- Title
- An efficient approach for the synthesis of dolutegravir and its analogue exploiting flow chemistry
- Creator
- Nqeketo, Sinazo
- Subject
- HIV (Viruses) – Enzymes –Inhibitors
- Subject
- Antiviral agents -- South Africa
- Date Issued
- 2023-04
- Date
- 2023-04
- Type
- Doctoral theses
- Type
- text
- Identifier
- http://hdl.handle.net/${Handle}
- Identifier
- vital:70635
- Description
- Africa has the highest Human Immunodeficiency Virus (HIV) prevalence in the world and has invested heavily in running its HIV programmes and conducting research of medical significance. Despite efforts in combating this disease the production, distribution, cost, and availability of antiretroviral (ARV) generics remains a major problem as they are imported from China and India. Exploring the recently emerged “enabling technique”, namely flow chemistry in the production of APIs has gained a lot of attention. This study was devoted on exploring the application of flow chemistry on the synthesis of a newly approved anti-HIV drug dolutegravir (DTG); an integrase inhibitor with a high genetic barrier to resistance with a daily dosing scheduled compared to other ARVs and its third-generation inhibitor analogue, cabotegravir. Chapter one covers a comprehensive background and literature review of the HIV epidemic, an introduction of antiretroviral therapy as well as detailed dolutegravir and cabotegravir synthesis. A brief introduction of continuous flow technology with its advantages and disadvantages is discussed in this chapter. The efficient seven-step continuous flow procedure afforded dolutegravir and cabotegravir in improved reaction times and yields compared to the traditional batch procedure was demonstrated. The significant advantage of this flow process includes the reduction of the overall reaction time from step one to step seven, from prolonged 68 hours in batch to 34 minutes. The overall yield of each reaction step improved dramatically upon flow optimization. The yields of the second step (selective ester hydrolysis), fourth step (cyclization) and fifth step (amidation) increased from 64 %, 40 % and 33 % in batch to 98 %, 71 % and 100 % yield by HPLC respectively. Other than improved yields and residence times which was aided advantages of microreactor technology including intensive mixing, the flow process is also much better because it is cost effective. Most importantly, a novel process on the formation of pyridinone intermediate using ion-exchange resin catalysts towards the synthesis of dolutegravir and cabotegravir was described in this study
- Description
- Thesis (PhD) -- Faculty of Science, School of Biomolecular and Chemical Science, 2023
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (250 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 | Nqeketo, S.pdf | 8 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | SOURCE2 | Adobe Acrobat PDF | 8 MB | Adobe Acrobat PDF | View Details Download |