Synthesis Of Catinoic Lipid DLin-MC3-DMA And 5α-chloro-androstane-6β, 19-epoxy-3, 17-dione

This thesis focuses on the synthesic methods of the cationic liposome DLin-MC3-DMA compounds and an important intermediate of steroids,5a-chloro-androstane-6β,19-epoxy-3,17-dione.1. Synthesis of series cationic liposome DLin-MC3-DMA compounds.RNA interfering (RNAi) is a ubiquitous and highly effective biological mechanism to control gene expression, which has attracted people’s attention, because its wide application in the field of gene therapy for malignant tumor. The small interfering RNA (siRNA) molecules can potently harness RNAi in humans and animal models, can inhibit specific tumor related to gene expression, in order to achieve the purpose of inhibiting tumor growth, invasion and metastasis. Unfortunately, siRNA itself cannot enter tumor cells, therefore, delivery systems is the critical issue of siRNA gene therapy. Cationic liposome is widely used in the delivery systems of siRNA as a non-viral vector, with the advantages of non-toxic, non-immunogenicity and good biocompatibility, also it can be naturally degradated and easily modified. Linoleic acid was used as starting material to obtain the target product DLin-MC3-DMA through five-step reactions, including reduction with lithium aluminum hydride, nucleophilic substitution (SN2) with bromine, Grignard reaction, hydrolysis and esterification. The structure of the compund was characterized by 1H and13C NMR, HRMS, which has been applied to the siRNA research. At the same time, a series of key intermediates (Lipid A～Lipid G) of cationic liposome were also synthesized.2. Synthesis of 5a-chloro-androstane-6β,19-epoxy-3,17-dione.5a-chloro-androstane-6β,19-epoxy-3,17-dione is the key intermediate of steroid drugs. At present, the world is facing unique and daunting environmental issues.The field of steroid chemistry is undergoing a great change and it is urgent to explore novel environment-friendly synthetic strategies to meet the requirement of potential economic development. This thesis reported an innovative synthetic approach of 5a-chloro-androstane-6β,19-epoxy-3,17-dione from a commercially available starting material androst-4-ene-3,17-dione. Through six-step reactions:esterification, reduction with sodium borohydride, esterification with acetic anhydride, nucleophilic addition, hydrolysis after cyclization and oxidation, the target product was obtained in a total yield of 58%. In this part, a simple, versatile, and highly efficient procedure was demonstrated for preparation of 5a-chloro-androstane-6β,19-epoxy-3,17-dione, which can be widely implemented in industry.