1-Hydroxybenzotriazole → (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid [1-(2,4-difluorophenyl)ethyl]amide

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To a DMF (5 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (250 mg) obtained in Example 418 and 1-(2,4-difluorophenyl)ethylamine (CAS#603951-43-5, 141 mg), IPEA (0.5 mL), EDC (430 mg) and HOBT (303 mg) were added one by one, and the reaction solution was agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system). (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid [1-(2,4-difluorophenyl)ethyl]amide was obtained. Sodium hydride (40% mineral oil content, 20 mg) was added to a DMF (5 mL) solution of this compound, and that reaction solution was agitated at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) 151 mg of (E)-1-(1-(2,4-difluorophenyl)ethyl)-3-(3-methoxy-4-(methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one racemate was obtained. This compound (25 mg) was separated in CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; hexane:ethanol=7:3), and the title optically active substance with a retention time of 25 minutes (Example 620: 11.8 mg; >99% ee) and the title optically active substance with a retention time of 45 minutes (Example 621: 11.2 mg; >99% ee) were obtained. The physical properties of the title optically active compound with a retention time of 25 minutes are as follows.

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