An efficient approach for the synthesis of dolutegravir and its analogue exploiting flow chemistry
- Authors: Nqeketo, Sinazo
- Date: 2023-04
- Subjects: HIV (Viruses) – Enzymes –Inhibitors , Antiviral agents -- South Africa
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/${Handle} , 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 , Thesis (PhD) -- Faculty of Science, School of Biomolecular and Chemical Science, 2023
- Full Text:
- Date Issued: 2023-04
- Authors: Nqeketo, Sinazo
- Date: 2023-04
- Subjects: HIV (Viruses) – Enzymes –Inhibitors , Antiviral agents -- South Africa
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/${Handle} , 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 , Thesis (PhD) -- Faculty of Science, School of Biomolecular and Chemical Science, 2023
- Full Text:
- Date Issued: 2023-04
Use of flow reactors for an improved synthesis of Tenofovir derivatives
- Authors: Sonti, Thembela
- Date: 2023-04
- Subjects: Antiviral agents -- South Africa , HIV infections –Treatment
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/61190 , 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. , Thesis (PhD) -- Faculty of Science, School of Biomolecular and Chemical Sciences, 2023
- Full Text:
- Date Issued: 2023-04
- Authors: Sonti, Thembela
- Date: 2023-04
- Subjects: Antiviral agents -- South Africa , HIV infections –Treatment
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/61190 , 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. , Thesis (PhD) -- Faculty of Science, School of Biomolecular and Chemical Sciences, 2023
- Full Text:
- Date Issued: 2023-04
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