Carbonate Ion → HCID 89923109, compound

HRID 921834Notes

Reaction equation

HRID 921834 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)CC2C=CC(OC)=CC=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.C(=O)([O-])[O-].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.[NH2:72][C:73]1[C:74]([Cl:90])=[CH:75][C:76]([CH2:81][CH2:82][CH2:83][N:84]2[CH2:89][CH2:88][O:87][CH2:86][CH2:85]2)=[C:77]([CH:80]=1)[C:78]#[N:79]>O1CCOCC1.CCOC(C)=O.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:90][C:74]1[CH:75]=[C:76]([CH2:81][CH2:82][CH2:83][N:84]2[CH2:89][CH2:88][O:87][CH2:86][CH2:85]2)[C:77]([C:78]#[N:79])=[CH:80][C:73]=1[NH:72][C:2]1[N:7]=[C:6]([NH:8][CH:18]2[CH2:19][CH2:20]2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1

Participants

9

Reactant 4

HCID 19660Carbonate IonHCID 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 89922873HCID 89922873, compound

Product 1

HCID 89923109HCID 89923109, compoundYield 6.7%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (53.2 mg, 0.15 mmol), ccsium carbonate (98 mg, 0.300 mmol), palladium(II) acetate (10.10 mg, 0.045 mmol), DPPF (8.32 mg, 0.015 mmol) and Xantphos (8.68 mg, 0.015 mmol) was added a solution of 5-amino-4-chloro-2-(3-morpholinopropyl)benzonitrile (46.2 mg, 0.165 mmol) in dioxane (1 mL). The reaction was heated to 100° C. for 1.5 h at which point LCMS showed full conversion. The reaction mixture was cooled to room temperature and diluted with EtOAc, filtered through a pad of celite, concentrated and purified by flash column chromatography. The intermediate was then treated with TFA/DCM/anisole (0.25 mL, 0.25 mL, 0.25 mL) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and then diluted with MeOH (3 ml), loaded onto an SCX column, washed with MeOH (3×4 mL), and then 7N NH3/MeOH (4 mL). The ammonia filtrate was collected, concentrated in vacuo, and purified by preparative HPLC to give 2-((2-chloro-5-cyano-4-(3-morpholinopropyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (4.8 mg) as an off-white solid.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationfiltered through a pad of celite,
  3. concentrationconcentrated
  4. custompurified by flash column chromatography
  5. additionThe intermediate was then treated with TFA/DCM/anisole (0.25 mL, 0.25 mL, 0.25 mL)
  6. concentrationThe reaction mixture was concentrated in vacuo
  7. additiondiluted with MeOH (3 ml)
  8. washwashed with MeOH (3×4 mL)
  9. customThe ammonia filtrate was collected
  10. concentrationconcentrated in vacuo
  11. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-5ffcb9423a944b43af032313fd7a4475
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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