Water → (R)-tert-butyl 3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate

HRID 2266214Notes

Reaction equation

HRID 2266214 reaction equation
[OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])(=O)=O.O>C1COCC1>[CH2:33]([O:32][CH2:31][CH2:30][CH2:29][O:1][C@@H:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1)[CH3:34]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 109761243-Ethoxypropyl methanesulfonateHCID 57388686(R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate

Product 1

HCID 59383014(R)-tert-butyl 3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylateYield 90%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

An oven dried flask was charged with (R)-tert-butyl 3-((R)hydroxy(phenyl)methyl)-piperidine-1-carboxylate (3.18 g, 10.9 mmol) and 60% NaH in mineral oil (2.19 g, 54.8, 5 equiv). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (100 mL) was added slowly. The mixture was allowed to warm to rt slowly. A solution of 3-ethoxypropyl methanesulfonate (6.0 g, 32.9 mmol, 3 equiv) in anhydrous THF (50 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction completed. The reaction mixture was cooled to 0° C. slowly and water was added dropwise to quench the reaction. After separation, the aqueous layer was extracted with ether three times. The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3, brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel cartridge eluted with a 0-30% EtOAc in hexanes gradient) to afford (R)-tert-butyl 3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (3.70 g, 90%) as a clear oil. Chiral HPLC indicated 95.5% purity. LC-MS (3 min) tR=2.38 min, m/z 400 (M+Na). 1H NMR (CDCl3) □ 7.26 (m, 5H), 4.39 (d, 1H), 3.89 (t, 2H), 3.53-3.40 (m, 4H), 3.38-3.23 (m, 2H), 2.75-2.60 (m, 2H), 1.85-1.47 (m, 4H), 1.45 (s, 9H), 1.40-1.22 (m, 2H), 1.15 (t, 3H), 1.10-0.96 (m, 1H).

Workup

  1. customAn oven dried flask
  2. customThe flask was purged with N2 gas
  3. additionanhydrous THF (100 mL) was added slowly
  4. temperatureto warm to rt slowly
  5. temperatureThe mixture was heated
  6. temperatureat reflux for 4 h
  7. temperatureThe reaction mixture was cooled to 0° C. slowly
  8. customto quench
  9. customthe reaction
  10. customAfter separation
  11. extractionthe aqueous layer was extracted with ether three times
  12. washThe combined organic layers were washed with 5% aq HCl
  13. dry with materialdried over Na2SO4
  14. concentrationAfter concentration
  15. customthe crude product was purified by flash chromatography on a 120-g silica gel cartridge
  16. washeluted with a 0-30% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-347dae479e5f4a6ab9f407860d0c671e
Source dataset
uspto-grants-2010_12
Patent number
US07858624B2

Reaction notes

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