反应详情

温度

0 °C

104.6 ml of a 1.6M solution of n-Butyl lithium in hexane is added dropwise at −75° C. to 200 ml tetrahydrofuran followed by 28.3 ml 2,2,6,6-tetramethylpiperidine and the resulting solution is allowed to warm to 0° C. and stirred for 30 min. The solution is cooled to −75° C. and a solution of 11 g 3-chloro-6-methoxypyridazine in 100 ml tetrahydrofuran is added at the same temperature. The reaction is stirred for 30 min at −75° C. A solution of 65.9 ml propionaldehyde in 200 ml tetrahydrofuran is cooled to −75° C. and added to the reaction. The solution is stirred at −75° C. for 90 min, then a mixture of 55 ml concentrated aqueous HCl, 220 ml ethanol and 275 ml tetrahydrofuran is added and the mixture is allowed to warm to room temperature. 150 ml of saturated aqueous sodium bicarbonate is slowly added, and the tetrahydrofuran is removed under reduced pressure. The resulting aqueous phase is extracted 3 times with dichloromethane. The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 12.25 g. LC-MS (ES+) 203 (M+H)+. NMR analysis indicated that the product contained approximately 15% of 1-(3-Chloro-6-methoxy-pyridazin-4-yl)-propan-1-ol.

1. temperatureThe solution is cooled to −75° C.
2. stirringThe reaction is stirred for 30 min at −75° C
3. additionadded to the reaction
4. stirringThe solution is stirred at −75° C. for 90 min
5. additionis added
6. temperatureto warm to room temperature
7. customthe tetrahydrofuran is removed under reduced pressure
8. extractionThe resulting aqueous phase is extracted 3 times with dichloromethane
9. dry with materialThe organic phase is dried (MgSO4)
10. filtrationfiltered
11. customevaporated under reduced pressure
12. customThe product is purified by silica gel chromatography
13. washeluting with a gradient of ethyl acetate in heptane