Potassium Carbonate → 2-(4-(3-Cyanoquinolin-7-yl)-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

온도

120 °C

To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (125 mg, 0.28 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (72 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL) was added potassium acetate (61 mg, 0.63 mmol) and PdCl2(dppf)-CH2Cl2 adduct (23 mg, 0.03 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromoquinoline-3-carbonitrile (66.2 mg, 0.28 mmol) and 2M aq K2CO3 (0.3 mL, 0.6 mmol) were added. The reaction mixture was purged with nitrogen and heated with stirring at 100° C. for 1 h. The cooled reaction mixture was diluted with dichloromethane (60 mL) and 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. The residue was purified by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) and the appropriate fractions were collected, combined and concentrated in vacuo to give expected product as a racemate (87 mg, 60%). Chiral HPLC was performed on this material in Example 63a. MS(ES)+ m/e 514 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.56-0.66 (m, 2 H) 0.75-0.87 (m, 2 H) 1.64-1.70 (m, 1 H) 1.72-1.77 (m, 1 H) 1.85-1.97 (m, 2 H) 2.31 (td, J=11.24, 2.53 Hz, 1 H) 2.56-2.61 (m, 1 H) 2.62-2.74 (m, 2 H) 2.77-2.86 (m, 1 H) 3.15 (s, 2 H) 4.00 (d, J=2.02 Hz, 2 H) 4.55 (s, 1 H) 5.65 (d, J=4.29 Hz, 1 H) 7.27 (d, J=4.04 Hz, 1 H) 7.49 (t, J=7.71 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.65 (dd, J=7.96, 1.89 Hz, 1 H) 8.00 (dd, J=8.34, 1.77 Hz, 1 H) 8.06 (d, J=8.34 Hz, 1 H) 8.39-8.47 (m, 1 H) 8.63 (dd, J=2.02, 0.76 Hz, 1 H) 9.10 (d, J=2.27 Hz, 1 H).

1. customThe reaction mixture was purged with nitrogen
2. temperatureThe reaction mixture was cooled
3. customThe reaction mixture was purged with nitrogen
4. temperatureheated
5. customThe cooled reaction mixture
6. filtrationwere filtered away
7. filtrationThe organic mixture was filtered through a plug of celite and sodium sulfate
8. additionthe filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min
9. filtrationThe mixture was filtered
10. concentrationconcentrated in vacuo
11. customThe residue was purified by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH)
12. customthe appropriate fractions were collected
13. concentrationconcentrated in vacuo

ORD 기록

ord-82bb954c532a42b2aa022fa2f4a03e35

출처 데이터셋

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09084794B2