Acetamide → N-(3-{2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide

HRID 510011Notes

Reaction equation

HRID 510011 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:19][CH2:20][C:21]4[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)=[N:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:36]([NH2:39])(=[O:38])[CH3:37].CNCCNC>O1CCOCC1.[Cl-].[Na+].O.[Cu]I.C(OCC)(=O)C>[F:18][C:17]1[C:12]([CH2:11][C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([NH:39][C:36](=[O:38])[CH3:37])[CH:3]=3)[NH:8][CH:9]=2)=[CH:13][CH:14]=[C:15]([NH:19][CH2:20][C:21]2[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)[N:16]=1

Participants

9

Reactant 4

HCID 178AcetamideHCID 8070N,N'-DimethylethylenediamineHCID 10796Cesium carbonateHCID 58259257[5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine

Product 1

HCID 52935809N-(3-{2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (P-1497, 1 equivalent) is dissolved in 25 mL of dioxane in a sealable vial. Cesium carbonate (2.1 equivalents), copper(I) iodide (1.5 equivalents), acetamide (174, 22 equivalents) and N,N′-dimethylethylenediamine (17 equivalents) are added. The vial is sealed and heated at 100° C. overnight. The reaction is added to ethyl acetate and brine and extracted. The organic layer is concentrated under vacuum and the resulting material dissolved in dichloromethane and purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions are concentrated, and the material dissolved in tetrahydrofuran for further purification on a C18 reverse phase column, eluting with 0-100% methanol (with 10% tetrahydrofuran)/water. Appropriated fractions are combined and concentrated under vacuum. The resulting material is triturated with methyl tert-butyl ether and filtered, washing with methyl tert-butyl ether, then heptane. The solid is dried under vacuum to provide the desired compound.

Workup

  1. customThe vial is sealed
  2. extractionextracted
  3. concentrationThe organic layer is concentrated under vacuum
  4. dissolutionthe resulting material dissolved in dichloromethane
  5. custompurified by silica gel column chromatography
  6. washeluting with 0-10% methanol in dichloromethane
  7. concentrationAppropriate fractions are concentrated
  8. dissolutionthe material dissolved in tetrahydrofuran for further purification on a C18 reverse phase column
  9. washeluting with 0-100% methanol (with 10% tetrahydrofuran)/water
  10. concentrationconcentrated under vacuum
  11. customThe resulting material is triturated with methyl tert-butyl ether
  12. filtrationfiltered
  13. washwashing with methyl tert-butyl ether
  14. customThe solid is dried under vacuum

Sources & evidence

ORD record
ord-6e7a1fcf7490466aa8a99a95c565c5ce
Source dataset
uspto-grants-2015_08
Patent number
US09096593B2

Reaction notes

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