Great Green Science at Chem21 AGM

November Blog – by Murray Brown (Project Coordinator)

I think everyone who was able to attend the second annual meeting of Chem21 in Graz will agree that the breadth and depth of green technologies on show was breathtaking from base metal catalysts for C-H activation to Synthetic Biology chassis for cascade reactions. On a personal note, it was an honour and a privilege to be elected by the GA to take over from Simon Dolan as Coordinator for the consortium and I’d like to recognise his leadership over the first two years to create such a well aligned and productive organisation from such a diverse grouping. I’m really looking forward to working with the whole consortium over the next two years to bring home the tangible benefits that we are all hoping for. There isn’t room here to detail all the excellent science presented, and all the slides and posters are available to members on the e-Room for those that weren’t able to get to the meeting in person. I would like to highlight a few areas, and echo the words from our Scientific Advisory Board (and it was great that Dave Lathbury and John Leonard were able to attend and take such an active role in the meeting). Work packages 1 and 5 have been referred to as topping and tailing the consortium and with them we’ve been working to find the glue that binds us all together. Firstly the work to identify greener routes to Essential Medicines has reached the next stage. We’ve decided to progress the Fluorination work developed at Durham to scale up sponsored by Sanofi at their strategic partner MEPI. The C-H activation chemistry developed at Antwerp will be investigated for a greener route to the anthelminthic drug Albendazole which forms part of GSK’s philanthropic donation portfolio. And perhaps most ambitiously we will seek to find enzymatic routes to Ethambutol, a key component of TB therapy. The next two years is where the rubber really hits the road in terms of proving that sustainable technologies can be industrialised and used at scale for pharmaceutical production. So beyond these key Essential Medicines the EFPIA members have identified focus areas where resources will be concentrated to demonstrate their applicability in industry. Another aspect that ties the workpackages together is the reaction database. The database is now live with the biocatalysis portion nearly complete and although Vilmos, Tony and Peter will continue to make improvements to its functionality all researchers should be entering their data. As well as allowing everyone to see your wonderful work, it provides a simple way to check how green your reactions are and it’s now a requirement to have entered the relevant reactions before publication approval. A further area highlighted by the SAB as unique and of great value is the Young Researcher Network. Work package 5 members did an excellent job in a tightly squeezed agenda to run a workshop that was by all accounts very well received. We hope to be able to hold other such workshops and increasingly will be looking to virtual technologies to try to recreate the energy and immediacy of a face to face meeting without the associated travel. I urge you all to engage fully with the YRN and participate in future events whether in cyberspace or IRL (thanks to my teenage daughters for the acronym).

Finally I look forward to meeting you all again at next year’s AGM which will be hosted by Sanofi in Paris (date to be announced, targeting early Sept) and many of you before that at as many WP F2F meetings as I can manage (again dates to be announced, targeting March/April).

Greetings from North of Europe!

August 2014 Blog – Leena Otsomaa, Orion Corporation, Orion Pharma

Summer is slowly turning into early autumn here and soon here it is time to pick up fruits and berries from forests and one’s garden. From the four seasons, the autumn is the time of harvesting and so it will be soon also time for us in Chem21 to harvest the results of our project. Today I am confident that our project is proceeding well and we can be pleased of it. In this blog,  I will highlight some reasons for my confidence in this blog from Orion perspective.

For me this project actually started already in the year 2010 when GSK, Sanofi and Orion had the first discussion on the phone for possible topics and the content in the field synthetic chemistry for IMI call 4.

The topics that were discussed at that time are the basis of the current WP’s in the Chem21. During further discussions the program became more matured and new members joined to the planning group. Eventually Call 4 was opened in the mid of 2011. It was already three years ago! It also was the time when academic groups of Chem21 started to form multidisciplinary teams to address the challenges that we in industry had identified. The academic groups used Chem21 name in their applications and finally it turned to be the name of our consortium. It is by the way a good name. Now we are close to the end of the first half of the whole Chem21 project phase, soon turning into harvesting…  and I can proudly say that we have already concrete results in our hands though many things are still in the progress.

As medicinal chemists we have learned that our scientific challenges in research are global. It doesn’t matter Mid or Big: chemistry is chemistry. PR&D and research have their different perspectives, but there also exists synergies.In chemistry future challenges of development are current problems of research. This makes challenges common for all of us. The aspect that consortium has representatives from both research and development of EFPIA partners makes Chem21 stronger. Yet not forgetting that learning from our colleagues in PR&D medicinal chemists can reduce their burden on environment and design better routes for the next phase. Academic groups have important role in developing novel more sustainable methodologies and technologies for the future use.

One of the real opportunities the consortium is delivering to the members – academia as well as companies – is the chance of networking & collaboration in various settings. After the initial -getting to know- phase this is one of the most important ways to boost research successes by utilizing more possibilities also in the future. For us in Orion (midsize pharma company from far north) this has been a great chance to extend our scientific network to Pan European research groups.

Below I have highlighted some thoughts on the four WPs,  we –at Orion- are involved actively.

WP1

Was very active during the first year of the project and delivered vision 2020. However, it also verified that the original starting points were valid. I personally wish that vision 2020 will be taken to the wide audience to activate debate between the experts in the field of chemistry and to improve our way of working worldwide.

WP2

Today in the middle of the project  the most valuable result in WP2 for us has been research activities in the field of CH activation. There has been debates that CH activation is too hot topic and it is true, if you only focus on academic publications. However, if you review patent applications, you can easily conclude that CH activation is not widely used by medicinal chemists. One reason e.g. in contrast of Suzuki type Pd-based chemistry, simply is that the field of CH activation as technology is not well known in practice. Scientist prefer to utilize technologies and methodologies they are morefamiliar with. WP2 has brought CH activation close to our scientists and new compounds (potential candidates) has been made utilizing methodologies developed under WP2 of Chem21.

WP3

I would highlight the technology transfer in the field of biotransformation from Manchester under WP3. We had post doc Susanne Herter here in Orion for four months working with our scientists and setting up the systems. We in Orion learned a lot from utilizing whole cells in organic synthesis as well as many handy tricks with isolated enzymes. She learned about industrial thinking among many other things. Borrowing her words, Scientists in academia asks ‘’what is possible to make with this’’ while in industry scientist asks ‘’does this work in my case’’. I am sure that her visit to Orion has influence on her future scientific work. Our vision in Orion is to have biocatalysis as one alternative tool for our scientists. Chem21 gives us good starting point towards our vision.

WP5

We in Orion have initiated as an in-house actions to implement solvent and reagent recommendation which are under development in Chem21, to our scientists daily practice. I have already heard encouraging comments from our scientist how helpful Chem21 guidelines (even if draft) have been in practice. As part of the work performed,  the green chemistry e-book has been written though final editing etc. are still to be done. However, when the e-book becomes available I highly recommend to read it and utilize it for training purposes. The motivation of academic partners on ensuring industry relevant education for next generation scientists, is on great to notice.

WP5 has also initiated the selection of philanthropic target molecules for educational purposes. The real benefit of these targets is that they are used through all WP activities, especially with the aim of industrialization of selected processes. It will be interesting to follow the progress of these activities.

Finally I would point out that scientific challenges are tackled around the word by many scientist,however,how we work together in Chem21 makes the difference. Hence, I courage to pay great attention to collaboration between various partners of consortium.

My sincere thanks to all colleagues from other EFPIA companies and scientists from academic/non-profits/ SME’s for everything.

‘’Keep the bunsen burning’’ as one professor supervising me said when I was still making my post graduate studies (though today use of this old technique is forbidden)!

 

Some thoughts on small molecule drugs of the future and attendant synthetic challenges…..

Blog April 2014 – Andy Wells, Charnwood Technical Consulting

It is interesting to follow the debate on small molecule API’s vs. biologics. In my view, the demise of small molecule API’s has been overstated , and moving forward, small molecules will have an important place alongside monoclonal antibodies, conjugates, vaccines , therapeutic enzymes and peptides in the fight against disease and maintaining wellbeing for mankind. The drop in the number of new molecular entities launched over the past 10 years or so, the ‘poor’ return on investment in pharma R&D has been extensively debated elsewhere, along with a myriad of suggestions to improve the success rate in small molecule research. As a scientist with an interest in developing greener and more sustainable chemical manufacturing technology, I believe that we should not only look at present and past challenges, but also look forward to the molecules of the future to ensure that we focus our chemistry toolboxes to meet future needs. Discussed below are some thoughts and synthetic challenges (by no means a comprehensive set) for pharmaceutical synthesis in 2020, illustrated by some recently launched molecules, or in mid/late phase clinical development.

Molecular complexity

Anyway, so we expect to see more complex structures – more saturated heterocyclic rings, fused rings, spiro systems, more chirality etc. Is more molecular complexity a necessity for success in the clinic? Well, not necessarily. Some small molecules can have big effects in biological systems – O2, NO, CO2, CO, HCN, H2S are well known –it surprised me to discover recently that Xenon is an effective and powerful general anaesthetic.

It can be seen from some recent launches, PIrfenidone, dimethyl fumarate and vortioxine –see below, that molecules with surprising ‘simple ‘ structures still get through. The 2013 prize for the simplest molecule launched has to go to dimethyl fumarate. As a point of interest, dimethyl fumarate has recently been banned in the EU under REACH legislation as an anti-fungal treatment for leather goods due to a number of severe chemical sensitization cases.

Media1

Thankfully as synthetic chemists who like a challenge, there are molecules coming through that will test our skills in assembling the molecular architecture and essential molecular decoration – see structures below. It has to be noted that any change in the small molecule portfolio is slow and evolutionary rather than revolutionary. Some new hetero-aromatic and saturated heterocyclic ring systems are coming through discovery into development. Contrary to popular belief, the number of chiral compounds being launched does not really seem to be increasing. The figure seems to be fairly constant at around 50% with the rest being achiral molecules with the occasional racemate. What does appear to be subtlety changing is the nature of chiral compounds. These seem to be polarising into molecules that have either one or multiple chiral centres, with fewer in the two to three chiral centre range figure 1. Drugs with five to eight chiral centres have never really been popular, falling into the region where natural products and synthetic chemistry don’t deliver/fear to tread.

Media2

Figure 1 V2020 Analysis of chiral compounds IN Organic Process R&D journal –number of molecules with X chiral centres vs. year.

A quick look at some of the molecules featured here will confirm the importance of chemical methodologies directed towards making complex chiral molecules.

Fluorine

The number of fluorinated small molecules entering the market varies from 14-35%, averaging ~25%,demonstrating the critical importance of fluorine chemistry to the industry. Typically aryl and heteroaryl fluorides have predominated, alongside trifluoromethyl groups. This pattern appears to be changing, with a more diverse set of aliphatic carbon – fluorine bonds appearing – see below.

media3

Bromine/Iodine

Although much less prevalent than Fluorine, the patterns of use of Bromine and Iodine are changing.

Often introduced as synthetic handles to impart certain reactivity or selectivity, and then removed during chemical transformations, the number of molecules retaining Bromine and Iodine in the final drug substance are slowly increasing – see some examples below.

media4

Reactive pharmacophores

The number of API’s with reactive pharmacophores is increasing – two are shown below –ibrutinib and carfilzomib. Dimethyl fumarate would also fall into this category. These molecules are typically irreversible enzyme inhibitors acting by forming covalent bonds between essential amino acid residues in an enzyme active site and an alkylating or Michael acceptor group.

media5

Natural products

Finally, each year one or two new drugs still enter the market that have their genesis in natural products. A good example is carfilzomib, based on epoxomicin – a naturally occurring selective proteasome inhibitor-structure below.

media6

Blog January 2014 – John Blacker, iPRD, University of Leeds

Since Sir Geoffrey Wilkinson invented a rhodium catalyst selective for the hydrogenation of cis-alkenes,1 the last several decades have seen an extraordinary rise in the use of precious metal-based catalysts. Soluble forms of palladium, platinum, gold, rhodium, iridium, ruthenium have been made with organic ligands that control the metal, and its environment, to facilitate chemo-, regio-, stereo- and selective chemical transformations. As a result of this, some of these catalysts have found application in the production of complex organic chemicals; but importantly, also because ways have been found to use them efficiently, either through high turnover, or recovery and recycle. Despite this the majority of precious metal catalysts, identified by a large number of academic groups throughout the world, are unusable, even in the high value pharma industry. This is because: the loadings are too high with consequent cost (anything above 0.1mol% is usually uneconomic, whilst most report 1-10mol%); recovery and recycle is frequently impractical. Furthermore these metals are toxic to biological systems with regulations that stipulate drug products must contain <10 ppm quantities.

The increasing global consumption of precious metals has raised international concern over their medium to long-term supply. Whilst by far the largest consumers are the automotive and electronics industries, the pharma industry is involved and needs to adopt sustainable precious metal use policies. This should include some of the Green Chemistry Principles around avoidance, higher efficiency, recovery and recycle.2 The Chem21 project is working to support these aims by evaluating the use of alternative organo-, bio- and base metal catalysts as well as more efficient processes and recovery recycle methods.

The recent Winter Process Conference held by iPRD,3 and organized by Scientific Update had a number of talks from Chem21 collaborators, setting the scene by covering new base-metal catalysts and applications in atom-efficient transformations. Prof. Beller form LIKAT, Rostock spoke, amongst many exciting developments, of new iron catalysts for chemoselective nitroaromatic-reductions;4 Dr Kai Rossen of Sanofi-Aventis spoke of their clean photocatalytic oxidation process in Artemisinin production;5 Prof. Bert Maes of University of Antwerp  spoke of their work on the use copper catalysts in aromatic C-H activations;6 I spoke of the Chem21 work done by Dr Andy Wells and Dr John Hayler and others in analyzing the impact of green chemical approaches over the last decade, gaps and areas of future concern including precious metal catalysts.

A paper recently published rather depressingly concludes that finding alternatives to precious metals is unlikely.7 Whilst this may be true regarding the material properties of these metals, with catalyst applications there are already some base metal alternatives and more are being reported every week in what has become an intensive area of research.

A further caution against a knee-jerk response in abandoning precious metals in catalysis, is that their availability follows standard supply and demand economics. As demand outstrips supply and prices increase, new mines become economic and prices can then fall. This recently happened with rhodium that became very expensive until a new gold seam was opened in which there was a higher abundance of the rhodium side-product.8 Despite refining more metals, the conservation of matter laws dictates that they don’t disappear, rather they change form. Consequently more effort needs to be put into identifying methods for recovering metals from catalytic converters, mobile phones and the like. Better still to design such products with recovery in mind. Likewise the community should design methods for catalyst separation and recovery from the outset. Chem21 is working to develop catalyst immobilization methods with partners Reaxa Ltd, and membrane separation methods, Vito Ltd.

To conclude, we should be cautious in redirecting research to sustainable catalysts, not to ignore the amazing progress made in using precious metal catalysts, but to find ways of using these more effectively to make products economically, safely and sustainably. Nevertheless the whole community should welcome the progress being made in new organo-, bio- and base metal catalysts which will give process chemists better alternatives to realize more sustainable and cost effective drug manufacture.

  1. Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G., Journal of the Chemical Society A, 1711–1732, 1966.
  2. Kletz, T.A., Chemistry and Industry, 287–292, 1978; Anastas, P. T., Warner, J. C., Green Chemistry Theory and Practice. New York: Oxford University Press, 1998
  3. www.iprd.leeds.ac.uk; www.chem21.eu/
  4. R. V. Jagadeesh, A.-E Surkus, H. Junge, M.-M. Pohl, J. Radnik, J. Rabeah, H. Huan, V. Schünemann, A. Brückner, M. Beller, Science, 29 November 2013: 1073-1076
  5. A. Burgard, M. P. Feth, K. Rossen, EPAppl. 2660234 A1, 20131106
  6. J. De Houwer, K. Abbaspour Tehrani, B. U. W. Maes, Angew. Chem. Int. Ed. Engl., 51, 2745, 2012
  7. Recycling of (critical) metals, G. Gunn, C. Hagelüken, Published Online: 27 DEC 2013, DOI: 10.1002/9781118755341.ch3
  8. http://www.platinum.matthey.com/publications/pgm-market-reviews/market-review-archive/platinum-2012

Reflecting on New Directions in Sustainable Catalyst Development – John Blacker

Since Sir Geoffrey Wilkinson invented a rhodium catalyst selective for the hydrogenation of cis-alkenes,1 the last several decades have seen an extraordinary rise in the use of precious metal-based catalysts. Soluble forms of palladium, platinum, gold, rhodium, iridium, ruthenium have been made with organic ligands that control the metal, and its environment, to facilitate chemo-, regio-, stereo- and selective chemical transformations. As a result of this, some of these catalysts have found application in the production of complex organic chemicals; but importantly, also because ways have been found to use them efficiently, either through high turnover, or recovery and recycle. Despite this the majority of precious metal catalysts, identified by a large number of academic groups throughout the world, are unusable, even in the high value pharma industry. This is because: the loadings are too high with consequent cost (anything above 0.1mol% is usually uneconomic, whilst most report 1-10mol%); recovery and recycle is frequently impractical. Furthermore these metals are toxic to biological systems with regulations that stipulate drug products must contain <10 ppm quantities.

The increasing global consumption of precious metals has raised international concern over their medium to long-term supply. Whilst by far the largest consumers are the automotive and electronics industries, the pharma industry is involved and needs to adopt sustainable precious metal use policies. This should include some of the Green Chemistry Principles around avoidance, higher efficiency, recovery and recycle.2 The Chem21 project is working to support these aims by evaluating the use of alternative organo-, bio- and base metal catalysts as well as more efficient processes and recovery recycle methods.

The recent Winter Process Conference held by iPRD,3 and organized by Scientific Update had a number of talks from Chem21 collaborators, setting the scene by covering new base-metal catalysts and applications in atom-efficient transformations. Prof. Beller form LIKAT, Rostock spoke, amongst many exciting developments, of new iron catalysts for chemoselective nitroaromatic-reductions;4 Dr Kai Rossen of Sanofi-Aventis spoke of their clean photocatalytic oxidation process in Artemisinin production;5 Prof. Bert Maes of University of Antwerp  spoke of their work on the use copper catalysts in aromatic C-H activations;6 I spoke of the Chem21 work done by Dr Andy Wells and Dr John Hayler and others in analyzing the impact of green chemical approaches over the last decade, gaps and areas of future concern including precious metal catalysts.

A paper recently published rather depressingly concludes that finding alternatives to precious metals is unlikely.7 Whilst this may be true regarding the material properties of these metals, with catalyst applications there are already some base metal alternatives and more are being reported every week in what has become an intensive area of research.

A further caution against a knee-jerk response in abandoning precious metals in catalysis, is that their availability follows standard supply and demand economics. As demand outstrips supply and prices increase, new mines become economic and prices can then fall. This recently happened with rhodium that became very expensive until a new gold seam was opened in which there was a higher abundance of the rhodium side-product.8 Despite refining more metals, the conservation of matter laws dictates that they don’t disappear, rather they change form. Consequently more effort needs to be put into identifying methods for recovering metals from catalytic converters, mobile phones and the like. Better still to design such products with recovery in mind. Likewise the community should design methods for catalyst separation and recovery from the outset. Chem21 is working to develop catalyst immobilization methods with partners Reaxa Ltd, and membrane separation methods, Vito Ltd.

To conclude, we should be cautious in redirecting research to sustainable catalysts, not to ignore the amazing progress made in using precious metal catalysts, but to find ways of using these more effectively to make products economically, safely and sustainably. Nevertheless the whole community should welcome the progress being made in new organo-, bio- and base metal catalysts which will give process chemists better alternatives to realize more sustainable and cost effective drug manufacture.

John Blacker – iPRD, University of Leeds

  1. Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G., Journal of the Chemical Society A, 1711–1732, 1966.
  2. Kletz, T.A., Chemistry and Industry, 287–292, 1978; Anastas, P. T., Warner, J. C., Green Chemistry Theory and Practice. New York: Oxford University Press, 1998
  3. www.iprd.leeds.ac.uk; www.chem21.eu/
  4. R. V. Jagadeesh, A.-E Surkus, H. Junge, M.-M. Pohl, J. Radnik, J. Rabeah, H. Huan, V. Schünemann, A. Brückner, M. Beller, Science, 29 November 2013: 1073-1076
  5. A. Burgard, M. P. Feth, K. Rossen, EPAppl. 2660234 A1, 20131106
  6. J. De Houwer, K. Abbaspour Tehrani, B. U. W. Maes, Angew. Chem. Int. Ed. Engl., 51, 2745, 2012
  7. Recycling of (critical) metals, G. Gunn, C. Hagelüken, Published Online: 27 DEC 2013, DOI: 10.1002/9781118755341.ch3
  8. http://www.platinum.matthey.com/publications/pgm-market-reviews/market-review-archive/platinum-2012

Blog December 2013 – Nick Turner

Blog December 2013 – Nick Turner

During the past 3 weeks I have attended three conferences in Europe, each dealing with various aspects of sustainable chemistry, industrial biocatalysis/biotechnology and synthetic biology. The first conference was the EcoChem meeting in Basel where the Swiss Industrial Biocatalysis Consortium (SIBC) hosted a one day seminar on 20th November focussing on current trends in biocatalysis and synthetic biology. The SIBC is a group of seven pharmaceutical/fine chemical companies based in Switzerland and includes Roche, Novartis and Syngenta amongst others. The meeting was jointly organised by our own Andy Wells together with Hans-Peter Meyer from Lonza and included talks from Bernhard Hauer, Jurgen Hansen (Evovla) and yours truly. At the end of the day there was a very interesting and stimulating panel discussion meeting during which a variety of topics were debated including the possibility of establishing a virtual European Centre of excellence in Biocatalysis. The panel also discussed at length ways in which biocatalysts might be both more rapidly developed and made available to those who wished to screen them in the pharmaceutical industry. Availability of an increasingly diverse toolbox of biocatalysts is rightly seen as a critical issue in the further uptake of biocatalysis in industry and of course is one of the challenges that is being addressed within the CHEM21 consortium. Another major CHEM21 theme, which I presented and which received considerable discussion, was that of ‘biocatalytic retrosynthesis’ – it was generally agreed that any future guidelines for retrosynthesis should simultaneously address recent developments in not only biocatalysis but also transition metal catalysis and organocatalysis.

On the following Monday 25th November I travelled to Malaga where I met up with Toni Glieder at the 2nd European Federation of Biotechnology Applied Synthetic Biology Meeting. This meeting reminded me that ‘synthetic biology’ can mean something very different depending upon your interpretation of this diverse field. In fact the meeting was more focussed on the development of circuits, chassis, host systems etc. with many very interesting presentations. I would strongly encourage younger scientists within CHEM21 to keep an eye open for details of the 3rd meeting in this series since it represents an excellent opportunity to network with like minded people and also present some of your work to a diverse audience.

Finally last week I spent three days in Brussels from 1st – 4th December attending a series of meetings relating to EU FP7 projects, particularly BIONEXGEN, which will soon finish at the end of January 2014, and BIOOX which started very recently on 1st October 2013. Both programmes involve multiple academic and industrial partners and both are managed by CoEBio3 at the University of Manchester. On the 3rd December we organised an outward facing one-day event in the Crowne Plaza aimed at disseminating many of the results from various EU FP7 programmes which we have been involved with. Again the day concluded with a very interesting panel discussion chaired by John Woodley from DTU Copenhagen. On this occasion the panel contained strong representation from SMEs involved in Industrial Biotechnology including Prozomix, CLEA technologies and Bioprodict. SMEs are seen as being vitally important by the EU in the future growth of IB within Europe and indeed the new Horizon 2020 programme, which will soon issue the first calls for proposals, presents many opportunities for the involvement of small and medium-sized companies. H2020 has a strong Industrial Biotechnology component and during the day we heard from both EuropaBio and a project officer from the EU regarding plans for allocation of the funds over the period 2014-2020.