Cesium carbonate → HCID 86680517, Verbindung

HRID 1184601Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1184601
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][CH:22]3[CH2:31][N:25]4[CH2:26][CH2:27][NH:28][C:29](=[O:30])[CH:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][C@H:22]3[CH2:31][N:25]4[CH2:26][CH2:27][N:28]([C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=5)[C:29](=[O:30])[C@@H:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1

Komponenten

6

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27829022-Bromo-6-(trifluoromethyl)pyridineHCID 86680516HCID 86680516, Verbindung

Produkt 1

HCID 86680517HCID 86680517, VerbindungAusbeute 17,66 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 167845palladium(II) acetateKatalysator

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

A 4 mL vial was charged with 2-bromo-6-(trifluoromethyl)pyridine (99 mg, 0.437 mmol), 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one [3:1 (7R,8aS: 7R,8aR) diastereomer ratio](100 mg, 0.365 mmol) from Example 163 Step 3, palladium(II) acetate (4.09 mg, 0.018 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS, 21.09 mg, 0.036 mmol), and cesium carbonate (178 mg, 0.547 mmol). The mixture was purged with nitrogen, and anhydrous dioxane (0.5 mL) was added. The reaction mixture was purged with nitrogen again and was subsequently heated at 110° C. for 16 hours. The mixture was directly loaded and separated by flash chromatography [12 g cartridge, a gradient 0-5% methanol/dichloromethane over 20 minutes] to give crude oily product. The crude product was further purified on 12 g cartridge eluted with a gradient of 0-100% ethyl acetate over 20 minutes to give the title compound (27 mg, 0.064 mmol, 17.66% yield) as the first eluting diastereomer as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=8.5 Hz, 1H), 8.12 (s, 1H), 7.95 (d, J=1.3 Hz, 1H), 7.85 (dd, J=10.4, 5.6 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 5.50 (d, J=5.0 Hz, 1H), 4.47 (ddd, J=7.1, 4.5, 1.7 Hz, 1H), 4.12-3.91 (m, 2H), 3.34 (dt, J=9.7, 4.8 Hz, 2H), 3.19-3.05 (m, 2H), 2.64 (dt, J=14.6, 7.3 Hz, 1H), 2.57-2.42 (m, 1H), 2.00 (tt, J=7.8, 5.3 Hz, 1H), 1.02-0.90 (m, 4H); MS (ESI+) m/z 420 (M+H)+.

Aufarbeitung

  1. customThe mixture was purged with nitrogen, and anhydrous dioxane (0.5 mL)
  2. additionwas added
  3. customThe reaction mixture was purged with nitrogen again
  4. customseparated by flash chromatography [12 g cartridge
  5. customa gradient 0-5% methanol/dichloromethane over 20 minutes] to give crude oily product
  6. customThe crude product was further purified on 12 g cartridge
  7. washeluted with a gradient of 0-100% ethyl acetate over 20 minutes

Quellen und Nachweise

ORD-Eintrag
ord-176c41633b3d48df8c892593052ee2ee
Quelldatensatz
uspto-grants-2014_03
Patentnummer
US08669255B2

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