反应详情

温度

-40 °C

To a solution of diisopropylamine (Aldrich) (0.640 mL, 4.57 mmol) in THF (10 mL) at −40° C. in 100 mL 3-neck round-bottom flask was added butyllithium solution, 1.6 m in hexanes (Aldrich) (2.85 mL, 4.57 mmol) dropwise via the addition funnel. After the addition, it was continued to stir at −40° C. for 20 min then cooled to −78° C. To this reaction mixture was added 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (Example 339 step 3) (0.800 g, 3.81 mmol) in THF (10 mL) dropwise via the addition funnel. It was continued to stir at −78° C. after the addition. After 1 h, triisopropyl borate (Aldrich) (1.309 mL, 5.71 mmol) was added into the reaction mixture dropwise via the addition funnel. After the addition, it was continued to stir at −78° C. for 20 min then removed the cooling bath and slowly warmed up to rt and stirred for 1 h. The reaction mixture was quenched with 1 N NaOH (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL)—the organic layer was discard; the aqueous layer was acidified to a pH of about 5 to 6 using 5N HCl. The resulting mixture was extracted with EtOAc (2×15 mL) and CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated to afford the product as a light brown amorphous solid (780 mg). MS (ESI pos. ion) m/z: 255.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (dd, J=11.44, 6.75 Hz, 3H) 2.36 (d, J=4.30 Hz, 2H) 2.45-2.60 (m, 2H) 3.35-3.47 (m, 1H) 3.63-3.77 (m, 4H) 8.15 (dd, J=9.00, 2.35 Hz, 1H) 8.19-8.27 (m, 2H) 8.33 (d, J=9.00 Hz, 1H).

1. additionAfter the addition, it
2. temperaturethen cooled to −78° C
3. stirringto stir at −78° C.
4. additionafter the addition
5. waitAfter 1 h
6. additionAfter the addition, it
7. stirringto stir at −78° C. for 20 min
8. customthen removed the cooling bath
9. temperatureslowly warmed up to rt
10. stirringstirred for 1 h
11. customThe reaction mixture was quenched with 1 N NaOH (15 mL)
12. extractionThe aqueous layer was extracted with EtOAc (2×15 mL)—the organic layer
13. extractionThe resulting mixture was extracted with EtOAc (2×15 mL) and CHCl3 (2×15 mL)
14. dry with materialThe combined organic layers were dried over MgSO4
15. concentrationconcentrated