多奈哌齐的合成研究和1-苯乙基-4-苯胺基哌啶的合成
摘要
老年痴呆症是一种神经退行性疾病,记忆认知功能逐步下降。
多奈哌齐通过选择性抑制乙酰胆碱酯酶的活性而达到治疗效果。
本文对多奈哌齐的合成进行改进,设计了三条新路线,首先改进已有路线,以4-哌啶甲酸乙酯(6)为原料,通过苄基化,还原,氧化,缩合,还原,取代得关键中间体α-[4’-(1’-苄基-哌啶基)甲基]-α-[3’,4’-二甲氧基苄基]丙二酸二乙酯(5)。用目标物所需的苄基代替保护基,以节省脱保护的步骤,缩短路线,提高反应收率,但该路线没成功。
其次设计路线以4-哌啶甲酸乙酯(6)为原料,还原,氯化得到1-苄基-4-(氯甲基)哌啶(12),化合物(12)与丙二酸二乙酯取代制备4’-(1’-苄基-哌啶基)亚甲基丙二酸二乙酯(13),由于丙二酸二乙酯活性太低未得到(13)。
最后用氰乙酸乙酯与化合物(12)成功地得到1-苄基-4-丙酸乙酯-(2-氰基)哌啶(14),化合物14与3,4-二甲氧基苄氯(C)得α-[4’-(1’-苄基-哌啶基)甲基]-α-[3’,4’二甲氧基苄基]氰乙酸乙酯化合物(15),未能从化合物15得到多奈哌齐。
本文对1-苯乙基-4-苯胺基哌啶的合成进行工艺研究。以苯乙胺为原料和丙烯酸甲酯为原料,经过迈克尔加成,迪克曼缩合,水解脱羧得中间体1-苯乙基-4-哌啶酮(6)。化合物(6)经过还原氨化制1-苯乙基-4-苯胺基哌啶,总收率为72%。
探索了迈克尔加成反应的最佳条件,发现丙烯酸甲酯和苯乙胺的投料比为2.5：1,在甲醇条件下回流反应8-10小时,收率可达98.6%。通过改变后处理方法将重要中间体1-苯乙基-4-哌啶酮(6)收率从59%提高到80%.化合物(6)和苯胺得1-苯乙基-4-苯胺基哌啶(1)的反应,本文合成路线采用还原氨化串联模型反应,于高压釜中将两步反应一锅烩,得到的化合物(1)纯度好,收率高,副产物少,还原剂利用率高。该路线缩短反应步骤,降低成本,减少污染,更利于工业化大规模生产。
Dementia is a neurodegenerative disorder and its characterization is progressive decline in memory with impairment of other cognitive function.
Donepezil takes effect on dementia patients by selectively inhibiting acetylcholinesterase (AChE).
In this paper, we have designed three new methods to synthesize Donepezil. First of all, ethyl piperidine-4-carboxylate was used as starting material to form important product diethyl 2-(3,4-dimethoxybenzyl)-2-((1-benzylpiperidin-4-yl)menthyl)malonate(5) through benzyl,reduction, oxidation, condensation and reduction. Compared to related reference, We take the place of protective group with benzyl to short steps and improve efficiency.
Then ethyl piperidine-4-carboxylate was used as starting material to form 1-benzyl-4-(chloromethyl)piperidine(12),then reacts with diethyl malonate to form diethyl ((1-benzylpiperidin-4-yl)methyl)malonate.(13).We fail to get product 13 through different conditions. Since diethyl Malonate is not active enough.
At last, product (12) reacts with ethyl 2-cyanoacetate to form ethyl 3-(1-benzylpiperidin-4-yl)-2-cyanopropanoate(14), then reacts with 4-(chloromethyl)-1,2-dimethoxybenzene (C) to form ethyl 2-((1-benzylpiperidin-4-yl)methyl)-2-cyano-3-(3,4-dimethoxyphenyl) propanoate (15), in this paper, we could not synthesize donepezil from product (15).
In this paper,we have studied the synthesis of 1-phenethyl-4-aniline-piperidine, 2-phenylethanamine and methyl acrylate were used as starting materials to form 1-phenylethyl-4-piperidone(6) through Miachel addition, Dieckman condensation, Hydrolysis. Then followed reductive amination to get 1-phenethyl-4-aniline-piperidine. The yield is 72%.
We have found the best reaction condition in Miachel addition. The proportion of Methyl acrylate and 2-phenylethanamine is 2.5:1. reflux for 8-10h, methanol as solvent. The yield is 98.6%. we have improved the product l-phenylethyl-4-piperidone(6)from 59% to 80% by changing methods after reaction. Reductive amination has been taken in the reaction from product (6) to product(l) in high-pressure. The yield of product (1) is 90% with good purity and little by-product. It is benefit for industrial large-scale production for less steps and environment friendly.
多奈哌齐通过选择性抑制乙酰胆碱酯酶的活性而达到治疗效果。
本文对多奈哌齐的合成进行改进,设计了三条新路线,首先改进已有路线,以4-哌啶甲酸乙酯(6)为原料,通过苄基化,还原,氧化,缩合,还原,取代得关键中间体α-[4’-(1’-苄基-哌啶基)甲基]-α-[3’,4’-二甲氧基苄基]丙二酸二乙酯(5)。用目标物所需的苄基代替保护基,以节省脱保护的步骤,缩短路线,提高反应收率,但该路线没成功。
其次设计路线以4-哌啶甲酸乙酯(6)为原料,还原,氯化得到1-苄基-4-(氯甲基)哌啶(12),化合物(12)与丙二酸二乙酯取代制备4’-(1’-苄基-哌啶基)亚甲基丙二酸二乙酯(13),由于丙二酸二乙酯活性太低未得到(13)。
最后用氰乙酸乙酯与化合物(12)成功地得到1-苄基-4-丙酸乙酯-(2-氰基)哌啶(14),化合物14与3,4-二甲氧基苄氯(C)得α-[4’-(1’-苄基-哌啶基)甲基]-α-[3’,4’二甲氧基苄基]氰乙酸乙酯化合物(15),未能从化合物15得到多奈哌齐。
本文对1-苯乙基-4-苯胺基哌啶的合成进行工艺研究。以苯乙胺为原料和丙烯酸甲酯为原料,经过迈克尔加成,迪克曼缩合,水解脱羧得中间体1-苯乙基-4-哌啶酮(6)。化合物(6)经过还原氨化制1-苯乙基-4-苯胺基哌啶,总收率为72%。
探索了迈克尔加成反应的最佳条件,发现丙烯酸甲酯和苯乙胺的投料比为2.5：1,在甲醇条件下回流反应8-10小时,收率可达98.6%。通过改变后处理方法将重要中间体1-苯乙基-4-哌啶酮(6)收率从59%提高到80%.化合物(6)和苯胺得1-苯乙基-4-苯胺基哌啶(1)的反应,本文合成路线采用还原氨化串联模型反应,于高压釜中将两步反应一锅烩,得到的化合物(1)纯度好,收率高,副产物少,还原剂利用率高。该路线缩短反应步骤,降低成本,减少污染,更利于工业化大规模生产。
Dementia is a neurodegenerative disorder and its characterization is progressive decline in memory with impairment of other cognitive function.
Donepezil takes effect on dementia patients by selectively inhibiting acetylcholinesterase (AChE).
In this paper, we have designed three new methods to synthesize Donepezil. First of all, ethyl piperidine-4-carboxylate was used as starting material to form important product diethyl 2-(3,4-dimethoxybenzyl)-2-((1-benzylpiperidin-4-yl)menthyl)malonate(5) through benzyl,reduction, oxidation, condensation and reduction. Compared to related reference, We take the place of protective group with benzyl to short steps and improve efficiency.
Then ethyl piperidine-4-carboxylate was used as starting material to form 1-benzyl-4-(chloromethyl)piperidine(12),then reacts with diethyl malonate to form diethyl ((1-benzylpiperidin-4-yl)methyl)malonate.(13).We fail to get product 13 through different conditions. Since diethyl Malonate is not active enough.
At last, product (12) reacts with ethyl 2-cyanoacetate to form ethyl 3-(1-benzylpiperidin-4-yl)-2-cyanopropanoate(14), then reacts with 4-(chloromethyl)-1,2-dimethoxybenzene (C) to form ethyl 2-((1-benzylpiperidin-4-yl)methyl)-2-cyano-3-(3,4-dimethoxyphenyl) propanoate (15), in this paper, we could not synthesize donepezil from product (15).
In this paper,we have studied the synthesis of 1-phenethyl-4-aniline-piperidine, 2-phenylethanamine and methyl acrylate were used as starting materials to form 1-phenylethyl-4-piperidone(6) through Miachel addition, Dieckman condensation, Hydrolysis. Then followed reductive amination to get 1-phenethyl-4-aniline-piperidine. The yield is 72%.
We have found the best reaction condition in Miachel addition. The proportion of Methyl acrylate and 2-phenylethanamine is 2.5:1. reflux for 8-10h, methanol as solvent. The yield is 98.6%. we have improved the product l-phenylethyl-4-piperidone(6)from 59% to 80% by changing methods after reaction. Reductive amination has been taken in the reaction from product (6) to product(l) in high-pressure. The yield of product (1) is 90% with good purity and little by-product. It is benefit for industrial large-scale production for less steps and environment friendly.
引文
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