Dimethylformamide → HCID 89781963, Verbindung

HRID 1056253

Reaktionsgleichung

Reaktionsgleichung von HRID 1056253
[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.CN(C=O)C.[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:19]([CH3:21])([CH3:20])[CH3:18])[N:8]=[CH:7]2

Komponenten

5

Edukt 3

HCID 6228DimethylformamideHCID 6385Tert-ButylamineHCID 457900618-Bromo-2-chloroquinazoline

Produkt 1

HCID 89781963HCID 89781963, VerbindungAusbeute 41,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 962WaterLösungsmittel

Versuchsvorschrift

8-Bromo-2-chloroquinazoline (D-L Chiral Chemicals, LLC, Princeton, N.J.) (200 mg, 0.82 mmol) was treated with DMF (2.0 mL) and 2-methylpropan-2-amine (Aldrich Chemical Company, 0.44 mL, 4.11 mmol) and stirred at RT overnight (17 h). The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine (2×), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (12 g Thomson SingleStep column, using a gradient of 0-50% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (94 mg, 0.34 mmol, 41% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (1H, s), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=7.9, 1.3 Hz), 7.05 (1H, t, J=7.7 Hz), 5.43 (1H, br. s.), 1.54 (9H, s). m/z (ESI, +ve ion) 280.0/282.0 (M+H)+. A 5-mL glass microwave reaction vessel was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (120 mg, 0.46 mmol), K2PO4 (182 mg, 0.86 mmol), Pd2dba3 (Strem Chemicals, 13.07 mg, 0.014 mmol), Xphos (Strem Chemicals, 13.61 mg, 0.03 mmol) and 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (80 mg, 0.29 mmol) in dioxane (2.5 mL) and water (0.80 mL). The reaction was stirred and heated in a heating block at 110° C. for 1 h. The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine and concentrated. The crude residue was purified on the ISCO Combiflash RF (25 g Thomson SingleStep column, using a gradient of 0-20% MeOH) affording 2-(2-(tert-butylamino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.9 mg, 0.16 mmol, 56% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br. s.), 9.17 (1H, s), 8.10 (1H, d, J=6.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.35 (1H, s), 7.25 (1H, t, J=7.6 Hz), 7.05 (1H, br. s.), 6.98 (1H, br. s.), 3.40-3.47 (3H, m), 2.92 (2H, br. s.), 1.52 (9H, s). m/z (ESI, +ve ion) 336.0 (M+H)+.

Aufarbeitung

  1. extractionextracted with EtOAc (30 mL)
  2. washwashed with brine (2×)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified on the ISCO Combiflash RF (12 g Thomson SingleStep column

Quellen und Nachweise

ORD-Eintrag
ord-ef6cb9876f7e4e88b4dcab1f52871225
Quelldatensatz
uspto-grants-2016_07
Patentnummer
US09394297B2

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