Potassium Iodide → (R)-[2-fluoro-4-(3-methyl-1,1-dioxo-1lambda6-isothiazolidin-2-yl)phenyl][4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone

HRID 2411550Notes

Reaction equation

HRID 2411550 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[NH:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[F:25][C:4]1[CH:3]=[C:2]([N:28]2[C@H:27]([CH3:26])[CH2:31][CH2:30][S:29]2(=[O:33])=[O:32])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]

Participants

9

Reactant 5

HCID 4875Potassium IodideHCID 8070N,N'-DimethylethylenediamineHCID 11430Potassium CarbonateHCID 16664802(R)-3-methylisothiazolidine 1,1-dioxideHCID 58484847(4-Bromo-2-fluorophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone

Product 1

HCID 71252952(R)-[2-fluoro-4-(3-methyl-1,1-dioxo-1lambda6-isothiazolidin-2-yl)phenyl][4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

To a mixture of (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (322 mg) described in Preparation Example 128, (R)-3-methylisothiazolidine 1,1-dioxide (107 mg) described in Preparation Example 2, potassium carbonate (220 mg), copper(I) iodide (76 mg) and potassium iodide (132 mg) were added toluene (1 mL) and N,N′-dimethylethylenediamine (80 μL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, the mixture was extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give (R)-[2-fluoro-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (R)-[2-fluoro-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (140 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.08 mL) was added, and the precipitate was collected by filtration to give the title compound (166 mg).

Workup

  1. temperaturewith heating
  2. temperatureunder reflux for 8 hr
  3. temperatureThe reaction mixture was cooled
  4. extractionthe mixture was extracted with chloroform
  5. customthe solvent was evaporated
  6. customThe obtained residue was purified by column chromatography (ethyl acetate:hexane)

Sources & evidence

ORD record
ord-550fda3d634c4ab380216e5e7f9e4fec
Source dataset
uspto-grants-2014_08
Patent number
US08816079B2

Reaction notes

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