简捷有效合成多肽渗透促进剂前体8-氨基辛酸的新方法

Concise and Effective New Syntheses of 8-Aminooctanoic Acid,a Precursor of Polypeptide Osmotic Accelerator

以己二酸单甲酯(2)作为起始原料,经酰氯化、Nenitzescu反应得6-氧代-8-氯辛酸甲酯(4),4经取代、缩合得(E)-8-(1,3-二氧代异吲哚啉-2-基)-6-(2-甲苯磺酰肼亚基)辛酸甲酯(6),6经过还原、肼解及水解反应,得8-氨基辛酸(1),该化合物是合成渗透增强剂N-[8-(2-羟基苯甲酰基)-氨基]辛酸钠(SNAC)的重要起始物。1的新合成路线总收率为58.9%(以2计),纯度99.83%。该工艺条件温和,原料经济易得,操作简单,具有良好的产业化前景。

Methyl 8-chloro-6-oxooctanoate(4)was synthesized by acylating chlorination and Nenitzescu reaction from the commercial available material 6-methoxy-6-oxohexanoic acid(2).Then methyl(E)-8-(1,3-dioxoisoindolin-2-yl)-6-(2-tosylhydrazineylidene)octanoate(6)was obtained by substitution and condensation of 4.Ultimately,8-aminooctanoic acid(1)was obtained by reduction,hydrazolysis and hydrolysis reaction from 6,which was an important starting material for the synthesis of the permeation enhancer sodium N-[8-(2-hydroxybenzoyl)amino]octanoate(SNAC).The total yield of this new synthetic route was 58.9%(based on 2)with the purity of 99.83%.This new process is suitable for industrial production with mild conditions,low raw material cost and simple operations.