Aluminium lithium hydride → trans-{1-[2-(4-Fluorophenyl)ethyl]-4-methylpiperidin-3-yl}-methanol

HRID 896537Notes

Reaction equation

HRID 896537 reaction equation
C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[CH2:10][C:9](=O)[N:8]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:7]1=O)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:8]2[CH2:9][CH2:10][C@@H:11]([CH3:12])[C@H:6]([CH2:4][OH:3])[CH2:7]2)=[CH:17][CH:18]=1

Participants

4

Reactant 2

HCID 21226445Aluminium lithium hydrideHCID 697363791-[2-(4-Fluorophenyl)ethyl]-4-methyl-2,6-dioxopiperidine-3-carboxylic Acid Ethyl Ester

Product 1

HCID 69736259trans-{1-[2-(4-Fluorophenyl)ethyl]-4-methylpiperidin-3-yl}-methanolYield 46.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1-[2-(4-Fluorophenyl)ethyl]-4-methyl-2,6-dioxopiperidine-3-carboxylic acid ethyl ester (2.0 g, 6.22 mmol) in tetrahydrofuran (10 mL) was added over 5 minutes to an ice-cold solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 28 mL, 28 mmol). The resulting solution was stirred at room temperature for 17 hours, then was quenched by the slow dropwise addition of water (1.06 mL), 15% aqueous sodium hydroxide (1.06 mL), and water (3.18 mL). The resulting suspension was stirred for 20 minutes, then filtered and the solid washed with ethyl acetate. The combined filtrates were concentrated under vacuum to provide an oil which slowly crystallized. This material was purified by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide a pale yellow solid (724 mg, 46%) as a mixture of cis- and trans isomers. Pure trans isomer was isolated by further chromatography. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.98 (t, J=9 Hz, 2H), 3.83 (dd, J=11, 3 Hz, 1H), 3.54 (dd, J=11, 7 Hz, 1H), 3.18 (dm, J=10 Hz, 1H), 2.95 (dm, J=12 Hz, 1H), 2.85 (m, 2H), 2.61 (m, 2H), 2.12 (dt, J=11, 3 Hz, 1H), 2.01 (t, J=11 Hz, 1H), 1.77 (m, 1H), 1.6-1.3 (m, 3H), 1.00 (d, J=6 Hz, 3H). Mass spec (ES+) m/z 252.1 (M+H+, 100%).

Workup

  1. customwas quenched by the slow dropwise addition of water (1.06 mL), 15% aqueous sodium hydroxide (1.06 mL), and water (3.18 mL)
  2. stirringThe resulting suspension was stirred for 20 minutes
  3. filtrationfiltered
  4. washthe solid washed with ethyl acetate
  5. concentrationThe combined filtrates were concentrated under vacuum
  6. customto provide an oil which
  7. customslowly crystallized
  8. customThis material was purified by flash chromatography
  9. washeluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide

Sources & evidence

ORD record
ord-211dde7b66ed4162a0b6f3f837ad6395
Source dataset
uspto-grants-2005_07
Patent number
US06919356B2

Reaction notes

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