Optimization On The Synthesis Of Donepezil Hydrochloride

Donepezil hydrochloride, named2-((1-benzylpiperidin-4-yl) methyl)-5,6-dime-thoxy-2,3-dihydro-lH-inden-l-one hydrochloride, is the second generation reversibility anticholinesterase inhibitor by the Eisai for treating Alzheime disease (AD) authorized by FDA. Donepezil Hydrochloride is a kind of reversible cholinergic inhibitors, compared with tacrine, on the selectivity of neuronal acetylcholinesterase, pHarmacodynamics, pHarmacokinetics, safety indicators excellent and well tolerated. It is a replacement for tacrine drugs.There are three possible routes,(1) and4-pyridyl aldehyde condensation system to give5,6-dimethoxy-2-(4-pyridyl-methylene)-1-indanone (2), and N-alkylation of benzyl bromide was the quaternary amine salt (3), and then using platinum dioxide as a catalyst hydrogenation salt formation; synthetic routes two is (1) and N-benzyl-4-pyridine aldehyde condensation system (4), then hydrogenated obtained; synthetic routes three is a (2) first hydride (5), and then with benzyl bromide by the N-alkoxy group, salt. Taking into account the N-benzyl-4-pyridine aldehyde is not easy to obtain, the pyridine ring by catalytic hydrogenation than the quaternary ammonium salts easily. Therefore, we propose to3,4-dimethyl group benzaldehyde as raw material with malonic acid in the alkaline under condensation conditions, the latter by the reduction, cyclization to give5,6-dimethyl-1-indanone, and then with4-pyridin-aldehyde condensation, and then by N-alkylation, reduction, salifiable route to synthesize hydrochloride donepezil. Including3-(3,4-dimethoxy-pHenyl)-acrylic acid, the reaction yield was72%,3-(3,4-dimethoxypHenyl) propionic acid, the reaction yield was69.5%,5,6-dimethoxy-1-indanone, the reaction yield was81%,5,6-dimethoxy-2-(4-pyridin-ylmethylene)-1-indanone, the reaction yield was80%bromide,5,6-dimethoxy-2-[1-(pHenylmethyl)-4-pyridylmethylene]-1-indanone, the reaction yield of78%, and donepezil hydrochloride, the reaction yield was65%.All products were characterized by modern analytical methods including UV, IR and1HNMR, and their structures are assured.