1-Butanol → 7-[(3-Chloro-4-fluoro-2-methylphenyl)carbonyl]-3-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine

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Reaction Steps

Trimethyloxonium tetrafluoroborate (138 mg, 0.887 mmol) was added under argon to a suspension of 4-[(3-chloro-4-fluoro-2-methylphenyl)carbonyl]-2-piperazinone (I59) (200 mg, 0.739 mmol) in dry dichloromethane (DCM) (3.694 ml). The reaction mixture was stirred at room temperature overnight—cloudy mixture. 1,3-thiazole-2-carbohydrazide (I51) (159 mg, 1.108 mmol) was added and the resulting mixture was stirred at room temperature 2 h—reaction mixture was in solution before that a precipitate had appeared. 1-Butanol (3.69 ml) was added—mixture went into solution—and the reaction mixture was stirred at reflux 2 h. The reaction mixture was cooled down to room temperature and DCM was removed in vacuo. The reaction mixture was heated at reflux for 2 h and left at room temperature overnight. The mixture was diluted with DCM (150 mL) and washed with sat. NaHCO3 (2×25 mL), water (25 mL) and brine (25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. NMR: lots of butanol left. The crude product was dissolved in DCM (150 mL) and washed with water (25 mL, 50 mL) and brine (25 mL). The resulting DCM layer was dried over MgSO4 and concentrated under reduced pressure. The foam residue was triturated with Et2O to afford a yellow solid (143.3 mg). The crude product was purified by MDAP (High pH). The obtained solid was dried at 50° C. under vacuum for 1.5 days. The solid was triturated with hexane to get remove the methanol and dried under vacuum at 50° C. to afford the desired product in 75.36 mg as a cream solid.

Provenance & Evidence