Hydrochloric Acid → (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanoic acid

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To a stirred mixture of crude (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (273 g, 0.512 mol, 83% pure) in 2-methyltetrahydrofuran (1030 mL) was added 2N sodium hydroxide (308 mL, 616 mmol) and the resulting mixture stirred at 21-26° C. for 20 min. To this mixture was added 2N sodium hydroxide (265 mL, 530 mmol) and the resulting mixture stirred vigorously for 2.5 h. The mixture was diluted with water (500 mL) and methyl t-butyl ether (300 mL) and stirred for 10 min. The aqueous layer was acidified with 2N hydrochloric acid (60.0 mL, 120 mmol) (pH=3) and extracted with ethyl acetate (300 mL). The organic layer was separated and washed with a sodium hydroxide solution (1N, 200 mL). The combined aqueous layers were washed with methyl t-butyl ether (500 mL). The aqueous layer was cooled to 15° C. before a hydrochloric acid solution (6N, 210 mL) was added over 20 min maintaining a temperature of 15-19° C. until a pH of 2.6 was obtained. To this solution was added dichloromethane (1000 mL) and the mixture was separated. The aqueous phase was extracted with dichloromethane (300 mL). The dichloromethane layers were combined and washed with an aqueous 20% sodium chloride solution (200 mL). The solution was evaporated and residue suspended in formic acid (1272 mL). The mixture was slowly stirred until a solution was achieved before water (1330 mL) and seed crystals (1 g) were added. The resulting mixture was stirred for 2.5 h at room temperature. The mixture was cooled to 5° C., filtered and the cake washed with water and dried under vacuum to give (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (111 g, 56.9%) as a beige solid.

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