Cesium carbonate → (+/-)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate

HRID 921680Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 921680
Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si:19]([O:26][C@H:27]1[C@H:32]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][NH:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[Si:19]([O:26][C@H:27]1[C@H:32]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:31][CH2:30][N:29]([C:2]2[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:28]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:20])[CH3:21]

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 86708481Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamateHCID 86708549(+/-)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)morpholine

Produkt 1

HCID 86708551(+/-)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamateAusbeute 75,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (116 mg, 0.349 mmol), (+/−)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)morpholine (100 mg, 0.333 mmol), Pd2dba3 (9.14 mg, 9.98 μmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (18.65 mg, 0.030 mmol), and cesium carbonate (217 mg, 0.666 mmol) in Dioxane (2 mL) was evacuated and filled with nitrogen three times and heated at 110° C. overnight. The reaction mixture was diluted with dichloromethane and filtered through Celite, the filtrate was concentrated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-25% ethyl acetate/hexanes). (+/−)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (138 mg) was obtained as a white solid.

Aufarbeitung

  1. customwas evacuated
  2. additionfilled with nitrogen three times
  3. additionThe reaction mixture was diluted with dichloromethane
  4. filtrationfiltered through Celite
  5. concentrationthe filtrate was concentrated
  6. customthe crude product was purified by flash chromatography on silica gel using
  7. washan automated ISCO system (24 g column, eluting with 5-25% ethyl acetate/hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-6cd3af96d7c74a59938f3a546f19d918
Quelldatensatz
uspto-grants-2016_03
Patentnummer
US09273057B2

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