The aim of this master's thesis is to present the application of copper-free Sonogashira reaction conditions in the formation of active pharmaceutical ingredients, starting from aryl chlorides or bromides and terminal acetylenes as substrates.
Aryl chlorides are an accessible and cheaper alternative to aryl bromides, the same as aryl bromides are to aryl iodides. The downside of using bromides and chlorides is their reactivity, which is strongly decreased because of the stronger interaction between the bromine and chlorine atom and the aromatic ring.
In this master’s thesis current industrial processes for the synthesis of three active pharmaceutical ingredients are presented, which include at least one step of Sonogashira reaction with Pd/Cu co-catalysis. This step was replaced by a copper-free Sonogashira reaction procedure and was optimized when necessary. Selected intermediates or end products were prepared.
Firstly, the reaction conditions for the conversion of aryl bromides via the copper-free Sonogashira reaction were applied to the synthesis of the active pharmaceutical ingredient Fenleuton. Secondly, the reaction conditions for the conversion of aryl bromides via the Sonogashira copper-free reaction were applied to a Candidiasis drug synthesis process. Finally, the copper-free Sonogashira reaction catalytic system for the cross-coupling of aryl chlorides and acetylenes was applied to the synthesis path of TRPV1 receptor antagonist. The reaction conditions were adapted to each case as needed.
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