1-Hydroxybenzotriazole → (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (6-fluoroindan-1-yl)amide

Participants

Reaction Steps

IPEA (0.58 mL), EDC (0.38 g) and HOBT (0.27 g) were added to a suspension of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 6-fluoroindan-1-ylamine (CAS #168902-77-0, 151 mg) in DMF (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (6-fluoroindan-1-yl)amide (270 mg). Sodium hydride (containing mineral oil at 40%, 60 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (6-fluoroindan-1-yl)amide (270 mg) in DMF (5 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain (E)-1-(6-fluoroindan-1-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate (200 mg). The compound (200 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 7.4 minutes (Example 994, 72 mg; >99% ee) and the title optically active substance with a retention time of 8.4 minutes (Example 993, 68 mg; >96% ee). The physical properties of the compounds are as follows.

Provenance & Evidence