Tricyclohexylphosphine → 5-amino-N-(2'-amino-6'-methyl-4,4'-bipyridin-3-yl)-3'-fluoro-2,2'-bipyridine-6-carboxamide

HRID 69974Notes

Reaction equation

HRID 69974 reaction equation
[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:19]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC([O-])=O.[K+].Br[C:83]1[C:88]([F:89])=[CH:87][CH:86]=[CH:85][N:84]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCOC(C)=O.O.O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:83]2[C:88]([F:89])=[CH:87][CH:86]=[CH:85][N:84]=2)=[N:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[CH:19]=1)=[O:10]

Participants

11

Reactant 5

HCID 75806TricyclohexylphosphineHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 27628032-Bromo-3-fluoropyridineHCID 86669206HCID 86669206, compound

Product 1

HCID 690430875-amino-N-(2'-amino-6'-methyl-4,4'-bipyridin-3-yl)-3'-fluoro-2,2'-bipyridine-6-carboxamide

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of degassed dioxane (0.03M) was added 3-amino-6-bromo-N-(2′-(di-BOC-amino)-6′-methyl-4,4′-bipyridin-3-yl)picolinamide (1.0 equiv.), bis(pinacolato)diboron (2.0 equiv.), Pd2(dba)3 (0.05 equiv.), PCy3 (0.075 equiv.), and KOAc (3.0 equiv.). The solution was heated to 90° C. for 16 hrs until all starting material was consumed. Filtered the reaction and concentrated the filtrate. The crude was dried under vacuo, then dissolved in DME/2M Na2CO3 (3:1, 0.05M), followed by addition of 2-bromo-3-fluoropyridine (2.0 equiv.) and Pd(dppf)Cl2-DCM (0.10 equiv.). The reaction was heated to 100° C. in an oil bath until consumption of the boronic ester. Cooled to room temperature, added H2O and EtOAc, the organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) and the pure product was concentrated and stirred in DCM/TFA (25%) until completion of the deprotection. The reaction was concentrated to dryness and purified via reverse phase HPLC to afford 5-amino-N-(2′-amino-6′-methyl-4,4′-bipyridin-3-yl)-3′-fluoro-2,2′-bipyridine-6-carboxamide. LCMS (m/z): 416.2 (MH+); LC Rt=1.77 min.

Workup

  1. customwas consumed
  2. filtrationFiltered
  3. customthe reaction
  4. concentrationconcentrated the filtrate
  5. customThe crude was dried under vacuo
  6. dissolutiondissolved in DME/2M Na2CO3 (3:1, 0.05M)
  7. temperatureCooled to room temperature
  8. washthe organic phase was washed with brine
  9. dry with materialdried with Na2SO4
  10. concentrationconcentrated
  11. customThe crude material was purified via SiO2 column chromatography
  12. washeluting with EtOAc and hexanes (1:1)
  13. concentrationthe pure product was concentrated
  14. concentrationThe reaction was concentrated to dryness
  15. custompurified via reverse phase HPLC

Sources & evidence

ORD record
ord-f361584948794b93b6105c5be7688f57
Source dataset
uspto-grants-2014_09
Patent number
US08822497B2

Reaction notes

Loading…