反应详情

温度

90 °C

To a mixture of sodium hydrogen carbonate (2.0 mmol) and PdCl2dppf:CH2Cl2 1:1 (0.05 eq, 0.03 mmol) under argon, was added a degassed solution of 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 0.65 mmol) in 10.5 mL dimethoxyethane and 3 mL of water. Cyclopropylboronic acid (1.3 mmol) was then added and the mixture was stirred at 90° C. for 3 h. Further cyclopropylboronic acid was then added (1.3 mmol), and the mixture was stirred overnight at 65° C. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (Column WATERS Sunfire C18.5 μm 50*150 mm, eluent:water/methanol/0.1% formic acid) to afford 49 mg of 4-[3-(5-chloro-2-thienyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine (25% yield).

1. stirringthe mixture was stirred overnight at 65° C
2. temperatureAfter cooling to room temperature
3. extractionThe aqueous layer was extracted with ethyl acetate
4. washthe combined organic extracts were washed with brine
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated
8. dissolutionThe residue was dissolved in 3 mL of trifluoroacetic acid
9. stirringstirred at 65° C. for 2 h
10. additionWater and ethyl acetate were added
11. extractionAnd the aqueous layer was extracted with ethyl acetate
12. washThe combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate
13. dry with materialdried over MgSO4
14. filtrationfiltered
15. concentrationconcentrated
16. customThe residue was purified by preparative HPLC (Column WATERS Sunfire C18.5 μm 50*150 mm, eluent:water/methanol/0.1% formic acid)