A carregar...
Publicação
Aplicação de métodos computacionais ao estudo de reações de síntese de substâncias farmacêuticas ativas
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 4.35 MB | Adobe PDF |
Orientador(es)
Resumo(s)
Neste trabalho, foram realizados estudos computacionais e experimentais, de reações químicas utilizadas em processos industriais de produção de substâncias ativas, com o objetivo de avaliar de que forma a utilização de métodos computacionais poderá apoiar o trabalho experimental envolvido no desenvolvimento de processos de fabrico. Como exemplo, foram estudadas diferentes vias de síntese, diferentes reagentes e postulada a formação de possíveis impurezas nas reações químicas utilizadas na formação das substâncias ativas, Palmitato de Paliperidona e Brometo de Umeclidínio. Os balanços energéticos das reações químicas envolvidas no processo de formação de produtos, a partir das matérias primas, bem como de espécies intermediárias formadas durante as reações foram calculados com o objetivo de melhor visualizar a evolução da energia relativa entre todas as espécies ao longo das reações e assim obter um conhecimento mais aprofundado das reações envolvidas.
Cinco vias de síntese para a formação do palmitato de paliperidona foram estudados por métodos computacionais. A partir dos resultados obtidos computacionalmente a via de síntese mais direta, “One-pot”, mostrou-se mais favorável e foi escolhida juntamente com as bases hidreto de sódio, hidróxido de potássio e hidróxido de sódio, e o solvente dimetilformamida. Todas as escolhas foram feitas considerando quais seriam as melhores condições para utilização num processo de produção industrial. Os resultados obtidos no trabalho laboratorial indicam que o hidreto de sódio seria a melhor base a usar, caso o seu manuseamento não fosse tão perigoso, seguido pelas bases hidróxido de sódio e hidróxido de potássio. As duas metodologias, computacional e experimental, obtêm os mesmos resultados.
O processo de formação de brometo de umeclidínio envolveu o estudo computacional da síntese de quinuclidínio-4-carboxilato de etilo, ou seja, a reação entre diisopropilamida de lítio (LDA) e o 1-(2-cloroetil)-piperidino-4-carboxilato de etilo. Calculou-se o balanço energético da reação principal, bem como a formação de espécies que podem ser geradas a partir de LDA, na presença e na ausência do solvente tetrahidrofurano. O reagente LDA é um dos limitantes da reação. Uma vez que a forma monomérica da estrutura da LDA é comprometida devido à sua reatividade, a reação principal será limitada, pois haverá preferencialmente mais espécies na forma de dímero ou trímero de LDA, levando à formação de agregados que, uma vez formados, impedirão a formação do produto desejado. Com base nestes resultados, é possível explicar o rendimento não muito elevado para a formação de quinuclidina-4-carboxilato de etilo.
A computational study was conducted aiming to evaluate whether in silico calculations could support the experiment work carried out to develop industrial manufacturing processes of active pharmaceutical substances. It is intended to understand the reactions mechanisms, to study different synthesis pathways and reagents, as well as, to explain impurities that may form in the synthesis pathway to gain a thorough knowledge of chemical transformations of the active pharmaceutical substances Paliperidone Palmitate and Umeclidinium Bromide. Energetic balances between raw materials and products as well as between these and intermediate species formed during the reactions were built and optimized aiming to better visualize the evolution of the relative energy between all the species along the reactions. Five synthesis pathways were computationally studied for the formation of Paliperidone Palmitate and the most direct pathway “One-pot” was chosen alongside with the chosen sodium hydride, potassium and sodium hydroxide bases and the dimethylformamide solvent. All the choices were made considering what would be best to use in the industrial manufacturing processes. The experimental work shows that the use of sodium hydride would be the best base to use, if it wasn’t so dangerous to work with, followed by the sodium hydroxide and potassium hydroxide bases. In silico studies were validated by these experimental results. The process of the formation of umeclidinium bromide involved the computational study of ethyl quinuclidine-4-carboxylate, the reaction between lithium diisopropylamide (LDA) with ethyl 1-(2-chloroethyl)piperidone-4-carboxylate. The energy balance for the main reaction was calculated as well as the formation of other species that can be generated from LDA, and even some other species formed in the presence of the tetrahydrofuran solvent. The LDA reagent is one of the limiters of the reaction. Once the monomeric form of the LDA structure is compromised due to its reactivity, the main reaction will be limited, as there will be mostly dimeric or trimeric species of LDA, leading to the formation of aggregates that once formed will prevent from obtaining the desired product and from having an high yield.
A computational study was conducted aiming to evaluate whether in silico calculations could support the experiment work carried out to develop industrial manufacturing processes of active pharmaceutical substances. It is intended to understand the reactions mechanisms, to study different synthesis pathways and reagents, as well as, to explain impurities that may form in the synthesis pathway to gain a thorough knowledge of chemical transformations of the active pharmaceutical substances Paliperidone Palmitate and Umeclidinium Bromide. Energetic balances between raw materials and products as well as between these and intermediate species formed during the reactions were built and optimized aiming to better visualize the evolution of the relative energy between all the species along the reactions. Five synthesis pathways were computationally studied for the formation of Paliperidone Palmitate and the most direct pathway “One-pot” was chosen alongside with the chosen sodium hydride, potassium and sodium hydroxide bases and the dimethylformamide solvent. All the choices were made considering what would be best to use in the industrial manufacturing processes. The experimental work shows that the use of sodium hydride would be the best base to use, if it wasn’t so dangerous to work with, followed by the sodium hydroxide and potassium hydroxide bases. In silico studies were validated by these experimental results. The process of the formation of umeclidinium bromide involved the computational study of ethyl quinuclidine-4-carboxylate, the reaction between lithium diisopropylamide (LDA) with ethyl 1-(2-chloroethyl)piperidone-4-carboxylate. The energy balance for the main reaction was calculated as well as the formation of other species that can be generated from LDA, and even some other species formed in the presence of the tetrahydrofuran solvent. The LDA reagent is one of the limiters of the reaction. Once the monomeric form of the LDA structure is compromised due to its reactivity, the main reaction will be limited, as there will be mostly dimeric or trimeric species of LDA, leading to the formation of aggregates that once formed will prevent from obtaining the desired product and from having an high yield.
Descrição
Tese de mestrado, Química Farmacêutica e Terapêutica, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Química computacional DFT Esterificação Dimerização Diisopropilamida de lítio Teses de mestrado - 2020