6-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ylamine → gamma-Secretase modulator 6

Participants

Reaction Conditions

Reaction Steps

Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (5.0 g, 24.48 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.73 g, 24.48 mmol), palladium (II) acetate (0.165 g, 0.73 mmol), rac-BINAP (0.762 g, 1.22 mmol), potassium carbonate (5.08 g, 36.72 mmol), and toluene (100 mL). The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 120 °C for 16 hours. HPLC-UV shows a small percentage (<5%) of starting materials remaining. Heating was continued for another 2 hours, then the heating block was removed and the mixture was allowed to cool to room temperature. Added 200 mL dichloromethane and adjusted the pH to 2 with 2.0N aqueous HCl. Separated the phases and basified the aqueous with 1.0N aqueous sodium hydroxide. Extracted with 200 mL DCM, followed by a second extraction with 100 mL DCM. The organics were dried with magnesium sulfate and concentrated by rotary evaporator to yield EN04092-37-001 (10.9 g, 24.63 mmol, 101 %) as an amber-coloured foam.

Provenance & Evidence