The Development of Conveniently Formatted Solid-Supported Reagents for Flow-Based Synthesis
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
The pharmaceutical discovery process is changing rapidly generating a greater need for conduct chemistry in a more efficient and timely fashion. As the global emphasis towards achieving the highest safety standards and sustainable practices unfolds, it is becoming necessary to re-evaluate how chemical synthesis is conducted. In medicinal chemistry in particular the acceleration of cycle times through high-throughput assaying and fast iterative design has put new emphasis on the reliability of processes and compound preparation times. A more integrated and continuous relay of information regarding the ongoing synthesis and its products in terms of basic characterization, physical properties and their functions needs to be captured. These requirements coupled with a desire for flexible synthetic implementation seem ideally suited to a flow-based approach to chemical synthesis. It is therefore our conclusion that future MedChem programmes will make increasing use of flow techniques and many of these will benefit from the use of solid-supported reagents and scavengers.Monoliths have been proposed and developed for use in solid-supported continuous flow synthesis. Monoliths are a single continuous piece of porous material which can be made from either organic or inorganic materials. These monoliths can be readily generated from various polymers or polymer blends and posses permanent, well-defined porous structures that are independent of the solvent or reagents used. In addition such constructs offer significantly higher mass transfer compared to oval beads as they rely on convective flow instead of diffusion factors (key for reproducible optimisation and small scale synthesis). They also have a higher loading than polymers prepared by suspension polymerization due to the fact that polymerisation occurs within a single phase avoiding the problem of partitioning. It is also possible to prepare these polymer units in any shape and size which is very advantageous for the translation between micro- and meso-flow systems by readily enabling scale up in a more consistent manner.This proposal describes the preparation and use of a series of active reagent functionalized monoliths to be used in flow base synthesis.
People |
ORCID iD |
Steven Ley (Principal Investigator) | |
Ian Baxendale (Co-Investigator) |
Publications
Smith C
(2011)
A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles
in Organic & Biomolecular Chemistry
Smith CJ
(2011)
Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent.
in Organic & biomolecular chemistry
Venturoni F
(2010)
The application of flow microreactors to the preparation of a family of casein kinase I inhibitors
in Organic & Biomolecular Chemistry
Baumann M
(2009)
Development of fluorination methods using continuous-flow microreactors
in Tetrahedron
Description | A key finding of the project was the development of processes that could easily and consistently produce suitable monoliths of high quality and specification. For convenience and reproducibility, a commercial glass column was installed inside a convective heater via two bespoke end fittings and two custom made adjustable plug adaptors enabling the introduction of the polymerisation precursor solution. The flow tube was designed in such a way that columns from 0.1 to 15mm diameter could be routinely and easily used for the polymerisation process. Using the above system, a large number of different monoliths were made reliably that are now commonly used in our laboratory. |
Exploitation Route | The monoliths find utilisation in medicinal chemistry where the acceleration of cycle times, through high throughput assaying and fast iterative design, has put new emphasis on the reliability of processes and shorter compound preparation times. Many issues associated with standard resin-bead immobilised reagents have been overcome by the discovery of processes that easily and consistently produce suitable monoliths of high quality and specification. The monoliths find utilisation in medicinal chemistry where the acceleration of cycle times, through high throughput assaying and fast iterative design, has put new emphasis on the reliability of processes and shorter compound preparation times. |
Sectors | Chemicals Pharmaceuticals and Medical Biotechnology |
Description | Immobilised reagents and their application are available as an option for molecule makers and synthesis teams. The techniques for their preparation and methods for their application are still comparatively new. There may may be still a requirement for knowledge transfer. |
First Year Of Impact | 2013 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | Collaboration/Partnership |
Organisation | Pfizer Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Collaboration/Partnership. The significance of this collaboration to the progress of the research is establishing a closer industry/academia engagement allowing validation of the techniques and approaches in real life industrial scenarios. |
Start Year | 2009 |
Title | Other Research Output |
Description | Physical Outputs >> New / Improved Technique / Technology |
Type Of Technology | New/Improved Technique/Technology |
Year Produced | 2010 |
Impact | The development of a new monolithic triphenylphosphine reagent allowed the safe preparation of organic azides for the first time whereby the multistep synthesis of imines and amines could be achieved under flow synthesis conditions. |