Studies On The Stability Of Remazolam Salt And The Synthesis Of Natural Product Combretastatin D-1

This paper is divided into two parts.The first part is the stability study of remazolam salt.Remazolam is an ultra-short-acting sedative anesthetic developed by Paion for colonoscopy,Its besylate is currently still in phase III clinical experimental stage because of its greater toxicity.The corresponding tosylate is currently in phase III clinical trials for gastroscopy and sedation and phase II clinical trials for general anesthesia.At present,only remazolam sulfonate is reported in the literature.Given that the sulfonate has certain toxicity,we synthesized remazolam and its seven salts,including remazolam.besylate,remazolam.tosylate,remazolam.2besylate,remazolam.HCl,remazolam.2HCl,remazolam.0.3H₃PO₄ and remazolam.0.5H₂SO₄.Our studies toward investigation of their stability showed that:?1?The reported corresponding besylate and tosylate are stable at room temperature.?2?Remazolam.2HCl and Remazolam.2besylate are stable at low temperature,and the former is more stable than the latter?3?remazolam.0.3H₃PO₄,remazolam.2HCl and remazolam.0.5H₂SO₄ are unstable even at low temperature.NMR data showed that the reason for its instability is mainly caused by the hydrolysis of side ester chain.The besylate and tosylate of remazolam are stable compounds.However,both have significant side effects in animal experiments.Therefore,the research in this part laid foundation for exploring the ideal remazolam derivatives and their salts,providing important suggestion for further research.The second part of the paper is the study on the total synthesis of natural product combretastatin D-1.Combretastatin,isolated from Combretum caffrum in South Africa,is a series of stilbene compounds with antitumor activity with similar structure to colchicine,D-1 is one of them.Structurally,combretastatin D-1 contains a 15-membered lactone ring and epoxy functional group.We have designed a new synthetic route for combretastatin D-1.Corey–Chaykovsky epoxidation was used as the key reaction to construct its15-membered ring skeleton.This paper is mainly divided into the following four chapters:The first chapter introduces the classification of anesthetics and structure of benzodiazepines as representative drugs of sedative hypnotics,including the physical and chemical properties and development process of remazolam.The second chapter described the synthesis of remazolam from?2-amino-5-bromophenyl??pyridine-2-yl?methanone via acylation,acidification with hydrochloric acid dioxane,intramolecular condensation,the nucleophilic reaction with?R?-1-amino-2 propanol and the final oxidation reaction,The synthesis of remazolam need 5steps in a total yield of 47%.Due to the instability of remazolam,we have synthesized several salts of remazolam,including remazolam.2besylate,remazolam.HCl,remazolam.2HCl,remazolam.0.5H₂SO₄,remazolam.0.3H₃PO₄.Investigation of their stability was carried out.The third chapter introduces combretastatin natural products and summarizes the synthetic route of D-1 in the literature.The fourth chapter introduces the concept of our synthetic design and experimental results of combretastatin D-1.Studies toward the total synthesis of combretastatin D-1showed that halogenation of the benzyl alcohol,oxidation of the monoester formed from ethylene glycol,and a late-stage Corey–Chaykovsky epoxidation was key for the successful of the total synthesis.Carefully investigation of the epoxidation reaction was performed and the target natural product was not obtained at present.