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

HRID 921788Notes

Reaction equation

HRID 921788 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.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:36][CH:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:46][O:45][CH2:44]3)[CH2:39][CH2:38]2)[C:34]=1[Cl:35])[C:30]#[N:31].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:35][C:34]1[C:33]([O:36][CH:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:44][O:45][CH2:46]3)[CH2:39][CH2:38]2)=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=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 86708682HCID 86708682, compound

Product 1

HCID 867086842-((2-Chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 49.3%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
60 °C

Procedure

A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (57.6 mg, 0.162 mmol), 3-amino-4-chloro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (50 mg, 0.162 mmol), palladium(II) acetate (9.67 mg, 0.043 mmol), xantphos (9.40 mg, 0.016 mmol), DPPF (9.01 mg, 0.016 mmol) and cesium carbonate (138 mg, 0.422 mmol) in dioxane (1 ml) was evacuated and back filled with nitrogen three time and was heated at 60° C. for 2 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 0-6% 2 N ammonia in methanol/dichloromethane). Compound from ISCO was suspended in methanol (1 ml) and the white precipitate was collected by filtration. 2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg) was obtained as a white solid.

Workup

  1. customwas evacuated
  2. additionback filled with nitrogen three time
  3. filtrationThe reaction mixture was filtered through a pad of celite
  4. concentrationthe filtrate was concentrated
  5. customthe crude product was purified by flash chromatography on silica gel using
  6. washan automated ISCO system (24 g gold column, eluting with 0-6% 2 N ammonia in methanol/dichloromethane)
  7. filtrationthe white precipitate was collected by filtration

Sources & evidence

ORD record
ord-f864a8b8788045e99b87e996e92e3bb8
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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