Potassium Carbonate → (+)-Methyl 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methoxyquinolin-7-yl)phenyl)acetate

Participants

Reaction Conditions

Reaction Steps

A solution of methyl 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (0.626 mmol) in 1,4-dioxane (2.5 mL) was treated with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.751 mmol), potassium acetate (0.939 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.031 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an oil bath at 80° C. overnight. The reaction mixture was cooled to room temperature and was treated with 7-bromo-3-methoxyquinoline (0.626 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.031 mmol), and 2M aq potassium carbonate (1.878 mmol). The solution was degassed with a stream of nitrogen for 3 min, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (100 mL) and was extracted three times with chloroform. The combined organic layers were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chiralpak IA column, methanol:acetonitrile-1:1) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid (94 mg, 26%). MS(ES)+ m/e 534.2 [M+H]+, >99% ee, αD=+58 deg (c=0.05, methanol:acetonitrile 1:1).

Provenance & Evidence