p-Toluenesulfonic acid → 4-Aminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine

HRID 962439Notes

Reaction equation

HRID 962439 reaction equation
[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.ClC1C=CC(C(=O)C)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]Br)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:39][CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=2)[CH2:5][CH2:4]1

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 7467P-ChloroacetophenoneHCID 235274-(Aminomethyl)piperidineHCID 956671-(2-Bromoethoxy)-4-methylbenzene

Product 1

HCID 190854114-Aminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8471TriethylamineSolvent

Procedure

A mixture of 4-aminomethylpiperidine (3.58 g) and 4'-chloroacetophenone (4.85 g) in toluene (100 ml) was boiled under reflux with a catalytic amount of p-toluenesulphonic acid for 5 hours, removing the water formed by means of a Dean and Stark apparatus, to give a solution. The solution was cooled and 2-bromoethyl 4-methylphenyl ether (6.68 g) was added, followed by triethylamine (4.4 ml). This mixture was boiled under reflux for 6 hours then evaporated to dryness. 6M Hydrochloric acid (50 ml) was added to the residue and the mixture heated on a steam bath for 16 hours. The mixture was evaporated to near dryness, water (50 ml) was added and the mixture was washed with ether. The aqueous layer was basified with 2M sodium hydroxide solution and extracted with dichloromethane to give 4-aminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine as an oil. The oil was cooled in ice and 98% formic acid (5.0 ml) and formaldehyde (5.0 ml, 38% aqueous solution) were added. The mixture was heated on a steam bath for 4 hours then evaporated to near dryness and the residue treated with 2M hydrochloric acid (50 ml). The solution obtained was washed with dichloromethane, basified with 2M sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled at 150° C. at 0.13 mbar. This distillate was dissolved in ether and the solution acidified with ethereal hydrogen chloride. The precipitate was collected by filtration, washed with ether and recrystallised from absolute ethanol to give 4-dimethylaminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine dihydrochloride, m.p. 278°-280° C.

Workup

  1. customremoving the water
  2. customformed by means of a Dean and Stark apparatus
  3. customto give a solution
  4. temperatureThe solution was cooled
  5. temperatureunder reflux for 6 hours
  6. customthen evaporated to dryness
  7. addition6M Hydrochloric acid (50 ml) was added to the residue
  8. temperaturethe mixture heated on a steam bath for 16 hours
  9. customThe mixture was evaporated
  10. additionwas added
  11. washthe mixture was washed with ether
  12. extractionextracted with dichloromethane

Sources & evidence

ORD record
ord-7e09da2a8dbb4a1bbc20aed203b2826e
Source dataset
uspto-grants-1998_06
Patent number
US05760035

Reaction notes

Loading…