Hydrochloric Acid → HCID 12933130, compound

Participants

Reaction Steps

The title compound was synthesized by referring to J. Org. Chem., 1971, 36, 3260. To a suspension of magnesium (2.7 g) in diethyl ether (5 ml) was added a solution of 3-methoxybenzyl chloride (15 ml) in diethyl ether (90 ml) dropwise on an ice bath under a nitrogen atmosphere, the solution was stirred for 20 minutes at room temperature. To a resulting solution of 3-methoxybenzyl magnesium chloride in diethyl ether, which was cooled on an ice, was added dropwise solution of diethyl 2-isopropylidenemalonate (14.8 g) in diethyl ether (9 ml) thereto, then diethyl ether (30 ml) was added thereto followed by stirring overnight at room temperature. The solution was brought to pH 2 by adding SN hydrochloric acid on an ice bath, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]malonic acid diethyl ester (19.7 g). To a solution of the total amount of this compound in ethanol (200 ml) was added an aqueous solution of 5N sodium hydroxide (40 ml), and the solution was refluxed overnight. Water was added thereto followed by stirring, then ethanol was evaporated in vacuo, then the solution was washed with diethyl ether, and the resulting aqueous solution was brought to pH 1 with concentrated hydrochloric acid. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was washed with a hexane-diethyl ether system, and the resulting 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]malonic acid (13.4 g) was heated for 30 minutes at 180° C. to provide 4-(3-methoxyphenyl)-3,3-dimethylbutyric acid (11.2 g). To a solution of the total amount of this compound in toluene (70 ml) was added thionyl chloride (15 ml), the solution was stirred for 1 hour at 100° C., then the solvent was evaporated in vacuo, and the resulting 4-(3-methoxyphenyl)-3,3-dimethylbutyryl chloride (12.5 g) was used according to an analogous synthetic method to Preparation Example 66 to provide the title compound (8.0 g).

Provenance & Evidence