Water → 4-(6-Fluoro-1,2-benzisoxazol-yl)-1-[3-(1-piperidinyl)propyl]piperidine difumarate

HRID 233209

Reaction equation

HRID 233209 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[C:28]([O-:31])([O-:30])=[O:29].[K+].[K+].[OH2:34]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:4]([OH:34])(=[O:8])/[CH:5]=[CH:15]/[C:28]([OH:31])=[O:30].[C:28]([OH:31])(=[O:29])/[CH:2]=[CH:3]/[C:4]([OH:8])=[O:34].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 79624N-(3-chloropropyl)piperidine hydrochlorideHCID 8494213-(4-Piperidyl)-6-fluoro-1,2-benzisoxazole

Product 1

HCID 670709964-(6-Fluoro-1,2-benzisoxazol-yl)-1-[3-(1-piperidinyl)propyl]piperidine difumarate

Reagents, catalysts & solvents 2

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 6342AcetonitrileSolvent

Procedure

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p.178°-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190°-192° C.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 16 hours
  3. washThe mixture was washed with brine
  4. customthe layers were separated
  5. concentrationThe organic solution was concentrated
  6. customThe crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l)
  7. customThe oil thus purified (4.5 g)
  8. additionwas treated with fumaric acid (1.6 g) in ethanol
  9. customThe solid was collected
  10. customRecrystallization from ethanol

Sources & evidence

ORD record
ord-dadb990fa9f94785ad49849b06a98397
Source dataset
uspto-grants-1997_01
Patent number
US05591745

Linked notes

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