Cesium carbonate → 2-((2-Chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921944Notes

Reaction equation

HRID 921944 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]([N:36]2[CH2:47][CH2:46][C:39]3([C:43](=[O:44])[N:42]([CH3:45])[CH2:41][CH2:40]3)[CH2:38][CH2:37]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]([N:36]2[CH2:37][CH2:38][C:39]3([C:43](=[O:44])[N:42]([CH3:45])[CH2:41][CH2:40]3)[CH2:46][CH2:47]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: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-carbonitrileHCID 899231433-Amino-4-chloro-5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzonitrile

Product 1

HCID 899236352-((2-Chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 45.7%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
80 °C

Procedure

A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (167 mg, 0.471 mmol), 3-amino-4-chloro-5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzonitrile (150 mg, 0.471 mmol), palladium(II) acetate (28.0 mg, 0.125 mmol), XANTPHOS (27.2 mg, 0.047 mmol), DPPF (26.1 mg, 0.047 mmol) and cesium carbonate (399 mg, 1.223 mmol) in dioxane (5 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 3 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 10% to 100% EtOAc in Hexane) to give (+/−)-2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (137 mg) as a light yellow solid.

Workup

  1. customwas evacuated
  2. additionback filled with nitrogen three time
  3. filtrationThe reaction mixture was filtered through a celite pad
  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 column, eluting with 10% to 100% EtOAc in Hexane)

Sources & evidence

ORD record
ord-459a4f4a5bf444deaee38a9472e77d55
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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