| 41% |
With triethylamine In dichloromethane at 20℃; Inert atmosphere; Cooling with ice; |
Synthesis of 2-(3,5-dichloro-2-fluorophenyl)isothiazol-3(2H)-one (ISFP5)
3,3'-Dithiodipropionic acid (1 g, 4.76 mmol) was placedunder an argon atmosphere in a dry round bottom ask(sealed with a turnover septum) and was dissolved in anhy-drous tetrahydrofuran (20 ml). The ask was then cooled on-ice followed by the dropwise addition of thionyl chloride(2.07 ml, 28.53 mmol) with stirring. N,N-dimethylformamide(74 μ l, 0.95 mmol) was then added to the stirring solution, andthe reaction was left to stir on ice for 20 min, at which pointthe ice was removed and the reaction was allowed to warm toroom temperature. The reaction was stirred at room temper-ature for a further 3 h at which point the ask was purged withargon and the solvent was carefully removed in vacuo using arotary evaporator (no heating). The resulting crude materialwas triturated twice using toluene followed by solvent removalin vacuo (no heating). The crude material was again dissolvedin tetrahydrofuran ( < 10 ml) and was evaporated to dryness invacuo (no heating). The crude material was subsequently usedwithout further puri cation.3,5-dichloro-2- uoroaniline (1 g, 5.5 mmol) was dissolved inanhydrous dichloromethane (5 ml) under an argon atmo-sphere. Triethylamine (6.95 mmol, 969 μ l) was then added tothe stirring solution and cooled on-ice. Separately, 3,30-disul-fanediyldipropionyl chloride from the rst reaction (344 mg,1.39 mmol) was suspended in anhydrous dichloromethane(5 ml) and was then added slowly to the stirring 3,5-dichloro-2- uoroaniline solution. The reaction was allowed to stir on-ice for 30 min, then warmed to room temperature, andallowed to stir overnight. The next day, a saturated aqueoussolution of sodium hydrogen carbonate (approx. 40 ml) wasadded slowly to the crude reaction mixture and the resultingsolution was extracted using dichloromethane (3 × 20 mlminimum). The organic phase was dried over sodium sulfate, ltered, and the solvent removed in vacuo (water bath at 35C). The crude material was dry loaded on silica and waspuri ed by ash chromatography (Heptane/Ethyl acetate (2:1)→ Ethyl acetate) (305 mg, 41% yield).The product, 3,30-disulfanediylbis(N-(3,5-dichloro-2- uorophenyl)propanamide) (210 mg, 0.39 mmol) was sus-pended (not dissolved) in anhydrous dichloromethane underan argon atmosphere and was cooled on-ice. A solution of1M sulfuryl chloride in dichloromethane ( 1 eq., 393 μ l) wasthen added to the stirring ask and was stirred for 15 min.Over the course of the following 1 to 2 h, an additional 4 to 5equivalents of sulfuryl chloride solution was added to thestirring solution until the solubility of the material in the ask improved. At this point, the reaction mixture wasallowed to warm to room temperature and stirred overnight.The next day, saturated brine solution (approx. 20 ml) was added to the off-white suspension followed by extractionwith ethyl acetate (3 × 20 ml minimum). The organic phasewas dried over sodium sulfate, ltered, and the solventremoved in vacuo (water bath at 30C) to the point wherethe solid crude product became visible in the ask. At thispoint, the reaction mixture was resolubilized with the mini-mum amount of solvent and was dry loaded onto silica for ash puri cation (Heptane/ethyl acetate (1:1) → ethyl ace-tate). The ash puri ed material then underwent a furtherpuri cation by reverse phase C18 HPLC (see supplementaryinformation for methods) (R f : 0.65; heptane/ethyl acetate,1:1) (19 mg, postlyophilisation, 18% yield). |
| 41% |
With triethylamine In dichloromethane at 20℃; Inert atmosphere; Cooling with ice; |
Synthesis of 2-(3,5-dichloro-2-fluorophenyl)isothiazol-3(2H)-one (ISFP5)
3,3'-Dithiodipropionic acid (1 g, 4.76 mmol) was placedunder an argon atmosphere in a dry round bottom ask(sealed with a turnover septum) and was dissolved in anhy-drous tetrahydrofuran (20 ml). The ask was then cooled on-ice followed by the dropwise addition of thionyl chloride(2.07 ml, 28.53 mmol) with stirring. N,N-dimethylformamide(74 μ l, 0.95 mmol) was then added to the stirring solution, andthe reaction was left to stir on ice for 20 min, at which pointthe ice was removed and the reaction was allowed to warm toroom temperature. The reaction was stirred at room temper-ature for a further 3 h at which point the ask was purged withargon and the solvent was carefully removed in vacuo using arotary evaporator (no heating). The resulting crude materialwas triturated twice using toluene followed by solvent removalin vacuo (no heating). The crude material was again dissolvedin tetrahydrofuran ( < 10 ml) and was evaporated to dryness invacuo (no heating). The crude material was subsequently usedwithout further puri cation.3,5-dichloro-2- uoroaniline (1 g, 5.5 mmol) was dissolved inanhydrous dichloromethane (5 ml) under an argon atmo-sphere. Triethylamine (6.95 mmol, 969 μ l) was then added tothe stirring solution and cooled on-ice. Separately, 3,30-disul-fanediyldipropionyl chloride from the rst reaction (344 mg,1.39 mmol) was suspended in anhydrous dichloromethane(5 ml) and was then added slowly to the stirring 3,5-dichloro-2- uoroaniline solution. The reaction was allowed to stir on-ice for 30 min, then warmed to room temperature, andallowed to stir overnight. The next day, a saturated aqueoussolution of sodium hydrogen carbonate (approx. 40 ml) wasadded slowly to the crude reaction mixture and the resultingsolution was extracted using dichloromethane (3 × 20 mlminimum). The organic phase was dried over sodium sulfate, ltered, and the solvent removed in vacuo (water bath at 35C). The crude material was dry loaded on silica and waspuri ed by ash chromatography (Heptane/Ethyl acetate (2:1)→ Ethyl acetate) (305 mg, 41% yield).The product, 3,30-disulfanediylbis(N-(3,5-dichloro-2- uorophenyl)propanamide) (210 mg, 0.39 mmol) was sus-pended (not dissolved) in anhydrous dichloromethane underan argon atmosphere and was cooled on-ice. A solution of1M sulfuryl chloride in dichloromethane ( 1 eq., 393 μ l) wasthen added to the stirring ask and was stirred for 15 min.Over the course of the following 1 to 2 h, an additional 4 to 5equivalents of sulfuryl chloride solution was added to thestirring solution until the solubility of the material in the ask improved. At this point, the reaction mixture wasallowed to warm to room temperature and stirred overnight.The next day, saturated brine solution (approx. 20 ml) was added to the off-white suspension followed by extractionwith ethyl acetate (3 × 20 ml minimum). The organic phasewas dried over sodium sulfate, ltered, and the solventremoved in vacuo (water bath at 30C) to the point wherethe solid crude product became visible in the ask. At thispoint, the reaction mixture was resolubilized with the mini-mum amount of solvent and was dry loaded onto silica for ash puri cation (Heptane/ethyl acetate (1:1) → ethyl ace-tate). The ash puri ed material then underwent a furtherpuri cation by reverse phase C18 HPLC (see supplementaryinformation for methods) (R f : 0.65; heptane/ethyl acetate,1:1) (19 mg, postlyophilisation, 18% yield). |
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