STUDY OF ACECLIDINE SEMISYNTHESIS VIA CINCHONA ALKALOID TRANSFORMATION

• Main Author: Vera Nanda S Pd, Elsa
• Format: Theses
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/33988
• Institution: Institut Teknologi Bandung

Cinchona spesies is a medicinal plant that has been used as an antimalarial since centuries ago. The production of quinine in Indonesia reaches 150 tons per years. Currently, the use of quinine has been greatly reduced due to resistance of Plasmodium paracite and replaced by other drugs such as artemisinin and chloroquine. In the other hand, Cinchona alkaloid is also used as ligands for asymmetric reactions or as chiral pool. In general, the aim of quinine transformation is to obtain the new method in catalytic asymmetric synthesis. In this study, we designed cinchona alkaloid as chiral pool for drug synthesis. One of the application of quinine as a chiral pool can be done utilizing quinuclidine and quinoline ring. This study aims to conduct studies relating to semisynthesis aceclidine compounds, by utilizing the cinchona alkaloid as chiral pool in efforts to use quinine production in Indonesia. Aceclidine compound is a glaucoma drug that has quinuclidine framework. To achieve these objectives quinuclidine unit is expected to be obtained through the stages of oxidation reaction. Quinine can be oxidized to produce quinotoxine. The existence of ketone group at quinotoxine allows the termination of carbon-carbon bond via Beckmann rearrangement reaction to obtain the amide product which can then be hydrolyzed to obtain vinyl quinotoxine ring. In this research, the variation of substrates and reagents in Beckmann rearrangement method focus on study of the effectiveness of this method in the vinyl quinotoxine ring termination. Oxidation of hydroxyl groups conducted by reacting quinine with acetic acid and water. Quinotoxine formation is characterized by the appearance of the carbonyl signal at 13C spectrum with chemical shift value of 203 ppm. In addition, the alkenes signal exist in the area of 5.73 ppm with a multiplicity of multiplet and also in the area of 5.17 ppm with an integration of 2 H. As for the product of Beckmann rearrangement reaction with quinotoxine as the substrate, NMR spectral data showed the shift of proton signal 1H and the presence of carbon signals in 160 ppm, indicate that the product, oxime quinotoxine, has been formed. The next step in the transformation of vinyl group into a ketone group quinuclidine can be synthesized by Wacker method which uses a palladium catalyst. At the end, the aceclidine will be obtained as a result Baeyer Villager reaction of the ketone group, which was oxidized to Wacker product, to obtain ester group. We have successfully obtained oxime quinitoxine of quinine through two stages of the reaction. Oxime product is a precursor for the synthesis aceclidine to go through three stages, namely the termination reaction quinuclidine ring, Wacker reaction and subsequent Baeyer Villager reaction.