- Title
- Continuous flow synthesis of imatinib intermediates
- Creator
- Rupapa, Harold Takunda
- Subject
- Flow chemistry
- Date Issued
- 2020
- Date
- 2020
- Type
- Thesis
- Type
- Masters
- Type
- MSc
- Identifier
- http://hdl.handle.net/10948/47464
- Identifier
- 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.
- Format
- viii, 99 leaves
- Format
- Publisher
- Nelson Mandela University
- Publisher
- Faculty of Science
- Language
- English
- Rights
- Nelson Mandela University
- Hits: 706
- Visitors: 767
- Downloads: 116
Thumbnail | File | Description | Size | Format | |||
---|---|---|---|---|---|---|---|
View Details Download | SOURCE1 | Rupapa, HT 212275070 Dissertation April 2020.pdf | 2 MB | Adobe Acrobat PDF | View Details Download |