Réaction #484
ord-23ee6c17726e43148570d3de230c90b7
Équation de réaction
Solvants
Conditions de réaction
Mode opératoire
To a 250 mL roundbottomed flask was added 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (6 g, 25.21 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (7.10 g, 25.21 mmol), Palladium(II)acetate (0.171 g, 0.76 mmol), rac-BINAP (0.801 g, 1.26 mmol), Potassium carbonate (5.23 g, 37.81 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 18 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 3 h, approx. 2% starting material remained according to LCMS (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) (140 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 200 mL). The aq phase was extracted with dichloromethane (200 mL) and re-extracted with another portion of dichloromethane (70 mL). Since an oily residue containing product had precipitated upon addition of acid/ base, the aq phase together with 100 mL dichloromethane was added to the residue in an attempt to dissolve it. More 1M NaOH (aq) was added to assure basic pH and the layers were separated. The combined organic layers were evaporated and the residue was dried under vacuum o.n. EN04391-36-001 (12.2 g, 27.6 mmol, 109 %) was obtained as a brown solid. To the solid was added isopropanol (48 mL, 4 mL/g crude prod) and the thick suspension was heated at 95 °C. After 30 min, the slurry was allowed to cool to r.t and left stirring over night. The still thick slurry was cooled on an ice bath at 0-5 °C for 1 h before it was filtered. The solid was washed with 4x15 mL of cold isopropanol and dried at 40 °C under vacuum o.n, yielding EN04391-36-002 (2.05 g, 4.63 mmol, 18.38 %) as a pale yellow solid The mother liquor that still contained product was concentrated. An orange- brown foam was obtained. Toluene was added and evaporated and the residue (8 g) was dissolved in MeCN (13.5 mL) and purified by chromatography (200 g SiO2 in a filter funnel, elutent: EtOAc (750 mL) followed by MeCN (1 L) and MeCN:MeOH 9:1 (1 L)). Fractions 10-13 were combined, concentrated and dried, yielding EN04391-36-003 (5.5 g, 12.43 mmol, 49.3 %) as a solid. EN04391-36-002 and EN04391-36-003 were further purified on page EN04391-38.