1-(5-氟戊基)-1H-吲哚-3-羧酸的公斤级合成工艺研究

A Kilo-scale Process for the Preparation of 1-(5-Fluoropentyl)-1H-indole-3-carboxylic Acid

对1-(5-氟戊基)-1H-吲哚-3-羧酸的合成工艺进行了优化,以价廉易得的吲哚为起始原料,经傅-克酰化、卤仿反应、 N-烷基化、水解4步反应制备了目标化合物1-(5-氟戊基)-1H-吲哚-3-羧酸,总收率43.6%,产物纯度>99%,其结构经1H NMR和13C NMR表征确证。对吲哚N-烷基化的工艺进行了优化,采用温和易得的混合碱[n(LiOH·H2O)∶n(KOH)=5∶1]一步引入5-氟戊基侧链,革除了NaH的使用,工艺过程操作简便,反应条件温和,溶剂低毒且可回收套用,大大提升了反应的安全性,适用于工业化生产同时为其他吲哚N-烷基化反应的工业化生产提供了新的思路。

1-(5-Fluoropentyl)-1 H-indole-3-carboxylic acid was synthesized from cheap and easy-afforded indole through a four-steps reactions including Friedel-Crafts acylation,haloform reaction,N-alkylation and hydrolyzation with an overall yield of 43.6%and a purity of 99%.The product structure was confirmed by1 H NMR and13 C NMR.The N-acylation process of indole emphatically screened.A facile and easy-afforded mixed base of n(LiOH·H2 O)∶n(KOH)=5∶1 was chose to induced 5-fluoropentyl side chain in one step.The process avoided utilization of NaH and improved the reaction security.Meanwhile,the process provided a new idea for industrial synthesis of other indole N-alkylation products.This improved synthetic route had the advantages of easy preparation and mild reaction conditions.The reaction solvents was of low toxic and reutilization and suitable for industrial production.