(Tetrahydro-2H-pyran-4-yl)hydrazine dihydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-iodo-2-methoxynicotinic acid (1.75 g) obtained in Step C of Example 6, tetrahydro-2H-pyran-4-ylhydrazine dihydrochloride (0.957 g), DIEA (2.2 mL), EDCI hydrochloride (1.44 g) and HOBt (1.02 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (1.55 g). the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) the obtained solid was washed with ethyl acetate/diisopropyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-iodo-2-methoxynicotinic acid (1.75 g) obtained in Step C of Example 6, tetrahydro-2H-pyran-4-ylhydrazine dihydrochloride (0.957 g), DIEA (2.2 mL), EDCI hydrochloride (1.44 g) and HOBt (1.02 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (1.55 g). the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) the obtained solid was washed with ethyl acetate/diisopropyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (1.82 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (1.52 g). cooling The reaction mixture was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (1.82 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (1.52 g). cooling The reaction mixture was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (1.82 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (1.52 g). cooling The reaction mixture was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 6.0 g of tetrahydro-2H-pyran-4-ylhydrazine dihydrochloride and 175 mL of N-methylpyrrolidone was added 11 mL of DIPEA, followed by stirring at room temperature for 20 minutes. To the reaction mixture was added 8.86 g of N-{4-bromo-2-[(2E)-3-(dimethylamino)prop-2-enoyl]-5-(trifluoromethyl)phenyl}-2,2,2-trifluoroacetamide, followed by stirring at 110° C. for 1 hour. To the reaction mixture was added water, followed by extraction with isopropyl acetate, and the organic layer was washed with saturated brine. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol). The obtained oil was triturated with diethyl ether/n-hexane to obtain 4.19 g of N-{4-bromo-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-5-(trifluoromethyl)phenyl}-2,2,2-trifluoroacetamide. by stirring at 110° C. for 1 hour followed by extraction with isopropyl acetate the organic layer was washed with saturated brine The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (chloroform/methanol) The obtained oil was triturated with diethyl ether/n-hexane