Potassium Carbonate → 2-(4-Ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methylquinolin-7-yl)phenyl)acetamide

HRID 1525938Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1525938
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([CH3:61])[CH:57]=[N:58]2)=[CH:53][CH:52]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:51]4[CH:60]=[C:59]5[C:54]([CH:55]=[C:56]([CH3:61])[CH:57]=[N:58]5)=[CH:53][CH:52]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]

Komponenten

8

Edukt 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 189422807-Bromo-3-methylquinolineHCID 712709392-(4-Bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

Produkt 1

HCID 712707492-(4-Ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methylquinolin-7-yl)phenyl)acetamideAusbeute 53,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418807HCID 178418807, VerbindungKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (212 mg, 0.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (126 mg, 0.5 mmol), and potassium acetate (97 mg, 0.99 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (40 mg, 0.05 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromo-3-methylquinoline (110 mg, 0.5 mmol) and 2M aq K2CO3 (0.55 mL, 1.09 mmol) were added. The reaction mixture was purged with nitrogen and was heated with stirring at 100° C. for 1 h. The reaction mixture was diluted with dichloromethane (60 mL) and any salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate. The filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) provided the title product (131 mg, 51% yield). MS(ES)+ m/e 491 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 1.63-1.86 (m, 3 H) 1.86-2.05 (m, 2 H) 2.29-2.41 (m, 1 H) 2.53-2.59 (m, 3 H) 2.59-2.74 (m, 2 H) 2.79 (d, J=11.62 Hz, 1 H) 3.41 (q, J=7.33 Hz, 2 H) 3.95-4.10 (m, 2 H) 4.52 (s, 1 H) 5.87 (d, J=4.04 Hz, 1 H) 7.28 (d, J=3.54 Hz, 1 H) 7.41-7.50 (m, 1 H) 7.55 (dd, J=11.37, 1.77 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.82 (dd, J=8.46, 1.89 Hz, 1 H) 7.90 (d, J=8.59 Hz, 1 H) 7.97-8.05 (m, 1 H) 8.27-8.36 (m, 1 H) 8.83 (d, J=2.27 Hz, 1 H).

Aufarbeitung

  1. customThe reaction mixture was purged with nitrogen
  2. temperatureThe reaction mixture was cooled
  3. customThe reaction mixture was purged with nitrogen
  4. temperaturewas heated
  5. additionThe reaction mixture was diluted with dichloromethane (60 mL)
  6. filtrationany salts were filtered away
  7. filtrationThe organic mixture was filtered through a plug of celite and sodium sulfate
  8. additionThe filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min
  9. filtrationThe mixture was filtered
  10. concentrationconcentrated in vacuo
  11. customPurification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH)

Quellen und Nachweise

ORD-Eintrag
ord-bfd722d655fb45adaa464e37a8bfde87
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09084794B2

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