反应详情

温度

-85 °C

A 2-L 3-neck RB flask, equipped a mechanical stirrer, addition funnel, thermometer and nitrogen gas inlet was charged with Intermediate 8, 1-(4-bromo-2-fluorobenzyl)pyrrolidine (69.86 g, 0.27 mol) and 700 mL of anhydrous THF. The system was flushed with nitrogen and cooled to −85° C. with liquid nitrogen with an ether/MeOH (1:1) bath. Then n-BuLi (10M in hexane, 30 mL, 0.298 mol) was added dropwise through an addition funnel at T<−80° C. The mixture was stirred at this temperature for an additional 15 min, then a solution of 3-oxocyclobutanecarboxylic acid (dried under vacuum for 2 days, 15.4 g, 0.135 mol) in 300 mL of anhydrous THF was added dropwise through an addition funnel keeping T<−80° C. The mixture was allowed to warm to RT and evaporated. The residue was mixed with 500 mL of water and washed with ether (2×300 mL). Then the aqueous solution was acidified to pH 1 with conc. HCl and washed with ether (2×300 mL). Then the aqueous solution was neutralized to pH 6-5 with NaOH and coevaporated three times with iPrOH (300 mL each time). Then the mixture was coevaporated with THF (200 mL) and dried to give gummy residue containing the product with inorganic salts LCMS (M+H): 294.4

1. customA 2-L 3-neck RB flask, equipped
2. additiona mechanical stirrer, addition funnel
3. customThe system was flushed with nitrogen
4. customT<−80° C
5. temperatureto warm to RT
6. customevaporated
7. additionThe residue was mixed with 500 mL of water
8. washwashed with ether (2×300 mL)
9. washwashed with ether (2×300 mL)
10. customdried
11. customto give gummy residue
12. additioncontaining the product with inorganic salts LCMS (M+H)