Bromine → Ethyl 3-bromo-4-oxopiperidine-1-carboxylate

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Reaction Steps

1-carbethoxy-4-piperidone 1 reacts with bromine in an inert solvent such as dichloromethane to give high yields of 1-carbethoxy-3-bromo-4-piperidone 2. The bromo compound 2 reacts with sodium methoxide in methanol to give 1-carbethoxy-3-hydroxy-4,4-dimethoxypiperidine 3, which in turn is alkylated to the corresponding 3-methoxy analog 4 with iodomethane in dimethylformamide in the presence of sodium hydride. The ketal 4 is hydrolyzed to 1-carbethoxy-3-methoxy-4-piperidone 5 by stirring in 1% sulfuric acid at room temperature. The amine 6 of cis-configuration is then readily obtained by reductive alkylation of 5 with benzylamine in the presence of hydrogen gas and 10% Pd/C with a small amount of thiophene. Further hydrogenolysis of the benzyl moiety with Pd/C and no thiophene gives the primary amine 7. Compound 7 in turn reacts with the commercially available 4-amino-5-chloro-2-methoxybenzoic acid in the presence of DCC and dimethyaminopyridine in dichloromethane to give the benzamide 8. Compound 8 is then hydrolyzed to the intermediate 9 with potassium hydroxide in ethanol/water.

Provenance & Evidence