Cesium carbonate → Tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate

HRID 63360

Reaktionsgleichung

Reaktionsgleichung von HRID 63360
Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:28]([C:30]1[N:35]=[C:34]([NH2:36])[CH:33]=[N:32][CH:31]=1)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CO.C(Cl)Cl.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].CC(C)=O.CO.CCO>[CH2:28]([C:30]1[N:35]=[C:34]([NH:36][C:2]2[CH:7]=[C:6]([CH2:8][O:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:12][CH:11]=3)[CH:5]=[CH:4][N:3]=2)[CH:33]=[N:32][CH:31]=1)[CH3:29]

Komponenten

10

Edukt 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 457882966-Ethylpyrazin-2-amineHCID 118317288Tert-butyl (4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate2×

Produkt 1

HCID 118317293Tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamateAusbeute 28 %

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 180AcetoneLösungsmittelHCID 312751,4-DioxaneLösungsmittel2×HCID 18681192Ethanol, mixt. with methanolLösungsmittelHCID 21226129Dichloromethane methanolLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A mixture of tert-butyl (4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (Intermediate C) (1050 mg, 2.73 mmol), 6-ethylpyrazin-2-amine (437 mg, 3.55 mmol), and cesium carbonate (1333 mg, 4.09 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen for 5 min. A solution of Pd2(dba)3 (125 mg, 0.136 mmol) and BINAP (170 mg, 0.273 mmol) in 1,4-dioxane (5 mL) was added, and the reaction mixture stirred at 90° C. for 6 h. The reaction mixture was allowed to cool and was stirred at room temperature for 16 h, then diluted with 10% MeOH/DCM (25 mL) and filtered through a plug of Celite, washing with additional 10% MeOH/DCM (15 mL). The solvent was removed in vacuo and the crude product was combined with MeOH (15 mL) and slurried for 3 h. The resulting orange solid was isolated by filtration, then combined with MeOH/EtOH (5 mL) solution and stirred for 72 h. Again the resulting orange solid was isolated by filtration, then acetone (20 mL) was added and the mixture was slurried for 2 h. The residual solid was filtered off, and the filtrate was evaporated to give the subtitle compound tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (360 mg, 27%); Rt 2.6 min (Method 2); m/z 472 (M+H)+ (ES+); 1H NMR δ: 1.18 (3H, t), 1.47 (9H, s), 2.63 (2H, q), 5.36 (2H, s), 6.99 (1H, d), 7.06 (1H, d), 7.36 (1H, d), 7.53-7.63 (2H, m), 7.90-8.06 (3H, overlapping m), 8.29 (1H, d), 8.36 (1H, m), 8.91 (1H, s), 8.96 (1H, s), 10.06 (1H, s).

Aufarbeitung

  1. customwas degassed with nitrogen for 5 min
  2. temperatureto cool
  3. stirringwas stirred at room temperature for 16 h
  4. filtrationfiltered through a plug of Celite
  5. washwashing with additional 10% MeOH/DCM (15 mL)
  6. customThe solvent was removed in vacuo
  7. waitslurried for 3 h
  8. customThe resulting orange solid was isolated by filtration
  9. stirringstirred for 72 h
  10. customAgain the resulting orange solid was isolated by filtration
  11. waitthe mixture was slurried for 2 h
  12. filtrationThe residual solid was filtered off
  13. customthe filtrate was evaporated

Quellen und Nachweise

ORD-Eintrag
ord-509bcbf0b7be4a46ba318479dc1eb7e9
Quelldatensatz
uspto-grants-2016_09
Patentnummer
US09447076B2

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