Cesium carbonate → Tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate

HRID 921825Notes

Reaction equation

HRID 921825 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[C:28]([Cl:53])=[C:29]([N:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:37]([C:48](=[O:52])[N:49]([CH3:51])[CH3:50])[CH2:36]2)[CH:30]=[C:31]([C:33]#[N:34])[CH:32]=1.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+]>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].O1CCOCC1>[Cl:53][C:28]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:20][CH2:19]3)[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[CH:32][C:31]([C:33]#[N:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH:37]([C:48](=[O:52])[N:49]([CH3:50])[CH3:51])[CH2:36]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 89922619HCID 89922619, compound

Product 1

HCID 89922541Tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylateYield 79.6%

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-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (197 mg, 0.555 mmol), tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate (227 mg, 0.557 mmol), palladium (II) acetate (37.4 mg, 0.167 mmol), DPPF (30.8 mg, 0.056 mmol), Xantphos (32.1 mg, 0.056 mmol), and cesium carbonate (271 mg, 0.833 mmol) were combined in a 100 ml round bottom flask and dioxane (5 mL) was added. The flask was evacuated and backfilled with N2 3×, then heated at 100° C. for 1 h. Some SM remaining by LCMS. The reaction was cooled to room temperature and an additional 0.15 eq. catalyst and 0.05 eq of each ligand was added. The flask was purged with N2 and heated for an additional 30 min. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo to leave a brown solid. The crude material was purified by flash column chromatography (0-40% EtOAc/DCM; 40 g column). Tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate (321 mg) was obtained as a yellow solid.

Workup

  1. customThe flask was evacuated
  2. temperatureThe reaction was cooled to room temperature
  3. customThe flask was purged with N2
  4. temperatureheated for an additional 30 min
  5. temperatureThe reaction was cooled to room temperature
  6. filtrationfiltered through celite
  7. washrinsing with EtOAc
  8. customThe solvent was removed in vacuo
  9. customto leave a brown solid
  10. customThe crude material was purified by flash column chromatography (0-40% EtOAc/DCM; 40 g column)

Sources & evidence

ORD record
ord-15660d7554714f2b993a8f65a73a9722
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

Loading…