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

HRID 2201088

Reaction equation

HRID 2201088 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]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]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]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2)#[N:17]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 113736-AminoquinolineHCID 634876Binap, (A+-)-HCID 86666160(R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)butanamide

Product 1

HCID 67508846(R)-2-(5-cyano-3-fluoro-6-(quinolin-6-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 (235 mg, 0.92 mmol), 6-aminoquinoline (288 mg, 2.0 mmol), Pd(OAc)2 (44 mg, 0.22 mmol), racemic BINAP (136 mg, 0.22 mmol) and fine-powder cesium carbonate (1.0 g, 3.1 mmol) in 30 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-6-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 (210 mg). UV: 268, 297, 330 nm. M+H found for C19H19FN6O2: 383.4. NMR (CD3OD): 9.12 (1H, d, J=8.8 Hz), 8.90 (1H, s), 8.82 (1H, d, J=5.2 Hz), 8.03 (1H, d, J=8.8 Hz), 7.92 (1H, d, J=10.0 Hz), 7.85-7.82 (2H, m), 4.39 (1H, m), 2.09 (2H, m), 1.16 (3H, t, J=7.6 Hz) ppm.

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-876bdac73ccb402cb734ff74767becb0
Source dataset
uspto-grants-2016_06
Patent number
US09359375B2

Linked notes

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