Synthesis Of Substituted Piperidines As Intermediate Of Halofuginone

This thesis focuses on the synthesis of substituted 2-acetonylpiperidines as the key intermediate of Halofuginone. Several synthetic methods including Darzens reaction, ozonation reaction and wacker reaction had been examined to construct the acetonyl group.Using 3-pyridinol as starting material, through Mannich reaction, hydrolyzation, selective protection, oxidation etc,3-(benzyloxy)picolinaldehyde was obtained, then it reacted with a wittig reagent to get 3-(3-methoxypyridin-2-yl)-2-methylacrylate. These two products were tried to synthesis substitueted 2-acetonylpyridine through Darzens reaction and stepwise process of Darzens reaction, respectively.Using 3-pyridinol as starting material, through bromination, etherification, selective Kumada reaction catalyzed by Cul etc,3-methoxy-2-(2-methylallyl)pyridine was synthesized in satisfied yield. Then it was further converted into 1-benzyl-2-(2-methylallyl)piperidin-3-yl acetate through saltification, reduction, hydrolyzation, protection etc. These two compounds were then oxidized with ozone, respectively. The desired product (methoxypyridin-2-yl)propan-2-one was obtained from the latter compound, but only in low yields.Using 3-pyridinol as starting material, through bromination, etherification, Kumada reaction etc,3-methoxy-2-allylpyridine was obtained, then further transformation was done to synthesize 2-allyl-l-benzylpiperidin-3-yl acetate through saltification, reduction, hydrolyzation, reduction, protection etc.; using same starting material, through saltification, reduction, von Braun reaction, Claisen rearrangement, protection etc, benzyl 2-allyl-3-methoxypiperidine-l-carboxylate was obtained in high yield. These two compounds were examined to synthesize 2-acetonylpiperidines by Wacker oxidation catalyzed by PdCl2 and CuCl, respectively. Desired products 1-(1-benzyl-3-hydroxypiperidin-2-yl)propan-2-one and benzyl 3-methoxy-2-(2-oxopropyl)piperidine-l-carboxylate were obtained. Reaction conditions of each step were optimized so that this procedure can be used in the large scale.