Acetonitrile → 6-Fluoro-3-[1-[3-[(1H-indol-4-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

HRID 2229674Notes

Reaction equation

HRID 2229674 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.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[CH:30]=[CH:31][NH:32]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1

Participants

6

Reactant 4

HCID 6342AcetonitrileHCID 11430Potassium Carbonate2×HCID 8494213-(4-Piperidyl)-6-fluoro-1,2-benzisoxazoleHCID 116941694-(3-chloropropoxy)-1H-indole

Product 1

HCID 158169466-Fluoro-3-[1-[3-[(1H-indol-4-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16 mmol), K2CO3 (22 g, 16 mmol), KI (200 mg), 4-(3chloropropoxy)indole (3.0 g, 14 mm CH3CN (100 ml) was stirred at reflux under N2 for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours whereupon a TLC revealed incomplete reaction. K2CO3 (0.5 g, 4 mmol) was added and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H2O and saturated NaCl and after drying over MgSO4 the solvent was removed to afford 5.7 g of a beige solid. The product was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 4% MeOH—CH2Cl2. as eluent) to yield 3.4 g (61%) of a beige solid. Two consecutive recrystallizations from ETOH provided 2.3 g (41%) of a white powder, m.p.=129-131° C.

Workup

  1. temperatureat reflux under N2 for 7 hours
  2. temperatureReflux
  3. waitwas resumed for an additional 6 hours whereupon a TLC
  4. customreaction
  5. stirringthe reaction was stirred
  6. temperatureat reflux for 17 hours
  7. customThe cooled reaction
  8. extractionthe aqueous mixture was extracted with EtOAc
  9. extractionThe organic extract
  10. washwas washed with H2O and saturated NaCl
  11. dry with materialafter drying over MgSO4 the solvent
  12. customwas removed

Sources & evidence

ORD record
ord-8f124e71e7fb4daba8ca50b94eb6a026
Source dataset
uspto-grants-2002_07
Patent number
US06420390B1

Reaction notes

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