Potassium Phosphate, Tribasic → 2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921934Notes

Reaction equation

HRID 921934 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])CC2C=CC(OC)=CC=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[CH:27]=[C:28]([CH:31]=[C:32]([N:35]2[CH2:40][C@@H:39]3[CH2:41][C@H:36]2[CH2:37][N:38]3[CH3:42])[C:33]=1[Cl:34])[C:29]#[N:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].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>[Cl:34][C:33]1[C:32]([N:35]2[CH2:40][C@@H:39]3[CH2:41][C@H:36]2[CH2:37][N:38]3[CH3:42])=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[NH:25][C:2]1[N:7]=[C:6]([NH:8][CH2:18][CH3:19])[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 867084732-Chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileHCID 899225793-amino-4-chloro-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzonitrile

Product 1

HCID 899232632-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 191.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)Catalyst

Conditions

Temperature
80 °C

Procedure

A 5 ml microwave vial was loaded with 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (71.8 mg, 0.209 mmol), 3-amino-4-chloro-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzonitrile (50 mg, 0.190 mmol), Pd(OAc)2 (6.41 mg, 0.029 mmol), XANTPHOS (17.62 mg, 0.030 mmol) and Potassium phosphate (145 mg, 0.685 mmol). The vial was evacuated and back-filled with nitrogen 4 times. Toluene (2 ml) was added and the flask was again evacuated and back-filled with nitrogen 4 times, and then heated with stirring to 80° C. for 5 hours. The reaction mixture was cooled to room temperature, filtered through Celite and solids washed with dichloromethane. Evaporation to dryness gave 163 mg crude product 2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, which was used “as is” in the following deprotection reaction.

Workup

  1. customThe vial was evacuated
  2. additionback-filled with nitrogen 4 times
  3. additionToluene (2 ml) was added
  4. customthe flask was again evacuated
  5. additionback-filled with nitrogen 4 times
  6. temperatureheated
  7. temperatureThe reaction mixture was cooled to room temperature
  8. filtrationfiltered through Celite and solids
  9. washwashed with dichloromethane
  10. customEvaporation to dryness

Sources & evidence

ORD record
ord-a89a1d96f82642e2a2fe3c791c743133
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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