Sulfuric Acid → Neramexane

HRID 2364110Notes

Reaction equation

HRID 2364110 reaction equation
O[C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C[Si](C#[N:18])(C)C.S(=O)(=O)(O)O>C(OCC)(=O)C.O.CCOCC.[OH-].[Na+]>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([NH2:18])([CH3:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5]1

Participants

8

Reactant 3

HCID 1118Sulfuric AcidHCID 82115Trimethylsilyl cyanideHCID 1422881,3,3,5,5-Pentamethylcyclohexanol

Product 1

HCID 6433106NeramexaneYield 91.5%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolventHCID 14798Sodium HydroxideSolvent

Procedure

To a vigorously stirred solution of 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane (3.4 g; 20 mmol) and trimethylsilyl cyanide (2.58 g; 26 mmol; 1.3 eq.) in ethyl acetate (4 ml), 95% sulfuric acid (3.2 ml; 60 mmol; 3.1 eq) are added during 1 hour keeping the temperature at −10° C. for 15 min, and then allowing the mixture to reach ambient temperature. After stirring at ambient temperature for 15 hours, the mixture is diluted with 20 ml ice water. Subsequently, the mixture is refluxed with stirring for 10 hours, cooled to ambient temperature, diluted with 40 ml water and 20 ml ether and neutralized with 20% aqueous sodium hydroxide until a pH of 10. The organic phase is separated and dried. Dry hydrogen chloride is passed through the solution until the ether becomes acidic. Solvent is removed and the residue is washed with ether to give 3.1 g Neramexane in the form of its hydrochloride.

Workup

  1. customat −10° C.
  2. customfor 15 min
  3. customto reach ambient temperature
  4. temperatureSubsequently, the mixture is refluxed
  5. stirringwith stirring for 10 hours
  6. temperaturecooled to ambient temperature
  7. customThe organic phase is separated
  8. customdried
  9. customSolvent is removed
  10. washthe residue is washed with ether

Sources & evidence

ORD record
ord-e24bb8f67a984882903524580600ffbb
Source dataset
uspto-grants-2014_04
Patent number
US08692021B2

Reaction notes

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