Study On The Synthesis Of Donepezil Hydrochloride

Donepezil Hydrochloride, named 1 -benzyl-4- [(5,6-dimethoxy-1 -indanon)-2-yl] methyl pieridine hydrochloride, was the second generation reversibility anticholinesterase inhibitor and the second medicament for treating Alzheime disease (AD) authorized by FDA.5,6-dimethoxy-l-indanone, the key intermediate for synthesizing Donepezil Hydrochloride, and veratraldehyde, which was the key material for manufacturing of 5,6-dimethoxy-l-indanone, were prepared firstly in this study.In the preparation of veratraldehyde, veratrether was treated with polyformaldehyde and dry hydrogen chloride with catalysts of Lewis acid and phase-transfer catalyst in non-aqueous organic solvent to undergo chloromethyl reaction. Temperature and reaction time were controlled to reduce the probability of formating resinic byproducts. The crude intermediate without distillation was treated directly with hexamethylenetetramine to form salts, avoiding the reaction of active chloromethyl intermediate with unconverted veratrether. And the unconverted veratrether in the solvent can be separated easily from salts dissolved in water, the solvent and the unconverted veratrether can be recycled. The salts was hydrolyzed to form the crude product veratraldehyde, followed by distillating under reduced pressure to give pale yellow crystal with the yield of 70%, m.p.42-43, the content analyzed by GC was 99.7%. Low cost and less pollutions were the merits of this process.5,6-dimethoxy-l-indanone was synthesized from veratraldehyde by steps of Knovenagel-Doebuer condensation, catalytic reduction in the presence of catalyst and cyclization with polyphosphoric acid. The total yield is 74.5%, m.p. 116¹18°. The structure of synthetic was conformed by melting point and IR. In Knovenagel-Doebuer condensation, the yield was improved with the piperizine catalyst. The appropriate mol ratio of veratraldehyde and malonic acid was 1:1.2. Meanwhile the probability of producing byproducts was decreased by controlling the reaction temperature which was low in first stage and high in later stage. Catalytic reduction procedure was done in the presence of Raney-nickel catalyst in sodiumhydrate aqueous at 80 temperature under 1.5MPa pressure with the yield of 87%. This resulted less cost of catalyst and easier operations. Polyphosphoric acid was employed in cyclization at the mass ratio of 1:10 to materials, leading faster reaction speed, higher yield and better purity.By comparison of the merits and demerits of the processes for the preparation of Donepezil Hydrochloride, on the objective of being friendly to entironment, employing cheaper and easily available raw materials, employing less number of reaction steps and consuming less time, being convenient and safe to carry out, giving high yield and purity of products, and being suitable for industrial scale up, the route invented by Bayer company was adopted as the experiment route of this paper, and some of its operation conditions were modified on the basis of other document. Firstly, 4-cyanopyridine was treated with anhydrous SnCl₂ and drying HC1 in anhydrous ether, followed by vapor distilling to afford pyridine-4-aldehyde with the yield, of 86.4%, which was the other key intermediate used in Bayer company's route. Then condensation of pyridine-4-aldehyde with 5,6-dimethoxy-l-indanone in the presence of p-toluenesulphonic acid under reflux 5h in toluene, followed by catalytic reduction for 3h in the presence of catalyst PtO₂ in acetic acid-methanol mixture solvent at room temperature under IMPa pressure with the yield of 99%, then reaction with benzyl bromide in the presence of triethyl amine under reflux for 3h in methylene dichloride to obtain the donepezil free base and treatment with methanolic-HCl to give donepezil hydrochloride in the yield of 92%. The total yield was 79.2%, which was higher than that of Bayer company's route. Furthermore the time of catalytic reaction was shortened sharply.