Part 1 The Research About Synthesis Of Donepezil

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.