84449-80-9

93148-78-8

2008-75-5

99-76-3

84449-80-9

Example 4 Preparation of 4-[2-piperidine-1-ethoxy]benzoic acid hydrochloride A mechanical stirrer, condenser tube and a heating unit comprising a heating jacket connected via a temperature controller and an RTD temperature probe were assembled in a 250 mL three-neck flask and operated under nitrogen protection. 7.61 g of methyl 4-hydroxybenzoate (nipagin methyl ester), 11.05 g of 1-(2-chloroethyl)piperidine hydrochloride, 16.59 g of powdered potassium carbonate and 60 mL of isopropyl acetate were added sequentially. The reaction mixture was slowly heated to 80 °C and after 5 hours of reaction, high performance liquid chromatography (HPLC) analysis showed that the reaction was 90% complete. The reaction was continued at 80 °C overnight to ensure complete reaction. Upon completion of the reaction, the mixture was cooled to room temperature, 60 mL of deionized water was added and stirred until all solids were dissolved. The aqueous layer was separated and discarded. The organic layer was extracted three times with 20 mL of 4N hydrochloric acid solution. The extracts containing ethyl 4-[2-piperidin-1-ethoxy]benzoate were combined and heated to reflux (92°C for about 30 minutes to reach reflux). After refluxing for 7.5 hours, about 10 mL of water was removed by distillation, followed by cooling the mixture in an ice bath for 15 minutes. The precipitated 4-[2-piperidine-1-ethoxy]benzoic acid hydrochloride crystals were collected by filtration, washed with acetone and dried. A final product of 12.53 g was obtained in 87.7% yield of the theoretical value.