Potassium Carbonate → 6-Fluoro-3-[(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl)methyl]-1,2-benzisothiazole Hydrochloride

HRID 10209Notes

Reaction equation

HRID 10209 reaction equation
Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[S:5][N:4]=1.[ClH:13].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH:25]2[CH2:28][NH:27][CH2:26]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[OH-].[Na+]>[ClH:13].[F:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:2][N:27]3[CH2:28][CH:25]([CH2:24][S:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)(=[O:23])=[O:22])[CH2:26]3)=[N:4][S:5][C:6]=2[CH:11]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 219783933-{[(4-Fluorophenyl)sulfonyl]methyl}azetidine hydrochlorideHCID 219784071,2-Benzisothiazole, 3-(bromomethyl)-6-fluoro-

Product 1

HCID 116044116-Fluoro-3-[(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl)methyl]-1,2-benzisothiazole HydrochlorideYield 23.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 14798Sodium HydroxideSolvent

Procedure

3-Bromomethyl-6-fluoro-1,2-benzisothiazole (73 mg, 0.3 mmol) was added to a mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (57 mg, 0.21 mmol) and potassium carbonate (91 mg, 0.66 mmol) in DMF (2 mL) and the resulting mixture stirred at room temperature for 18 h. The mixture was diluted with 0.5M sodium hydroxide solution (20 mL) and extracted with EtOAc (2×10 mL). The organic extracts were washed with saturated brine (10 mL), combined, dried (MgSO4) and concentrated. The residue was purified by preparative thin layer chromatography, eluting with 2.5% MeOH/DCM, to afford an oil which crystallised on standing (35 mg, 41%). The solid was dissolved in EtOAc, the resulting solution heated and treated with 1M HCl in diethyl ether (0.11 mL). The mixture was allowed to cool to give a crystalline solid which was collected under suction to afford the title compound (21 mg). 1H NMR (400 MHz, CD3OD) δ 3.33–3.41 (1H, m), 3.72 (2H, d, J=7.6 Hz), 4.23–4.28 (2H, m), 4.44–4.49 (2H, m), 4.96 (2H, s), 7.35–7.46 (3H, m), 7.87–7.90 (1H, m), 7.99–8.04 (2H, m), 8.10–8.13 (1H, m). (471 MHz, CD3OD)δF −105.2, −112.7. m/z (ES+) 395 (M+H)+.

Workup

  1. extractionextracted with EtOAc (2×10 mL)
  2. washThe organic extracts were washed with saturated brine (10 mL)
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. customThe residue was purified by preparative thin layer chromatography
  6. washeluting with 2.5% MeOH/DCM
  7. customto afford an oil which
  8. customcrystallised
  9. dissolutionThe solid was dissolved in EtOAc
  10. temperaturethe resulting solution heated
  11. additiontreated with 1M HCl in diethyl ether (0.11 mL)
  12. temperatureto cool
  13. customto give a crystalline solid which
  14. customwas collected under suction

Sources & evidence

ORD record
ord-07009c0944cf4a4698a88d07fc9fee5f
Source dataset
uspto-grants-2006_08
Patent number
US07094777B2

Reaction notes

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