Trifluoroacetic acid → 2-((2-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921667Notes

Reaction equation

HRID 921667 reaction equation
[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([CH:18]([F:20])[F:19])=[CH:4][C:3]=1[NH:21][C:22]1[N:27]=[C:26]([N:28]([CH:38]2[CH2:40][CH2:39]2)CC2C=CC(OC)=CC=2)[C:25]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]2[N:23]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([CH:18]([F:19])[F:20])=[CH:4][C:3]=1[NH:21][C:22]1[N:27]=[C:26]([NH:28][CH:38]2[CH2:40][CH2:39]2)[C:25]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]2[N:23]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 867085322-((2-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 867085332-((2-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 26.2%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
40 °C

Procedure

2-((2-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (69 mg, 0.108 mmol) was dissolved in DCE (1 mL) at room temperature. Anisole (59.2 μl, 0.542 mmol) followed by 200 μL of TFA were added and the reaction was stirred at 40° C. overnight and concentrated. The residue was dissolved in MeOH and loaded onto a 1 g/6 mL Strata SCX ion exchange column, washing with CH3OH. The desired product was eluted with 7 N NH3—CH3OH, concentrated under a stream of N2. Column chromatography (12 g SiO2, 0 to 20% CH3OH—CH2Cl2 gradient elution) followed by trituration with ACN afforded 2-((2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (14.6 mg).

Workup

  1. additionwere added
  2. concentrationconcentrated
  3. dissolutionThe residue was dissolved in MeOH
  4. washwashing with CH3OH
  5. washThe desired product was eluted with 7 N NH3—CH3OH
  6. concentrationconcentrated under a stream of N2
  7. washColumn chromatography (12 g SiO2, 0 to 20% CH3OH—CH2Cl2 gradient elution)

Sources & evidence

ORD record
ord-37cdd36e0a34462ba9b1d79978901b24
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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