Route Optimization and Manufacture of Multihundred Grams of a Ghrelin Receptor Agonist

被引：8

作者：

Karlsson, Staffan ^{[1
]}

Gardelli, Cristina ^{[2
]}

Lindhagen, Marika ^{[1
]}

Nikitidis, Grigorios ^{[1
]}

Svensson, Tor ^{[2
]}

机构：

[1] AstraZeneca Gothenburg, IMED Biotech Unit, Pharmaceut Sci, Early Chem Dev, SE-43183 Molndal, Sweden

[2] AstraZeneca Gothenburg, IMED Biotech Unit, Resp Inflammat & Autoimmun, Med Chem, SE-43183 Molndal, Sweden

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2018年 / 22卷 / 09期

关键词：

enzymatic resolution; desymmetrization; Curtius rearrangement; allylzinc; selective hydrolysis; hydroboration; ASYMMETRIC-SYNTHESIS; INHIBITOR; CACHEXIA; REARRANGEMENT; INTERMEDIATE; DISCOVERY; REAGENTS; CATALYST; ESTERS; SCALE;

D O I：

10.1021/acs.oprd.8b00179

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

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.

引用

页码：1174 / 1187

页数：14

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