4-Toluenesulfonyl chloride → (R)-N-(2-(2-(2-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester

HRID 1614810Notes

Reaction equation

HRID 1614810 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:15]1C=CC=CC=1)=CCOCCO.C([Li])C[CH2:23][CH3:24].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29](S(Cl)(=O)=O)=[CH:28][CH:27]=1.[NH:37]1[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]1.C(=O)([O-])[O-:49].[K+].[K+]>C1COCC1>[CH2:46]([O:45][C:43]([C@@H:39]1[CH2:40][CH2:41][CH2:42][N:37]([CH2:24][CH2:23][O:49][CH2:15][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:36][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:38]1)=[O:44])[CH3:47]

Participants

7

Reactant 5

HCID 73974-Toluenesulfonyl chlorideHCID 11430Potassium CarbonateHCID 185582ethyl (3R)-piperidine-3-carboxylateHCID 539527602-(3-(2-Methylphenyl)-3-phenyl-2-propen-1-yloxy)ethanolHCID 178418339Butyllithium

Product 1

HCID 53716596(R)-N-(2-(2-(2-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl esterYield 45%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

A solution of 2-(3-(2-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethanol (3.4 g, 12.5 mmol) in dry THF (30 ml) kept under a nitrogen atmosphere was cooled to 10° C. and a solution of n-butyllithium in hexanes (5.5 ml, 2.5 M) was added dropwise. The reaction mixture was stirred for 0.5 h at room temperature and p-toluenesulphonyl chloride (2.6 g, 13.8 mmol) was added. The mixture was stirred at room temperature for 1.5 h. Ethyl (R)-3-piperidinecarboxylate (2.9 g, 18.8 mmol) and potassium carbonate (2.6 g, 18.8 mmol) were added and the mixture was heated at reflux temperature for 18 h. The cooled reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts was washed with a 10% sodium citrate buffer solution (2×100 ml, pH 6). The organic phase was extracted with a 5% citric acid solution (4×75 ml) and the combined acidic aqueous extracts was washed with toluene (50 ml). To the acidic aqueous solution was added a 4 N sodium hydroxide solution until pH 9 and this solution was immediately extracted with ethyl acetate (2×100 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo to give 2.3 g (45%) of (R)-N-(2-(2-(2-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.23 (SiO2 ; n-heptane/THF=7:3).

Workup

  1. stirringThe mixture was stirred at room temperature for 1.5 h
  2. temperaturethe mixture was heated
  3. temperatureat reflux temperature for 18 h
  4. customThe cooled reaction mixture
  5. extractionextracted with ethyl acetate (2×100 ml)
  6. washThe combined organic extracts was washed with a 10% sodium citrate buffer solution (2×100 ml, pH 6)
  7. extractionThe organic phase was extracted with a 5% citric acid solution (4×75 ml)
  8. washthe combined acidic aqueous extracts was washed with toluene (50 ml)
  9. additionTo the acidic aqueous solution was added a 4 N sodium hydroxide solution until pH 9
  10. extractionthis solution was immediately extracted with ethyl acetate (2×100 ml)
  11. dry with materialThe combined organic extracts was dried over sodium sulphate
  12. customthe solvent evaporated in vacuo

Sources & evidence

ORD record
ord-f0f9cfe62613494bb2f95689dcf51569
Source dataset
uspto-grants-1993_03
Patent number
US05198451

Reaction notes

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