Atipamezole (or Antisedan, Scheme 1, 1) is a synthetic a2-adrenergic receptor antagonist having high affinity with the two alpha-2 adrenoceptor subtypes (a2A and a2B). 2,3 Although it is a drug of choice in veterinary medicine for countering the anesthesia and sedation produced by such a2 adrenergic agonists as Medetomidine and Xylazine, it may ultimately also have a role in human medicine. Focus on the a2 agonists and their antagonists have spurred on their synthesis. A number of methods for the synthesis of Atipamezole have been reported. Significant among these methods has been the one shown in Scheme 1. In the present report, we describe a re-investigation of this method for the synthesis of Atipamezole, including the characterization of some crucial intermediates and several new analogs of 1. Our work followed the order shown in Schemes 2A (Atipamezole) and 2B (Analogs). In the event, the reaction of phthalide and 1-trityl-1H-imidazole-4-carboxaldehyde in ethyl acetate led without complication to the corresponding indanedione (Scheme 2a, 2, 76%). Treatment of the dione with potassium carbonate and a five-fold excess of ethyl iodide in acetone produced the alkylated product 3 (77%), as a readily-isolated crystalline product. Subsequently, an acidic solution of 3 was treated with Pd/C catalyst in a hydrogen autoclave system at 3.5-4.0 bar hydrogen pressure at 80 C for several hours to yield the target of synthesis 1 (56%) as its hydrochloride. This procedure offers the advantages of simplicity and convenience. The deprotection step (trityl cleavage) and reduction step have been combined in our work. Moreover, the precursor carboxaldehyde of our method is commercially available and is less expensive than the tritylated iodide of Scheme 1. In extending our work to analogs of Atipamezole, we prepared compounds 4-6 and fully characterized them, as well as their respective synthetic intermediates. In sum, we have re-investigated a significant procedure for the synthesis of the a2adrenergic receptor antagonist Atipamezole, leading to a simplification and shortening of the process. We have used our method for the preparation of several analogs of Atipamezole and have characterized the synthetic intermediates in their production. It is our hope that the data presented here and the convenience of our method will facilitate further investigation of this important class of compounds.

中文翻译：

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阿替美唑合成与新类似物制备的再研究

Atipamezole（或 Antisedan，Scheme 1, 1）是一种合成的 a2-肾上腺素能受体拮抗剂，与两种 α-2 肾上腺素受体亚型（a2A 和 a2B）具有高亲和力。2,3 虽然它是兽药中的首选药物，用于对抗由美托咪定和甲苯噻嗪等 2 肾上腺素激动剂产生的麻醉和镇静作用，但它最终也可能在人类医学中发挥作用。对 a2 激动剂及其拮抗剂的关注刺激了它们的合成。已经报道了多种合成阿替美唑的方法。这些方法中最重要的是方案 1 中所示的方法。在本报告中，我们描述了对这种合成阿替美唑的方法的重新研究，包括一些关键中间体和 1 的几种新类似物的表征。我们的工作遵循方案 2A（阿替美唑）和 2B（模拟）中所示的顺序。在这种情况下，邻苯二甲醚和 1-trityl-1H-imidazole-4-carboxaldehyde 在乙酸乙酯中的反应不会导致相应的茚二酮（方案 2a，2，76%）复杂化。用碳酸钾和五倍过量的碘乙烷在丙酮中处理二酮，产生烷基化产物 3 (77%)，作为容易分离的结晶产物。随后，3的酸性溶液在氢气高压釜系统中用Pd/C催化剂在3.5-4.0巴氢气压力和80°C下处理数小时以产生作为其盐酸盐的合成目标1（56%）。此过程提供了简单和方便的优点。脱保护步骤（三苯甲基裂解）和还原步骤已在我们的工作中结合。而且，我们方法的前体甲醛是可商购的，并且比方案 1 中的三苯甲基碘化物便宜。为了将我们的工作扩展到阿替美唑的类似物，我们制备了化合物 4-6 并对其进行了充分表征，以及它们各自的合成中间体。总之，我们重新研究了合成 a2 肾上腺素能受体拮抗剂阿替美唑的重要程序，从而简化和缩短了该过程。我们已经使用我们的方法制备了几种阿替美唑类似物，并在其生产过程中表征了合成中间体。我们希望这里提供的数据和我们方法的便利性将有助于进一步研究这一类重要的化合物。