CO.C([O:5][C:6](=[O:22])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C.[OH-].[Li+].Cl>O>[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:22])=[O:5])[CH2:13][CH2:12]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1Methanol (300 ml) and water (50 ml) were added to (4-benzoylpiperazin-1-yl)acetic acid ethyl ester (8.19 g), and lithium hydroxide (1.34 g) was added thereto with cooling in an ice water bath, followed by stirring for 10 minutes. The reaction mixture was brought to room temperature, followed by stirring for 24 hours. After adding 1N hydrochloric acid (55.9 ml), the reaction mixture was concentrated under reduced pressure, and ethanol (200 ml) was added to the resultant residue. The precipitated insoluble matter was removed by filtration through celite. The filtrate was concentrated under reduced pressure to give a crude product of (4-benzoylpiperazin-1-yl)acetic acid (8.6 g) as a white solid. N,N-Dimethylformamide (80 ml) was added to (4-benzoylpiperazin-1-yl)acetic acid (2 g) at room temperature under a nitrogen atmosphere, and azetidine hydrochloride (1.51 g), triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added in this order, followed by stirring at room temperature for 66 hours. Ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) were added to the reaction mixture, which was partitioned. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). The residue obtained by concentrating the fractions containing the target compound under reduced pressure was suspended by the addition of diethyl ether (10 ml). The solid was collected by filtration, and dried under aeration to give the title compound (731.5 mg) as white powder.
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