反应详情

To a stirred solution of 4-benzyloxy-3-methoxy-phenylacetic acid (10 mmol, 2.73 g), N,O-dimethylhydroxylamine hydrochloride (12 mmol, 1.17 g) and HBTU (12 mmol, 4.55 g) in DMF (20 mL), was added DIEA (24 mmol, 4.2 mL) drop-wise at room temperature and stirred for 1 hour. This was diluted with ethyl acetate and water. The organic layers were combined and concentrated under reduced pressure to get a pale-yellow solid, which was dissolved in anhydrous THF (20 mL) and cooled to 0° C. n-Butyl magnesium chloride (2.0 M solution in THF, 30 mmol, 15.0 mL) was added drop-wise. The reaction mixture was warmed to room temperature and stirred for 3 hours. It was then poured into ice-water, quenched with 1.0 N HCl, extracted with ethyl acetate/water. The organic layers were combined and condensed. The resultant residue was dissolved in THF (10 mL), a solution of ethyl glyoxalate (50% in toluene, 30 mmol, 6.2 mL) and triethylamine (4.3 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layers were combined and concentrated under reduced pressure. The resultant residue in acetic acid (20 mL) was added hydrazine hydrate (10 mL) heated at 120° C. for 4 h. The reaction mixture was then diluted with ethyl acetate and water. The organic layers were combined and concentrated under reduced pressure. The resultant residue in phosphorus(V) oxychloride (10 mL) was kept stirring at 70° C. for 2 h. The reaction mixture was added ice (100 g) and quenched slowly with NaHCO3. This was extracted with ethyl acetate and the combined organic layers were concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography using a mixture of hexanes in ethyl acetate (9:1) to yield 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-chloro-pyridazine (804 mg).

1. concentrationconcentrated under reduced pressure
2. customto get a pale-yellow solid, which
3. additionwas added drop-wise
4. stirringstirred for 3 hours
5. customquenched with 1.0 N HCl
6. extractionextracted with ethyl acetate/water
7. customcondensed
8. stirringthe mixture was stirred at room temperature for 16 hours
9. concentrationconcentrated under reduced pressure
10. additionThe resultant residue in acetic acid (20 mL) was added hydrazine hydrate (10 mL)
11. temperatureheated at 120° C. for 4 h
12. additionThe reaction mixture was then diluted with ethyl acetate and water
13. concentrationconcentrated under reduced pressure
14. stirringThe resultant residue in phosphorus(V) oxychloride (10 mL) was kept stirring at 70° C. for 2 h
15. additionThe reaction mixture was added ice (100 g)
16. customquenched slowly with NaHCO3
17. extractionThis was extracted with ethyl acetate
18. concentrationthe combined organic layers were concentrated under reduced pressure
19. customThe resultant residue was purified by silica gel flash chromatography
20. additiona mixture of hexanes in ethyl acetate (9:1)