Development of a manufacturing process for sibenadet hydrochloride, the active ingredient of viozan
Development of a manufacturing process for sibenadet hydrochloride, the active ingredient of viozan
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DOI：
10.1021/op049953y
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发表时间：
2004-07-01
影响因子：
3.4
通讯作者：
Smith, SJ
中科院分区：
文献类型：
--
作者：
Giles, ME;Thomson, C;Smith, SJ
已开发了用于商业化生产双重D-2-β（2）受体激动剂盐酸西贝那地的方法。该过程依赖于在最后阶段引入操作简单的化学反应，其中两个关键中间体反应以组装最终分子，通过结晶分离。开发了关键的胺盐酸盐中间体的九步合成序列，并对原工艺进行了改进。主要的战略性改进是在定义的最终路线的“侧链”前体分子，第二个关键中间体，围绕一个巯基自由基加成和随后的高产率的伸缩过程，用于合成这种高度结晶的苯甲酸酯。这些化学的发展进行了讨论，连同周围的最终验证的商业工艺的定义的一些问题。
A process for commercial manufacture of the dual D-2-beta(2) receptor agonist sibenadet hydrochloride has been developed. The process relies upon introduction of operationally simple chemistry at the final stages where two key intermediates are reacted to assemble the final molecule, isolated by crystallization. A nine-stage sequence for synthesis of the key amine hydrochloride intermediate was developed, and modifications to the original process are described. Major strategic improvements were made in definition of the final route to the "side chain" precursor molecule, the second key intermediate, hinging around a thiyl radical addition and subsequent high-yielding telescoped processes for synthesis of this highly crystalline benzoate ester. Development of these chemistries is discussed, together with some issues surrounding definition of the final validated commercial processes.