1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → (S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-N-(3'-fluoro-6'-methyl-2,2'-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

HRID 1522608Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1522608
[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([CH2:7][N:8]2[CH:17]=[C:11]3[N:12]=[CH:13][CH:14]=[C:15](I)[C:10]3=[N:9]2)[CH2:4][O:3]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[F:61][C:62]1[C:63]([C:69]2[CH:74]=[C:73]([NH2:75])[CH:72]=[CH:71][N:70]=2)=[N:64][C:65]([CH3:68])=[CH:66][CH:67]=1.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[CH3:18][C:2]1([CH3:1])[O:6][C@@H:5]([CH2:7][N:8]2[C:17]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[NH:75][C:73]3[CH:72]=[CH:71][N:70]=[C:69]([C:63]4[C:62]([F:61])=[CH:67][CH:66]=[C:65]([CH3:68])[N:64]=4)[CH:74]=3)[CH:10]=[N:9]2)[CH2:4][O:3]1

Komponenten

7

Edukt 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 674696053'-Fluoro-6'-methyl-2,2'-bipyridin-4-amineHCID 67469660(S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-7-iodo-2H-pyrazolo[4,3-b]pyridine

Produkt 1

HCID 67470506(S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-N-(3'-fluoro-6'-methyl-2,2'-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

(S)-2-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-7-iodo-2H-pyrazolo[4,3-b]pyridine (51 mg, 0.142 mmol), Tris(dibenzylideneacetone)dipalladium(0) (3.25 mg, 3.55 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.54 mg, 0.035 mmol), 3′-fluoro-6′-methyl-2,2′-bipyridin-4-amine (28.9 mg, 0.142 mmol) and sodium 2-methylpropan-2-olate (40.9 mg, 0.426 mmol) were combined in dioxane (5 mL). The mixture was heated at 120° C. for 2 hours, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 5-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give (S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine which was combined with methanol (5 mL) and 1N HCl (2 mL) and stirred at room temperature for 30 minutes before evaporation to afford the title compound (12.5 mg, 22.32% yield) as a HCl salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.57 (s, 3H) 3.41 (m, 1H) 3.49 (m, 1H) 3.97-4.10 (m, 1H) 4.51 (m, 1H) 4.69 (m, 1H) 7.51 (dd, J=8.59, 3.54 Hz, 1H) 7.64 (d, J=6.32 Hz, 1H) 7.71 (dd, J=11.24, 8.72 Hz, 1H) 8.01 (d, J=5.05 Hz, 1H) 8.53 (s, 1H) 8.63 (d, J=6.32 Hz, 1H) 8.66-8.71 (m, 2H). MP 182-184° C. MS [M+H] found 395.3.

Aufarbeitung

  1. temperaturecooled
  2. custompurified by preparative HPLC
  3. washeluting with a gradient of 5-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA)

Quellen und Nachweise

ORD-Eintrag
ord-3e5b2cad35ca45ebb96eaa779975d5b8
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09073918B2

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