Cesium carbonate → 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

HRID 921666Notes

Reaction equation

HRID 921666 reaction equation
[Cl:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:7][C:6]([CH:19]([F:21])[F:20])=[CH:5][C:3]=1[NH2:4].[CH:22]1([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:26]2[C:31]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:30]3[N:29]=[C:28](S(C)(=O)=O)[N:27]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][C:2]1[C:8]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH2:13][CH2:14]2)=[CH:7][C:6]([CH:19]([F:21])[F:20])=[CH:5][C:3]=1[NH:4][C:28]1[N:27]=[C:26]([N:25]([CH:22]2[CH2:24][CH2:23]2)[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:31]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:30]2[N:29]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 86708519HCID 86708519, compoundHCID 867085312-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline

Product 1

HCID 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-carbonitrileYield 76.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline (50 mg, 0.157 mmol), 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (94 mg, 0.236 mmol) and cesium carbonate (103 mg, 0.315 mmol) in DMF (1574 μl) was stirred at 40° C. for 72 h. The reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organics were washed with 10% LiCl solution and concentrated. Column chromatography (12 g SiO2, 0 to 100% EtOAc-hexane gradient elution) afforded 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 (76.7 mg).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. extractionextracted with EtOAc (3×)
  3. washThe combined organics were washed with 10% LiCl solution
  4. concentrationconcentrated
  5. washColumn chromatography (12 g SiO2, 0 to 100% EtOAc-hexane gradient elution)

Sources & evidence

ORD record
ord-3eab1eada2964a3ba61188b04c316a64
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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