5-{4-[4-(5-氰基-3-吲哚基)丁基]哌嗪基}苯并呋喃-2-甲酸合成方法的改进

Improvement of Synthetic Method for 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl) piperazin-1-yl)-benzofuran-2-carboxylic Acid

合成5-{4-[4-(5-氰基-3-吲哚基)丁基]哌嗪基}苯并呋喃-2-甲酸需要两个关键中间体,即,5-哌嗪基-苯并呋喃-2-甲酸乙酯盐酸盐和3-(4’-氯丁基)-5-氰基吲哚。前者的合成工艺较为成熟,后者的合成较为困难,目前的方法是将5-氰基吲哚先与4-氯丁酰氯在异丁基二氯化铝的存在下进行Friedel-Crafts酰化反应,生成的酰化物再用二氢双(2-甲氧乙氧基)铝酸钠将羰基还原制得。此方法不仅收率低(两步反应的收率18.98%),而且每步反应的产物都需要用硅胶柱层析纯化后才能进行后续反应。现研究将5-氰基吲哚先与对甲基苯磺酰氯反应制得N-对甲基苯磺酰基-5-氰基吲哚后再与4-氯丁酰氯在无水三氯化铝的催化下进行Friedel-Crafts反应,生成的N-对甲基苯磺酰基-3-(4’-氯丁酰基)-5-氰基吲哚用Na BH4/TFA将其中的羰基还原,得到的N-对甲基苯磺酰基-3-(4’-氯丁基)-5-氰基吲哚可直接与5-哌嗪基-苯并呋喃-2-甲酸乙酯盐酸盐反应,生成的产物再经水解反应得到5-{4-[4-(5-氰基-3-吲哚基)丁基]哌嗪基}苯并呋喃-2-甲酸,五步反应的总收率60.39%。此外,采用该方法只需要对每一步反应产物用重结晶纯化就可以进行后续反应。

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-lH-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-lH-indole-5-carbonitrile is reduced by NaBH4 in TFA. 3-（4＇-chlorobutyl）-1-tosyl-lH-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.