Cesium carbonate → ethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate

HRID 921707Notes

Reaction equation

HRID 921707 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[C:27]([Cl:47])=[C:28]([N:34]2[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:45])[O:42][CH2:43][CH3:44])[C@H:36]([OH:46])[CH2:35]2)[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].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>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:47][C:27]1[C:26]([NH:25][C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:31][C:30]([C:32]#[N:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:45])[O:42][CH2:43][CH3:44])[C@H:36]([OH:46])[CH2:35]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 867084732-Chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileHCID 131732395ethyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate

Product 1

HCID 131732396ethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamateYield 65.7%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (42 mg, 0.123 mmol), ethyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (40 mg, 0.118 mmol), DPPF (4.58 mg, 8.26 umol), Cs2CO3 (65.4 mg, 0.201 mmol), Xantphos (6.83 mg, 0.012 mmol), Palladium(II)Acetate (7.95 mg, 0.035 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture cooled to 25° C., diluted with EtOAc and washed with brine and dried (Na2SO4). The solvents were removed and the material purified on silica gel 25% EtOAc in DCM to afford ethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (50 mg).

Workup

  1. customThe vial was evacuated
  2. temperatureThe reaction mixture cooled to 25° C.
  3. additiondiluted with EtOAc
  4. washwashed with brine
  5. dry with materialdried (Na2SO4)
  6. customThe solvents were removed
  7. customthe material purified on silica gel 25% EtOAc in DCM

Sources & evidence

ORD record
ord-7683a3521fda4a54a67493e6a6a5a83e
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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