反应详情

温度

55 °C

To a suspension of sodium hydride (29 mg, 1.2 mmol) in dimethylformamide (1 mL) was added N-(1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl)-2,2,2-trifluoroacetamide (Preparation 209, 239 mg, 0.661 mmol) and stirred for 30 minutes. To this was added tert-butyl 5-chloro-2,4-difluorophenylsulfonyl(thiazol-4-yl)carbamate (Preparation 453, 206 mg, 0.501 mmol) and stirred for 24 hours. After this time only a small amount of product was observed, so potassium carbonate (40 mg, 0.3 mmol) was added and the reaction heated at 55° C. for 3 days. The reaction was cooled, diluted with ethyl acetate and the organic extract washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by automated flash column chromatography eluting with ethyl acetate:hexanes (gradient 0:1 to 1:0, by volume) afforded fully protected product. This residue was dissolved in methanol (1 mL) and sodium carbonate solution (2 M aqueous, 0.08 mL, 0.2 mmol) and water (0.2 mL) added. The reaction was stirred at room temperature for 6 hours and then heated at 55° C. for 16 hours before concentrating in vacuo and passing through a short silica gel column eluting with methanol:dichloromethane (gradient 0:1 to 1:9, by volume). All product related fractions were combined, concentrated in vacuo, dissolved in methanol (saturated in gaseous hydrogen chloride) and heated at 50° C. for 16 hours. Purification by preparative HPLC afforded the title compound as a white solid, 31 mg, 12% yield.

1. stirringstirred for 24 hours
2. additionwas added
3. temperatureThe reaction was cooled
4. extractionthe organic extract
5. washwashed with water and saturated aqueous sodium chloride solution
6. dry with materialdried over magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customPurification by automated flash column chromatography
10. washeluting with ethyl acetate
11. customhexanes (gradient 0:1 to 1:0, by volume) afforded fully protected product
12. stirringThe reaction was stirred at room temperature for 6 hours
13. temperatureheated at 55° C. for 16 hours
14. concentrationbefore concentrating in vacuo
15. washeluting with methanol
16. concentrationconcentrated in vacuo
17. dissolutiondissolved in methanol (saturated in gaseous hydrogen chloride)
18. temperatureheated at 50° C. for 16 hours
19. customPurification by preparative HPLC