Late-stage oxygenation of active ingredients

Tese de mestrado, Química (Química), 2022, Universidade de Lisboa, Faculdade de Ciências ; The safety profile analysis of active ingredients (AIs) is essential for the development of agrochemicals. This includes identification and toxicity determination of the corresponding metabolites, which ultimately requires preparation of metabolites. C-oxygenation is recurrent in phase I metabolism, catalyzed in vivo by cytochrome P450 enzymes. Thus, the synthesis of hydroxylated AI metabolites is important to agrochemical producing companies, such as ASCENZA Agro. In this work, reported methodologies employing bis(methanesulfonyl) peroxide as an oxidant were selected for the late-stage aromatic and benzylic oxygenation of agrochemical AIs. Screening of several methods for the preparation of bis(methanesulfonyl) peroxide was performed, along with the optimization of a method for the synthesis of this reagent. The aromatic C-oxygenation of several agrochemical AIs, including pyrimethanil, bentazone and deltamethrin, using bis(methanesulfonyl) peroxide is shown, along with the preparation of two pyrimethanil hydroxylated derivatives, one of which is a known metabolite. Additionally, the applicability of the benzylic hydroxylation method for pyrimethanil and deltamethrin was studied. Progress towards the preparation of a florasulam hydroxylated metabolite was achieved, including the design of a total synthesis route that showed promising results. ; O setor agrícola é, enquanto setor primário, essencial para o desenvolvimento de um país. Uma vez que os agroquímicos são cruciais para a agricultura, o desenvolvimento destes compostos revela-se de extrema importância. A determinação dos perfis de segurança de princípios ativos é fundamental para o desenvolvimento de agroquímicos, e inclui a preparação e a determinação da toxicidade dos seus metabolitos. As reações de oxigenação aromática e benzílica são um passo recorrente no metabolismo de fase I, sendo catalisadas in vivo por enzimas citocromo P450. Consequentemente, a síntese ...