MASPGREEN · Mechanically-Assisted Synthesis of Pharmaceuticals: A Greener Energy Input

Mechanically-Assisted Synthesis of Pharmaceuticals: A Greener Energy Input

Remarkable advances have been made in the development of environmentally-friendly approaches for the rapid and simple construction of Active Pharmaceutical Ingredients (APIs) and natural products with relevant biological activity. These include: (i) the use of ball milling and microwave irradiation as greener alternatives − compared to conventional heating − to provide the energy needed for chemical transformations and (ii) the development of new catalytic methods for the selective formation of versatile compounds, avoiding the formation of by-products, and, therefore, waste. In particular, we have developed new strategies for the sustainable synthesis of barbiturates and two Selective Serotonin Reuptake Inhibitor drugs, Fluoxetine and Duloxetine, by means of mechanochemical and microwave irradiation methods. We have also made important discoveries in the catalytic enantioselective addition of organometallic reagents to carbonyl compounds, to generate optically active secondary alcohols (very important and frequent motifs in the pharmaceutical industry) in very good selectivities. Last, we have tackled the biocatalysed transamination reaction of ketoenone substrates by developing a highly efficient methodology for the synthesis of enantiomerically pure nitrogen containing heterocycles, recurrent scaffolds in natural products and biologically active compounds. The objectives of our proposal have been achieved on either the original and/or modified targets. We have developed, optimised and assessed the application of mechanochemistry to the “sustainable” production of two important class of biologically-active pharmaceutical products, barbiturates and Selective Serotonin Reuptake Inhibitors (SSRIs). In addition, we have explored the application of microwave irradiation as an alternative to conventional heating and as a complementary methodology to the mechanosynthesis. We have developed an efficient methodology for the synthesis of molecular imprinted polymers able to selectively detect SSRIs, which could have future applications as biosensors. In addition, we have also made important discoveries in the catalytic enantioselective addition of organometallic reagents to carbonyl compounds, to generate optically active secondary alcohols (very important and frequent motifs in the pharmaceutical industry) in very good selectivities. And last, we have tackled the biocatalysed transamination reaction of ketoenone substrates by developing a highly efficient methodology for the synthesis of enantiomerically pure nitrogen containing heterocycles, recurrent scaffolds in natural products and biologically active compounds. Full details of all our progress have been summarised in the corresponding periodic reports. This grant has allowed the opening of a successful area of research. Our current investigations are focused on the evaluation of the scope of the developed methodologies as well as on performing mechanistic studies, in order to get a deeper insight in those processes and understand how to improve them. Our work has raised interest within the academic and industrial community during the conferences where we presented our work. Two international, one national and two internal academic collaborations has been established and resulted very fruitful (see periodic report 2). We have had 2 international PhD students joining our laboratories as visiting researchers during the grant period, which is also indicative of the impact of our research in the scientific community. A collaboration with the company Syntor was established during the summer of 2013 to look at the sustainable synthesis of several building blocks for polymer synthesis. The company was interested in our approaches towards the use of mechanochemical methods and the avoidance of solvents for the chemical transformations. The grant has covered the fees and salaries for 1 PhD student (3 years) and 2 postdoctoral researchers (2 x 6 months), and the consumables for their research and the research of 5 visiting students and 1 Master student. We have exceeded our targets for publications. We have produced 13 international publications (9 research articles and 3 review papers) and 1 book chapter. Two more outputs are very close to submission (see periodic report 2). The research group of the fellow BMR grew in number of students and productivity during the grant period. Thanks to the funding of this Marie Curie Integration grant, the fellow obtained preliminary results to apply for an EPSRC grant and a RS travel grant. Both applications were successful. The Faculty of Science and Engineering at MMU supported the fellow and awarded a PhD studentship. In conclusion, our research has significantly contributed to an emerging and relevant area of research and BMR has grown as an independent researcher.

Data: CORDIS, © European Union