Sodium Chloride → HCID 12788472, compound

HRID 851025Notes

Reaction equation

HRID 851025 reaction equation
[H-].[Na+].C(O)(=O)C(O)=O.[CH3:9][N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20](C(F)(F)F)=[CH:19][CH:18]=2)[C@H:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11]1.[Cl:33]C1C=C(F)C=CC=1.[Na+].[Cl-:42]>CN(C=O)C.CCOCC>[ClH:33].[Cl:42][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C@@H:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][C@H:12]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1

Participants

7

Reactant 4

HCID 5234Sodium Chloride2×HCID 24758Sodium hydride2×HCID 2230871-Chloro-3-fluorobenzeneHCID 12788391HCID 12788391, compound

Product 1

HCID 12788472HCID 12788472, compound

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent2×

Procedure

A mixture of 1.9 g of sodium hydride, 12.07 g of 1-methyl-3-phenyl-4-piperidinol (mixture of isomers of Example 1) and 70 ml. of dry DMF is heated at approximately 100° C. for 1 hour, under nitrogen, then cooled to room temperature. A solution of 16.45 g of 3-chlorofluorobenzene in 40 ml of DMF is added all at once, and the mixture is stirred for 18 hours at room temperature, then heated slowly so that after 4 hours the pot temperature is 68° C. After stirring for about 48 hours at room temperature, another 0.76 g of sodium hydride is added, and the mixture is again heated slowly to approximately 70° C. After 2 hours the mixture is cooled and treated with saturated aqueous NaCl solution, then poured into a mixture of saturated aqueous NaCl solution and ether. The phases are separated and the aqueous phase is extracted with ether. The combined ether extracts are washed with water, saturated aqueous NaCl solution, and concentrated in vacuo. The residue is partitioned between dichloromethane and water. The phases are separated, the aqueous phase is extracted with more dichloromethane, and the combined dichloromethane phases are extracted with 2 N HCl solution, then washed successively with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, and dried over anhydrous Na2SO4. Concentration is vacuo affords an oil which is a mixture of product isomers. This mixture is chromatographed on silica gel, using acetone as the initial solvent. The trans product is eluted with 25% methanol/acetone as solvent. The fractions containing the trans isomer are combined and concentrated in vacuo to an oil. This oil is taken up in ether, dried over anhydrous Na2SO4, filtered, and treated dropwise with HCl-saturated ether solution. The ether and excess HCl are removed in vacuo and the resulting gummy solid is triturated with fresh ether until completely solid. This solid is filtered, washed with ether and dried to afford a crude salt, mp s 211.5°, 213°-214.5° C. Recrystallization from acetone affords needles of trans-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride having the same melting point.

Workup

  1. temperatureheated slowly so that after 4 hours the pot temperature
  2. customis 68° C
  3. stirringAfter stirring for about 48 hours at room temperature
  4. temperaturethe mixture is again heated slowly to approximately 70° C
  5. temperatureAfter 2 hours the mixture is cooled
  6. customThe phases are separated
  7. extractionthe aqueous phase is extracted with ether
  8. washThe combined ether extracts are washed with water, saturated aqueous NaCl solution
  9. concentrationconcentrated in vacuo
  10. customThe residue is partitioned between dichloromethane and water
  11. customThe phases are separated
  12. extractionthe aqueous phase is extracted with more dichloromethane
  13. extractionthe combined dichloromethane phases are extracted with 2 N HCl solution
  14. washwashed successively with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution
  15. dry with materialdried over anhydrous Na2SO4
  16. concentrationConcentration
  17. customaffords an oil which
  18. additiona mixture of product isomers
  19. customThis mixture is chromatographed on silica gel
  20. washThe trans product is eluted with 25% methanol/acetone as solvent
  21. additionThe fractions containing the trans isomer
  22. concentrationconcentrated in vacuo to an oil
  23. dry with materialdried over anhydrous Na2SO4
  24. filtrationfiltered
  25. additiontreated dropwise with HCl-saturated ether solution
  26. customThe ether and excess HCl are removed in vacuo
  27. customthe resulting gummy solid is triturated with fresh ether until completely solid
  28. filtrationThis solid is filtered
  29. washwashed with ether
  30. customdried
  31. customto afford a crude salt, mp
  32. customs 211.5°, 213°-214.5° C
  33. customRecrystallization from acetone

Sources & evidence

ORD record
ord-c446395649ae4e9a94be5402d64fd285
Source dataset
uspto-grants-1983_05
Patent number
US04382141

Reaction notes

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