Water → 1-(1-Trifluoromethyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester

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Reaction Conditions

Reaction Steps

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.

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