تفاعل #79532

معادلة التفاعل

α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

EtOAc

→

(R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

المردود 52.0%

(R)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

المردود 52.0%

المذيبات

t-BuOMe

phosphate

ظروف التفاعل

المعالجة

1. 1
   تركيزThe resulting slurry was concentrated (35° C./20 torr)
2. 2
   أخرىto give a light yellow powder
3. 3
   workup.ADDITIONA mixture of the powder, partially purified Candida cylindracea lipase (17.1 g
4. 4
   أخرىSolid material was removed by filtration
5. 5
   أخرىthe two phases in the filtrate were separated
6. 6
   استخلاصBoth the solid and aqueous layer were extracted with EtOAc (2 L)
7. 7
   تركيزThe combined organic solutions were concentrated (35° C./20 torr) to a residue which
8. 8
   أخرىwas 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. 9
   تركيزconcentrated (35° C./20 torr) to a residue which
10. 10
    workup.DISSOLUTIONwas dissolved in methylene chloride (800 mL)
11. 11
    غسيلThe solution was washed with 0.5N NaOH (2×600 mL), brine (600 mL)
12. 12
    تجفيفdried (MgSO4)
13. 13
    ترشيحThe mixture was filtered
14. 14
    تركيزthe filtrate was concentrated (30° C./20 torr)
15. 15
    أخرىto give a solid which
16. 16
    أخرىwas recrystallized from cyclohexane (2 L)

الإجراء التجريبي

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).

المصدر