Reacción #483
ord-7d5963f655d84875bf61ad4d09b53b49
Ecuación de reacción
Disolventes
Condiciones de reacción
Procedimiento
To a 250 mL roundbottomed flask was added 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (5.5 g, 23.11 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.50 g, 23.11 mmol), Palladium(II)acetate (0.157 g, 0.69 mmol), rac-BINAP (0.734 g, 1.16 mmol), Potassium carbonate (4.79 g, 34.66 mmol) and toluene (100 mL). The atmosphere was exchanged to nitrogen through consecutive vacuum- nitrogen purge cycles after which the mixture was heated at 120 °C for 16 h. Still some starting material left according to HPLC and LCMS (IPC 1), so another 25 mg of Pd(OAc)2 and 116 mg of BINAP was added, and heating continued. After another 4 h, no further progress was detected (IPC 2), so the mixture was allowed to cool to r.t. Dichloromethane (200 mL) was added and pH was adjusted to 2 by addition of 2M HCl (aq) (80 mL was added, but made too acidic). The phases were separated and the aq phase was made basic by addition of 1M NaOH (aq) (ca 70 mL). The aq phase was extracted with dichloromethane (200 mL) and re-extracted with another portion of dichloromethane (70 mL). Since the aq phase still contained some product, another portion of 1M NaOH (aq) (20 mL) was added and the aq phase was extracted with dichloromethane (100 mL). The combined organic layers were evaporated and toluene was added to co-evaporate water. The resulting brown solid was dried under vacuum o.n, yielding EN04391-37-001 (12 g, 27.1 mmol, 117 %). To the solid was added EtOAc (55 mL) and the slurry was stirred at r.t for 1 h. Stirring was turned off and the solid was allowed to sediment for 2 h. The solid was filtered off and washed with 2x 12 mL cold EtOAc, yielding EN04391-37-002 (5.7 g, 12.88 mmol, 55.7 %). The mother liquor still contained product so it was concentrated and to the residue was added isopropanol (18 mL, 2 mL/ g crude). The mixture was heated to dissolve everything (50 °C for 5 min) and was then stirred at r.t over night. A white precipitate had formed. The mixture was cooled on an ice bath (0-5 °C) for 1 h after which the solid was filtered off, washed with 2x10 mL cold isopropanol and dried at 40 °C under vacuum, yielding EN04391-37-003 (2.3 g, 5.20 mmol, 22.49 %). EN04391-37-002 and EN04391-37-003 were combined with EN04391-36-002 and EN04391-36-003 and further purified, see page EN04391-38.