Agrochemicals: exciting technical challenges and new business opportunities 26th April 2021
By Dr Rob Bryant Agranova E: email@example.com Website: www.agranova.co.uk
Agrochemicals consultant Dr Rob Bryant says keeping up with the demands of continuing developments in agrochemical science has been a prime driver for fine chemical companies and that the agrochemical industry continues to present exciting synthetic challenges for organic chemists
The development of the global fine chemical industry has taken place in partnership with many downstream sectors. In terms of sales value, the agrochemical sector has remained the second most important bioscience-based industrial outlet (the pharmaceuticals sector being more valuable) for those companies offering competence in organic chemistry since the 1950s.
Keeping up with the demands of the continuing developments in agrochemical science has been a prime driver for fine chemical companies, be it in novel raw materials, the latest breakthroughs in synthetic techniques, or the changing demands for novel structural elements. This last topic will be covered In this short review, which will borrow from an annual review of new agrochemical actives and biologicals that began in 1982, the Ag Chem New Compound Review.
At the time of launching by an Elanco sales and marketing director, Bill Hopkins, this review was in fact a round-up of the information that was pooled from direct reports from the leading research and development groups around the world. Such openness has become uncommon these days, alas, and the collection of new agrochemical leads gradually declined during the period 2005-2010, probably as a result of the increasing costs of getting new chemistries approved and launched.
The need for managing investor-expectations was another regrettable factor in this reduction of industry co-operation. In spite of greater challenges needed to continue the report’s annual publications, it has continued to offer a useful insight into the new technologies being adopted by the market. From the perspective of companies hoping to offer their services to the agrochemical industry, the report offers a valuable source of the new active ingredients and (indirectly) intermediates for which supply contracts might become available. This review, principally intended for organic chemists, examines the main structural elements currently being included in new agrochemical actives. In order to set the scene, Table 1 offers a historical summary of a range of chemical features (“chemistries”) that have been important during the period 1950-2021.
Chemical classes of continuing/increasing importance
In the latest volume of the Ag Chem New Compound Review, 251 chemical actives are listed. These compounds have reached active development (beyond greenhouse tests), have been awarded recent approvals, or have just been launched (there are another 74 biologicals, mainly insect predators or microorganisms).
The more common molecular classes of industrial organic compounds are presented in Table 1. The numbers of commercial agrochemical actives featuring each one, together with their earliest and latest use, is shown, demonstrating their utility. A few comments on the leading classes help to illustrate the reasons for their incorporation into so many compounds. Figure 1 shows four of these structures.
- The importance of fluorine as a molecular feature in agrochemicals cannot be over-exaggerated. The improved lipid solubility of organofluorines is just as important to medicinal chemists developing pharmaceutical actives. This year’s report (Volume 39) profiles over 50 compounds that contain at least one fluorinated moeity. Many include polyfluorinated substituents, the technologies for which have been created to accommodate demand created by the agrochemical research community.
- Pyrimidines continue to be a favourite structural feature, with 15 appearing in Volume 39. UST East China has a plant disease resistance inducer in development that combines a pyrimidine and pyrazole (as well as a substituted fluorophenyl group).
- Pyridines offer an attractive aromatic ring, which (unlike benzene) has basic properties and thus enables a combination of a hydrophobic site close to a basic point of co-ordination (this is useful in maximizing the fit with the enzyme receptor site being targeted). Many active ingredients are made using pyridine or a picoline (one of the three methylpyridines) as the ultimate raw material. However, when a challenging substitution pattern is required, ab-initio synthetic routes are often used.
- Derivatives of pyrazole-4-carboxamide, often with fluorinated side-chains, have become very popular, with the first appearing in 1997, when Sumitomo Chemical launched the rice fungicide, furametpyr. Nine AIs carrying this side-chain are profiled in Volume 39.
In Table 2, a list of recent agrochemical actives that are still in some stage of development is presented. It demonstrates very well the wide range of chemistries being used to create new compounds with new or improved modes of action. A few interesting examples are worth pointing out:
- Several benzoxaboroles have recently reached early testing stage. Boragen appears to have transferred the germicidal activity that similar compounds have exhibited into the agrochemical sector.
- Many compounds under development in the US, Europe and Japan make use of pyrazoles, very often substituted pyrazole-4-carboxamides (see Figure 2, which illustrates how Sumitomo Chemical’s furametpyr subsequently inspired new lead compounds in the R&D laboratories of several European agrochemical companies). This very popular substructural feature, most often found in insecticides, is usually produced from a suitably substituted hydrazide and a 1,3-diketo compound.
- A recent herbicide candidate, introduced by Nissan Chemical, contains an azetidinone. This is far more familiar in beta-lactam antibiotics, where its reactivity leads to an irreversible reaction with the receptor site.
- In Table 1, thiazoles, together with their reduced forms, are listed as a common chemical feature. There are eight under active development at the time of writing, emphasizing their continuing importance in new agrochemical actives.
Given the three dimensional receptor sites in which these molecules must interact with the receptor site, it might be thought that homochiral compounds would predominate. However, although there was a strong trend towards such compounds between 2000-2015, the additional hurdles involved with achieving regulatory approval proved to be a deterrent. Ideally, new active ingredients should lack chiral centres.
This point leads nicely to the final important factor that must always be borne in mind when developing an agrochemical; cost of production and thus the final price of the finished formulation.
Successful agrochemical products usually contain active ingredients that are priced at no more than $150/kg and very often less than $80/kg. This usually constrains the complexity and length of manufacturing processes but, of course, there are exceptions, where the activity of the product (in grams/hectare) is high. However, these tend to be exceptional. Many good products have failed to reach their full potential by being too costly and this lesson has been well learned within the industry.
This short review illustrates the importance of the ever-improving palette of new chemistries being adopted by both bioscience industries, pharmaceuticals and agrochemicals. Keeping up with these latest developments has been a very enjoyable pursuit for the editors of the Ag Chem New Compound Review. Being able to alert those involved in applying agrochemistry around the world has proved to be a worthwhile activity and should be maintained as long as crop pests continue to resist the world’s farmers’ best efforts to keep us fed.