涉及常山酮中间体—取代哌啶类化合物合成的研究
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摘要
本论文研究了常山酮关键中间体2-丙酮基哌啶类化合物的合成,尝试了以Darzens反应、臭氧化反应与Wacker反应构建丙酮基的方法。
以3-羟基吡啶为原料,通过Mannich反应、乙酰化、水解、选择性保护、氧化等步骤制得3-烷氧基-2-吡啶醛,并以此为原料经Wittiing反应制得2-(2’-烷氧羰基-2’-甲基乙烯基)-3-烷氧基吡啶。以所得的两个化合物分别尝试直接法Darzens反应和分步法Darzens反应合成2-丙酮基-3-烷氧基哌啶的前体。
以3-羟基毗啶为原料,经溴化、醚化、以CuI催化的Kumada偶联反应选择性制备2-甲基烯丙基-3-甲氧基吡啶,并以此为原料经成盐、还原、水解、保护等步骤制得N-苄基-2-甲基烯丙基-3-乙酰氧基哌啶。分别以N-苄基-2-甲基烯丙基-3-乙酰氧基哌啶和2-甲基烯丙基-3-甲氧基吡啶尝试臭氧化反应,后者反应产物为2-丙酮基-3-烷氧基哌啶的前体2-丙酮基-3-甲氧基吡啶,但收率较低。
以3-羟基吡啶为原料经溴化、醚化、Kumada偶联反应制得2-烯丙基-3-甲氧基吡啶,然后经成盐、还原、水解、再还原、保护等步骤得到N-苄基-2-烯丙基-3-乙酰氧基哌啶；还以3-羟基吡啶为原料,通过成盐、还原、von Braun反应、Claisen重排、保护等多步反应制得N-苄氧羰基-2-烯丙基-3-甲氧基吡啶。所合成的两个化合物分别在催化量的PdCl2和CuCl存在下,通氧气分别进行Wacker反应,成功得到常山酮中间体2-丙酮基哌啶类化合物：前者反应产物为N-苄基-2-丙酮基-3-羟基哌啶,后者反应产物为N-苄氧羰基-2-丙酮基-3-甲氧基哌啶。对以上每步的反应条件都进行了优化,相比较,后者合成路线更具实用化。
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.
以3-羟基吡啶为原料,通过Mannich反应、乙酰化、水解、选择性保护、氧化等步骤制得3-烷氧基-2-吡啶醛,并以此为原料经Wittiing反应制得2-(2’-烷氧羰基-2’-甲基乙烯基)-3-烷氧基吡啶。以所得的两个化合物分别尝试直接法Darzens反应和分步法Darzens反应合成2-丙酮基-3-烷氧基哌啶的前体。
以3-羟基毗啶为原料,经溴化、醚化、以CuI催化的Kumada偶联反应选择性制备2-甲基烯丙基-3-甲氧基吡啶,并以此为原料经成盐、还原、水解、保护等步骤制得N-苄基-2-甲基烯丙基-3-乙酰氧基哌啶。分别以N-苄基-2-甲基烯丙基-3-乙酰氧基哌啶和2-甲基烯丙基-3-甲氧基吡啶尝试臭氧化反应,后者反应产物为2-丙酮基-3-烷氧基哌啶的前体2-丙酮基-3-甲氧基吡啶,但收率较低。
以3-羟基吡啶为原料经溴化、醚化、Kumada偶联反应制得2-烯丙基-3-甲氧基吡啶,然后经成盐、还原、水解、再还原、保护等步骤得到N-苄基-2-烯丙基-3-乙酰氧基哌啶；还以3-羟基吡啶为原料,通过成盐、还原、von Braun反应、Claisen重排、保护等多步反应制得N-苄氧羰基-2-烯丙基-3-甲氧基吡啶。所合成的两个化合物分别在催化量的PdCl2和CuCl存在下,通氧气分别进行Wacker反应,成功得到常山酮中间体2-丙酮基哌啶类化合物：前者反应产物为N-苄基-2-丙酮基-3-羟基哌啶,后者反应产物为N-苄氧羰基-2-丙酮基-3-甲氧基哌啶。对以上每步的反应条件都进行了优化,相比较,后者合成路线更具实用化。
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.
引文
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