rel-(2R,6S)-2,6-dimethylpiperazine → 1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

HRID 1818794Notes

Reaction equation

HRID 1818794 reaction equation
Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5]1(=[O:20])=[O:19].[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][C@@H:24]([CH3:28])[NH:23]1>C(O)C>[CH3:21][C@H:22]1[NH:23][C@@H:24]([CH3:28])[CH2:25][N:26]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:5]2(=[O:20])=[O:19])[CH2:27]1

Participants

4

Reactant 2

HCID 6950261rel-(2R,6S)-2,6-dimethylpiperazineHCID 687112711-(2-Bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

Product 1

HCID 578862581-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxideYield 70%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (212 mg, 0.600 mmol), cis-2,6-dimethylpiperazine (411 mg, 3.60 mmol, 6 equiv.) and ethanol (5 mL) in a sealed reaction vessel was heated at 90° C. for 8 h. After cooling, solvent was removed, and the residue was dissolved in ethyl acetate (15 mL). The resulting solution was washed with an aqueous potassium carbonate solution, water, dried (anhydrous sodium sulfate), and concentrated. The crude oil was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (4-g redisep silica gel column, 1-18% methanol/dichloromethane, with 1% triethylamine as eluent additive) to give 162 mg (70%) of 1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a viscous, colorless liquid. This free base was dissolved in ethanol (2 mL), and was treated with an ethereal solution of hydrochloric acid (1 M, 3.0 mL, 3.0 mmol in ethyl ether). To the resulting solution was added ethyl ether until it became cloudy, then cooled to −25° C. in a freezer overnight. The white crystals formed was collected, washed with hexane, and dried in vacuo to yield 176 mg of 1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride. HRMS: calculated for C20H26N4O2S+H+, 387.1849; found (ESI, [M+H]+), 387.1861.

Workup

  1. customin a sealed reaction vessel
  2. temperatureAfter cooling
  3. customsolvent was removed
  4. dissolutionthe residue was dissolved in ethyl acetate (15 mL)
  5. washThe resulting solution was washed with an aqueous potassium carbonate solution, water
  6. dry with materialdried (anhydrous sodium sulfate)
  7. concentrationconcentrated
  8. custompurified via Isco flash column chromatography (4-g redisep silica gel column, 1-18% methanol/dichloromethane, with 1% triethylamine as eluent additive)

Sources & evidence

ORD record
ord-95bf1a9feed444aa88fe1660bfdbe65c
Source dataset
uspto-grants-2009_10
Patent number
US07601722B2

Reaction notes

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