Fine chemical technologies for novel agrochemical ingredients Common carder bee on lavender Presentation to the 33rd SCI Process Development Symposium April 2016

Agenda Market for crop treatment agrochemicals Production of fine chemicals for the agrochemical industry Latest developments in agrochemical technologies Selected examples of promising technologies Opportunities for suppliers Object of my talk is to offer a brief review of newer, commercially important agrochemical chemistries, some of which may offer attractive directions for developing improved fine chemical process technologies My last presentation to the SCI was in 1987 (5th SCI PDS)

Market for agrochemicals

Global crop sales of agrochemicals Source of estimates: Cropnosis Ltd

Crop sales of agrochemicals by country Estimates for the Chinese market are certainly low

Sales of major companies in crop protection Source: Agrochemicals - Executive Review (24th edition) 2013, published by Agranova Makhteshim-Agan renamed Adama after its acquisition by ChemChina in 2014 Du Pont and Dow Agrosciences have agreed to merge in 2016. The takeover of Syngenta by ChemChina is still being negotiated, but appears to be on-track.

Sources of fine chemicals to the agrochemical industry

Disappearing European and US discovery companies: 1960s -2017 1980 European and US companies no longer dominate global innovation as once they did. 2000 2010 2017? After slides prepared by Andresen and Sparks

Major inventing institutions (2012) Japanese companies have overtaken US and Europeans as the top source of new agrochemicals

Production of agrochemical ingredients in Japan Japan is a leading creator of new technologies and its leading companies tend to foster local suppliers. Over the past 10 years, China and India have increased their share of the supply to Japan, although generally business opportunities have been for older AIs and intermediates Western licensees usually purchase AI from the licensor, at least during the initial years of market development Production costs in Japan continue to be higher than elsewhere. This may create opportunities for foreign producers.

Japanese AI production statistics Volume decreases from >7,000 - 200 metric tons Source: Information reported by producers to government agency and published annually in Japanese

Production of fine chemicals Originators* of agrochemical active Licensees/developers* of agrochemical active Companies making product after exclusivity expiry Sub-contractors to license-holder Independent producers (especially intermediates) *or group company Hard to enter this market without something special to offer

Latest developments in agrochemical technologies

Agrochemicals with newer MoAs nicotinic acetylchloline receptor agonist (IRAC: 4A) Diamide RyR receptor modulator (IRAC code: 28X) SDHI - respiration interference (FRAC code: F-C2) 4-hydroxyphenylpyruvate dioxygenase inhibitors Examples of commercial groups of AIs possessing the same modes of action (sales values in USD millions)

Few recent herbicides with novel MoAs

More insecticides with novel MoAs

And also new fungicide MoAs

promising technologies Selected examples of promising technologies

New group of antiparasitics under development for controlling of fleas It seems that these insecticides are unsuitable for use in the field and will be used only as animal health products. The process technology for making sarolaner is discussed overleaf

Components of sarolaner synthesis Major isoxazolines in development are shown overleaf. Target sales > USD 1 bn are expected for the most successful, which are expected to replace the more toxic fipronil (Headline) and environmentally-challenged Advantage II (imidacloprid)

Other isoxazoline antiparasitics Lotilaner (5S) Novartis Animal Health Sarolaner (5S) Pfizer - Zoetis Afoxolaner (5R,S) DuPont-Merial Fluralaner (5R,S) Nissan Chemical - MSD Animal Health Syngenta also has patents in this area, but not known if any are in development. These insecticides are GABA-R agonists, acting similarly (but at different site on receptor) to the organochlorine insecticides* (eg endosulfan) and fiproles (eg fipronil). * now defunct

Meta-diamide insecticide The chemistry of this lead candidate is similar to the successful RyR agonist insecticides* (ortho-diamides, such as chlorantraniliprole). However, this meta-diamide interacts with the same GABA-R site as isoxazolines, interfering with the chloride ion pump, not the calcium ion one. Broflanilide is being developed as a crop treatment. * This is how it was discovered serendipidously

pyrazole-4-carboxylic moeity. Example of the use of the important 1-methyl-pyrazole-4-carboxamide side-chain A newer example of an important chemical class of agrochemicals containing pyrazole-4-carboxylic moeity.

SDHI pyrazole-4-carboxamide fungicides Sumitomo Chemical launched furametpyr in 1997, followed by Mitsui Chemical’s pentathiopyrad in 1998 In 2010, Syngenta commercialised isopyrazam, followed by sedaxane in 2011 and benzovindiflupyr in 2014 In 2011, BCS bixafen, followed by penflufen in 2012 and BASF launched fluxapyroxad in 2011. A common intermediate that emerged is ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate

Solvay published an interesting paper on the industrial synthesis of the common intermediate: ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFMMP) Source of diagram: Org. Process Res. Dev. 2014, 18, 1055- 1059 The five illustrated fungicides can all be made using DFMMP

Opportunities for suppliers

Opportunities for fine chemical development in agrochemicals Cost-effective processes to synthesise pyrazoles, isoxazolines, biphenyls and polysubstituted benzene compounds. Offer more than just the ability to run third party processes, where your profits are under customer’s control European companies should consider developing commercial relationships with Japanese innovators (Nihon Nohyaku, Nissan Chemical, Kumiai, Meiji Seika, SDS and many others) Production costs are far more important for success in the agrochemical industry than in pharmaceuticals, so improving processes is also much more important.

See websites: www.agranova.co.uk and www.brychem.co.uk About Agranova Produces a biannual publication on the global development of new agrochemical technologies, plus a cumulative index Ag Chem New Compound Review (in 34th year of publication) Ag Chem Base (online technical profiles of > 3,500 AIs) Produces annual review of global sales and consumption of commercial agrochemical technologies (1997 -2014 data) Crop Protection Actives (online database) Prepares detailed reports on an exclusive basis, often in collaboration with Brychem and Cropnosis Ltd See websites: www.agranova.co.uk and www.brychem.co.uk

Agranova If you have been, thank you for listening. Dr Rob Bryant 34 The Drive Orpington, Kent BR6 9AP United Kingdom Tel: +44 1689 600 501, Fax: +44 1689 897 786 Email: rob@agranova.co.uk Websites: www.agranova.co.uk and www.brychem.co.uk