Potassium Iodide → 4-{1-[Bis(4-fluorophenyl)-methyl]-piperidin-4-yl}-butan-1-ol

HRID 1280771Notes

Reaction equation

HRID 1280771 reaction equation
Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)Cl)=[CH:39][CH:38]=1.[I-].[K+]>O1C=CCCC1>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]2)=[CH:41][CH:42]=1

Participants

7

Reactant 5

HCID 4875Potassium IodideHCID 11430Potassium Carbonate2×HCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)HCID 27237731,1'-(Chloromethylene)bis(4-fluorobenzene)HCID 27846674-(4-Piperidyl)-1-butanol hydrochloride

Product 1

HCID 184257114-{1-[Bis(4-fluorophenyl)-methyl]-piperidin-4-yl}-butan-1-ol

Reagents, catalysts & solvents 1

HCID 80803,4-dihydro-2H-pyranSolvent

Procedure

20 g (103 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are suspended in 70 ml 3,4-dihydro-2H-pyrane and added to 1.0 g pyridinium tosylate. The mixture is stirred for two days at RT. After addition of 5 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[4-tetrahydropyran-2-yloxy)-butyl)-piperidine is dissolved without further purification in 100 ml acetonitrile and added to 25.1 g (105 mmol) bis-(4-fluorophenyl)-chloromethane, 30 g (217 mmol) potassium carbonate and 5.0 g (30 mmol) potassium iodide and stirred for four days at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-[bis-(4-fluorophenyl)-methyl]-4-[4-(tetrahydropyran-2-yloxy)-butyl]-piperldine is dissolved without further purification in 150 ml methanol, added to enough 6 M methanolic hydrochloric acid until the pH of the mixture is acidic and left to stand for two days at RT. Subsequently, the solvent is drawn off under vacuum and the residue is dispersed between sodium hydroxide solution and acetic acid ethyl ester. The aqueous solution is extracted three times with acetic acid. The combined organic phases are dried over sodium sulfate and the residue is chromatographically purified over silica gel with CH2Cl2/CH3OH(99/1 to 94/4). Yield: 23.8 g (63%).

Workup

  1. concentrationthis is concentrated under vacuum to dryness
  2. dissolutionThe resulting 4-[4-tetrahydropyran-2-yloxy)-butyl)-piperidine is dissolved without further purification in 100 ml acetonitrile
  3. stirringstirred for four days at RT
  4. filtrationThe mixture is filtered
  5. customthe solvent is removed under vacuum
  6. dissolutionThe resulting 1-[bis-(4-fluorophenyl)-methyl]-4-[4-(tetrahydropyran-2-yloxy)-butyl]-piperldine is dissolved without further purification in 150 ml methanol
  7. additionadded to enough 6 M methanolic hydrochloric acid until the pH of the mixture
  8. waitleft
  9. waitto stand for two days at RT
  10. additionthe residue is dispersed between sodium hydroxide solution and acetic acid ethyl ester
  11. extractionThe aqueous solution is extracted three times with acetic acid
  12. dry with materialThe combined organic phases are dried over sodium sulfate
  13. customthe residue is chromatographically purified over silica gel with CH2Cl2/CH3OH(99/1 to 94/4)

Sources & evidence

ORD record
ord-d673043b76384503ad5d52020d1ab56a
Source dataset
uspto-grants-2002_09
Patent number
US06451816B1

Reaction notes

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