Trifluoroacetic acid → 2-((2-Chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921922Notes

Reaction equation

HRID 921922 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:36]2[C:37]([CH3:43])=[N:38][N:39]([CH3:42])[C:40]=2[CH3:41])[C:34]=1[Cl:35])[C:30]#[N:31].C(O)(C(F)(F)F)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:35][C:34]1[C:33]([C:36]2[C:37]([CH3:43])=[N:38][N:39]([CH3:42])[C:40]=2[CH3:41])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 867084772-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileHCID 1182533303-amino-4-chloro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzonitrile

Product 1

HCID 899229142-((2-Chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (42.6 mg, 0.120 mmol), 3-amino-4-chloro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzonitrile, TFA (45 mg, 0.120 mmol), palladium acetate (8.09 mg, 0.036 mmol), DPPF (6.66 mg, 0.012 mmol), Xantphos (6.95 mg, 0.012 mmol), and cesium carbonate (117 mg, 0.360 mmol) were combined in a vial and dioxane (801 μl) was added. The vial was evacuated and backfilled with nitrogen (3×), then heated at 100° C. 4 h. The reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo and the crude material purified by column chromatography on the ISCO system (12 g, 0-5% MeOH/CH2Cl2). 2-((2-Chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg) was isolated as a pale yellow solid.

Workup

  1. additionwas added
  2. customThe vial was evacuated
  3. custom4 h
  4. additionThe reaction mixture was diluted with ethyl acetate and vacuum
  5. filtrationfiltered through a pad of Celite
  6. concentrationThe filtrate was concentrated in vacuo
  7. customthe crude material purified by column chromatography on the ISCO system (12 g, 0-5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-1339cce5ab8a4b65af9b15fb4c98cff3
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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