Martinelli Andrea, Volpicelli Raffaella, Verzini Massimo, Cotarca Livius, Maini Lucia, Pengo Paolo, Pasquato Lucia
Department of Chemical and Pharmaceutical Sciences, University of Trieste, via L. Giorgieri 1, 34127 Trieste, Italy.
Research and Development Laboratories, ZaCh System, via Dovaro, 36045 Almisano di Lonigo, Vicenza, Italy.
ACS Omega. 2023 Jul 21;8(31):28851-28858. doi: 10.1021/acsomega.3c03959. eCollection 2023 Aug 8.
The key intermediate in the synthesis of dorzolamide, (4,6)-methyl-5,6-dihydro-4-thieno[2,3-]thiopyran-4-ol-7,7-dioxide, can be obtained in the diastereoisomerically pure form in two straightforward steps starting from diastereoisomeric mixtures of /-(6)-6-methyl-5,6-dihydro-4-thieno[2,3-]thiopyran-4-yl acetate, regardless of their ratio. The reaction of crucial importance in this scheme is a remarkably stereoselective solvolysis of the acetate ester in an acetone/phosphate buffer mixture as the solvent system. Investigation of this so far unrecognized stereoselective reaction reveals that it proceeds via an S1-like pathway as indicated by the correlation of the solvolysis rate constants with the values of different solvent mixtures and by trapping of the reaction intermediate with sodium azide. The structure of (4,6)-methyl-5,6-dihydro-4-thieno[2,3-]thiopyran-4-ol-7,7-dioxide was confirmed by single-crystal X-ray analysis.
多佐胺合成中的关键中间体，即(4,6)-甲基-5,6-二氢-4-噻吩并[2,3-]噻喃-4-醇-7,7-二氧化物，可从/-(6)-6-甲基-5,6-二氢-4-噻吩并[2,3-]噻喃-4-基乙酸酯的非对映异构体混合物出发，通过两个直接步骤以非对映异构体纯的形式获得，而不论它们的比例如何。该方案中至关重要的反应是在丙酮/磷酸盐缓冲液混合物作为溶剂体系中，乙酸酯的显著立体选择性溶剂解反应。对这种迄今未被认识的立体选择性反应的研究表明，它通过类似S1的途径进行，这一点由溶剂解速率常数与不同溶剂混合物的 值的相关性以及用叠氮化钠捕获反应中间体所表明。(4,6)-甲基-5,6-二氢-4-噻吩并[2,3-]噻喃-4-醇-7,7-二氧化物的结构通过单晶X射线分析得以确证。
