- Title
- Use of flow reactors for an improved synthesis of Tenofovir derivatives
- Creator
- Sonti, Thembela
- Subject
- Antiviral agents -- South Africa
- Subject
- HIV infections –Treatment
- Date Issued
- 2023-04
- Date
- 2023-04
- Type
- Doctoral theses
- Type
- text
- Identifier
- http://hdl.handle.net/10948/61190
- Identifier
- vital:69792
- Description
- Tenofovir disoproxil fumarate (TDF) is a prescription drug used to treat and prevent human immunodeficiency virus (HIV) infections. It aids in the reduction of HIV in the body, allowing the immune system to function more effectively. This reduces the risk of HIV complications, such as infections, whilst improving the quality of life. TDF belongs to the nucleotide reverse transcriptase inhibitors category of drugs. These drugs limit the ability of the reverse transcriptase, an enzyme essential for each virus to replicate itself. A reduction in the cost of HIV treatment could improve supply security and make it more accessible to patients in need. Thus, this project aims to use flow technology to achieve a guaranteed supply chain and access. In this thesis, a method for the synthesis of TDF was developed using microreactors starting from the readily available adenine. The method was adapted from the traditional batch synthesis as currently there is no literature on the synthesis of TDF in flow chemistry. The batch methods used for the synthesis of the working standards were successfully translated to flow systems. For the best results to be obtained, optimisation of the reaction temperature, reagent molar equivalents and concentration was critical. From the optimisation studies, an improvement in conversion is evident throughout all stages. The flow synthesis of the first intermediate resulted in a conversion of 100 % in N,N-dimethylformamide in 6 min residence time. This study was conducted at 200 °C, which is higher than the boiling point of the solvent with the aid of a back pressure regulator. A key reagent in the synthesis of tenofovir, namely ((tosyloxy)methyl)phosphonic acid, had to be synthesised and it was successfully produced in 96 % yield. The second intermediate was synthesised through a successful coupling reaction between (R)-9-(2-hydroxypropyl)adenine and ((tosyloxy)methyl)- phosphonic acid, which afforded a 100 % conversion of tenofovir in 20 min total residence time. The multistep synthesis of tenofovir was a success as it afforded a 65 % overall conversion. The prodrug TDF was successfully synthesised at 120 °C with a 30 min residence time, yielding a conversion of 100 %. ii | P a g e This thesis consists of four chapters. Chapter one describes the background on HIV and a literature review on HIV drugs. This chapter also demonstrates flow chemistry and microreactors in detail and different routes for the synthesis of TDF in traditional batch methods. Chapter two provides a detailed methodology for batch synthesis and flow synthesis with analytical data. 1H-NMR, 13C-NMR and FTIR spectroscopy was used to evaluate all the compounds synthesised in this chapter. Chapter three thoroughly discusses the results that were obtained graphically, showing that the flow synthesis gives better yields than batch synthesis. In chapter 4, the conclusion of the whole investigation is stated along with the future work for the preparation of TDF.
- Description
- Thesis (PhD) -- Faculty of Science, School of Biomolecular and Chemical Sciences, 2023
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (154 pages)
- Format
- Publisher
- Nelson Mandela University
- Publisher
- Faculty of Science
- Language
- English
- Rights
- Nelson Mandela University
- Rights
- All Rights Reserved
- Rights
- Open Access
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NMU School of BioMolecular and Chemical Sciences
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | Sonti, TC.pdf | 4 MB | Adobe Acrobat PDF | View Details Download |