Cesium carbonate → 2-((2-Chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921773Notes

Reaction equation

HRID 921773 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.[Cl:26][C:27]1[C:33]([N:34]2[CH2:37][CH:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH2:35]2)=[CH:32][C:31]([O:45][CH:46]([F:48])[F:47])=[CH:30][C:28]=1[NH2:29].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+]>O1CCOCC1.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]>[Cl:26][C:27]1[C:33]([N:34]2[CH2:37][CH:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH2:35]2)=[CH:32][C:31]([O:45][CH:46]([F:48])[F:47])=[CH:30][C:28]=1[NH:29][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

Participants

8

Reactant 4

HCID 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-carbonitrile2×HCID 867086602-Chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)aniline

Product 1

HCID 899199012-((2-Chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 62.2%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
105 °C

Procedure

2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(120 mg, 0.338 mmol), 2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)aniline (129 mg, 0.372 mmol), palladium(ii) acetate (22.78 mg, 0.101 mmol), XANTPHOS (19.57 mg, 0.034 mmol), DPPF (18.75 mg, 0.034 mmol) and CESIUM CARBONATE (220 mg, 0.676 mmol) were suspended in Dioxane (3382 μl) at rt. The reaction vessel was evacuated and purged with N2 (4 times) and then heated to 105° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through celite and concentrated. Column chromatography (40 g SiO2, 0 to 10% CH3OH—CH2Cl2 gradient elution) gave 2-((2-Chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (139.8 mg).

Workup

  1. customThe reaction vessel was evacuated
  2. custompurged with N2 (4 times)
  3. temperatureAfter cooling to room temperature
  4. additionthe reaction mixture was diluted with EtOAc
  5. filtrationfiltered through celite and
  6. concentrationconcentrated
  7. washColumn chromatography (40 g SiO2, 0 to 10% CH3OH—CH2Cl2 gradient elution)

Sources & evidence

ORD record
ord-2d9d6961bf244992b56b9b62028d0157
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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