反应详情

温度

-78 °C

A solution of ethylmagnesium bromide, 3M in diethyl ether (28.2 mL) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (13.09 mL,) and 2-(benzyloxy)-3-fluorobenzonitrile (Example 283a, 9.6 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1 h 30 min. An ice bath was placed around the reaction and boron trifluoride etherate (10.71 mL) was added as a slow stream (caution exothermic) and the mixture was stirred for 30 min. The reaction was cooled (ice bath) and quenched with 1 M aqueous HCl (400 mL added portionwise). The aqueous layer was separated and the diethyl ether layer further extracted into 1M HCl (2×200 mL) (ethyl acetate added to the diethyl ether to aid solubility). The aqueous layer was cooled in an ice bath and basified with stirring with a 10M aqueous NaOH solution. The resulting precipitate was filtered through Celite, washing the pad with water (200 mL) then DCM (4×200 mL) then DCM/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted with DCM (2×200 mL). The combined organics were dried (MgSO4) and evaporated, the residue was purified on SCX resin (50 g) eluting with DCM, methanol (discarded) and flushing with 20% ammonia in methanol to give the subtitle compound as an oil (2.54 g).

1. temperaturewarmed to room temperature over 1 h 30 min
2. additionwas added as a slow stream (caution exothermic)
3. stirringthe mixture was stirred for 30 min
4. temperatureThe reaction was cooled (ice bath)
5. customquenched with 1 M aqueous HCl (400 mL
6. additionadded portionwise)
7. customThe aqueous layer was separated
8. extractionthe diethyl ether layer further extracted into 1M HCl (2×200 mL) (ethyl acetate
9. additionadded to the diethyl ether to aid solubility)
10. temperatureThe aqueous layer was cooled in an ice bath
11. stirringwith stirring with a 10M aqueous NaOH solution
12. filtrationThe resulting precipitate was filtered through Celite
13. washwashing the pad with water (200 mL)
14. customThe combined filtrates were separated
15. extractionthe aqueous layer further extracted with DCM (2×200 mL)
16. dry with materialThe combined organics were dried (MgSO4)
17. customevaporated
18. customthe residue was purified on SCX resin (50 g)
19. washeluting with DCM, methanol (discarded)
20. customflushing with 20% ammonia in methanol