Hydrochloric Acid → trans-4-(2-Chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride

HRID 1106331Notes

Reaction equation

HRID 1106331 reaction equation
N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1O.Cl>C1C=CC=CC=1.CCOCC.C(OCC)(=O)C.CC(C)=O>[ClH:46].[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[O:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 72452-ChlorophenolHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 12788379cis-1-Methyl-3-phenyl-4-piperidinol

Product 1

HCID 12788512trans-4-(2-Chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride

Reagents, catalysts & solvents 4

HCID 180AcetoneSolventHCID 241BenzeneSolvent2×HCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 4.79 g of diethyl azodicarboxylate in 125 ml of anhydrous benzene is added dropwise at 4° C. under nitrogen over a 90 minute period to a mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol of Example 1g, 7.21 g of triphenylphosphine, 3.54 g of 2-chlorophenol and 125 ml of anhydrous benzene. The mixture is stirred 18 hours at room temperature under nitrogen and then is filtered. The solid is washed well with hexane and the filtrate is concentrated in vacuo. The residue is triturated 18 hours with 250 ml of hexane and then filtered. The solid is washed well with hexane, triturated with ether and then filtered. The filtrates are combined and concentrated in vacuo to an oil. An ether solution of this material is made and is then extracted with 2 N HCl solution. The acid extracts are washed with ether, followed by extraction with dichloromethane. The dichloromethane extracts are washed with 10% aqueous NaOH solution, then with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo to an oil. This material is chromatographed on silica gel, using acetone as a solvent to obtain an oil. This oil is dissolved in ether and treated dropwise with an HCl-saturated ether solution to yield a salt. The salt is filtered and washed with ether to afford a solid, mp s 230°, 232°-234° C. This material suspended in 25 ml of boiling ethyl acetate and acetone is gradually added to the boiling mixture until a solution is obtained. The solution is filtered hot and boiled down to start crystallization to yield a solid, mp 233°-235.5° C. of trans-4-(2-chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride.

Workup

  1. filtrationis filtered
  2. washThe solid is washed well with hexane
  3. concentrationthe filtrate is concentrated in vacuo
  4. customThe residue is triturated 18 hours with 250 ml of hexane
  5. filtrationfiltered
  6. washThe solid is washed well with hexane
  7. customtriturated with ether
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo to an oil
  10. extractionis then extracted with 2 N HCl solution
  11. washThe acid extracts are washed with ether
  12. extractionfollowed by extraction with dichloromethane
  13. washThe dichloromethane extracts are washed with 10% aqueous NaOH solution
  14. dry with materialwith saturated NaCl solution, dried over anhydrous Na2SO4
  15. concentrationconcentrated in vacuo to an oil
  16. customThis material is chromatographed on silica gel
  17. customto obtain an oil
  18. customto yield a salt
  19. filtrationThe salt is filtered
  20. washwashed with ether
  21. customto afford a solid
  22. custommp s 230°, 232°-234° C
  23. customis obtained
  24. filtrationThe solution is filtered hot
  25. customcrystallization

Sources & evidence

ORD record
ord-868474e9cbec4ec6a959ddfde457969d
Source dataset
uspto-grants-1982_01
Patent number
US04312876

Reaction notes

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