Diethyl Malonate → Ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate

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Reaction Steps

In 80 ml of ethanol is dissolved 0.95 g of sodium, and 7.2 g of diethyl malonate is added to the solution, followed by stirring. 5(1-Benzyloxycarbonyl-4-piperidyl)pentyl p-toluenesulfonate (13.7 g) is added to the mixture, followed by refluxing with stirring for 2 hours. Further, a mixture of 0.25 g of sodium, 25 ml of ethanol and 1.8 g of diethyl malonate is added, and the reaction solution is refluxed with stirring for 2 hours. Ethanol is evaporated off under reduced pressure, and 200 ml of water is added to the residue, which is then extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an oily material. This product is dissolved in 30 ml of ethanol, and a solution of 6 g of sodium hydroxide in 50 ml of water is added dropwise to the solution with stirring. After the addition is completed, 150 ml of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is made acidic with conc. hydrochloric acid and extracted with 300 ml of ethyl acetate, and the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oily material. This product is heated at 160° to 165° C. with stirring for 1 hour, and the resulting oily material is purified by silica-gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give 6.4 g of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid as an oily material.

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