Sodium hydride → 4-(6-Cyano-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester

HRID 720389Notes

Reaction equation

HRID 720389 reaction equation
[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].S(O[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH:7]=[CH:8]2)[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 851461H-indole-6-carbonitrileHCID 218920784-(Toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid benzyl ester

Product 1

HCID 692060854-(6-Cyano-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl esterYield 98.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To 6-cyanoindole (1.7 g, 12 mmol) in N,N-dimethylformamide (100 mL) was added a 60% mineral oil dispersion of sodium hydride (0.48 g, 12 mmol). The mixture was stirred at room temperature under nitrogen for 30 min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.8 g, 12 mmol) added and the mixture heated at 80° C. under nitrogen for 15 hours. The solvent was removed in vacuum and replaced with methylene chloride (400 mL). The solution was washed with 350 mL portions of water, saturated aqueous sodium bicarbonate, and saturated brine and dried over sodium sulfate. Filtration, concentration in vacuum and column chromatography on silica gel with methylene chloride as eluent gave 4.4 g of 4-(6-cyano-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester. This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon (0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixture refluxed under nitrogen for 15 hours. Filtration through celite, followed by concentration in vacuum gave 1.9 g of the title compound as a white solid. 1H-NMR (CDCl3): doublet 7.6 δ (1 H); singlet 7.55 δ (1 H); doublet 7.2 δ (1 H); singlet 7.13 δ (1 H); singlet 6.25 δ (1 H); doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet 2.45 δ (2 H); doublet 1.45 δ (2 H); multiplet 1.18 δ (2 H).

Workup

  1. temperaturethe mixture heated at 80° C. under nitrogen for 15 hours
  2. customThe solvent was removed in vacuum
  3. washThe solution was washed with 350 mL portions of water, saturated aqueous sodium bicarbonate, and saturated brine
  4. dry with materialdried over sodium sulfate
  5. filtrationFiltration, concentration in vacuum and column chromatography on silica gel with methylene chloride as eluent

Sources & evidence

ORD record
ord-7182c4dc61c94e7b836ab5444917c4d1
Source dataset
uspto-grants-2006_11
Patent number
US07135479B2

Reaction notes

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