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Design de uma nova via sintética para um API da família das te-traciclinas
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As tetraciclinas são antibióticos provenientes da fermentação de Streptomyces aureofaciens, utilizadas para o tratamento de uma diversidade de doenças como problemas dermatológicos (acne e rosácea), infeções urinária, respiratória e intestinal. A molécula alvo (A) é uma tetraciclina obtida por semi-síntese a partir da molécula B, e tratando-se de um intermediário extremamente importante na obtenção de outras tetraciclinas de 2ª e 3ª geração, de elevada relevância clínica. A síntese da molécula alvo (A) começa pela remoção do cloro da molécula B, formando a molécula C, que é posteriormente sujeita a desoxigenação com hidrogénio e Rh/C. Esta tese insere-se no âmbito do Protocolo de Cooperação cele-brado entre a Faculdade de Ciências da Universidade de Lisboa e a CIPAN- Companhia Industrial Pro-dutora de Antibióticos, S.A., e tem como objetivo a otimização da reação de desoxigenação com Rh/C, eventualmente sem a utilização de metais, com vista a tornar o processo mais económico, uma vez que o preço do ródio tem vindo a aumentar exponencialmente nos últimos anos, a nível mundial. Visto que, nunca se recorreu a uma abordagem à escala laboratorial com o objetivo de retirar o grupo hidroxilo sem recurso a reações de hidrogenação, fez-se um primeiro screeening para este tipo de rea-ções, com a possibilidade de um scale-up à escala industrial caso se obtenha resultados positivos. [Con-fidencial] Uma vez que a abordagem anterior não permitiu alcançar os resultados pretendidos, o foco voltou-se para as reações de hidrogenação catalítica, com vista quer à diminuição da quantidade de catalisador ou à sua substituição, quer ao aumento da seletividade da reação. Para tal, testaram-se a adição de aditivos a catalisadores de Rh/C ou Pd/C, a substituição parcial do ródio por outros metais mais económicos, a diminuição da quantidade de ródio utilizada e respetivas reutilizações, a utilização de diferentes tipos de carvão ativado no catalisador de ródio e, por fim, a utilização de sílica como um suporte diferente para o catalisador de ródio. Este trabalho contribuiu para a consolidação do processo atual da molécula alvo (A) e apontou novos caminhos de otimização no futuro, nomeadamente através do foco no estudo das reutilizações do catalisador de Rh/C.
Tetracyclines are antibiotics derived from the fermentation of Streptomyces aureofaciens, used for the treatment of a variety of diseases such as dermatological problems, urinary, and respiratory or intestinal infections. The target molecule (A) is a tetracycline obtained by semi-synthesis from molecule B, and it is an extremely important intermediate in the need for other highly clinical 2nd and 3rd generation tet-racyclines. The synthesis of the target molecule (A) begins by removing the chlorine of the molecule B, forming molecule C, which is subsequently completed by the deoxygenation with hydrogen and Rh/C. This thesis is part of the collaboration between FCUL and the Pharmaceutical Industry CIPAN and aims to optimize the deoxygenation reaction with Rh/C, possibly without the use of precious metals, to make the process economically advantageous, since the price of rhodium has been increasing exponentially in recent years, globally. As a laboratory-scale approach was never used with the objective of removing the hydroxyl group with-out recourse to hydrogenation reactions, a first screening was carried out for this type of reaction, with the possibility of a scale-up on an industrial scale if positive results are obtained. [confidencial] Since the classical approach did not yield the intended results, the focus turned to catalytic hydrogena-tion reactions, aiming at either decreasing in the amount of catalyst, replacing it with more economical alternatives, or increasing the selectivity of the reaction. To this end, tests the addition of additives to Rh/C or Pd/C catalysts was tested, as well as the partial replacement of rhodium by other cheaper metals, the reduction of the amount of rhodium used, different types of activated carbon in the rhodium catalyst and, finally, the use of silica as different support for the rhodium catalyst. This work contributed to the consolidation of the current process of the target molecule A and pointed out new paths of optimization in the future, namely pointing the focus to the study of the reuses of the Rh/C catalyst.
Tetracyclines are antibiotics derived from the fermentation of Streptomyces aureofaciens, used for the treatment of a variety of diseases such as dermatological problems, urinary, and respiratory or intestinal infections. The target molecule (A) is a tetracycline obtained by semi-synthesis from molecule B, and it is an extremely important intermediate in the need for other highly clinical 2nd and 3rd generation tet-racyclines. The synthesis of the target molecule (A) begins by removing the chlorine of the molecule B, forming molecule C, which is subsequently completed by the deoxygenation with hydrogen and Rh/C. This thesis is part of the collaboration between FCUL and the Pharmaceutical Industry CIPAN and aims to optimize the deoxygenation reaction with Rh/C, possibly without the use of precious metals, to make the process economically advantageous, since the price of rhodium has been increasing exponentially in recent years, globally. As a laboratory-scale approach was never used with the objective of removing the hydroxyl group with-out recourse to hydrogenation reactions, a first screening was carried out for this type of reaction, with the possibility of a scale-up on an industrial scale if positive results are obtained. [confidencial] Since the classical approach did not yield the intended results, the focus turned to catalytic hydrogena-tion reactions, aiming at either decreasing in the amount of catalyst, replacing it with more economical alternatives, or increasing the selectivity of the reaction. To this end, tests the addition of additives to Rh/C or Pd/C catalysts was tested, as well as the partial replacement of rhodium by other cheaper metals, the reduction of the amount of rhodium used, different types of activated carbon in the rhodium catalyst and, finally, the use of silica as different support for the rhodium catalyst. This work contributed to the consolidation of the current process of the target molecule A and pointed out new paths of optimization in the future, namely pointing the focus to the study of the reuses of the Rh/C catalyst.
Descrição
Tese de mestrado, Química (Química) Universidade de Lisboa, Faculdade de Ciências, 2021
Palavras-chave
API hidrogenação catalítica Ródio Teses de mestrado - 2021