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

HRID 921769Notes

Reaction equation

HRID 921769 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]=1[Cl:10])[C:5]#[N:6].Cl[C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=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]>[Cl:10][C:9]1[C:8]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1

Participants

6

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 867086563-Amino-4-chloro-5-(morpholinomethyl)benzonitrile

Product 1

HCID 867086582-((2-Chloro-5-cyano-3-(morpholinomethyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 44.5%

Reagents, catalysts & solvents 1

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
100 °C

Procedure

A mixture of 3-amino-4-chloro-5-(morpholinomethyl)benzonitrile (32 mg, 0.13 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(47 mg, 0.13 mmol), Cs2CO3 (85 mg, 0.262 mmol), DPPF (7.3 mg, 0.013 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (7.6 mg, 0.013 mmol) in a microwave vial was flushed with nitrogen. Dioxane (1 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-((2-chloro-5-cyano-3-(morpholinomethyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (33 mg, 44% yield) as an oil. This was dissolved in DCM (1.5 mL) and anisole (0.158 mL, 1.447 mmol) and TFA (0.9 mL) were added. After stirring at room temperature overnight, the solvent was removed and the residue was dissolved in MeOH and applied onto a SCX column. This was washed with MeOH and then eluted with 2 N NH3 in MeOH with DCM. Silica gel radial chromatography eluting with DCM containing 1% MeOH gave the title compound (19 mg) as a white solid.

Workup

  1. customwas flushed with nitrogen
  2. additionDioxane (1 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-020565c1b890447abfc288ade0817ea7
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

Loading…