Cesium carbonate → (R)-2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)butanamide

HRID 2201141

Reaction equation

HRID 2201141 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])[C:5]([F:15])=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([C:3]1[CH:4]=[C:5]([F:15])[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)#[N:17]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 113753-AminoquinolineHCID 634876Binap, (A+-)-HCID 86666160(R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)butanamide

Product 1

HCID 67508532(R)-2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)butanamide

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

The mixture of (R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)butanamide (120 mg, 0.46 mmol), 3-aminoquinoline (150 mg, 1.0 mmol), Pd(OAc)2 (22 mg, 0.11 mmol), racemic BINAP (68 mg, 0.11 mmol) and fine-powder cesium carbonate (0.50 g, 1.65 mmol) in 20 mL dioxane was degassed using argon stream for 3 min. It was then stirred at 100° C. in argon atmosphere for overnight. The mixture was cooled to RT, concentrated in vacuo, taken into 200 mL EtOAc and 50 mL water. The organic phase was separated and washed with brine. It was dried, concentrated and purified using silica flash column (35% EtOAc in DCM) to give (R)-2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)butanamide. It was dissolved in 4 mL DMSO. To it were added 2 mL 50% H2O2 and then powder potassium carbonate (91 mg, 0.66 mmol). The mixture was stirred at RT for 30 min. It was diluted with 4 mL 1N HCl. The mixture was subjected to reverse prep HPLC to isolate the title compound as HCl salt (102 mg).

Workup

  1. customwas degassed
  2. customfor 3 min
  3. temperatureThe mixture was cooled to RT
  4. concentrationconcentrated in vacuo
  5. customThe organic phase was separated
  6. washwashed with brine
  7. customIt was dried
  8. concentrationconcentrated
  9. custompurified

Sources & evidence

ORD record
ord-475bc413738649b3a778df380d761b32
Source dataset
uspto-grants-2016_06
Patent number
US09359375B2

Linked notes

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