P-Cresol → trans-1-Methyl-3-phenyl-4-(4-tolyl)piperidine maleate

HRID 1855899Notes

Reaction equation

HRID 1855899 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][C@H:5](O)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:34]1[C:39](O)=[CH:38][CH:37]=[C:36]([CH3:41])[CH:35]=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([OH:59])=[O:58]>C1C=CC=CC=1.ClCCl.CCOCC>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([OH:59])=[O:58].[CH3:1][N:2]1[CH2:7][CH2:6][C@@H:5]([C:39]2[CH:38]=[CH:37][C:36]([CH3:41])=[CH:35][CH:34]=2)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1

Participants

9

Reactant 5

HCID 2879P-CresolHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 444266Maleic AcidHCID 12788379cis-1-Methyl-3-phenyl-4-piperidinol

Product 1

HCID 86737140trans-1-Methyl-3-phenyl-4-(4-tolyl)piperidine maleate

Reagents, catalysts & solvents 3

HCID 241BenzeneSolvent2×HCID 3283Diethyl EtherSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
6 °C

Procedure

A mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol of Example 22, 7.21 g of triphenylphosphine, 2.97 g of p-cresol and 125 ml of anhydrous benzene is cooled to 6° C. and a solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added dropwise under nitrogen over a 90-minute period. The temperature is allowed to rise gradually so that at completion of the addition it is 22° C. After stirring for 18 hours at room temperature, the suspended solid is filtered off, washed with hexane, and the filtrate concentrated in vacuo to an oil. This material is triturated with 200 ml of hexane for 90 minutes, the liquid is decanted, and the solid triturated for a few minutes with another 200 ml of hexane. Concentration in vacuo of the hexane extracts affords an oil, which is dissolved in 250 ml of dichloromethane and extracted with 2 N HCl solution. The dichloromethane phase is washed successively with 10% aqueous NaOH solution, water, and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a mixture of a solid and an oil. This mixture is triturated with hexane, filtered, and the filtrate is concentrated in vacuo to afford an oil. This oil is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent. The fractions containing product are combined and concentrated in vacuo to an oil which is taken up in ether and filtered through a Celite pad. The filtrate affords an oil which is triturated with boiling hexane and filtered hot. The filtrate is cooled and the resultant precipitated solid is filtered off and the filtrate concentrated in vacuo to yield an oil. This oil is dissolved in 50 ml of ether and added dropwise to a solution of 1.36 g of maleic acid in 25 ml of ether. The resulting solid is filtered, washed with ether, and dried to afford crude salt, melting near 100° C. Recrystallization from ethyl acetate affords a solid of trans-1-methyl-3-phenyl-4-(4-tolyl)piperidine maleate, mp s 130°, 131°-132° C.

Workup

  1. additionto rise gradually so that at completion of the addition it
  2. customis 22° C
  3. filtrationthe suspended solid is filtered off
  4. washwashed with hexane
  5. concentrationthe filtrate concentrated in vacuo to an oil
  6. customThis material is triturated with 200 ml of hexane for 90 minutes
  7. customthe liquid is decanted
  8. customthe solid triturated for a few minutes with another 200 ml of hexane
  9. concentrationConcentration in vacuo of the hexane
  10. customextracts affords an oil, which
  11. extractionextracted with 2 N HCl solution
  12. washThe dichloromethane phase is washed successively with 10% aqueous NaOH solution, water, and saturated aqueous NaCl solution
  13. dry with materialdried over anhydrous Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo to a mixture of a solid
  16. customThis mixture is triturated with hexane
  17. filtrationfiltered
  18. concentrationthe filtrate is concentrated in vacuo
  19. customto afford an oil
  20. customThis oil is chromatographed on silica gel
  21. additionThe fractions containing product
  22. concentrationconcentrated in vacuo to an oil which
  23. filtrationfiltered through a Celite pad
  24. customThe filtrate affords an oil which
  25. customis triturated with boiling hexane
  26. filtrationfiltered hot
  27. temperatureThe filtrate is cooled
  28. customthe resultant precipitated solid
  29. filtrationis filtered off
  30. concentrationthe filtrate concentrated in vacuo
  31. customto yield an oil
  32. filtrationThe resulting solid is filtered
  33. washwashed with ether
  34. customdried
  35. customto afford crude salt
  36. custommelting near 100° C
  37. customRecrystallization from ethyl acetate

Sources & evidence

ORD record
ord-4910e9f7a40a4bd7a0a8d1f5f3c2c5d6
Source dataset
uspto-grants-1980_08
Patent number
US04216218

Reaction notes

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