Cesium carbonate → HCID 89922727, compound

HRID 921845Notes

Reaction equation

HRID 921845 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-].[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.[NH2:74][C:75]1[C:76]([Cl:93])=[CH:77][C:78]([CH2:83][CH2:84][CH2:85][CH2:86][N:87]2[CH2:92][CH2:91][O:90][CH2:89][CH2:88]2)=[C:79]([CH:82]=1)[C:80]#[N:81]>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:93][C:76]1[CH:77]=[C:78]([CH2:83][CH2:84][CH2:85][CH2:86][N:87]2[CH2:88][CH2:89][O:90][CH2:91][CH2:92]2)[C:79]([C:80]#[N:81])=[CH:82][C:75]=1[NH:74][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 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 89922616HCID 89922616, compound

Product 1

HCID 89922727HCID 89922727, compoundYield 14.2%

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), cesium 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-(4-morpholinobutyl)benzonitrile (48.5 mg, 0.165 mmol) in dioxane (1 mL). The reaction was heated at 100° C. for 1.5 h at which point LCMS showed full conversation. The reaction 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/DCManisole (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-(4-morpholinobutyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.5 mg) as an off-white solid.

Workup

  1. temperatureThe reaction 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/DCManisole (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-f57c2bdb7c7e4679b7c8d740dd242a18
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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