Thionyl Chloride → Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate

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Reaction Steps

To the solution of piperidine-4-carboxylic acid (1.3 g, 10 mmol) of water (20 ml) was added sodium hydroxide (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.2 g of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid was obtained. To a stirred solution of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (1.05 g, 4 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (0.573 g, 4.81 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate. To a stirred solution of ethyl 3-amino-2-hydroxybenzoate (0.501 g, 3.0 mmol) and triethylamine (0.455 g, 4.5 mmol) in anhydrous dichloromethane (20 mL) was added dropwise a solution of crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate (1.014 g, 3.6 mmol) in anhydrous dichloromethane (5 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=30:1 to 5:1) to give benzyl-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (0.25 g, yield 20%; LC-MS (ESI) m/z: 413 (M+1)+) and 1-benzyl 4-(2-(1-(benzyloxycarbonyl)piperidine-4-carboxamido)-6-(methoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (1.0 g, yield 51%; LC-MS (ESI) m/z: 658 (M+1)+).

Provenance & Evidence