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

HRID 1456500Notes

Reaction equation

HRID 1456500 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].O.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>CC(C)=O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[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

8

Reactant 4

HCID 962Water2×HCID 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 3

HCID 11433187Bis(tetrabutylammonium) sulphateCatalystHCID 180AcetoneSolventHCID 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), K2 CO3 (2.7 g, 20 mmol), tetrabutylammonium sulfate (0.058 g), CH3 CN (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-6fbcafc6e7f346b8a2532d988d48097f
Source dataset
uspto-grants-1998_12
Patent number
US05843949

Reaction notes

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