Methyl iodide → trans-1-(2-Methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

HRID 32231Notes

Reaction equation

HRID 32231 reaction equation
[H-].[Na+].[CH3:3][C:4]1([CH3:30])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C@@H:25]3[CH2:27][C@H:26]3[CH2:28][OH:29])[CH2:20][CH2:19]2)[CH2:5]1.I[CH3:32]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:32][O:29][CH2:28][C@@H:26]1[CH2:27][C@H:25]1[CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:6]2[CH2:7][C:8]([CH3:10])([CH3:11])[CH2:9][C:4]([CH3:30])([CH3:3])[CH2:5]2)[CH2:19][CH2:20]1

Participants

7

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 59769446trans-(2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol

Product 1

HCID 59769391trans-1-(2-Methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineYield 45%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Sodium hydride (60%, oily) (31 mg, 0.78 mmol) was suspended in dimethylformamide (3 mL), and the suspension was stirred at room temperature under a nitrogen atmosphere. To the suspension was added a solution of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol (60 mg, 0.156 mmol) produced in Example (91a) in dimethylformamide (3 mL), and the mixture was stirred for 30 minutes under the same conditions. The reaction mixture was cooled in ice water, and then iodomethane (0.015 mL, 0.241 mmol) was added. The reaction mixture was then stirred for 3 hours and 30 minutes while increasing the temperature to room temperature. The reaction mixture was cooled at an external temperature of 0C, and water was carefully added while blowing nitrogen. Then, ethyl acetate and water were added thereto and extraction was performed with ethyl acetate. The separated organic layer was washed twice with water and then once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 28 mg of trans-1-(2-methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.

Workup

  1. stirringthe mixture was stirred for 30 minutes under the same conditions
  2. stirringThe reaction mixture was then stirred for 3 hours and 30 minutes
  3. temperaturewhile increasing the temperature to room temperature
  4. additionwas carefully added
  5. extractionextraction
  6. washThe separated organic layer was washed twice with water
  7. dry with materialonce with brine, and dried over anhydrous sodium sulfate
  8. filtrationThe desiccant was filtered off
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customThe resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane)

Sources & evidence

ORD record
ord-fa4c2286e77d41258906e09f367ea067
Source dataset
uspto-grants-2008_09
Patent number
US07425554B2

Reaction notes

Loading…