N-Methylbenzylamine → Ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylate

HRID 981299Notes

Reaction equation

HRID 981299 reaction equation
[CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[OH:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C@H:1]1[N:14]([CH3:13])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:7][C@H:1]1[C@H:6]([N:14]([CH3:13])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]1

Participants

5

Reactant 2

HCID 7669N-MethylbenzylamineHCID 12414163Ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

Product 2

HCID 67928745Ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylateHCID 67928764Ethyl trans-4-hydroxy-3-[methyl(phenylmethyl)amino-]1-piperidinecarboxylate

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

(a-1) A mixture of 51.3 parts of ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. 36.4 parts of N-methylbenzenemethanamine and 480 parts of ethanol was stirred and refluxed for 42 hours. The reaction mixture was evaporated and the residue was taken up in a dilute hydrochloric acid solution. The aqueous phase was washed three times with 2,2'-oxybispropane and alkalized with a sodium hydroxide solution 50%. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 45 9 parts (52.3%) of a mixture of ethyl trans-4-hydroxy-3-[methyl(phenylmethyl)amino-]1-piperidinecarboxylate and ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylate (interm. 6) in the proportion of 62.3% and 32.9%. Intermediate 6 was also prepared according to the following procedure:

Workup

  1. temperaturerefluxed for 42 hours
  2. customThe reaction mixture was evaporated
  3. washThe aqueous phase was washed three times with 2,2'-oxybispropane
  4. extractionThe product was extracted with dichloromethane
  5. washThe extract was washed with water
  6. customdried
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by column chromatography over silica gel using
  10. additiona mixture of trichloromethane and methanol (97:3 by volume) as eluent
  11. customThe pure fractions were collected
  12. customthe eluent was evaporated

Sources & evidence

ORD record
ord-f857c950ecc2453c8efd3441fca4730d
Source dataset
uspto-grants-1991_02
Patent number
US04990521

Reaction notes

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