Cesium carbonate → 2-((5-Cyano-2,4-difluorophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 1430960Notes

Reaction equation

HRID 1430960 reaction equation
[NH2:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:13]1[N:18]=[C:17]([N:19]([CH:29]2[CH2:31][CH2:30]2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:15]2[N:14]=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]>[C:7]([C:6]1[C:5]([F:10])=[CH:4][C:3]([F:11])=[C:2]([NH:1][C:13]2[N:18]=[C:17]([N:19]([CH:29]3[CH2:31][CH2:30]3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:15]3[N:14]=2)[CH:9]=1)#[N:8]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 668484065-Amino-2,4-difluorobenzonitrileHCID 867084772-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile2×

Product 1

HCID 867086762-((5-Cyano-2,4-difluorophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 86.9%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A mixture of 5-amino-2,4-difluorobenzonitrile (300 mg, 1.947 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (691 mg, 1.947 mmol), Cs2CO3 (1268 mg, 3.89 mmol), DPPF (108 mg, 0.195 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (113 mg, 0.195 mmol), and Pd(OAc)2 (131 mg, 0.584 mmol) in a microwave vial was flushed with nitrogen. Dioxane (16 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 and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded 2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (799 mg) as a foam.

Workup

  1. customwas flushed with nitrogen
  2. additionDioxane (16 mL) was added
  3. customthe vial was sealed
  4. additionThe reaction was diluted with EtOAc
  5. filtrationfiltered through celite
  6. customThe solvent was removed
  7. washradial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc

Sources & evidence

ORD record
ord-f5b00c8ad0be4ba68a933be474ca8451
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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