Methyl Isobutyl Ketone → trans-3-hydroxy-N,N,gamma-trimethyl-alpha,alpha-diphenyl-4-[(phenylmethyl)amino]-1-piperidinebutanamide

HRID 981306Notes

Reaction equation

HRID 981306 reaction equation
[C:1]1([CH2:7][NH:8][C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[Br-].[CH3:30][CH:31]1[O:35][C:34](=[N+:36]([CH3:38])[CH3:37])[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32]1>O>[OH:15][C@H:10]1[C@H:9]([NH:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:14][CH2:13][N:12]([CH:31]([CH3:30])[CH2:32][C:33]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH2:11]1

Participants

6

Reactant 4

HCID 7909Methyl Isobutyl KetoneHCID 10340Sodium CarbonateHCID 13677852rac-(3R,4R)-4-(benzylamino)piperidin-3-olHCID 20071674N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide

Product 1

HCID 67928753trans-3-hydroxy-N,N,gamma-trimethyl-alpha,alpha-diphenyl-4-[(phenylmethyl)amino]-1-piperidinebutanamideYield 45%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A mixture of 17.6 parts of trans-4-[(phenylmethyl)amino]-3-piperidinol, 27 parts of sodium carbonate and 680 parts of 4-methyl-2-pentanone was stirred and refluxed for 45 minutes using a water separator. After cooling, 33.8 parts of N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide were added and stirring was continued for 24 hours at reflux. The mixture was cooled and washed with water. The organic layer was dried, filtered and evaporated. The residue was dissolved in 1,1'-oxybisethane and acidified with 2-propanol, saturated with hydrogen chloride. The liquid was decanted and the half solid precipitated product was dissolved in water and treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The desired fractions were collected and the eluent was evaporated. The residue was solidified on scratching in petroleum ether. The product was filtered off and crystallized twice from acetonitrile. The product was filtered off and dried, yielding 18.8 parts (45%) of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[(phenylmethyl)amino]-1-piperidinebutanamide; mp. 134.5° C. (interm. 18).

Workup

  1. temperaturerefluxed for 45 minutes
  2. temperatureAfter cooling
  3. stirringstirring
  4. temperatureat reflux
  5. temperatureThe mixture was cooled
  6. washwashed with water
  7. customThe organic layer was dried
  8. filtrationfiltered
  9. customevaporated
  10. dissolutionThe residue was dissolved in 1,1'-oxybisethane
  11. customThe liquid was decanted
  12. customthe half solid precipitated product
  13. dissolutionwas dissolved in water
  14. additiontreated with ammonium hydroxide
  15. extractionThe product was extracted with trichloromethane
  16. customThe extract was dried
  17. filtrationfiltered
  18. customevaporated
  19. customThe residue was purified by column chromatography over silica gel using
  20. additiona mixture of trichloromethane and methanol
  21. customThe desired fractions were collected
  22. customthe eluent was evaporated
  23. filtrationThe product was filtered off
  24. customcrystallized twice from acetonitrile
  25. filtrationThe product was filtered off
  26. customdried

Sources & evidence

ORD record
ord-6effa170eb0448f9b19f600eed25bf1a
Source dataset
uspto-grants-1991_02
Patent number
US04990521

Reaction notes

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