Cesium carbonate → HCID 131734955, compound

HRID 921936Notes

Reaction equation

HRID 921936 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[CH3:25][N:26]([CH2:28][C@@H:29]1[CH2:31][C@H:30]1[C:32]1[C:40]2[C:35](=[CH:36][C:37]([C:41]#[N:42])=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[CH3:27].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:41]([C:37]1[CH:36]=[C:35]2[C:40]([C:32]([C@@H:30]3[CH2:31][C@H:29]3[CH2:28][N:26]([CH3:27])[CH3:25])=[CH:33][N:34]2[C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:39][CH:38]=1)#[N:42]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 25112535BrettphosHCID 867084732-Chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile2×HCID 118253361HCID 118253361, compound

Product 1

HCID 131734955HCID 131734955, compoundYield 78%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
110 °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 (Intermediate 10) (110 mg, 0.321 mmol), rac-3-((1r,2r)-2-((dimethylamino)methyl)cyclopropyl)-1H-indole-6-carbonitrile (50 mg, 0.209 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Brettphos (CAS 1070663-78-3) (35 mg, 0.065 mmol) and Cs2CO3 (powder, 80 mesh, 210 mg, 0.645 mmol). The vial was sealed, evacuated and flushed with nitrogen 4×. Dioxane (3 ml) was added and the vial evacuated and backfilled with nitrogen 4 times. The reaction was heated to 110° C. for 12 hours. LCMS shows m/e+=546, consistent with [M+H]+ of product. Only trace of indole starting material remaining. The reaction mixture was allowed to cool to room temperature, diluted with acetonitrile and filtered through Celite. The Celite was washed with acetonitrile. The combined solutions were evaporated to dryness. The crude was purified by column chromatography on silica. (40 g cartridge, load sample as solution in dichloromethane, elute with gradient from 100% DCM to 100% EtOAc (product doesn't elute), then a gradient from 100% dichloromethane to 80% DCM+20% (MeOH+1% aq, conc. NH4OH). Product containing fractions were combined and evaporated to dryness to give 92.8 mg pale yellow film (+/−)-2-(6-cyano-3-((1r,2r)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-1-yl)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (92.8 mg, 0.163 mmol)

Workup

  1. customThe vial was sealed
  2. customevacuated
  3. customflushed with nitrogen 4×
  4. additionDioxane (3 ml) was added
  5. customthe vial evacuated
  6. temperatureto cool to room temperature
  7. additiondiluted with acetonitrile
  8. filtrationfiltered through Celite
  9. washThe Celite was washed with acetonitrile
  10. customThe combined solutions were evaporated to dryness
  11. customThe crude was purified by column chromatography on silica
  12. wash(40 g cartridge, load sample as solution in dichloromethane, elute with gradient from 100% DCM to 100% EtOAc (product doesn't elute)
  13. additionProduct containing fractions
  14. customevaporated to dryness

Sources & evidence

ORD record
ord-5a32199d817d4731ab113be047933ee2
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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