A More Sustainable Process for Preparation of the Muscarinic Acetylcholine Antagonist Umeclidinium Bromide,ChemMedChem

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A More Sustainable Process for Preparation of the Muscarinic Acetylcholine Antagonist Umeclidinium Bromide
ChemMedChem ( IF 3.6 ) Pub Date : 2018-08-31 , DOI: 10.1002/cmdc.201800387
Margarida Espadinha ₁ , Nuno M. T. Lourenço ₂ , Luis Sobral ₂ , Rafael Antunes ₂ , Maria M. M. Santos ₁

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A more sustainable process for the synthesis of the long‐acting muscarinic acetylcholine antagonist umeclidinium bromide is described. Specifically, we report the synthesis of ethyl 1‐(2‐chloroethyl)‐4‐piperidinecarboxylate, a key intermediate in the preparation of umeclidinium bromide, in good yields using triethylamine, as well as the identification and characterization of the by‐product formed in this reaction. This new method of synthesis leads to an improvement in yield over that of previously reported protocols using potassium carbonate as base (65.6 % versus 38.6 %). Moreover, in the final synthetic step of the process to obtain umeclidinium bromide, we were able to replace the use of toxic solvents (acetonitrile/chloroform) with water. The use of this green solvent allowed precipitation of the active pharmaceutical ingredient (API) from the reaction medium with high purity and in high yield. Overall, we have developed a more efficient and environmentally friendly process for the synthesis of the umeclidinium bromide API with a higher overall yield (37.8 % versus previously reported overall yield of 9.7 %).

中文翻译：

制备毒蕈碱型乙酰胆碱拮抗剂Umeclidinium Bromide的更可持续的方法

描述了一种长效毒蕈碱型乙酰胆碱拮抗剂溴化乌米地林的更可持续的合成方法。具体而言，我们报告了使用三乙胺以高收率合成1-（2-氯乙基）-4-哌啶甲酸乙酯（一种制备溴乌梅啶鎓的关键中间体）的合成方法，以及对在其中形成的副产物进行鉴定和表征的方法。这个反应。与以前报道的使用碳酸钾为碱的方案相比，这种新的合成方法可提高收率（65.6％比38.6％）。此外，在获得溴化乌梅地铵的过程的最后合成步骤中，我们能够用水代替有毒溶剂（乙腈/氯仿）的使用。使用这种绿色溶剂可使活性药物成分（API）从反应介质中以高纯度和高收率沉淀出来。总体而言，我们已经开发出了一种效率更高，对环境更友好的方法，以更高的总收率（37.8％对比之前报道的9.7％的总收率）合成溴化乌米地铵API。

更新日期：2018-08-31

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