Synthesis of gatifloxacin, an important fluoroquinolone antibiotic using continuous flow technology
- Authors: Moyo, McQuillan
- Date: 2024-04
- Subjects: Antibiotics , Drug resistance in microorganisms , Chemical processes
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/64204 , vital:73664
- Description: Gatifloxacin belongs to an important class of antibiotics known as fluoroquinolones (the fourth generation). Bristol-Myers Squibb (BMS) introduced gatifloxacin to the market in 1999 under the brand name Tequin® for treating respiratory tract infections. It has recently been widely employed as an ophthalmic solution for treating bacterial conjunctivitis. There is limited literature describing the complete synthesis of gatifloxacin; however, ciprofloxacin, a similar fluoroquinolone, has received much attention recently and is a good guide in the synthesis. Even though there are several similarities between ciprofloxacin and gatifloxacin, key reactions towards the synthesis of gatifloxacin have not been reported, which forms a knowledge gap, for instance, the three steps leading to the synthesis of the benzoyl chloride intermediate. It is estimated that 70-90 % of the active pharmaceutical ingredients (APIs) in drugs consumed in sub-Saharan Africa are imported, mainly from India, China and Europe. To reduce dependence and improve access to life-saving drugs, Africa needs to develop cutting-edge technology that is more advanced than traditional means. We envisage that employing continuous flow technology in synthesising gatifloxacin, previously developed in a batch setup, will offer an improved, future-proof process. Thus, this research aimed to create a more efficient multi-step continuous flow process for synthesising gatifloxacin compared to the current batch methods. The first chapter of this thesis provides an extensive literature review on the synthesis of gatifloxacin and its sister drug, ciprofloxacin. The foreground is based on the manufacture and consumption of APIs, particularly antibiotics. Continuous flow technology is also introduced and discussed as the solution to bridging the gap in Africa’s demand for API manufacturing, which significantly lags. Chapter two describes the results and discusses findings on the continuous flow synthesis of gatifloxacin. A seven-step process is described with reaction optimisation studies for each step, starting from 2,4,5-trifluoro-3-hydroxybenzoic acid. An alternative shorter route (with six steps) is also offered, incorporating microwave-assisted technology instead of the traditional batch process. We also describe several elegant multistep processes for synthesising gatifloxacin and its intermediates, achieved by combining several compatible, optimised steps. Subsequently, Chapter 3 describes all the experimental details of our research. In this study, efficient continuous flow procedures were developed to synthesise gatifloxacin. The seven-step continuous flow procedure we developed afforded gatifloxacin (54 % overall isolated yield) in a total residence time of 15.6 mins, a significant improvement from the reported batch process (52 % overall yield and over 103 hours reaction time). , Thesis (PhD) -- Faculty of Science, School of Biomolecular & Chemical Sciences, 2024
- Full Text:
- Date Issued: 2024-04
- Authors: Moyo, McQuillan
- Date: 2024-04
- Subjects: Antibiotics , Drug resistance in microorganisms , Chemical processes
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/64204 , vital:73664
- Description: Gatifloxacin belongs to an important class of antibiotics known as fluoroquinolones (the fourth generation). Bristol-Myers Squibb (BMS) introduced gatifloxacin to the market in 1999 under the brand name Tequin® for treating respiratory tract infections. It has recently been widely employed as an ophthalmic solution for treating bacterial conjunctivitis. There is limited literature describing the complete synthesis of gatifloxacin; however, ciprofloxacin, a similar fluoroquinolone, has received much attention recently and is a good guide in the synthesis. Even though there are several similarities between ciprofloxacin and gatifloxacin, key reactions towards the synthesis of gatifloxacin have not been reported, which forms a knowledge gap, for instance, the three steps leading to the synthesis of the benzoyl chloride intermediate. It is estimated that 70-90 % of the active pharmaceutical ingredients (APIs) in drugs consumed in sub-Saharan Africa are imported, mainly from India, China and Europe. To reduce dependence and improve access to life-saving drugs, Africa needs to develop cutting-edge technology that is more advanced than traditional means. We envisage that employing continuous flow technology in synthesising gatifloxacin, previously developed in a batch setup, will offer an improved, future-proof process. Thus, this research aimed to create a more efficient multi-step continuous flow process for synthesising gatifloxacin compared to the current batch methods. The first chapter of this thesis provides an extensive literature review on the synthesis of gatifloxacin and its sister drug, ciprofloxacin. The foreground is based on the manufacture and consumption of APIs, particularly antibiotics. Continuous flow technology is also introduced and discussed as the solution to bridging the gap in Africa’s demand for API manufacturing, which significantly lags. Chapter two describes the results and discusses findings on the continuous flow synthesis of gatifloxacin. A seven-step process is described with reaction optimisation studies for each step, starting from 2,4,5-trifluoro-3-hydroxybenzoic acid. An alternative shorter route (with six steps) is also offered, incorporating microwave-assisted technology instead of the traditional batch process. We also describe several elegant multistep processes for synthesising gatifloxacin and its intermediates, achieved by combining several compatible, optimised steps. Subsequently, Chapter 3 describes all the experimental details of our research. In this study, efficient continuous flow procedures were developed to synthesise gatifloxacin. The seven-step continuous flow procedure we developed afforded gatifloxacin (54 % overall isolated yield) in a total residence time of 15.6 mins, a significant improvement from the reported batch process (52 % overall yield and over 103 hours reaction time). , Thesis (PhD) -- Faculty of Science, School of Biomolecular & Chemical Sciences, 2024
- Full Text:
- Date Issued: 2024-04
Scalable chemistry involving diazonium salts
- Authors: Akwi, Faith Mary
- Date: 2016
- Subjects: Azo compounds -- Synthesis , Chemical processes
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10948/6909 , vital:21162
- Description: Herein an alternative approach aimed at reducing the cost of numbering up technique as a scale up strategy for chemical processes from the laboratory bench top to the industry is explored. The effect of increasing channel size on the reaction conversion of the synthesis of azo compounds is investigated. This was achieved via a systematic investigative understanding of the synthesis in microreactors where a proof of concept study was performed to determine the optimum reaction parameters in azo coupling reactions involving couplers with aminated or hydroxylated groups in Little Things Factory-MS microreactors (Channel diameter: 1.0 mm) It was found that at slightly alkaline conditions (pH 8.55) and at a temperature of 25 °C, excellent conversions were attained in the azo coupling reaction of the diazonium salt solution of 2,4-dimethylaniline to 2-naphthol. On the other hand, the azo coupling reaction of the diazonium salt solution of p-nitroaniline to diphenylamine was found to thrive at a pH of 5.71 and at a temperature of 25 °C. Using, these optimized reaction parameters, the in-situ and reactive quench of diazonium salts in LTF-MS microreactors was investigated where it was found that at a flow rate of 0.2 ml/min, 0.03 ml/min and 0.07 ml/min of diazotizable amine & HCl, sodium nitrite and coupler solutions respectively, a conversion of 98% is achieved in approximately 2.4 minutes. A library of azo compounds was thus generated under these reaction conditions from couplers with aminated or hydroxylated aromatic aromatic systems. The scaled up synthesis of these compounds in a homemade PTFE tubing (ID 1.5 mm) reactor system was thereafter investigated and comparable conversions were observed. Capitalizing on the benefits of a large surface area and the short molecular diffusion distances observed in microreactors, in-situ phase transfer catalyzed azo coupling reaction of diphenylamine to p-nitroaniline was also explored. In this investigation a rapid and easy optimization protocol that yielded a 99%, 22% and 33% conversion of diphenylamine, carbazole and triphenylamine respectively in approximately 2.4 minutes using Chemtrix microreactors was established. On increasing the microreactor channel internal diameter in the scaled up synthesis approach, it was found that a 0.5 mm increase in channel internal diameter does result in lower reaction conversions.
- Full Text:
- Date Issued: 2016
- Authors: Akwi, Faith Mary
- Date: 2016
- Subjects: Azo compounds -- Synthesis , Chemical processes
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10948/6909 , vital:21162
- Description: Herein an alternative approach aimed at reducing the cost of numbering up technique as a scale up strategy for chemical processes from the laboratory bench top to the industry is explored. The effect of increasing channel size on the reaction conversion of the synthesis of azo compounds is investigated. This was achieved via a systematic investigative understanding of the synthesis in microreactors where a proof of concept study was performed to determine the optimum reaction parameters in azo coupling reactions involving couplers with aminated or hydroxylated groups in Little Things Factory-MS microreactors (Channel diameter: 1.0 mm) It was found that at slightly alkaline conditions (pH 8.55) and at a temperature of 25 °C, excellent conversions were attained in the azo coupling reaction of the diazonium salt solution of 2,4-dimethylaniline to 2-naphthol. On the other hand, the azo coupling reaction of the diazonium salt solution of p-nitroaniline to diphenylamine was found to thrive at a pH of 5.71 and at a temperature of 25 °C. Using, these optimized reaction parameters, the in-situ and reactive quench of diazonium salts in LTF-MS microreactors was investigated where it was found that at a flow rate of 0.2 ml/min, 0.03 ml/min and 0.07 ml/min of diazotizable amine & HCl, sodium nitrite and coupler solutions respectively, a conversion of 98% is achieved in approximately 2.4 minutes. A library of azo compounds was thus generated under these reaction conditions from couplers with aminated or hydroxylated aromatic aromatic systems. The scaled up synthesis of these compounds in a homemade PTFE tubing (ID 1.5 mm) reactor system was thereafter investigated and comparable conversions were observed. Capitalizing on the benefits of a large surface area and the short molecular diffusion distances observed in microreactors, in-situ phase transfer catalyzed azo coupling reaction of diphenylamine to p-nitroaniline was also explored. In this investigation a rapid and easy optimization protocol that yielded a 99%, 22% and 33% conversion of diphenylamine, carbazole and triphenylamine respectively in approximately 2.4 minutes using Chemtrix microreactors was established. On increasing the microreactor channel internal diameter in the scaled up synthesis approach, it was found that a 0.5 mm increase in channel internal diameter does result in lower reaction conversions.
- Full Text:
- Date Issued: 2016
Surface modifications of InAs: effect of chemical processing on electronic structure and photoluminescent properties
- Eassa, Nahswa Abo Alhassan Eassa
- Authors: Eassa, Nahswa Abo Alhassan Eassa
- Date: 2012
- Subjects: Indium arsenide , Chemical processes , Photoluminescence
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10948/8714 , vital:26423
- Description: In this thesis, the effects of various chemical treatments on the surface modification of bulk InAs are investigated. The study focuses on the chemical processes that occur upon the exposure of the surface to sulphur-, chlorine- and bromine-containing solutions and oxygen, and the resulting changes to the electronic structure of the surface, as deduced from photoluminescence (PL) measurements, X-ray photoelectron spectroscopy (XPS), Auger electron spectroscopy (AES), Raman scattering and scanning electron microscopy (SEM). Three processing treatments were evaluated: i) treatment with sulphur-based solutions (Na2S:9H2O, (NH4)2S + S, [(NH4)2S / (NH4)2SO4] + S); ii) etching in halogen-based solutions (bromine-methanol and HCl: H2O); and iii) thermal oxidation. A significant overall enhancement in PL response was observed after chemical treatment or thermal oxidation, which is associated with a reduction in surface band bending. These changes correlate with the removal of the native oxide, in addition to the formation of well-ordered layers of In-S (or In-As)O as a passivating layer, indicating that electronic passivation occurs at the surface. The passivating effect on sulphide treated surfaces is unstable, however, with an increase in band bending, due to reoxidation, observed over periods of a few days. The lowest re-oxidation rate was observed for ([(NH4)2S / (NH4)2SO4] + S). Etching in HCl:H2O and Br-methanol solutions of appropriate concentrations and for moderate times (1 min) resulted in smooth and defect-free InAs surfaces. Etching completely removed the native oxides from the surface and enhanced the PL response. The adsorption of bromine and chlorine onto the InAs surface led to the formation of As-Brx , In-Brx, As-Clx and In-Clxcompounds (x = 1, 2, 3), as inferred from changes in the In 3d3/2; 5/2 and As 3d core level binding energies. The etch rate was found to decrease because of strong anisotropic effects. The improvements in surface properties were reversed, however, if the concentrations of the etchants increased or the etch time was too long. In the worst cases, pit formation and inverted pyramids with {111} side facets were observed. Surface treatments or thermal oxidisation significantly enhanced the PL intensity relative to that of the as-received samples. This was due to a reduction in the surface state density upon de-oxidation, or in some cases, to the formation of a well ordered oxide layer on the surface. The overall increase in PL intensity after treatment is ascribed to a reduction in band bending near the surface. This allows several welldefined peaks not observed or reported previously for bulk InAs (with a carrier concentration n~2x1016 cm-3), to be studied. A combination of PL and XPS measurements before and after the various treatments was used to identify the chemical nature of the impurities giving rise to bound exciton recombination in InAs (111).
- Full Text:
- Date Issued: 2012
- Authors: Eassa, Nahswa Abo Alhassan Eassa
- Date: 2012
- Subjects: Indium arsenide , Chemical processes , Photoluminescence
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10948/8714 , vital:26423
- Description: In this thesis, the effects of various chemical treatments on the surface modification of bulk InAs are investigated. The study focuses on the chemical processes that occur upon the exposure of the surface to sulphur-, chlorine- and bromine-containing solutions and oxygen, and the resulting changes to the electronic structure of the surface, as deduced from photoluminescence (PL) measurements, X-ray photoelectron spectroscopy (XPS), Auger electron spectroscopy (AES), Raman scattering and scanning electron microscopy (SEM). Three processing treatments were evaluated: i) treatment with sulphur-based solutions (Na2S:9H2O, (NH4)2S + S, [(NH4)2S / (NH4)2SO4] + S); ii) etching in halogen-based solutions (bromine-methanol and HCl: H2O); and iii) thermal oxidation. A significant overall enhancement in PL response was observed after chemical treatment or thermal oxidation, which is associated with a reduction in surface band bending. These changes correlate with the removal of the native oxide, in addition to the formation of well-ordered layers of In-S (or In-As)O as a passivating layer, indicating that electronic passivation occurs at the surface. The passivating effect on sulphide treated surfaces is unstable, however, with an increase in band bending, due to reoxidation, observed over periods of a few days. The lowest re-oxidation rate was observed for ([(NH4)2S / (NH4)2SO4] + S). Etching in HCl:H2O and Br-methanol solutions of appropriate concentrations and for moderate times (1 min) resulted in smooth and defect-free InAs surfaces. Etching completely removed the native oxides from the surface and enhanced the PL response. The adsorption of bromine and chlorine onto the InAs surface led to the formation of As-Brx , In-Brx, As-Clx and In-Clxcompounds (x = 1, 2, 3), as inferred from changes in the In 3d3/2; 5/2 and As 3d core level binding energies. The etch rate was found to decrease because of strong anisotropic effects. The improvements in surface properties were reversed, however, if the concentrations of the etchants increased or the etch time was too long. In the worst cases, pit formation and inverted pyramids with {111} side facets were observed. Surface treatments or thermal oxidisation significantly enhanced the PL intensity relative to that of the as-received samples. This was due to a reduction in the surface state density upon de-oxidation, or in some cases, to the formation of a well ordered oxide layer on the surface. The overall increase in PL intensity after treatment is ascribed to a reduction in band bending near the surface. This allows several welldefined peaks not observed or reported previously for bulk InAs (with a carrier concentration n~2x1016 cm-3), to be studied. A combination of PL and XPS measurements before and after the various treatments was used to identify the chemical nature of the impurities giving rise to bound exciton recombination in InAs (111).
- Full Text:
- Date Issued: 2012
- «
- ‹
- 1
- ›
- »