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Doctoral Thesis
DOI
https://doi.org/10.11606/T.9.2021.tde-07022022-103647
Document
Author
Full name
Paulo Victor Cuesta Calvo
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2021
Supervisor
Committee
Palma, Mauri Sergio Alves (President)
Santana, Harrson Silva
Vianna, Fernanda Cristina
Vilar, Vítor Jorge Pais
Title in Portuguese
Desenvolvimento de rota sintética da Rosiglitazona em processo batelada e microrreator capilar
Keywords in Portuguese
Density Functional Theory - DFT
Elucidação teórica
Glitazonas
Síntese em fluxo
Síntese orgânica
Transposição batelada para fluxo contínuo
Abstract in Portuguese
Para que os fármacos possam ser comercializados economicamente, a sua escala de produção deve ser aumentada para atender à demanda do mercado. Atualmente, a maior parte dos fármacos são sintetizados em processos batelada que possuem limitações quanto à eficiência de mistura, temperatura e pressão. O uso de microrreatores surge como alternativa na indústria químico-farmacêutica, aumentando a eficiência dos processos de maneira segura. Ferramentas utilizadas no segmento computacional multidisciplinar teórico, como o DFT (Density Functional Theory), podem prever e compreender o comportamento das reações químicas, podendo ter grande utilidade na síntese de novos fármacos economizando tempo, investimento e reduzindo a geração de resíduos. A diabetes mellitus é uma doença de caráter epidêmico, que a cada ano vem aumentando o número de casos. O emprego de fármacos derivados das glitazonas no tratamento de diabetes mellitus tipo 2 é recomendado devido ao excelente controle glicêmico que esta classe de fármacos oferece. Neste trabalho, foi sintetizada a Rosiglitazona, um fármaco derivado das glitazonas, que auxilia no tratamento da diabetes mellitus tipo 2, sendo estudadas duas rotas de síntese distintas, que foram otimizadas com o intuito de maximizar o rendimento de seus intermediários, obtendo a Rosiglitazona com pureza de cerca de 94%. Foi realizada, para os intermediários, aqui denominados, 1R, 2R2 e 3R2 a síntese one-pot e para os intermediários 1R, 2R1 e 3R2 foi realizada a transposição do processo usual em batelada para fluxo contínuo no microrreator, com rendimentos de até 93%. Com o auxílio da química quântica computacional, a reação de síntese do intermediário 1R, foi elucidada teoricamente e determinadas as grandezas termodinâmicas (ΔH, ΔG e ΔS) no estado de transição, que foram comparadas com os valores experimentais, sendo constatada uma boa concordância, com desvio máximo de 14%.
Title in English
Rosiglitazone synthetic route development in batch process and capillary microreactor
Keywords in English
Density Functional Theory - DFT
Flow synthesis
Glitazones
Organic synthesis
Theoretical elucidation
Transposition from batch to flow
Abstract in English
In order for drugs to be commercialized economically, their production scale must be increased to meet market demand. Currently, most drugs are synthesized in batch processes that have limitations in terms of mixing efficiency, temperature and pressure. The use of microreactors appears as an alternative in the chemical-pharmaceutical industry, increasing the efficiency of the synthesis processes in a safe way. Tools used in the theoretical multidisciplinary computational segment, such as DFT (Density Functional Theory), can predict and understand the behavior of chemical reactions, and can be very useful in the synthesis of new drugs, saving time, investment and reducing waste generation. Diabetes mellitus is an epidemic disease that has been increasing the number of cases every year. The use of drugs derived from glitazones in the treatment of type 2 diabetes mellitus is recommended due to the excellent glycemic control that this class of drugs offers. In this work, Rosiglitazone, a drug derived from glitazones, which helps in the treatment of type 2 diabetes mellitus, was synthesized. Two different synthetic routes were studied and optimized in order to maximize the yield of its intermediates, obtaining Rosiglitazone with purity of about 94%. One-pot synthesis was performed to 1R, 2R2 and 3R2 intermediates, and the transposition from the usual batch process to continuous flow in microreactor was performed to 1R, 2R1 and 3R2 intermediates, with yields of up to 93%. With the aid of computational quantum chemistry, the intermediate 1R synthesis reaction was theoretically elucidated and the thermodynamic properties were determined (ΔH, ΔG and ΔS) in the transition state, which were compared with the experimental results, obtaining good agreement, with a maximum deviation of 14%.
 
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Publishing Date
2022-02-07
 
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