Continuous flow synthesis of 5-formyl-2,4- dimethyl-1h-pyrrole-3-carboxylic acid, a key intermediate towards the synthesis of sunitinib anti-cancer drug
- Authors: Gqokoma, Zizo
- Date: 2020
- Subjects: Flow chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/48356 , vital:40852
- Description: The present trend in the pharmaceutical industry is towards adapting continuous flow processing with the main driving force behind this being the need to reduce environmental and economic costs. Continuous flow systems have proven to produce better quality products at lower costs, time and energy. As a result, this technique has diversified and expanded to provide novel, and practical solutions to not only organic synthesis but also renewable fuels and material science. The focus of this research work was to exploit continuous flow systems, to develop a continuous flow process that is energy and time effective, using commercial micro reactors to synthesize 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, a key intermediate towards the synthesis of sunitinib, an anti-cancer drug. In this thesis, a successful study on the individual translation of a 5 step batch synthesis of 5- formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid into optimised continuous flow syntheses is demonstrated. A comprehensive literature review and background on cancer, and an introduction to pyrrole rings, their role in disease treatments in addition to a brief introduction to continuous flow technology with its advantages, and comparison to classical batch methods are provided in the first chapter. Chapter two is detailing the experimental procedures utilised for both batch and continuous flow syntheses. The continuous flow synthesis of the four intermediates towards the target compound in this work proved to be far superior compared to their batch syntheses; excellent improvements in reaction yields and selectivity in addition to tremendously shorter reaction times were observed. This is expounded in chapter three with detailed discussions of the results attained during the continuous flow optimisation of each step within the scope of this research, are provided. The concluding remarks, the impact of this study and future work are elucidated in chapter four.
- Full Text:
- Date Issued: 2020
- Authors: Gqokoma, Zizo
- Date: 2020
- Subjects: Flow chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/48356 , vital:40852
- Description: The present trend in the pharmaceutical industry is towards adapting continuous flow processing with the main driving force behind this being the need to reduce environmental and economic costs. Continuous flow systems have proven to produce better quality products at lower costs, time and energy. As a result, this technique has diversified and expanded to provide novel, and practical solutions to not only organic synthesis but also renewable fuels and material science. The focus of this research work was to exploit continuous flow systems, to develop a continuous flow process that is energy and time effective, using commercial micro reactors to synthesize 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, a key intermediate towards the synthesis of sunitinib, an anti-cancer drug. In this thesis, a successful study on the individual translation of a 5 step batch synthesis of 5- formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid into optimised continuous flow syntheses is demonstrated. A comprehensive literature review and background on cancer, and an introduction to pyrrole rings, their role in disease treatments in addition to a brief introduction to continuous flow technology with its advantages, and comparison to classical batch methods are provided in the first chapter. Chapter two is detailing the experimental procedures utilised for both batch and continuous flow syntheses. The continuous flow synthesis of the four intermediates towards the target compound in this work proved to be far superior compared to their batch syntheses; excellent improvements in reaction yields and selectivity in addition to tremendously shorter reaction times were observed. This is expounded in chapter three with detailed discussions of the results attained during the continuous flow optimisation of each step within the scope of this research, are provided. The concluding remarks, the impact of this study and future work are elucidated in chapter four.
- Full Text:
- Date Issued: 2020
Continuous flow synthesis of imatinib intermediates
- Authors: Rupapa, Harold Takunda
- Date: 2020
- Subjects: Flow chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/47464 , vital:39993
- Description: In this thesis, an alternative approach using continuous flow chemistry towards imatinib intermediates is described; an important drug in the treatment of acute myeloid leukemia. Various protocols that describe the multistep batch organic synthesis of imatinib are outlined. Many of the batch synthetic protocols require long reaction times in the multistep synthesis towards the various imatinib intermediates. A broad description into the cancer epidemic such as myeloid leukemia, the cost of drug manufacture and the effect that the high cost of manufacture has on the accessibility to such treatment in Africa is outlined. Use of continuous flow reactors, the exploitation of various technologies and their advantages on organic synthesis compared to batch synthesis are also described. The batch reaction conditions needed for the multistep transformation towards imatinib were adapted to a continuous flow set up. The optimization investigation shows an improvement in the conversion in the various steps. The flow synthesis of the enaminone provided a conversion of 99% when in o-xylene and the ability to use backpressure regulators assisted the investigation at high temperatures. Solution-phase flow synthesis of the guanidinium nitrate, which gave low yields in batch, also showed an improvement in conversion, where in 30 minutes a conversion of 99% was confirmed by altering the co-solvent mixture. The cycloaddition reaction of the enaminone and the guanidinium nitrate salt, achieved 90% conversion to the 2-aminopyridine core at 180 oC. The nitro group reduction was achieved in the presence of a greener catalyst, namely iron pentanedionate, in the presence of hydrazine hydrate. The effect of temperature, molar equivalence and solvent on reaction conversions could be observed in these steps. The thesis is concluded in chapter 4, with the conclusion and recommendations for future work towards a scalable continuous flow synthesis of the imatinib intermediates.
- Full Text:
- Date Issued: 2020
- Authors: Rupapa, Harold Takunda
- Date: 2020
- Subjects: Flow chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/47464 , vital:39993
- Description: In this thesis, an alternative approach using continuous flow chemistry towards imatinib intermediates is described; an important drug in the treatment of acute myeloid leukemia. Various protocols that describe the multistep batch organic synthesis of imatinib are outlined. Many of the batch synthetic protocols require long reaction times in the multistep synthesis towards the various imatinib intermediates. A broad description into the cancer epidemic such as myeloid leukemia, the cost of drug manufacture and the effect that the high cost of manufacture has on the accessibility to such treatment in Africa is outlined. Use of continuous flow reactors, the exploitation of various technologies and their advantages on organic synthesis compared to batch synthesis are also described. The batch reaction conditions needed for the multistep transformation towards imatinib were adapted to a continuous flow set up. The optimization investigation shows an improvement in the conversion in the various steps. The flow synthesis of the enaminone provided a conversion of 99% when in o-xylene and the ability to use backpressure regulators assisted the investigation at high temperatures. Solution-phase flow synthesis of the guanidinium nitrate, which gave low yields in batch, also showed an improvement in conversion, where in 30 minutes a conversion of 99% was confirmed by altering the co-solvent mixture. The cycloaddition reaction of the enaminone and the guanidinium nitrate salt, achieved 90% conversion to the 2-aminopyridine core at 180 oC. The nitro group reduction was achieved in the presence of a greener catalyst, namely iron pentanedionate, in the presence of hydrazine hydrate. The effect of temperature, molar equivalence and solvent on reaction conversions could be observed in these steps. The thesis is concluded in chapter 4, with the conclusion and recommendations for future work towards a scalable continuous flow synthesis of the imatinib intermediates.
- Full Text:
- Date Issued: 2020
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