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

HRID 332847Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 332847
[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

Komponenten

11

Edukt 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

Produkt 1

HCID 895721845-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-3-(pyrazolo[1,5-a]pyridin-3-ylamino)pyrazine-2-carboxamideAusbeute 14,3 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 167845palladium(II) acetateKatalysatorHCID 679Dimethyl SulfoxideLösungsmittelHCID 887MethanolLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
115 °C

Versuchsvorschrift

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 C18H20F2N8O 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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-ca22f79561aa46f7a3d6d4e4e773df39
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08877760B2

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