Macrocycles are an important feature of many pharmaceutical compounds.
They combine high target selectivity and lower metabolic degradation than acyclic analogues but are difficult to synthesise and mostly extracted from natural sources. With the discovery of olefin metathesis reaction, cycles of different sizes can now be obtained efficiently via Ring Closing Metathesis (RCM). To avoid side-product formation, the cyclization is done in extremely diluted conditions. This approach requires large amounts of solvents, is expensive and not environmentally sustainable.
This thesis investigated two strategies for the synthesis of macrocycles via olefin metathesis using membrane technology to reduce the solvent load and improve the process mass intensity (PMI).
The first approach was to work at high concentrations, separate the side-products using Organic Solvent Nanofiltration (OSN) and convert them back into acyclic starting material exploiting the reversibility of the olefin metathesis. This work investigated the influence of several parameters on the RCM of an Active Pharmaceutical Ingredient (API). It looked at the feasibility of the membrane separation and explored the reversibility of the olefin metathesis reaction.
The importance of pre-organization of the acyclic substrate in favouring the intramolecular reaction was proved comparing the reactivity of a chosen substrate and its derivatives. A partial removal of side-products was achieved using OSN membranes and the limits of the reverse reaction were tested, proving that oligomers and polymers were hardly recyclable.
The second approach was to limit the formation of side-products working at high dilution, coupling the RCM reaction with in-line solvent recycling via OSN. The study was done on a model substrate whose cyclization occurred in a mixture constantly circulated through a membrane that separated the product and permeated pure solvent into the reaction vessel. No yield loss was observed in comparison to the same batch reaction and the PMI was increased.
This proof-of-concept study showed the potential of nanofiltration to make macrocyclization reactions more efficient and sustainable. The flexibility of this technique makes it applicable to different reactions and scalable for industrial applications.