Large-scale synthesis of a cyclic hexapeptide analog of somatostatin
Large-scale synthesis of a cyclic hexapeptide analog of somatostatin
复制标题
生长抑素环状六肽类似物的大规模合成
DOI：
10.1021/jo00381a011
复制
发表时间：
1987
影响因子：
3.6
通讯作者：
D. Veber
中科院分区：
文献类型：
--
作者：
S. Brady;R. Freidinger;W. J. Paleveda;C. D. Colton;C. Homnick;W. L. Whitter;P. Curley;R. Nutt;D. Veber
我们实验室最近的一份报告描述了高效环六肽生长抑素类似物1的制备和生物学性质。本文详细报道了1的大规模合成，为临床研究提供原料。合成完全通过溶液化学，通过从酪氨酸甲酯开始逐步延长氨基酸链来完成。使用混合酸酐程序允许偶联而不需要保护酪氨酸羟基。通过结晶纯化几种中间体，包括被保护的六肽10。以碳酸氢钠为碱，用叠氮磷酸二苯酯进行环化反应，产率高。在倒数第二个环肽12的阶段，仅需要单个色谱程序。使用该合成路线，我们已经能够以40-50 g的批次制备> 99%纯度的最终产物1。基于每个组成残基的产率范围为17%（Boc-丙氨酸）至52%（Boc-D-色氨酸）。该过程作为一个例子的各种考虑因素的重要性，快速和有效的大规模合成肽。
A recent report from our laboratories describes the preparation and biological properties of the highly potent cyclic hexapeptide somatostatin analogue 1. Herein we report the details of the large-scale synthesis of 1 developed to provide supplies for clinical study. The synthesis was accomplished entirely via solution chemistry, by stepwise elongation of the amino acid chain, starting from tyrosine methyl ester. Use of the mixed anhydride procedure allowed coupling without the need for protection of the tyrosine hydroxyl. Several intermediates were purified by crystallization, including the protected hexapeptide 10. Cyclization was achieved in high yield employing an improved technique using diphenylphosphoryl azide, with sodium bicarbonate as base. Only a single chromatographic procedure was required, at the stage of the penultimate cyclic peptide 12. Using this synthetic route we have been able to prepare> 99% pure final product 1 in batches of 40-50 g. Yields based on each of the constituent residues ranged from 17%(Boc-alanine) to 52%(Boc-D-tryptophan). The process serves as an example of the kinds of considerations important for rapid and efficient large-scale synthesis of peptides.