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

Participants

Reaction Steps

To a DMF (2 mL) suspension of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid trifluoroacetic acid salt (50 mg) obtained in Example 418 and 6-methoxyindan-1-ylamine (CAS#103028-81-5) (27 mg), IPEA (0.06 mL), EDC (64 mg) and HOBT (45 mg) were added at room temperature, and the reaction solution was agitated at room temperature for 12 hours. Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed one by one with a saturated ammonium chloride solution and water, and also saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (elution solvent: methanol-ethyl acetate system) and (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid (6-methoxyindan-1-yl)amide (29 mg) was obtained. To a DMF (2 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (6-methoxyindan-1-yl)amide (29 mg) obtained, sodium hydride (40% mineral oil content, 20 mg) was added at room temperature, and the reaction solution was agitated for 10 minutes at room temperature. Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed one by one in a saturated ammonium chloride solution and water, and also saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (elution solvent: methanol-ethyl acetate system), and (E)-1-(6-methoxyindan-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one racemate (17 mg) was obtained. This compound (17 mg) was separated by CHIRALCEL™ AD-H available from Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; ethanol), and the title optically-active substance with a retention time of 36 minutes (6 mg; >99% ee) and the title optically-active substance with a retention time of 43 minutes (6 mg; >95% ee) were obtained. The physical properties of the title optically-active substance with a retention time of 36 minutes (Example 421) is as follows.

Provenance & Evidence