反应详情

温度

-78 °C

Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 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 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g). 1H NMR δ (CDCl3) 7.49-7.44 (2H, m), 7.42-7.36 (2H, m), 7.36-7.29 (1H, m), 6.99-6.92 (1H, m), 6.88-6.82 (2H, m), 5.13 (2H, s), 2.13 (2H, s), 1.00-0.95 (2H, m), 0.86-0.82 (2H, m).

1. temperaturewarmed to room temperature over 1.5 h
2. stirringthe mixture was stirred for 30 min
3. customThe reaction was quenched with 1 M HCl (400 ml)
4. customthe aqueous layer was separated
5. extractionThe diethyl ether layer was further extracted into 1M HCl (2×200 mL)
6. temperatureThe combined aqueous layers were cooled in an ice bath
7. filtrationThe resulting precipitate was filtered through celite
8. washwashing the pad extensively with water (200 mL), dichloromethane (4×200 mL)
9. customThe combined filtrates were separated
10. extractionthe aqueous layer further extracted into dichloromethane (2×200 mL)
11. dry with materialThe combined organics were dried (MgSO4)
12. customevaporated
13. customresidue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol)
14. customThe basic fractions were evaporated