Tetrahydrofuran → 4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridine

HRID 751293

Reaktionsgleichung

Reaktionsgleichung von HRID 751293
C1COCC1.Br[C:7]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24](B(O)O)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>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].[Pd].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C.C1COCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([C:7]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1

Komponenten

8

Edukt 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 124225274-Bromo-1,8-naphthyridineHCID 59710031(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid

Produkt 1

HCID 117230954-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridineAusbeute 35,2 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 2724231Bis(1,2-bis(diphenylphosphino)ethane)palladium(0)KatalysatorHCID 9811564Bis(dibenzylideneacetone)palladiumKatalysator2×HCID 21974620tetrahydrofuran N,N-dimethylformamideLösungsmittel

Versuchsvorschrift

Add THF (1 mL) to 4-bromo-[1,8]naphthyridine (Barlin, G. B. and Tan, W-L. Australian J. Chem. 1984, 37, 1065-1073; 66 mg, 0.31 mmol) and purge the solution with nitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) and bis(1,2-bis(diphenylphosphino)ethane) palladium(0) (24 mg, 0.026 mmol), purge the reaction mixture with nitrogen for 2 min, and stir the reaction at room temperature for 20 min. Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5, 60 mg, 0.26 mmol) in 1:1 DMF/THF (1 mL) and stir for 10 min. Add 2.0 M aqueous potassium carbonate (0.32 mL, 0.63 mmol) and heat the reaction to 40° C. Add additional tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) after 1 h and 3.5 h. Stir the reaction at 40 DC for 24 h and concentrate in vacuo. Load the crude reaction mixture onto SCX resin with methanol, wash the resin with methanol (100 mL), and elute with methanolic ammonia solution (2M, 100 mL). Concentrate the ammonia fraction in vacuo, purify by flash column chromatography and triturate with hexanes to provide the title compound (28.7 mg, 35%) as a tan solid. MS ESI+ m/e 314 (M+1). 1H NMR (CDCl3) δ 9.11 (m, 1H), 9.07 (m, 1H), 8.25 (m, 1H), 8.10 (m, 1H), 7.35-7.50 (m, 3H), 7.04 (m, 2H), 4.38 (m, 2H), 2.88 (m, 2H), 2.70 (m, 2H). HPLC: 94.8%, Rt=6.75 min. TLC (SiO2): Rf0.3 (1:1 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).

Aufarbeitung

  1. custompurge the solution with nitrogen for 10 min
  2. customthe reaction at room temperature for 20 min
  3. temperatureheat
  4. customthe reaction to 40° C
  5. custom3.5 h
  6. stirringStir
  7. customthe reaction at 40 DC for 24 h
  8. concentrationconcentrate in vacuo
  9. customLoad the crude reaction mixture onto SCX resin with methanol
  10. washwash the resin with methanol (100 mL)
  11. washelute with methanolic ammonia solution (2M, 100 mL)
  12. concentrationConcentrate the ammonia fraction in vacuo
  13. custompurify by flash column chromatography
  14. customtriturate with hexanes

Quellen und Nachweise

ORD-Eintrag
ord-e6f9e291873b4596b85c20c6255bf251
Quelldatensatz
uspto-grants-2008_07
Patentnummer
US07405299B2

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