Improved Epoxidation Methodology for Synthesis of the Highly Selective β2-Adrenoceptor Antagonist ICI 118551 [erythro (±)-3-Isopropylamino-1-(7-methylindan-4-yloxy)butan-2-ol]
Improved Epoxidation Methodology for Synthesis of the Highly Selective β2-Adrenoceptor Antagonist ICI 118551 [erythro (±)-3-Isopropylamino-1-(7-methylindan-4-yloxy)butan-2-ol]
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用于合成高选择性 β2-肾上腺素受体拮抗剂 ICI 118551 [赤式 (±)-3-异丙氨基-1-(7-甲基茚满-4-基氧基)丁-2-醇] 的改进环氧化方法
DOI：
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发表时间：
1999
期刊：
影响因子：
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通讯作者：
M. Sillence
中科院分区：
文献类型：
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作者：
G. Pegg;T. Badran;A. Hoey;Clifford M. Jackson;M. Sillence
在本文中，我们描述了一种大大改进的合成选择性β2-肾上腺素受体拮抗剂ICI 118551（1）的方法，该方法克服了其原始制备中描述的反复无常的分级结晶和环氧化方法。我们的方法涉及关键环氧化物中间体（7）的溴代醇前体，得到（7）的苏式/反式异构体的85：15混合物，其可以通过在胺预处理的二氧化硅上的快速色谱法方便地分离。这种新方法证明比如原始专利文献中所述的通过分级结晶分离前体烯烃异构体（6）的尝试成功得多。当在体外和体内测试时，发现通过使用我们的方法获得的产物（1）具有与真实ICI 118551相同的药理学性质。
In this communication we describe a much improved methodology for the synthesis of the selective β2-adrenoceptor antagonist ICI 118551 (1), a procedure which overcomes capricious fractional crystallization and epoxidation methodologies described for its original preparation. Our approach involving a bromohydrin precursor to the key epoxide intermediate (7) yielded an 85 : 15 mixture of the in threo/erythro isomers of (7) which could be conveniently separated by flash chromatography on amine-pretreated silica. This new approach proved much more successful than attempts to separate the precursor alkene isomers (6) by fractional crystallization as described in the original patent literature. The product (1) obtained by using our methodology was found to have identical pharmacological properties to authentic ICI 118551 when tested both in vitro and in vivo.