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

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Reaction Steps

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.

Provenance & Evidence