Sodium Carbonate → 5-(8-(Cyclohexylamino)imidazo[1,2-a]pyrazin-5-yl)isoindolin-1-one

HRID 1095463

Reaktionsgleichung

Reaktionsgleichung von HRID 1095463
Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[NH:30][CH2:29]3)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd].C(OCC)C.C1(C)C=CC=CC=1>[CH:12]1([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:35])[NH:30][CH2:29]4)=[CH:3][N:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1

Komponenten

8

Edukt 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 219557955-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-oneHCID 576994875-bromo-N-cyclohexylimidazo[1,2-a]pyrazin-8-amine

Produkt 1

HCID 251153785-(8-(Cyclohexylamino)imidazo[1,2-a]pyrazin-5-yl)isoindolin-1-oneAusbeute 37 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 86600928Tetrakis palladium triphenylphosphineKatalysatorHCID 1140TolueneLösungsmittelHCID 3283Diethyl EtherLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

The product of Step 1 (70 mg, 0.24 mmol), Intermediate 4 (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one, 77 mg, 0.3 mmol), tetrakis palladium triphenylphosphine (69 mg, 0.06 mmol), sodium carbonate solution (1.5 M, 1.28 mL, 1.92 mmol) and dioxane (3.8 mL) are combined in a flask. The mixture is degassed with nitrogen for 10 min then sealed and heated at 90° C. for 16 h. Brine is added and the mixture is washed with dichloromethane followed by ethyl acetate. The combined organic layers are dried over MgSO4 and evaporated in vacuo to afford a brown oil. The crude material is purified by column chromatography, eluting with 5% methanolic ammonia (7 N) in dichloromethane to give a brown solid. Trituration with 1:1 toluene:diethyl ether yielded the title compound as an off-white solid (30 mg, 37%). 1H-NMR (400 MHz, d6-DMSO) =1.22-1.29 (m, 1H), 1.32-1.49 (m, 4H), 1.64 (d, 1H, J=15.2 Hz), 1.77 (d, 2H, J=12.8 Hz), 1.92 (d, 2H, J=15.2 Hz), 3.97-4.01 (1H, m), 7.33 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.63 (s, 1H), 7.92 (s, 1H). LCMS: Rt 2.24 min (99.6%), m/z (APCI) 348 (M+H)+.

Aufarbeitung

  1. customThe mixture is degassed with nitrogen for 10 min
  2. customthen sealed
  3. additionBrine is added
  4. washthe mixture is washed with dichloromethane
  5. dry with materialThe combined organic layers are dried over MgSO4
  6. customevaporated in vacuo
  7. customto afford a brown oil
  8. customThe crude material is purified by column chromatography
  9. washeluting with 5% methanolic ammonia (7 N) in dichloromethane
  10. customto give a brown solid

Quellen und Nachweise

ORD-Eintrag
ord-f1293bd210e44f8e96d80f06326790f4
Quelldatensatz
uspto-grants-2012_03
Patentnummer
US08138193B2

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