Sodium Hydroxide → N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-(4-fluorophenyl)-1-benzofuran-2-carboxamide

HRID 1012726

Reaktionsgleichung

Reaktionsgleichung von HRID 1012726
[F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([NH:19][C:20]([C:22]1[O:23][C:24]3[C:30](Br)=[CH:29][C:28]([F:32])=[CH:27][C:25]=3[CH:26]=1)=[O:21])[CH2:12]2.[OH-].[Na+]>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].CN(C=O)C>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]1)[C@@H:13]([NH:19][C:20]([C:22]1[O:23][C:24]3[C:30]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:29][C:28]([F:32])=[CH:27][C:25]=3[CH:26]=1)=[O:21])[CH2:12]2

Komponenten

6

Edukt 3

HCID 14798Sodium HydroxideHCID 2856454-Fluorophenylboronic acidHCID 59341405N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide

Produkt 1

HCID 58485573N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-(4-fluorophenyl)-1-benzofuran-2-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

A mixture of 40 mg (0.29 mmol) of 4-fluorophenylboronic acid, 70 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide (Example 5A), 0.57 ml (0.57 mmol) of 1N sodium hydroxide solution, 14 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is mixed with 1N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane, again with methanol, with THF and finally once more with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. Silica gel 60 (Merck, Darmstadt; eluent: dichloromethane/triethylamine 100:1, then dichloromethane/methanol/triethylamine 100:1:1 to dichloromethane/methanol/triethylamine 100:10:1) is used for final purification. The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 51 mg (70% of theory) of the title compound are isolated.

Aufarbeitung

  1. customThe solvent is removed under reduced pressure
  2. additionThe crude product is mixed with 1N sodium hydroxide solution
  3. extractionextracted three times with a total of 100 ml of ethyl acetate
  4. dry with materialThe combined organic phases are dried over magnesium sulphate
  5. customthe solvent is removed under reduced pressure
  6. washThe loaded ion exchanger is washed three times with 30 ml of methanol each time
  7. washThe product is eluted with methanol/triethylamine 95:5
  8. customThe solvent is removed in a rotary evaporator under reduced pressure
  9. custompurification
  10. customThe solvent is removed under reduced pressure
  11. customFinally, the last residues of solvent are removed under high vacuum

Quellen und Nachweise

ORD-Eintrag
ord-ef5817228f45461fb84076d60a807a42
Quelldatensatz
uspto-grants-2011_07
Patentnummer
US07977485B2

Verknüpfte Notizen

Wird geladen…