Hydrochloric Acid → N-(3,4-Difluorophenyl)-alpha-(4-fluorophenyl)-1-[3-(2-naphthalenyloxy)propyl]-4-piperidinemethanamine dihydrochloride

HRID 1614653Notes

Reaction equation

HRID 1614653 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1.C(=O)(O)[O-].[Na+].[I-].[Na+].[ClH:46]>C(O)CCC.C(Cl)Cl>[ClH:24].[ClH:46].[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:11]2[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 5238Sodium IodideHCID 516892Sodium BicarbonateHCID 116872053-(2-Naphthyloxy)-1-chloropropaneHCID 197720314-[[(3,4-Difluorophenyl)amino](4-fluorophenyl)methyl]piperidine

Product 1

HCID 19772057N-(3,4-Difluorophenyl)-alpha-(4-fluorophenyl)-1-[3-(2-naphthalenyloxy)propyl]-4-piperidinemethanamine dihydrochlorideYield 59.8%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine (4.70 g, 0.0147 mol), 2-(3-chloropropyloxy)naphthalene) (3.23 g, 0.0147 mol), and sodium bicarbonate (5.53 g, 0.0658 mol) in 350 mL of 1-butanol containing sodium iodide was heated at reflux for 24 h. The butanol was removed by rotary evaporator and the residue partitioned between chloroform and water. The chloroform layer was washed with 5% sodium hydroxide, dried (Na2SO4) and filtered. Chloroform was removed to give a brown oil. This oil was dissolved in methylene chloride and placed on a 300 g silica gel column for flash chromatography. Elution was accomplshed using methylene chloride, 1% methanol-methylene chloride, and 2% methanol-methylene chloride. Fractions of similar purity were combined and solvents removed to give a dark brown oil. This material was converted to the HCl salt and recrystallized from methanol-diethyl ether. A white solid was isolated and dried 16 h in vacuo at 80° C. This procedure produced 5.08 g (59.8%) of white crystalline solid, mp 225°-226° C.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 24 h
  3. customThe butanol was removed by rotary evaporator
  4. customthe residue partitioned between chloroform and water
  5. washThe chloroform layer was washed with 5% sodium hydroxide
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. customChloroform was removed
  9. customto give a brown oil
  10. washElution
  11. customsolvents removed
  12. customto give a dark brown oil
  13. customrecrystallized from methanol-diethyl ether
  14. customA white solid was isolated
  15. customdried 16 h in vacuo at 80° C

Sources & evidence

ORD record
ord-a30a00e0d48340a9ad387e4868eefab1
Source dataset
uspto-grants-1993_03
Patent number
US05198449

Reaction notes

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