Shi Jian-me
2015
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Journal
Journal of Chemical Engineering of Chinese Universities
Abstract
Synthesizing 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-benzofuran-2-carboxylic acid requires two key intermediates, i.e., 5-piperazinyl-benofuran- 2-carboxylate hydrochloride and 3-(4'-chlorobutyryl)-5-cyano-indole. The synthetic process of the former is almost perfect, while that of the latter is more troublesome. The current approach is that 5-cyanoindole reacts with 4- chlorobutyryl chloride by Friedel-Crafts acylation in the presence of isobutyl aluminum dichloride. The carbonyl of generated acylate is reduced by dihydro-bis(2-methoxyethoxy) aluminum sodium. Not only the approach has poor yield(yielding 18.98% with the two-step reactions), but also the product of each reaction step need to be purified by silica gel column chromatography before subsequent reactions. We improved the process and let 5-cyanoindole react with p-toluenesulfonic chloride to get 1-tosyl-1H-indole-5-carbonitrile, which reacts with 4- chlorobutyryl chloride to form 3-(4'-chlorobutanoyl)-1-tosyl-1H-indole-5-carbonitrile in the presence of anhydrous aluminum chloride. The carbonyl in 3-(4'-chlorobutanoyl)-1-tosyl-1H-indole-5-carbonitrile is reduced by NaB H4 in TFA. 3-(4'-chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile directly reacts with 5-piperazinyl benzofuran- 2-carboxylate hydrochloride, to generate 5-(4-(4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)-benzofuran-2-carboxylic acid, which is followed by deprotection and esterolysis reactions, leading to an overall yield of 60.39%(based on 5-cyanoindole). Moreover, the purification of the products of each step only needs recrystallisation before the next reaction.