Behzad Karrabi, H. Fakhraian, A. Moghimi
Jul 4, 2019
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Organic Preparations and Procedures International
Abstract
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.