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

Temperature

27.5 °C

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.

1. temperaturecooled to 10˜20° C
2. stirringThe mixture is stirred at 25-30° C. for 18˜20 h
3. concentrationthe solution is concentrated to ˜1 L of volume
4. customto remove most of tetrahydrofuran
5. extractionThe resulting solution is extracted with dichloromethane (2×)
6. washThe combined organic layers are washed with 3 volumes of 0.5 M hydrochloric acid
7. concentrationconcentrated
8. addition500 mL of methyl tert-butyl ether is added
9. concentrationthe solution is concentrated
10. concentrationThe organic layer is concentrated

ORD record

ord-b5b830ef52044a1ab1fe6bf1e477e46f

Source dataset

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08207344B2