Hydrogen Peroxide → (R)-5-((1-amino-1-oxobutan-2-yl)amino)-3-(pyrazolo[1,5-a]pyridin-3-ylamino)pyrazine-2-carboxamide

HRID 332838Notes

Reaction equation

HRID 332838 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:15]#[N:16].Cl.Cl.[N:19]1[N:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]2=[C:21]([NH2:28])[CH:20]=1.C(=O)([O-])[O-:30].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[K+].OO>O1CCOCC1.CO.CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:12][C:10](=[O:11])[C@H:9]([NH:8][C:6]1[N:7]=[C:2]([NH:28][C:21]2[CH:20]=[N:19][N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=23)[C:3]([C:15]([NH2:16])=[O:30])=[N:4][CH:5]=1)[CH2:13][CH3:14]

Participants

11

Reactant 6

HCID 784Hydrogen PeroxideHCID 10796Cesium carbonateHCID 14797Potassium HydroxideHCID 634876Binap, (A+-)-HCID 74889838Pyrazolo[1,5-a]pyridin-3-amine dihydrochlorideHCID 86685581(R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide

Product 1

HCID 86685629(R)-5-((1-amino-1-oxobutan-2-yl)amino)-3-(pyrazolo[1,5-a]pyridin-3-ylamino)pyrazine-2-carboxamideYield 9.4%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

The mixture of (R)-2-((6-chloro-5-cyanopyrazin-2-yl)amino)butanamide (65 mg, 0.27 mmol), pyrazolo[1,5-a]pyridin-3-amine dihydrochloride (56 mg, 0.27 mmol), powder cesium carbonate (360 mg, 1.08 mmol), BINAP (31 mg, 0.05 mmol), Pd(OAc)2 (11 mg, 0.05 mmol) in 15 mL dioxane was degassed with argon stream. It was stirred in argon atmosphere at 115° C. for 16 h. The mixture was cooled, diluted with 100 mL EtOAc, vigorously stirred, and filtered through celite. The filtrate was concentrated and subjected to silica flash column with 0-8% MeOH in DCM to isolate the coupling product. It was dissolved in 8 mL MeOH and 2 mL DMSO. To the solution were added KOH (100 mg) and then 1 mL of H2O2 (50%). The mixture was stirred at RT for 30 m, quenched with acetonitrile and then TFA, concentrated in vacuo and subjected to reverse phase preparative HPLC to isolate the title compound (9 mg). MS found for C16H18N8O2 as (M+H)+ 355.4. UV: λ=297 nm. 1H NMR: (CD3OD) δ 8.33 (2H, m), 7.46 (1H, d, J=9.2 Hz), 7.32 (1H, s), 7.09 (1H, dd, J=8.8; 6.8 Hz), 6.78 (1H, t, J=7.2 Hz), 4.18 (1H, m), 1.83 (1H, m), 1.68 (1H, m), 0.92 (3H, t, J=7.2 Hz) ppm.

Workup

  1. customwas degassed with argon stream
  2. temperatureThe mixture was cooled
  3. additiondiluted with 100 mL EtOAc
  4. stirringvigorously stirred
  5. filtrationfiltered through celite
  6. concentrationThe filtrate was concentrated
  7. customto isolate the coupling product
  8. stirringThe mixture was stirred at RT for 30 m
  9. customquenched with acetonitrile
  10. concentrationTFA, concentrated in vacuo

Sources & evidence

ORD record
ord-ca2ac7535cdd4cfdb0a0e7926185d8c6
Source dataset
uspto-grants-2014_11
Patent number
US08877760B2

Reaction notes

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