. extractionextracted with ethyl acetate from the aqueous layer
  3. concentrationconcentrated in vacuum
  4. customThe compound was further purified by column chromatography

Sources & evidence

ORD record
ord-8d45adfbc26f4570b5e14dfd35441ef9
Source dataset
uspto-grants-2016_04
Patent number
US09309225B2

Reaction notes

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