Aniline → 2-((2-Chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921860Notes

Reaction equation

HRID 921860 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:9]=1[Cl:10])[C:5]#[N:6].C(O)(C(F)(F)F)=O.NC1C=CC=CC=1.Cl[C:36]1[N:41]=[C:40]([N:42]([CH:52]2[CH2:54][CH2:53]2)[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:39]2=[N:55][CH:56]=[C:57]([C:58]#[N:59])[N:38]2[N:37]=1.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+]>CO.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:10][C:9]1[C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:36]1[N:41]=[C:40]([N:42]([CH:52]2[CH2:54][CH2:53]2)[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:39]2=[N:55][CH:56]=[C:57]([C:58]#[N:59])[N:38]2[N:37]=1

Participants

11

Reactant 6

HCID 6115AnilineHCID 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 899230483-Amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile

Product 1

HCID 899225532-((2-Chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile, TFA (104 mg) was converted to the free base by dissolving in MeOH and passing through an SCX column, first rinsing with MeOH, then 2N NH3 in MeOH to release the material. To this aniline (38.8 mg, 0.132 mmol) in a 2 dram vial was added 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (47 mg, 0.132 mmol), palladium(II) acetate (8.92 mg, 0.040 mmol), DPPF (7.34 mg, 0.013 mmol), Xantphos (7.67 mg, 0.013 mmol), cesium carbonate (86 mg, 0.265 mmol) and dioxane (Iml). The vial was evacuated and backfilled with N2 3×, then heated at 100° C. for 1 h. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the material purified by flash column chromatography (0-10% MeOH/DCM; 24 g column). 2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (48 mg) was obtained as a yellow glass.

Workup

  1. washfirst rinsing with MeOH
  2. customThe vial was evacuated
  3. temperatureThe reaction was cooled to room temperature
  4. filtrationfiltered through celite
  5. washrinsing with EtOAc
  6. customThe solvent was removed in vacuo
  7. customthe material purified by flash column chromatography (0-10% MeOH/DCM; 24 g column)

Sources & evidence

ORD record
ord-ffa1b5cfbf1b4716b0ecb17e973a6d8f
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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