Ethyl pyridine-4-acetate → Ethyl 2-(piperidin-4-yl)acetate

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Reaction Steps

Ethyl-4-pyridylacetate (5 g) is dissolved in ethanol (30 mL), treated with platinum oxide catalyst (30 mg) and hydrogenated on a Parr apparatus for 4 hr. The catalyst is filtered off and the ethyl-4-piperidinylacetate is isolated by removal of the solvent under vacuum. This material is then dissolved in acetonitrile (50 mL) and treated with 4-chlorobenzyl chloride (4.9 g) and sodium carbonate (10 g). The resulting mixture is heated in methanol (30 mL) and treated with a solution of lithium hydroxide (2 g) in water (10 mL). The mixture is allowed to stand overnight. Addition of 47.6 mL of 1 N HCI solution followed by concentration and extraction of the residue with chloroform provides the desired 1-(4-chlorobenzyl)-4-piperidylacetic acid. A portion of this material (1 g) is dissolved in methylene chloride and treated with 1,1′-carbonyldiimidazole (0.65 g) and allowed to stand overnight. This solution is then treated with 2-methylindoline (0.5 g). After 2 h the resulting mixture is washed 3 times with water dried and concentrated. Purification by column chromatography on silica gel provides 1.2 g of the desired 2-(1-[4-chlorobenzyl]piperidin-4-yl)-1-(2-methylindolin-1-yl)-1-ethanone (Compound 1). The dihydrochloride salt is subsequently prepared (Compound 1a).

Provenance & Evidence