Ethyl Acetate → [(6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetic acid

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(±)-4-(4-Chlorophenyl)-6-ethoxycarbonyl-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (82 g) and cinchonidine (50 g) are thoroughly dissolved in methanol (1 l), and the solvent is distilled away to give an amorphous product. Ethyl acetate (980 ml) is added and the amorphous product is dissolved in a similar way. The mixture is left standing overnight at room temperature, and a salt precipitated is removed by filtering by suction. The solvent is distilled away from the filtrate (S-isomer 76% ee) under reduced pressure, and chloroform (500 ml) is added to the residue. The mixture is washed twice with 10% hydrochloric acid, and the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (3720 ml) is added to the residue (62 g), and the residue is completely dissolved. The resulting mixture is left standing overnight at room temperature, and a precipitated racemate is removed by filtering by suction. The solvent is distilled away under reduced pressure from the filtrate, and ethanol (500 ml) is added to the residue (43 g) (94% ee). A 2N aqueous solution (182 ml) of sodium hydroxide is added at room temperature with stirring, and the mixture is stirred at 50° C. overnight. After the completion of the reaction, ethanol is distilled away, and the resulting mixture is adjusted to pH 4 with acetic acid. The mixture is stirred at 60° C. for 30 minutes. The reaction mixture is extracted with chloroform, and the organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent is distilled away, ethanol (1920 ml) is added to the residue (32 g) (92% ee) and the mixture is stirred. The insoluble racemate is removed by filtering by suction, and the solvent is distilled away under reduced pressure from the filtrate. The residue is crystallized from chloroform to give an S-isomer [(S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid](20 g) as white powdery crystals (>99% ee). An R-isomer [(R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid], melting point 166-177° C., is obtained by similarly treating the crystals precipitated as a cinchonidine salt.

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