反应详情

温度

110 °C

A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (266 mg, 0.47 mmol) in dry 1,4-dioxane (3 mL) was treated with bis(pinacolato)diboron (142 mg, 0.56 mmol), potassium acetate (49 mg, 0.5 mmol) and PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol). The reaction mixture was degassed with nitrogen for ˜3 min and the vessel was purged with nitrogen, sealed, and heated to 110° C. for 3 h. Analysis of a reaction mixture aliquot indicated complete conversion of the starting material to the boronate intermediate. To the cooled reaction mixture was added 7-bromo-3-fluoroquinoline (105 mg, 0.47 mmol), PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol) and 2M aq K2CO3 (0.7 mL, 1.4 mmol). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC (5-75% acetonitrile:water with 0.1% NH4OH) afforded the racemic title product, which was resolved by chiral HPLC (Lux Cell 4, methanol) to afford the title product in 95% ee (29 mg, 12% yield). αD=+26 deg (c=0.14, methanol); MS(ES)+ m/e 495 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.06-1.18 (m, 3 H) 1.63-1.84 (m, 2 H) 1.90-1.97 (m, 2 H) 2.27-2.39 (m, 1 H) 2.53-2.73 (m, 2 H) 2.80 (d, J=11.37 Hz, 1 H) 3.18 (s, 2 H) 3.41 (q, J=7.07 Hz, 2 H) 3.95-4.08 (m, 2 H) 4.53 (s, 1 H) 6.28 (br. s., 1 H) 7.29 (br. s., 1 H) 7.47 (t, J=7.71 Hz, 1 H) 7.55 (dd, J=11.24, 1.89 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.83-7.93 (m, 2 H) 7.93-8.00 (m, 1 H) 8.37 (d, J=1.77 Hz, 1 H) 8.88 (d, J=2.53 Hz, 1 H).

1. customThe reaction mixture was degassed with nitrogen for ˜3 min
2. customthe vessel was purged with nitrogen
3. customsealed
4. customTo the cooled reaction mixture
5. customThe reaction mixture was purged with nitrogen
6. customsealed
7. temperatureheated at 120° C. for 1 h
8. additionThe reaction mixture was diluted with water (50 mL)
9. extractionextracted with dichloromethane (3×100 mL)
10. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customPurification of the residue by reverse phase HPLC (5-75% acetonitrile:water with 0.1% NH4OH)