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

HRID 69974
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 69974
[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]
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

11

Edukt 5

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

Produkt 1

HCID 69043087
5-amino-N-(2'-amino-6'-methyl-4,4'-bipyridin-3-yl)-3'-fluoro-2,2'-bipyridine-6-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 178418807HCID 178418807, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-f361584948794b93b6105c5be7688f57
Quelldatensatz
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08822497B2

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