Ručilová Veronika Ph.D.

Development of Strategies for Solid-Phase Synthesis of Nitrogenous Heterocyclic Compounds Based on the 2- and 4-Nitrobenzenesulfonamide Chemistry

The submitted doctoral thesis deals with the development of simple procedures applicable for the preparation of libraries of selected heterocyclic compounds. In all of the introduced procedures, the immobilized 2- or 4-nitrobenzenesulfonamides were used as the key intermediates. Different scenarios have been used in which the nitrobenzenesulfonyl (Nos) group was applied (1) only as a protective/activating group for Fukuyama selective monoalkylation followed by the cleavage of the sulfonamide scaffold, (2) as a building block after previous Fukuyma alkylation, or (3) as a building block without application of Fukuyama alkylation. The key intermediates were further modified and converted to the target products under different cyclization conditions. During our long-term research we have developed high-throughput solid-phase syntheses of various heterocyclic compounds involving six types of different scaffolds.

Preparation of bisheterocyclic derivatives of 3-hydroxy-4(1H)-quinolinone-7-carboxamides

The focus of the submitted Diploma thesis is the solid phase synthesis of new bisheterocyclic derivatives of 2-substituted-3-hydroxyquinolin-4(1H)-one-7-carboxamides. The first part of literature search summarizes the threee main points: synthesis, biological and fluorescence properties of known derivatives of hydroxyquinolones. The conclusion of the theoretical part is devoted to the synthesis of o-phenylenediamines which are used as a building bloks of nitrogen heterocycles. The experimental part is focused on the development and optimalization of the above mentioned precursores . There are also attempts to a cyclization of correspondent intermediate to benzimidazole-hydroxyquinolones.

Solid-Phase synthesis of precursors of bisheterocyclic derivatives of 3-hydroxy-4(1H)-quinolinone.

The main target of this work was preparation of the precursors leading to the new type of 3-hydroxy-4-(1H)-quinolinone derivatives, compounds with potential biological importance. In this regard, we first focused our attention on the synthesis of intermediates resulting in the connection of the heterocycle and hydroxyquinoline skelet in position 7 via spacer with amide group. For this purpose we prepared a model intermediate methyl 4-((3-hydroxypropyl)carbamoyl)-2-nitrobenzoate using the solid-phase synthesis. Later, we worked on the successful conversion of hydroxy group of model intermediate to primary or secondary amino group. After synthesis of target intermediate, we tried to prepare a model bisheterocycle of hydroxyquinoline-thiazole. Unfortunately, the attempt was not successful and it will be necessary to focus on optimisation of the final reaction step.