The Methodology Study For The Synthesis Of Phthalides And Its Application For The Preparation Of Tetrahydroisoquinolines

Phthalides, heterocycles with the skeleton of isobenzofuran-1(3H)-one, show extensive bioactivity and some of them were widely used as drugs. Phthalide-3-carboxylic acids are important synthon for the synthesis of phthalide isoquinolines and benzo-peptide triazines.Here summarized the research and development of phthalide-isoquinolines, the background knowledge of their configuration, activities and so on. It was also summarized in this thesis, the various synthetic methods for constructing the scaffold of phthalide-isoquinolines,among which was a very efficient synthetic strategy via Bischler-Napieralski reaction from phthalide-3-carboxylic acids. Nevertheless, the updated methods for the synthesis of phthalide-3-carboxylic acids were very complicated.We designed and tuned a novel methodology for the concise synthesis of phthalide-3-carboxylic acids via a acid-catalyzed, "one-pot" reaction of aryl acids with glyoxylic acid. The reaction conditions such as the mole ratio of starting materials loaded, type and amount of catalysts, reaction solvent and temperature were extensively studied, and it was also studied the scope and limitation of this reaction. Six new phthalide-3-carboxylic acids and five novel 3-oxo-isochroman-carboxylic acids were prepared in this thesis.Based upon the obtained results, our attention was then paid to the synthesis of some phthalide isoquinoline alkaloids and their analogues. Hence,6 erythro alkaloids and 3 not yet reported alkaloids were successfully prepared. The conditions of the reactions were preliminarily studied so that it might be a good beginning for the further study of this topic.All the key intermediates and target compounds were identified by MS and 1H-NMR.