Potassium Carbonate → (S)-6-Fluoro-3-[1-(3-hydroxy-2-methylpropyl)-4-piperidinyl]-1,2-benzisothiazole fumarate

HRID 233901

Reaction equation

HRID 233901 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][S:8][C:4]=2[CH:3]=1.Br[CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CC(C)=O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O.CC#N>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1

Participants

10

Reactant 4

HCID 11430Potassium CarbonateHCID 444972Fumaric AcidHCID 10441885(R)-(-)-3-Bromo-2-methyl-1-propanolHCID 185049766-Fluoro-3-(4-piperidinyl)-1,2-benzisothiazole

Product 1

HCID 22868569(S)-6-Fluoro-3-[1-(3-hydroxy-2-methylpropyl)-4-piperidinyl]-1,2-benzisothiazole fumarateYield 69.1%

Reagents, catalysts & solvents 5

HCID 11433187Bis(tetrabutylammonium) sulphateCatalystHCID 180AcetoneSolventHCID 962WaterSolvent2×HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.6 g, 20 mmol), (R)-(-)-3-bromo-2-methyl-1-propanol (3.0 g, 20 mmol), K2CO3 (2.7 g, 20 mmol), tetrabutylammonium sulfate (0.058 g), CH3CN (95 ml) and H2O (19 ml) was stirred and refluxed for 4.5 hours. After standing at ambient temperature for 16 hours, the reaction was poured into H2O, and subsequent extractive workup of the aqueous with EtOAc yielded 6.8 g of a partially solidified oil. The product was purified by flash chromatography on silica gel, eluting the column with CH2Cl2, then 2% MeOH--CH2Cl2 and finally 5% MeOH--CH2Cl2. Concentration of the appropriate fractions yielded 5.2 g of a waxy solid. The solid was dissolved in acetone and fumaric acid (1.9 g, 1.0 eq) was added and the reaction briefly heated at reflux. The resultant fumarate salt precipitated from solution yielding 4.8 g of white solid. The compound was recrystallized from acetonitrile to yield 3.1 g (36%) of the alcohol as a white solid, m.p.=151°-153° C.

Workup

  1. temperaturerefluxed for 4.5 hours
  2. customyielded 6.8 g of a partially solidified oil
  3. customThe product was purified by flash chromatography on silica gel
  4. washeluting the column with CH2Cl2
  5. customConcentration of the appropriate fractions yielded 5.2 g of a waxy solid
  6. customthe reaction
  7. temperaturebriefly heated
  8. temperatureat reflux
  9. customThe resultant fumarate salt precipitated from solution

Sources & evidence

ORD record
ord-611ff1f53e754f7bad856b90f0429528
Source dataset
uspto-grants-1997_01
Patent number
US05593995

Linked notes

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