(2,3-Dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol → (+)-alpha-(2,3-Dimethoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidinemethanol

HRID 2055854

Reaction equation

HRID 2055854 reaction equation
[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[OH:12]>C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[OH:12]

Participants

3

Reactant 1

HCID 60858(2,3-Dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol

Product 1

HCID 5311271(+)-alpha-(2,3-Dimethoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidinemethanol

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
45 °C

Procedure

To a solution of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5a) (2.77 g, 6.2 mmol) in t-BuOMe (10 mL), Baker silica (8.3 g, 40 μ) was added. After evaporation of the ether, the silica was transferred to 180 mL of 0.1M phosphate buffer (pH 7.0) and then 25 mL of the partially purified lipase (100 g crude=230 mL of a solution) was added. The suspension was stirred at 45° C. for 4 days. The reaction was stopped by filtering the reaction mixture. Both filtrate and silica were extracted with ethyl acetate (300 mL). The organic layer was dried over MgSO4, evaporated under vacuum to give a residue, which was purified by column chromatography (60 g Baker silica (40 μ); EtOAc/heptane=3:1). (Rf0.45 for (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5b) and 0.06 for (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3)). After the ester was eluted, the eluant was changed to MeOH/EtOAc=3:7 to recover (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a yellow oil (1.08 g, 46%, 98% ee). Recrystallization twice from EtOAc/heptane gave (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a white crystalline compound (770 mg, 33%, 99% ee); m.p.=114-116° C.; [α]D=14.3 (c=1; CHCl3).

Workup

  1. customAfter evaporation of the ether
  2. addition25 mL of the partially purified lipase (100 g crude=230 mL of a solution) was added
  3. filtrationby filtering the reaction mixture
  4. extractionBoth filtrate and silica were extracted with ethyl acetate (300 mL)
  5. dry with materialThe organic layer was dried over MgSO4
  6. customevaporated under vacuum
  7. customto give a residue, which
  8. customwas purified by column chromatography (60 g Baker silica (40 μ); EtOAc/heptane=3:1)
  9. washAfter the ester was eluted
  10. customto recover (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a yellow oil (1.08 g, 46%, 98% ee)
  11. customRecrystallization twice from EtOAc/heptane

Sources & evidence

ORD record
ord-f4a2cf4b7504403b92e419cf1595d635
Source dataset
uspto-grants-2008_02
Patent number
US07332607B2

Linked notes

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