Route Optimization and Manufacture of Multihundred Grams of a Ghrelin Receptor Agonist,Organic Process Research & Development

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Route Optimization and Manufacture of Multihundred Grams of a Ghrelin Receptor Agonist
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-09-05 00:00:00 , DOI: 10.1021/acs.oprd.8b00179
Staffan Karlsson ₁ , Cristina Gardelli ₂ , Marika Lindhagen ₁ , Grigorios Nikitidis ₁ , Tor Svensson ₂

Affiliation

A linear 14-step sequence was developed for the synthesis of an oxaspirocyclic cyclopentane-based candidate drug 1 containing four chiral centers. Compared with the first-generation synthesis with an overall yield of 0.7%, which also included several chromatographic purifications, the large-scale approach furnished >800 g of API 1 in 19% overall yield, and chromatography was avoided in all but two steps. The major achievements were the development of a Curtius rearrangement where hazards were minimized, a robust and safer dose-controlled allylzinc addition to a ketone, and a selective monohydrolysis of a diester.

中文翻译：

Ghrelin受体激动剂的数百克路线优化和制造

开发了线性的14步序列，用于合成含有四个手性中心的基于氧杂螺环环戊烷的候选药物1。与总产率为0.7％的第一代合成法（其中还包括多次色谱纯化）相比，大规模方法提供的总产率为19％的原料中提供了超过800 g的API 1，除两步外均避免了色谱法。主要成就是开发了Curtius重排，可最大程度地减少危害，向酮中添加功能强大且更安全的剂量控制烯丙基锌，以及二酯的选择性单水解反应。

更新日期：2018-09-05

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