Síntese de intermediários chaves na produção de gliflozinas e canabinóides sintéticos, e sua possível transferência em reatores de fluxo contínuo

Abstract

Continuous flow process has allowed both the intensification and the optimization of important steps in the production of bioactive compounds. The main goal of this work was to evaluate and adapt, under continuous flow conditions, potential synthetic routes for the preparation of important precursors in the synthesis of hypoglycemic agents belonging to the family of gliflozins and, for the preparation of terpenic intermediates of bioactive cannabinoids. The study has two chapters. In the first chapter, the synthesis of C-β-glycopyranoside was performed and its possible application in the production of canagliflozin (1). The study comprised three important steps: 1) obtaining benzyl chloride (50) in a continuous flow as a protective reagent; 2) the batch synthesis of O-protected glycones with benzyl group (Bn) and trimethylsilane (TMS), 16 and 17, derivatives of δ–gluconolactone (46) and 3) the application of glycosylated intermediates in the stereoselective formation of canagliflozin (1). In the first study, a photochemical process was adapted and optimized to obtain the benzyl chloride (44) and its application as a protecting group. This study provided information on the possibility of using TCCA as a selective chlorination reagent for toluene in the benzyl position to obtain 50 in batch and continuous flow reactors. Also, we study the optimization of batch processes in the formation of intermediates 16 and 17, and its application in obtaining canagliflozin as a model. However, the synthesis of canagliflozin (1) and its evaluation in continuous flow reactors was not possible to be performed under the conditions tested here. In the second chapter, we have investigated the synthesis of p-mentha-2,8-dien-1-ol (67) as a cannabinoid precursor by photochemical oxidation of (R)-limonene (106) with singlet oxygen (1O2) in the presence of a photosensitizer. The study includes the adaptation and optimization of a methodology for the photo-oxidation of (R) -limonene in batch reactors and, the implementation of home-made engineered set-ups, coupled to an in-line oxygen saturation system, in continuous flow conditions. The study began with the screening of photosensitizers for the photo-oxidation of 106 in the batch reactors. The use of tetrafenilporphyrin (TPP, of 118) allowed obtaining selective quantitative conversions of around 48% using substrate concentrations of up to 0.1 M. On the optimized conditions, we performed the 67 syntheses in continuous flow conditions using different customized photoreactors. We used four types of customized photoreactors. The application continuous flow reactor allowed the reduction of photosensitizer load in up to 20 times and, increase process productivity up to 100 times when compared to batch processes. Also, the use of a low-temperature photoreactor allowed to increase the level of regioselectivity to obtain the terpene intermediate by 18%, the selectivity of the reaction, however, with lower conversion rates.