Hydrochloric Acid → 1-(4-Bromo-3-fluorophenyl)cyclopropanecarbohydrazide

A solution of the compound (12.8 g, 47.8 mmol) obtained in Example 25-1) and sodium cyanide (2.58 g, 52.6 mmol) in ethanol (20 ml) and water (5 ml) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure, and then extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 1-Bromo-2-chloroethane (18.9 g, 132 mmol), benzyltriethylammonium chloride (0.48 g, 2.34 mmol), potassium hydroxide (41.5 g, 739 mmol), and water (40 mL) were added to the residue, and the mixture was stirred at 50° C. for 7.5 h. The reaction mixture was cooled to room temperature and extracted with dichloromethane, and the organic layer was washed with water, a 1 M aqueous hydrochloric acid solution, and saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Potassium hydroxide (21.4 g, 382 mmol), ethanol (100 ml), and water (25 ml) were added to the obtained residue, and the mixture was heated to reflux for 9 h. The reaction mixture was cooled to room temperature, then 5 N hydrochloric acid was added until the reaction mixture was rendered acidic, and then the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane, dried with anhydrous sodium sulfate, and then filtered, and the solvent in the filtrate was distilled off under reduced pressure. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.36 g, 38.9 mmol), 1-hydroxybenzotriazole monohydrate (5.88 g, 112.7 mmol), triethylamine (14.6 mL, 105 mmol), tert-butoxycarbonylhydrazide (5.53 g, 41.9 mmol), and N,N-dimethylformamide (100 mL) were added to the obtained residue, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. A 4 M solution (20 mL) of hydrochloric acid in 1,4-dioxane and methanol (100 mL) were added to the obtained partially purified product, and the mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, ethyl acetate:dichloromethane=0:100 to 100:0, gradient) to obtain the title compound (4.17 g, 44%) as a brown solid.

1. temperatureto reflux for 3 h
2. concentrationconcentrated under reduced pressure
3. extractionextracted with ethyl acetate
4. washthe organic layer was washed with saturated sodium chloride solution
5. dry with materialdried with anhydrous sodium sulfate
6. filtrationAfter filtration
7. concentrationthe filtrate was concentrated under reduced pressure
8. temperatureThe reaction mixture was cooled to room temperature
9. extractionextracted with dichloromethane
10. washthe organic layer was washed with water
11. dry with materiala 1 M aqueous hydrochloric acid solution, and saturated sodium chloride solution and dried with anhydrous sodium sulfate
12. filtrationAfter filtration
13. concentrationthe filtrate was concentrated under reduced pressure
14. temperaturethe mixture was heated
15. temperatureto reflux for 9 h
16. temperatureThe reaction mixture was cooled to room temperature
17. concentrationthe mixture was concentrated under reduced pressure
18. extractionThe residue was extracted with dichloromethane
19. dry with materialdried with anhydrous sodium sulfate
20. filtrationfiltered
21. distillationthe solvent in the filtrate was distilled off under reduced pressure
22. stirringthe mixture was stirred overnight at room temperature
23. extractionthe mixture was extracted with ethyl acetate
24. washthe organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution
25. dry with materialdried with anhydrous sodium sulfate
26. filtrationAfter filtration
27. concentrationthe filtrate was concentrated under reduced pressure
28. additionA 4 M solution (20 mL) of hydrochloric acid in 1,4-dioxane and methanol (100 mL) were added to the
29. customobtained partially purified product
30. stirringthe mixture was stirred at room temperature for 6 h
31. concentrationThe reaction mixture was concentrated under reduced pressure, dichloromethane
32. additionwas added to the residue
33. washthe organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution
34. dry with materialdried with anhydrous sodium sulfate
35. filtrationAfter filtration
36. concentrationthe filtrate was concentrated under reduced pressure
37. customthe residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, ethyl acetate:dichloromethane=0:100 to 100:0, gradient)

ORD record

ord-916c0813889145af83b33dd05dae7fe2

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08927536B2