反应详情

温度

-78 °C

To a stirring mixture of THF (2000 mL) and diisopropylamine (79.3 mL, 0.56 mol) at −78° C. was added n-BuLi (244 mL, 0.56 mol) dropwise. After stirring for 20 min at −78° C., a solution of 5-((t-butyldimethylsilyloxy)methyl)thiazole (110.9 g, 0.49 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than −70° C. After the addition was complete, the reaction was stirred for an additional 30 min and a solution of zinc bromide (126.6 g, 0.56 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than −65° C. The reaction was warmed to 0° C., stirred for 30 min, and added to a stirring mixture of t-butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (100 g, 0.26 mol), tetrakis(triphenylphosphine)palladium(0) (56 g, 0.05 mol), and THF (2000 mL) heated to 80° C. The reaction mixture was stirred overnight at 80° C. The reaction was concentrated and then slurried in ethyl acetate and brine. The resultant solid was filtered off, and the filtrate was dried over sodium sulfate, concentrated, and purified twice by silica gel chromatography (EtOAc/hexanes) to afford 112.5 g of t-butyl 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a dark oil.

1. temperaturewhile maintaining a temperature less than −70° C
2. additionAfter the addition
3. stirringthe reaction was stirred for an additional 30 min
4. temperaturewhile maintaining a temperature less than −65° C
5. temperatureThe reaction was warmed to 0° C.
6. stirringstirred for 30 min
7. temperatureheated to 80° C
8. stirringThe reaction mixture was stirred overnight at 80° C
9. concentrationThe reaction was concentrated
10. filtrationThe resultant solid was filtered off
11. dry with materialthe filtrate was dried over sodium sulfate
12. concentrationconcentrated
13. custompurified twice by silica gel chromatography (EtOAc/hexanes)