Triethylamine → (6S,9aR)-6-(4-chlorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one

Participants

Reaction Steps

Triethylamine (2.20 mL), vinylacetic acid (1.16 mL), and BOPCl (3.47 g) were sequentially added to a solution of [(2R,6S)-6-(4-chlorophenyl)piperidin-2-yl]methanol (2.36 g) in THF at 0° C., and the reaction solution was stirred at room temperature for five hours. An ethyl acetate-toluene (1:1) mixed solution and 0.5 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with a 0.5 N sodium hydroxide solution, a saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 1-[(2S,6R)-2-(4-chlorophenyl)-6-(hydroxymethyl)piperidin-1-yl]-(3-buten)-1-one. DMSO (1.04 mL) was added to a solution of oxalyl chloride (1.20 mL) in dichloromethane (70 mL) in a nitrogen atmosphere at −78° C. over five minutes, and the reaction solution was stirred at −78° C. for 10 minutes. A solution of 1-[(2S,6R)-2-(4-chlorophenyl)-6-(hydroxymethyl)piperidin-1-yl]-(3-buten)-1-one in dichloromethane (10 mL) was added to the reaction solution at −78° C. over 20 minutes, and the reaction solution was stirred at −78° C. for 20 minutes. Triethylamine (7.64 mL) was added to the reaction solution at −78° C. over 10 minutes, and then the reaction solution was stirred at −50° C. for one hour. The reaction solution was added to water, followed by extraction with ethyl acetate. The resulting extract was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude aldehyde compound (2.68 g). Trimethyl phosphonoacetate (2.73 mL) was added to a mixed solution of 60% sodium hydride (413 mg) in THF (50 mL)-DMF (10 mL) at 0° C., and the reaction solution was stirred at room temperature for 30 minutes. A solution of the crude aldehyde compound obtained above (2.41 g) in THF (10 mL) was added to the reaction solution at 0° C., and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was added to a cooled ammonium chloride solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain a low-polar isomer of methyl 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylate (0.65 g) and a high-polar isomer of methyl 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylate (1.10 g). A solution of the low-polar isomer of methyl 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylate (0.65 g) and Grubbs catalyst 2nd generation (158 mg) in methylene chloride (60 mL) was heated under reflux in a nitrogen atmosphere for three hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.26 mL) was added to the reaction solution, which was then stirred at room temperature for 10 minutes and concentrated under reduced pressure. Likewise, a solution of the high-polar isomer of methyl 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylate (1.10 g) and Grubbs catalyst 2nd generation (268 mg) in methylene chloride (100 mL) was heated under reflux in a nitrogen atmosphere for three hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.44 mL) was added to the reaction solution, which was then stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residues obtained from both isomers were combined and purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.09 g of the title compound. The property value of the compound is as follows.

Provenance & Evidence