- Title
- The development of a flow route to synthesize 3- benzyl-6-bromo-2-methoxyquinoline, an intermediate of an anti-TB drug, bedaquilin
- Creator
- Mpalala, Anele
- Subject
- Multidrug-resistant tuberculosis -- South Africa
- Subject
- Tuberculosis --Chemotherapy -- South Africa
- Date Issued
- 2022-12
- Date
- 2022-12
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10948/59864
- Identifier
- vital:62455
- Description
- SA has a high number of reported cases of multidrug-resistant tuberculosis (MDR-TB). Bedaquiline is a newly approved active ingredient of an anti-tuberculosis drug with high potency against MDR-TB. The limited access to this life-saving medicine to many people in the world has driven a great deal of research effort by the scientific community to find new, better and more practical approaches to this drug. However, many of the reported synthetic procedures suffer from long reaction times, which in turn require many hours of effort by the chemists conducting the reactions. This has prompted us to investigate an efficient process towards the synthesis to produce the key intermediates of bedaquiline using continuous flow technology. Additionally, since there is not much literature on continuous flow synthesis of bedaquiline, this research revealed interesting continuous flow processes towards the drug. Chapter 1: In order to provide insight, the first chapter of this dissertation presents a comprehensive background and literature review on tuberculosis; its pathogenesis, impact, medicines available for the treatment as well as the drug classes with novel mode of action and new chemical entities. Furthermore, bedaquiline is discussed in detail with the various synthetic protocols of the drug. An introduction to continuous flow chemistry is discussed, along with an outline of its advantages and disadvantages. Chapter 2: The second chapter encompasses the experimental procedures utilized for both batch and continuous flow syntheses. The three key intermediates of bedaquiline were synthesized in batch synthesis and these compounds were characterized using 1H-NMR, 13C-NMR and FT-IR spectroscopy. Subsequently, the continuous flow synthesis protocols for the preparations of these intermediates and their optimization are outlined. Chapter 3: The results are explained in this chapter with detailed discussions of the batch synthesis and the continuous flow optimization of each step within the scope of this research. The investigation started with the batch preparation of the primary intermediate, N-(4-bromophenyl)-3-phenylpropanamide via an amidation reaction between 3-phenylpropanoyl chloride and p-bromoaniline. The primary intermediate then undergoes a subsequent formylation and cyclization via a Vilsmeier–Haack reaction to yield 3-benzyl-6-bromo-2-chloroquinoline. The chloroquinoline ii intermediate undergoes a methoxylation reaction to form 3-benzyl-6-bromo-2- methoxyquinoline. Subsequently, the batch protocol was transferred into continuous flow systems, optimized by varying reaction parameters within the synthesis route to achieve the as much yield as possible. The optimization studies showed an improvement in conversions in the various steps with shorter reaction times. The first step was optimized in a 0.2ml microreactor and because of the enhanced safety of flow chemistry, this exothermic amidation reaction was optimised at elevated temperatures to afford the primary intermediate at a 100% conversion within a residence time of 5 seconds using DMF as a solvent with DIPEA as a base. Next, the Vilsmier-Haack cyclization and chlorination was optimised in flow to afford the 2-chloroquinoline intermediate. The ability to use a back pressure regulator allowed for investigation of the effect of high temperature on the reaction and the 2- chloroquinoline intermediate was obtained at 78% conversion in a residence time of 30 min at 150 ⁰C using acetonitrile as a solvent. Subsequently, the optimization of the third step in flow to afford the central core intermediate of bedaquiline, 3-benzyl-6-bromo-2-methoxyquinoline, achieved 100% conversion in DMSO/MeOH solvent system at a residence time of 5 min. The effect of temperature, molar equivalence and solvent on reaction conversions could be observed in these steps. The results obtained from this study clearly demonstrated the successful establishment of an efficient flow chemistry protocol that can be used to successfully synthesize all intermediates within the scope of this research.
- Description
- Thesis (MSc) -- Faculty of Science, School of Biomolecular and Chemical Sciences, 2022
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (XXX 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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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | Mpalala A Dec 2022.pdf | 3 MB | Adobe Acrobat PDF | View Details Download |