[F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[C:11](N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][O:24][C:25]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26].O>O1CCCC1>[CH2:23]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:6]([C:3]2([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]2)=[O:7])[CH2:29][CH2:28]1)=[O:26])[CH3:11]1-(Trifluoromethyl)cyclopropanecarboxylic acid (400 g, 2.6 mol) is dissolved in 3.2 L of tetrahydrofuran and cooled to 10˜20° C. Carbonyldiimidazole (462.4 g, 1.1 eq) is added in portions. The mixture is stirred at 25-30° C. for 20 min. Then piperidine-4-carboxylic acid methyl ester (445.6 g, 1.2 eq) is added dropwise at <30° C. The mixture is stirred at 25-30° C. for 18˜20 h. 3.2 L of water are added dropwise at <30° C. and the solution is concentrated to ˜1 L of volume to remove most of tetrahydrofuran. The resulting solution is extracted with dichloromethane (2×). The combined organic layers are washed with 3 volumes of 0.5 M hydrochloric acid and concentrated. 500 mL of methyl tert-butyl ether is added and the solution is concentrated. This process is run twice. The organic layer is concentrated to provide 567 g of the title compound in 95% purity.
Wird geladen…
