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

2. 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)

3. Market for agrochemicals

4. Global crop sales of agrochemicals
Source of estimates: Cropnosis Ltd

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

6. 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 The takeover of
Syngenta by ChemChina is still being negotiated, but appears to be on-track.

7. Sources of fine chemicals to the agrochemical industry

8. 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

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

10. 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.

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

12. 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

13. Latest developments in agrochemical technologies

14. 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)

15. Few recent herbicides with novel MoAs

16. More insecticides with novel MoAs

17. And also new fungicide MoAs

18. promising technologies
Selected examples of
promising technologies

19. 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

20. 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)

21. 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

22. 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

23. 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.

24. 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

25. 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,
The five illustrated fungicides can all be made using DFMMP

26. Opportunities for suppliers

27. 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.

28. 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 ( data)
Crop Protection Actives (online database)
Prepares detailed reports on an exclusive basis, often in
collaboration with Brychem and Cropnosis Ltd
See websites: and

29. Agranova If you have been, thank you for listening. Dr Rob Bryant
34 The Drive
Orpington, Kent BR6 9AP
United Kingdom
Tel: , Fax:
Websites: and