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Example 1; 3-(5-Methyl-3-phenyl-isoxazol-4-yl)-imidazo[l,5-a]pyridinea) S-Methyl-S-phenyl-isoxazole-φcarboxyric acid (pyridin-2-ylmethyl)-amide A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (4.06 g, 20 mmol, commercially available) and thionyl chloride (5 mL) was heated under reflux for 3 h. Evaporation of all volatiles afforded 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (4.4 g, 93%) as yellow oil, which was used without further purification in the next reaction. To a mixture of an aqueous solution of 2-picolylamine (0.182 g, 1.68 mmol) in water (2 mL) and ethyl acetate (4 mL) were added sodium hydrogen carbonate (362 mg, 4.2 mmol) in one portion. Then 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (0.31 g, 1.4 mmol) in ethyl acetate (2 mL) was added dropwise with vigorous stirring under ice-bath cooling keeping the temperature at 0 0C. After addition, the reaction mixture was stirred at room temperature for 18 h. The resulting solution was then diluted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were then washed with brine, dried over sodium sulphate, and concentrated to afford the title compound (0.38 g, 93%) as a white solid. MS: m/e: 294.1 [M+H]+.
93%
With thionyl chloride; for 3h;Reflux;
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (l .Og, 4.9mmol, commercially available) and thionyl chloride (5ml) was heated under reflux for 3 h. Removal of excess volatiles by evaporation afforded 5-methyl-3-phenyl-isoxazole-4-carbonyl chloride (1.01 g, 93%) as a yellow oil, which was used without further purification in the next reaction.
With phosphorus pentachloride; In dichloromethane; for 1h;Heating / reflux;
A solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid (1 g) and PCIS (1 g) in dichloromethane (20 mL) was refluxed for one hour. Then dichloromethane and POCI3 were removed under reduced pressure to give 5-methyl-3-phenylisoxazole-4-carbonyl chloride.
With thionyl chloride;
EXAMPLE 8 5-Methyl-3-phenyl-isoxazole-4-carbonyl Chloride. 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid (0.54 g, 2.56 mmol) was treated with SOCl2 (2 mL) at 70 C. for 1 hr. Concentration in vacuum gave a yellow oil which was used without purification.
With thionyl chloride; at 60℃; for 0.5h;Neat (no solvent);
Example 13 N,N-Diethyl-5-methyl-3-phenylisoxazole-4-carboxamide To 3-phenyl-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60 C. After 30 min, excess thionyl chloride was evaporated and neat diethylamine was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (20 mg). HRMS (ESI, pos. ion) m/z calcd for C15H18N2O2: 258.1368, found 258.1378.; Example 14 N,N-Diisopropyl-5-methyl-3-phenylisoxazole-4-carboxamide To 3-phenyl-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60 C. After 30 min, excess thionyl chloride was evaporated and neat diisopropylamine was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (15 mg). HRMS (ESI, pos. ion) m/z calcd for C17H22N2O2: 286.1681, found 286.1678.; Example 15 4-(Azetidin-1-ylcarbonyl)-5-methyl-3-phenylisoxazole To 3-phenyl-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60 C. After 30 min, excess thionyl chloride was evaporated and neat trimethylene imine was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (18 mg). HRMS (ESI, pos. ion) m/z calcd for C14H14N2O2: 242.1055, found 242.1063.
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