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

Participants

Reaction Conditions

Reaction Steps

To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (198 mg, 0.46 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (117 mg, 0.46 mmol), and potassium acetate (91 mg, 0.92 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (38 mg, 0.046 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromo-3-methoxyquinoline (110 mg, 0.46 mmol) and 2M aq K2CO3 (0.51 mL, 1.02 mmol) were added. The reaction mixture was purged with nitrogen and was heated with stirring at 100° C. for 1 h. The reaction mixture was diluted with dichloromethane (60 mL) and any salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate and the filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) afforded the racemic title product, which was resolved by chiral HPLC (Chromegachiral CC4, methanol) to afford the title product in >98% ee (45 mg, 19% yield). αD=+56° (c=0.02, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.07 Hz, 3 H) 1.68-1.80 (m, 2 H) 1.90-2.02 (m, 2 H) 2.31-2.41 (m, 1 H) 2.58-2.71 (m, 2 H) 2.72-2.80 (m, 1 H) 3.18 (s, 2 H) 3.41 (d, J=7.33 Hz, 2 H) 4.01 (s, 3 H) 4.02 (d, J=1.77 Hz, 2 H) 4.52 (s, 1 H) 5.65 (d, J=4.55 Hz, 1 H) 7.21-7.33 (m, 1 H) 7.44-7.56 (m, 3 H) 7.61 (dd, J=7.96, 1.89 Hz, 1 H) 7.81-7.94 (m, 2 H) 8.30 (s, 1 H) 8.71 (d, J=3.03 Hz, 1 H).

Provenance & Evidence