Cesium carbonate → 2-((2-Chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921763Notes

Reaction equation

HRID 921763 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:11]=[CH2:12])[C:9]=1[Cl:10])[C:5]#[N:6].Cl[C:14]1[N:19]=[C:18]([N:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:10][C:9]1[C:8]([CH:11]=[CH2:12])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:14]1[N:19]=[C:18]([N:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1

Participants

7

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 867086473-Amino-4-chloro-5-vinylbenzonitrile

Product 1

HCID 867086462-((2-Chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 51%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
100 °C

Procedure

A mixture of 3-amino-4-chloro-5-vinylbenzonitrile (75 mg, 0.42 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(149 mg, 0.420 mmol), Cs2CO3 (274 mg, 0.840 mmol), DPPF (23 mg, 0.042 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (24 mg, 0.042 mmol), and Pd(OAc)2 (28 mg, 0.13 mmol) in a microwave vial was flushed with nitrogen. Dioxane (3.5 mL) was added and the vial was sealed and heated at 100° C. for 4 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed from the filtrate and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded 2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (106 mg, 51% yield) as an oil. This was dissolved in DCM (3 mL) and anisole (0.582 mL, 5.33 mmol) and TFA (3 mL) were added. After stirring at room temperature overnight, the solvent was removed and the yellow solid was dissolved in DCM. This was washed with a saturated aq. NaHCO3 solution and the organic phase was separated. The aqueous phase contained some suspended yellow solid and was exacted 2× with DCM. The combined organic phases were dried with sodium sulfate and the solvent was removed. The residue was suspended in a mixture of EtOAc: hexane=1:1 and filtration gave the title compound (59 mg) as a light yellow solid.

Workup

  1. customwas flushed with nitrogen
  2. additionDioxane (3.5 mL) was added
  3. customthe vial was sealed
  4. additionThe reaction was diluted with EtOAc
  5. filtrationfiltered through celite
  6. customThe solvent was removed from the filtrate and radial silica gel chromatography
  7. washeluting with hexane containing 5 to 40% EtOAc

Sources & evidence

ORD record
ord-2adbd8ad584e44f0ab754299c6b4b3a8
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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