Ammonium → (r)-(+)-5,6-Dimethoxy-2-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)isoindoline

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To a solution of 1,2-bischloromethylveratrol (675.9 g) in toluene (4000 ml) was added dropwise a solution of (+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (800 g) and N-ethyldiisopropylamine (943.2 g) in toluene (3867 ml) under nitrogen stream, with heating at the inner temperature of 100° C. for 4.5 hr. After dropping, the mixture was further stirred at 100° C. for 1 hr. The mixture was cooled to the inner temperature of 45° C., methanol (1040 ml) was added thereto and concentrated hydrochloric acid (333.6 ml) was added dropwise thereto. After the crystals were precipitated, the mixture was stirred at 50° C. for 30 min and stirred at 5° C. for 1 hr. The crystals were collected by filtration, and washed with toluene and 50% ethanol to give (R)-(+)-5,6-dimethoxy-2-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl) isoindoline hydrochloride (1119 g, 83.6%). This hydrochloride was dissolved in a mixed solution of 90% ethanol (5600 ml) and concentrated hydrochloric acid (110 ml), and 2,6-di-tert-butyl-4-hydroxytoluene (8.0 g) was added thereto. To the solution was added dropwise 6.25% aqueous ammonium at 50° C. to adjust the pH to 8.0, and water (640 ml) was added thereto. The mixture was stirred at 50° C. for 30 min and stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed with 70% ethanol to give the title compound (935 g, yield 75.5%).

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