Potassium Carbonate → 2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(2-hydroxyquinolin-7-yl)phenyl)acetamide

Participants

Reaction Conditions

Reaction Steps

A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.302 mmol) in 1,4-dioxane (1.5 mL) was treated with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.362 mmol), potassium acetate (0.453 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.030 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 stirred in an oil bath at 90° C. overnight. The reaction mixture was cooled to room temperature and was treated with 7-chloroquinolin-2-ol (0.302 mmol), 2M aq potassium carbonate (0.906 mmol), and Pd-XPhos Precatalyst (Strem 46-0268) (0.030 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an bath at 90° C. for 16 h. The resulting black mixture was diluted with water (50 mL) and brine (20 mL) and was extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by reverse phase HPLC (10-40% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜7 with saturated aq sodium bicarbonate. This mixture was concentrated to a minimal volume in vacuo and was then extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by chiral HPLC (Chiralpak AS-H column, acetonitrile:methanol 9:1) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid (20 mg, 12%). MS(ES)+ m/e 505.2 [M+H]+, >99% ee, αD=+43 deg (c=0.02, acetonitrile:methano19:1).

Provenance & Evidence