Cesium carbonate → (+/-) Tert-butyl(2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate

HRID 921697Notes

Reaction equation

HRID 921697 reaction equation
[CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([N:39]2[CH2:44][CH2:43][N:42]([CH:45]3[CH2:48][O:47][CH2:46]3)[CH:41]([C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:50])[CH2:40]2)[C:37]=1[Cl:38])[C:33]#[N:34].[CH3:57][C:58]1(C)[C:84]2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=C[C:59]1=2.[C:99](=[O:102])([O-])[O-:100].[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:38][C:37]1[C:36]([N:39]2[CH2:44][CH2:43][N:42]([CH:45]3[CH2:48][O:47][CH2:46]3)[CH:41]([C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:50])[CH2:40]2)=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[NH:29][C:7]1[N:6]=[C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:99](=[O:102])[O:100][C:58]([CH3:84])([CH3:59])[CH3:57])[C:10]2=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]2[N:8]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86708519HCID 86708519, compound2×HCID 867085723-Amino-4-chloro-5-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile

Product 1

HCID 86708573(+/-) Tert-butyl(2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamateYield 71%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

(+/−) Tert-butyl (2-chloro-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate (Intermediate 1)(30 mg, 0.090 mmol), 3-amino-4-chloro-5-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (36.4 mg, 0.090 mmol), palladium (II) acetate (6.04 mg, 0.027 mmol), dppf (4.97 mg, 8.96 μmol), Xantphos (5.19 mg, 8.96 mol), and cesium carbonate (52.6 mg, 0.161 mmol) were combined in a 10 ml flask and Dioxane (1 mL) was added. The flask was evacuated and backfilled with N2 3×, then heated at 100° C. for 1 h. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the crude material was purified by flash column (0-5% MeOH/DCM). (+/−) Tert-butyl (2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate (45 mg) was obtained as a yellow glass.

Workup

  1. customThe flask was evacuated
  2. temperatureThe reaction was cooled to room temperature
  3. filtrationfiltered through celite
  4. washrinsing with EtOAc
  5. customThe solvent was removed in vacuo
  6. customthe crude material was purified by flash column (0-5% MeOH/DCM)

Sources & evidence

ORD record
ord-7aad47e2919d4deaa5223f0f408ad357
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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