反应详情

Silica gel (EM Sciences, 230-400 mesh, 215 g) was added to a solution of (R)-enriched α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5a) (72 g, 0.16 mol, 82% ee) in t-BuOMe (320 mL). The resulting slurry was concentrated (35° C./20 torr) to give a light yellow powder. A mixture of the powder, partially purified Candida cylindracea lipase (17.1 g, equivalent to 522 g of crude enzyme from Sigma) in phosphate buffer (0.1M, pH 7, 5.2 L) was stirred at 45° C. for 4 days. EtOAc (4 L) was added and the mixture was stirred at room temperature for 1 hour. Solid material was removed by filtration, and the two phases in the filtrate were separated. Both the solid and aqueous layer were extracted with EtOAc (2 L). The combined organic solutions were concentrated (35° C./20 torr) to a residue which was purified by flash chromatography (SiO2, 10 cm×15 cm, eluted with 1:1 EtOAc; hexane (8 L) and 1:19 EtOAc: MeOH (8 L)). The desired fractions (TLC, Rf 0.16, acetone) were combined and concentrated (35° C./20 torr) to a residue which was dissolved in methylene chloride (800 mL). The solution was washed with 0.5N NaOH (2×600 mL), brine (600 mL) and dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30° C./20 torr) to give a solid which was recrystallized from cyclohexane (2 L) to give (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a white solid (31 g, 52% yield, 99.9% ee); m.p. 113-114° C., [α]D20+14.0° (c 0.49, CHCl3).

1. concentrationThe resulting slurry was concentrated (35° C./20 torr)
2. customto give a light yellow powder
3. additionA mixture of the powder, partially purified Candida cylindracea lipase (17.1 g
4. customSolid material was removed by filtration
5. customthe two phases in the filtrate were separated
6. extractionBoth the solid and aqueous layer were extracted with EtOAc (2 L)
7. concentrationThe combined organic solutions were concentrated (35° C./20 torr) to a residue which
8. customwas purified by flash chromatography (SiO2, 10 cm×15 cm, eluted with 1:1 EtOAc; hexane (8 L) and 1:19 EtOAc: MeOH (8 L))
9. concentrationconcentrated (35° C./20 torr) to a residue which
10. dissolutionwas dissolved in methylene chloride (800 mL)
11. washThe solution was washed with 0.5N NaOH (2×600 mL), brine (600 mL)
12. dry with materialdried (MgSO4)
13. filtrationThe mixture was filtered
14. concentrationthe filtrate was concentrated (30° C./20 torr)
15. customto give a solid which
16. customwas recrystallized from cyclohexane (2 L)