Slides for 33rd SCI process development symposium

Slides for 33rd SCI process development symposium

Fine chemical technologies for novel agrochemical ingredients Common carder bee on lavender Presentation AGRANOVA 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) AGRANOVA Market for agrochemicals AGRANOVA Global crop sales of agrochemicals Global sales of agrochemicals (all sectors) in USD mn 2008-2016E 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 2008 2009 2010 Insecticides Fungicides Source of estimates: Cropnosis Ltd AGRANOVA

2011 2012 Herbicides 2013 2014 2015E Agrochemicals (all sectors) 2016E Crop sales of agrochemicals by country Brazil USA Japan China France Argentina Australia Germany Canada South Korea India Italy UK Spain Mexico RoW Estimates for the Chinese market are certainly low AGRANOVA Sales of major companies in crop protection Agrochemical sales only (USD millions) 2004

2011 2012 Syngenta Bayer CropScience BASF Dow AgroSciences Monsanto Du Pont Makhteshim-Agan Nufarm Sumitomo Chemical Arysta LifeScience 6,030 6,799 3,223 3,079 2,842 2,518 1,244 939 865 685 10,162 8,947 5,791 4,605 3,502 2,856 2,551 2,143 1,723 1,485 10,710 9,470 5,864 5,017 3,994 3,172 2,654 2,248 1,669 1,557 Switzerland Germany Germany USA USA USA Israel

Australia Japan Japan 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. AGRANOVA Sources of fine chemicals to the agrochemical industry AGRANOVA Disappearing European and US discovery companies: 1960s -2017 1960 Allied Chemical American Cyanamid BASF Bayer Boots Ciba Diamond Shamrock Dow Dupont E. Merck Esso Fisons FMC Geigy Gulf Hercules Hoechst Hoffman LaRoche Hooker ICI Merck MGK Monsanto Mortin Norwich Murphy Oil Olin Matheson Pennwalt Phillips Petroleum Rhne Poulenc Rohm & Haas Sandoz Stauffer Schering AGRANOVA

1980 Abbott American Cyanamid BASF Bayer Fison-Boots Company Celamerck Chevron Ciba-Geigy Dow Duphar Dupont Elanco FMC Gulf Hoechst Hoffman LaRoche ICI Maag Monsanto Mortin Norwich Monsanto Schering Rhne Poulenc Rohm & Haas Roussel-UCLAF Sandoz European and US companies no longer dominate global innovation as once they did. 2000 Agrevo American Cyanamid BASF Bayer Crompton (Uniroyal) Dow Dupont FMC Monsanto Mortin Norwich Monsanto 2010 BASF Bayer Chemtura Dow Dupont FMC

Monsanto After slides prepared by Andresen and Sparks 2017? BASF Bayer Dow-DuPont Monsanto 16 14 12 10 8 6 4 n u m b ers o f co m p o u n d s Major inventing institutions (2012) Agrochemicals in development by major inventing companies (2012) 18 2 0 Z C IR I S Y R IC I B ayer S y n g e n ta H R IC I BASF S D S B io te c h IS K D ow K u m ia i M its u i C h e m ic a l M e iji S e ik a Is a g ro D uP ont O ts u k a C h e m ic a l N is s a n C h e m ic a l N ip p o n S o d a N ih o n N o h y a k u

AGRANOVA S u m ito m o C h e m ic a l 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. AGRANOVA Japanese AI production statistics Production of AIs in Japan 2014 (in descending order of volume manufactured) Volume decreases from >7,000 - 200 metric tons DCP chloropicrin prosulfocarb chlorothalonil copper carbonate, basic thiophanate-methyl sulphur benthiocarb flumioxazin isoprothiolane cyhalofop-butyl diazinon buprofezin copper sulfate procymidone calcium oxide tepraloxydim sethoxydim flubendiamide clothianidin flutolanil acetamiprid copper oxychloride etofenprox dinotefuran cyhalofop+bentazone TCTP tiadinil

sodium chlorate penthiopyrad methyl bromide iminoctadine albesilate copper sulphate anh iminoctadine triacetate pyrazolate quizalofop-P-ethyl metconazole maneb Source: Information reported by producers to government agency and published annually in Japanese AGRANOVA 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 AGRANOVA Latest developments in agrochemical technologies AGRANOVA Agrochemicals with newer MoAs Common name thiamethoxam imidacloprid clothianidin acetamiprid thiacloprid dinotefuran nitenpyram Value 2014 1740 1735 675 442 209 151 21 Value 2009 735 1220

422 310 140 92 10 nicotinic acetylchloline receptor agonist (IRAC: 4A) Common name mesotrione isoxaflutole sulcotrione benzobicyclon pyrazolynate pyrazoxyfen benzofenap Value 2014 890 255 75 42 31 11 10 Value 2009 595 169 58 26 20 8 7 4-hydroxyphenylpyruvate dioxygenase inhibitors AGRANOVA Common name chlorantraniliprole flubendiamide cyantraniliprole Value 2014 1350 215 28 Value 2009 274 82

- Diamide RyR receptor modulator (IRAC code: 28X) Common name boscalid bixafen carboxin penthiopyrad flutolanil thifluzamide oxycarboxin mepronil furametpyr fenfuram Value 2014 510 246 77 72 33 26 23 17 11 0 Value 2009 327 0 63 7 28 17 21 10 17 0 SDHI - respiration interference (FRAC code: F-C2) Examples of commercial groups of AIs possessing the same modes of action (sales values in USD millions) Few recent herbicides with novel MoAs pinoxaden (NOA 407855) Syngenta Entry year: 2003 phenylpyrazolinone ACCase inhibitor [243973-20-8]

US 6 410 480 pyrasulfotole (AE 0317309) BayerCropScience Entry year: 2005 pyrazole 4-HPPD US 6 872 691 [365400-11-9 ] tembotrione (AE 0172747) BayerCropScience Entry year: 2006 benzoylcyclohexanedione 4-HPPD AGRANOVA WO 2003 020 033 [335104-84-2] More insecticides with novel MoAs flu h e x a fo n(S -1 8 7 1 )S u m ito m oC h e m ic a lL td E n tr yy e

a r :2 0 1 4 c y c lo h e x a m in o x im e(M o A ? ) C N C H 3 O S O 2 C F 3 N U S8 2 4 7 5 9 6(toS u m ito m oC h

e m ic a l) [1 0 9 7 6 3 0 -2 6 -6 ] c y e n o p y r a f e n ( S 1 8 7 1 )N i s s a n C h e m i c a l E n t r y

y e a r :2 0 0 3 1 ,2 p y r a z o l e 4 c a r b o x a m i d e ( M E T Ia c a r i c i d e s) C N C H 3 O O H

C 3 N N C H 3 W O 9 7 4 0 0 0 9 ;J P 2 0 0 3 2 0 1 2 8 0 ( p r o c e s s ) [ 5 6 0 1 2 1 5 2 0 ] d i c l

o r o m e z o t i a z ( D P X R D S 6 3 )D u P o n t E n t r y y e a r :2 0 1 4 m e s o i o n i c p y r i d o

[ 1 , 2 a ] p y r i m i d i n e C l S N C H 3 + N O N C l O AGRANOVA C l [ 1 2 6 3 6 2 9 3 9 5 ] And also new fungicide MoAs oxathiapiprolin(DPX-QGU42) DuPont

Entry year: 2012 Oxazolino-pyrazole-4-carboxamide CF3 O F O N N N N CH3 N S F WO2008013925, WO2010123791 (specific lead; process chemistry) [1003318-67-9] p y r a z iflu m id(N N F -0 7 2 1 )N ih o nN o h y a k u E n tr yy e

a r :2 0 1 4 b ip h e n y la n ilid e F F C F 3 H N N N O [9 4 2 5 1 5 -6 3 -1 ] Dow-M eiji cereal fungicide Entryyear:2013 Acyloxyquinoline CH3 O CF3O H3C AGRANOVA

US2013245271(toM eiji Seika, processpatent) O CH3 O N CH3 Selected examples of promising technologies AGRANOVA New group of antiparasitics under development for controlling of fleas sarolaner (PF-6450567) Zoetis Entry year: 2014 isozazoline Cl CF3 O N O N CH3 SO2 F Cl US2012232026 (process and use, to Pfizer) [1398609-39-6] 28 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 AGRANOVA Components of sarolaner synthesis Cl O

CF3 O N N SO2 CH3 F Cl CF3 Cl CH2 F HO N Br I O Cl NH CH3 SO2 Cl 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) AGRANOVA Other isoxazoline antiparasitics O CF3 N Cl CH3 Cl

S Cl Cl H N N O Cl CF3 N N CF3 O CH3 Cl O N CH3 H N SO2 F CF3 Afoxolaner (5R,S) DuPont-Merial F3C N NH CF3 O O O

H N Lotilaner (5S) Novartis Animal Health O O F3C Cl O O N H CF3 Cl Sarolaner (5S) Pfizer - Zoetis 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). AGRANOVA * now defunct Meta-diamide insecticide Broflanilide (MCI-8007) Mitsui Chemicals Agro Entry year: 2013 1,3-diamide F H N O US2011/0201687 O CF3 CF3 Br

F N CH3 CF3 [1207727-04-5] 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. AGRANOVA * This is how it was discovered serendipidously Example of the use of the important 1-methyl-pyrazole-4-carboxamide side-chain pydiflum etofen SYN545974(Syngenta) Entryyear: 2014 pyrazole-4-carboxam ide Cl H3C CH3 N O N N Cl Cl CH3 W O2013127764A1(20130906; toSyngenta, process) O CHF2 [1228284-64-7]

A newer example of an important chemical class of agrochemicals containing pyrazole-4-carboxylic moeity. AGRANOVA SDHI pyrazole-4-carboxamide fungicides Sumitomo Chemical launched furametpyr in 1997, followed by Mitsui Chemicals pentathiopyrad in 1998 O C F3 O S N CH3 O N H3 C In 2010, Syngenta commercialised isopyrazam, followed by sedaxane in 2011 and benzovindiflupyr in 2014 H H F F O NH N fu ram etp y r H F F

O H 3C H H N H 3C F F O Cl CH3 Cl NH N NH N N N H 3C * H 3C * H isop y raz am b en zov in d iflu p y r sed a x an e F CH3 Cl

Cl N N HN O b ix afen AGRANOVA N H 3C p en th io p y rad In 2011, BCS commercialised bixafen, followed by penflufen in 2012 and BASF launched fluxapyroxad in 2011. N H N H 3C N H CH3 Cl CH3 C H F2 H 3C O N H N N H 3C CH3 F

N F pen flu fen N HN F F O C H F2 flu x ap y ro x ad 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 AGRANOVA The five illustrated fungicides can all be made using DFMMP Opportunities for suppliers AGRANOVA 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 customers 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. AGRANOVA 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 Agranova 34 The Drive Orpington, Kent BR6 9AP United Kingdom Tel: +44 1689 600 501, Fax: +44 1689 897 786 Email: [email protected] Websites: www.agranova.co.uk and www.brychem.co.uk AGRANOVA

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