反应详情

A solution of 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (6.4 g, 31 mmol) in methanol (100 mL) was placed in a water bath, treated in a single portion with sodium methoxide (95%, 1.86 g, 32.7 mmol) and stirred for 30 minutes at room temperature. After removal of volatiles in vacuo, the sodium salt was concentrated twice from heptane (100 mL). It was then suspended in dichloromethane (100 mL) and treated with oxalyl chloride (3.15 mL, 35.9 mmol) followed by N,N-dimethylformamide (2 drops). The reaction was stirred for 20 hours at room temperature, then concentrated under reduced pressure. The solid residue was suspended in acetonitrile (100 mL), treated drop-wise with a solution of (trimethylsilyl)diazomethane in diethyl ether (2 M, 39.0 mL, 78.0 mmol) and stirred for 3 hours. The mixture was cooled to 0° C. and hydrogen bromide (33% in acetic acid, 21.9 mL, 125 mmol) was added drop-wise. After 1 hour at 0° C., the reaction mixture was concentrated, and the solid residue was mixed with heptane (250 mL) and reconcentrated. The residue was diluted with ethyl acetate (100 mL), and vigorously stirred with saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo; the crude product was purified via silica gel chromatography (Gradient: 12% to 100% ethyl acetate in heptane) to afford the product as an off-white solid, of approximately 85% purity by LCMS analysis. Yield: 8.10 g, approximately 78% (corrected for purity). LCMS m/z 282.8 (M+1). 1H NMR (500 MHz, CDCl3) δ 3.93 (s, 3H), 4.25 (s, 2H), 8.01 (s, 1H).

1. customAfter removal of volatiles in vacuo
2. concentrationthe sodium salt was concentrated twice from heptane (100 mL)
3. stirringThe reaction was stirred for 20 hours at room temperature
4. concentrationconcentrated under reduced pressure
5. stirringstirred for 3 hours
6. temperatureThe mixture was cooled to 0° C.
7. waitAfter 1 hour at 0° C.
8. concentrationthe reaction mixture was concentrated
9. additionthe solid residue was mixed with heptane (250 mL)
10. additionThe residue was diluted with ethyl acetate (100 mL)
11. stirringvigorously stirred with saturated aqueous sodium bicarbonate solution (100 mL)
12. dry with materialThe organic layer was dried over magnesium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customthe crude product was purified via silica gel chromatography (Gradient: 12% to 100% ethyl acetate in heptane)