Water → N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-fluorophenylamino)nicotinamide

HRID 626385Notes

Reaction equation

HRID 626385 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])=[CH:4][CH:3]=1.[N:21]([CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=1)=[N+:22]=[N-:23].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([CH:26]=[C:27]([O:33][CH3:34])[CH:28]=1)[CH2:24][N:21]1[CH:16]=[C:15]([CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][CH:19]=[N:20][C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:23]=[N:22]1

Participants

7

Reactant 4

HCID 962WaterHCID 115212321-(Azidomethyl)-3,5-dimethoxybenzeneHCID 128127942-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamideHCID 23667548Sodium Ascorbate

Product 1

HCID 90681009N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-fluorophenylamino)nicotinamideYield 71.6%

Reagents, catalysts & solvents 2

HCID 24462Copper SulfateCatalystHCID 6386tert-ButanolSolvent

Procedure

Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 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-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of from 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 116 mg, 0.61 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 6b (182 mg, 71%); mp: 209-211° C.; mp: 140-142° C.; 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 8.19 (dd, J=3.0, 1.5 Hz, 1H), 7.81 (dd, J=3.0, 1.5 Hz, 2H), 7.52-7.47 (m, 3H), 7.20 (d, J=9.0 Hz, 2H), 6.83 (t, J=7.5 Hz, 4H), 6.55-6.51 (m, 1H), 5.41 (s, 2H), 4.58 (d, J=4.5 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H); MS (ESI m/z): 463 [M+H]+ Yield: 71%

Workup

  1. additionwere added sequentially
  2. customcompletion of reaction
  3. concentrationThe reaction mixture was concentrated under vacuum
  4. extractionextracted with EtOAc
  5. customto give crude product
  6. customThe crude was purified by column chromatography

Sources & evidence

ORD record
ord-49da119ecb2e4afc867d2cdcff5e4697
Source dataset
uspto-grants-2016_04
Patent number
US09309225B2

Reaction notes

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