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

HRID 2200521Notes

Reaction equation

HRID 2200521 reaction equation
[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.Cl.Cl.[N:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=[C:24]([NH2:31])[CH:23]=1.C(=O)([O-])[O-:33].[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]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:31][C:24]2[CH:23]=[N:22][N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=23)[C:14]([C:17]([NH2:18])=[O:33])=[N:15][CH:16]=1

Participants

11

Reactant 6

HCID 784Hydrogen PeroxideHCID 10796Cesium carbonateHCID 14797Potassium HydroxideHCID 634876Binap, (A+-)-HCID 74889838Pyrazolo[1,5-a]pyridin-3-amine dihydrochlorideHCID 866855565-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile

Product 1

HCID 895721845-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-3-(pyrazolo[1,5-a]pyridin-3-ylamino)pyrazine-2-carboxamideYield 14.3%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
115 °C

Procedure

The mixture of 5-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-3-chloropyrazine-2-carbonitrile (115 mg, 0.40 mmol), pyrazolo[1,5-a]pyridin-3-amine dihydrochloride (247 mg, 1.20 mmol), powder cesium carbonate (1.04 g, 3.20 mmol), BINAP (50 mg, 0.08 mmol), Pd(OAc)2 (18 mg, 0.08 mmol) in 20 mL dioxane was degassed with argon stream. It was stirred in argon atmosphere at 115° C. for overnight. 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 0-9% MeOH in DCM to isolate the coupling product. It was dissolved in 10 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 (23 mg). MS found for C18H20F2N80 as (M+H)+403.6. UV: λ=289, 355 nm. 1H NMR: (CD3OD) δ 8.45 (1H, d, J=7.6 Hz), 8.23 (1H, s), 7.53 (1H, d, J=8.8 Hz), 7.47 (1H, s), 7.21 (1H, m), 6.89 (1H, t, J=6.8 Hz), 4.47 (1H, m), 3.93 (1H, m), 2.07-1.69 (6H, m) 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-dd55dcdb9b2c45a2a00dbc76e91125d5
Source dataset
uspto-grants-2016_06
Patent number
US09359308B2

Reaction notes

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