Periodic Reporting for period 2 - GreenX4Drug (Green Enantioselective Halogenation for Drug Discovery and Manufacture)
Período documentado: 2021-04-01 hasta 2023-12-31
Issue Addressed: The European pharmaceutical industry confronts challenges such as patent expirations and stricter environmental regulations, prompting a shift towards sustainable practices. GreenX4Drug has tackled these issues by pioneering eco-friendly methodologies for pharmaceutical synthesis.
Importance for Society: GreenX4Drug meets societal demands for accessible healthcare and environmental responsibility. By developing greener manufacturing processes, the project reduces the ecological impact of pharmaceutical production while addressing public health needs.
Objectives:
1. Develop "Green" Organocatalysts: GreenX4Drug aims to create efficient organocatalysts, reducing reliance on expensive and harmful metal catalysts in pharmaceutical synthesis.
2. Establish Halogenation Platform: The project seeks to demonstrate the versatility of these catalysts in halogenation processes, providing a synthetic platform for pharmaceutical compound preparation.
3. Synthesise Drugs: Production of halogenated pharmaceuticals and intermediates.
4. Scale-up: Demonstrating industrial viability by scaling up synthesis using batch and continuous flow methodologies.
Conclusions: GreenX4Drug has pioneered sustainable pharmaceutical manufacturing, addressing societal healthcare needs while promoting environmental stewardship. By leveraging academic and industry expertise, the project developed cost-effective and eco-friendly processes with the potential to transform the industry. While some deviations occurred, the project substantially achieved its scientific objectives, including the successful development of novel chiral scaffolds and methodologies for fast and selective synthesis of halogenated compounds. Ongoing evaluations aim to maintain enantiopurity, with adaptations for continuous flow methodology showing promise for scaled-up production.
Importance for Society: GreenX4Drug meets societal demands for accessible healthcare and environmental responsibility. By developing greener manufacturing processes, the project reduces the ecological impact of pharmaceutical production while addressing public health needs.
Objectives:
1. Develop "Green" Organocatalysts: GreenX4Drug aims to create efficient organocatalysts, reducing reliance on expensive and harmful metal catalysts in pharmaceutical synthesis.
2. Establish Halogenation Platform: The project seeks to demonstrate the versatility of these catalysts in halogenation processes, providing a synthetic platform for pharmaceutical compound preparation.
3. Synthesise Drugs: Production of halogenated pharmaceuticals and intermediates.
4. Scale-up: Demonstrating industrial viability by scaling up synthesis using batch and continuous flow methodologies.
Conclusions: GreenX4Drug has pioneered sustainable pharmaceutical manufacturing, addressing societal healthcare needs while promoting environmental stewardship. By leveraging academic and industry expertise, the project developed cost-effective and eco-friendly processes with the potential to transform the industry. While some deviations occurred, the project substantially achieved its scientific objectives, including the successful development of novel chiral scaffolds and methodologies for fast and selective synthesis of halogenated compounds. Ongoing evaluations aim to maintain enantiopurity, with adaptations for continuous flow methodology showing promise for scaled-up production.
The work in this project has focuses the development and exemplification of new catalysts and new green methodologies for effective enantioselective halogenation (chlorination, bromination and fluorination), constituting a new platforms for the discovery and cost-effective green manufacture of pharmaceutical compounds.
This work covered during the lifetime of the project has involved the following:
WP1. The design and synthesis of 2 ammonium salts and 4 bifunctional designer enantiopure compounds to be screened halogenation catalysts was performed. The syntheses of the target catalysts were met with some hurdles, however were each successfully prepared, including with additional support via the development of a novel microwave synthesis method which was published in an OA journal.
WP2. The development of synthetic procedures for enantiospecific halogenation was performed. Several advanced methods for the preparation of fluorinated targets has been developed with high yields, fast reaction times, and broad substrate tolerance. A method for the selective preparation of acetoxylated compounds was also discovered, further expanded the utility of the GreenX4Drug synthesis platform.
WP3. Halogenation methods from WP2 were used to syntheses of a range of halogenated compounds. Stereocontrol of the desulfurative halogenation was challenging due to competing reaction pathways favouring products with loss of chiral information. We performed an NMR-based study to further understand the interactions of our novel catalysts with findings published in an OA journal. The best methods developed in WP2 were used to target multiple halogenated pharmaceutical intermediates successfully.
WP4. The batch halogenation methods developed to prepare halogenated compounds were adapted to continuous flow protocols to target key halogenated intermediates towards pharmaceuticals. The behaviour of the halogenation chemistry was investigated using continuous flow systems, which involved careful evaluation of the system parameters to ensure high yields and reliability of the continuous flow methods. The desulfurative bromination of alpha-beta unsaturated compounds was investigated where factors such as flow rate, bromination reagent, solvent and residence time were evaluated. Using analytical methods included gas chromatography, high-performance liquid chromatography, and nuclear magnetic resonance, the continuous flow method for desulfurative bromination was successfully developed and exemplified against a range of substrates with broad functionalities bearing close relationship to pharmaceutical compounds. The methods developed were scaled to multi-gram quantities and findings were published in an OA journal. Plans for exploitation of the methods did not lead to publication of a patent before the end of the project, however the methods are still under development and the consortium plans to patent those methods as early as 2024.
This work covered during the lifetime of the project has involved the following:
WP1. The design and synthesis of 2 ammonium salts and 4 bifunctional designer enantiopure compounds to be screened halogenation catalysts was performed. The syntheses of the target catalysts were met with some hurdles, however were each successfully prepared, including with additional support via the development of a novel microwave synthesis method which was published in an OA journal.
WP2. The development of synthetic procedures for enantiospecific halogenation was performed. Several advanced methods for the preparation of fluorinated targets has been developed with high yields, fast reaction times, and broad substrate tolerance. A method for the selective preparation of acetoxylated compounds was also discovered, further expanded the utility of the GreenX4Drug synthesis platform.
WP3. Halogenation methods from WP2 were used to syntheses of a range of halogenated compounds. Stereocontrol of the desulfurative halogenation was challenging due to competing reaction pathways favouring products with loss of chiral information. We performed an NMR-based study to further understand the interactions of our novel catalysts with findings published in an OA journal. The best methods developed in WP2 were used to target multiple halogenated pharmaceutical intermediates successfully.
WP4. The batch halogenation methods developed to prepare halogenated compounds were adapted to continuous flow protocols to target key halogenated intermediates towards pharmaceuticals. The behaviour of the halogenation chemistry was investigated using continuous flow systems, which involved careful evaluation of the system parameters to ensure high yields and reliability of the continuous flow methods. The desulfurative bromination of alpha-beta unsaturated compounds was investigated where factors such as flow rate, bromination reagent, solvent and residence time were evaluated. Using analytical methods included gas chromatography, high-performance liquid chromatography, and nuclear magnetic resonance, the continuous flow method for desulfurative bromination was successfully developed and exemplified against a range of substrates with broad functionalities bearing close relationship to pharmaceutical compounds. The methods developed were scaled to multi-gram quantities and findings were published in an OA journal. Plans for exploitation of the methods did not lead to publication of a patent before the end of the project, however the methods are still under development and the consortium plans to patent those methods as early as 2024.
GreenX4Drug has introduced innovative methodologies using Phase Transfer Catalysis (PTC) and bifunctional organocatalysis as sustainable alternatives to metal catalysis in drug manufacturing. PTC, proven effective at a large scale, allows for catalyst recovery and recycling, enhancing economic viability. However, the limited design options for PTCs pose challenges in achieving high selectivity for key intermediates needed in industrial synthesis. GreenX4Drug addresses this by advancing the state of the art, particularly in halogenation processes crucial for drug synthesis and discovery. The project's methods, including desymmetrising halogenation and newly reported desulfurative halogenation, offer cost-efficient ways to produce advanced intermediates and their fluorinated analogues, essential for drug development. The developed fluorination methodology holds potential beyond the project scope, facilitating rapid and enantioselective introduction of fluorine-18 into APIs, advancing drug and diagnostic development.
Key innovations of GreenX4Drug have included a novel organocatalytic process using recyclable reagents, which with further development will enable the synthesis of enantiomers in both configurations. These methods have been successfully applied synthesise APIs like Duloxetine and Atomoxetine, while adaptation of the continuous flow methods offer scalability and significant solvent savings. Overall, GreenX4Drug's synthetic platform demonstrates versatility and potential for broad applicability in drug synthesis, including the incorporation of fluorine-18 into drug molecules for diagnostic purposes.
Key innovations of GreenX4Drug have included a novel organocatalytic process using recyclable reagents, which with further development will enable the synthesis of enantiomers in both configurations. These methods have been successfully applied synthesise APIs like Duloxetine and Atomoxetine, while adaptation of the continuous flow methods offer scalability and significant solvent savings. Overall, GreenX4Drug's synthetic platform demonstrates versatility and potential for broad applicability in drug synthesis, including the incorporation of fluorine-18 into drug molecules for diagnostic purposes.