How to synthesize Boscalid?

Introduction

The succinate dehydrogenase inhibitor (SDHI) fungicide boscalid is an excellent broad-spectrum fungicide. Still, it has not been registered in China to control Penicillium digitatum, the causal agent of the green mould of citrus[1]. It is a new-generation compound of the carboxamide family that acts by inhibiting fungal respiration by blocking the ubiquinone-binding sites in the mitochondrial complex II involved in the Krebs cycle. Since its placing on the market in 2002, boscalid has been intensively applied, mainly during the flowering period, for crop protection throughout the plant growth, especially for the control of white mold and foliar diseases in vineyards or fruits and vegetables such as corn, carrots, cabbage, beans or peas. Therefore, honeybees are likely to be in contact with this fungicide. Some recent works of David et al. have revealed the presence of boscalid in bumblebees (up to 9.8 ng/g) and pollens (up to 38 ng/g). Near mg/g levels of the fungicide were reported in wax samples or pollen.

Synthesis

750g of toluene was charged to a reaction vessel under a nitrogen atmosphere. 335g of 2-chloronicotinic acid was added with stirring at room temperature. 35g of dimethyl formamide (DMF) was added to the mixture, and the resulting reaction mixture was slowly heated to 40℃ with stirring. 300g of thionyl chloride was added over one hour. Hydrogen chloride (HCl) and sulphur dioxide (SO2) gases liberated by the reaction were removed by scrubbing. After that, the reaction mass was kept under a nitrogen atmosphere and maintained at 60℃ for 4 to 5 hours until a complete reaction of the acid had taken place (as monitored using HPLC). After that, excess thionyl chloride was removed at 60 to 75℃ under reduced pressure. The resulting mixture was cooled to room temperature[2].

With stirring, the cooled mixture was diluted with 500g of toluene and 200g of triethyl amine (TEA). To this homogeneous mixture, 400g of 4’-chlorobiphenyl-2-amine was added over a period of 30 to 45 minutes at 45℃, and the mixture was stirred for an additional 4 to 5 hours to allow the reaction to complete. The mixture was quenched by adding water and stirring for 2 to 3 hours.

The organic layer was separated and maintained at an elevated temperature of 60℃. The mixture was filtered to remove insoluble impurities. The mixture was finally cooled to 10 to 15℃ under slow stirring. The solid was isolated by filtration and drying to give 450 to 480g of boscalid.

Uses

Boscalid is a fungicide consisting of two formulated end-use products for food crops. The wettable granule (WG) Endura Fungicide contains 70% active ingredient, and the wettable granule (WG) Pristine contains a mixture of boscalid (25.2% active) and pyraclostrobin (12.8% active). Endura™ is intended for use on beans, berries, bulb vegetables, canola, carrots, fruiting vegetables, grapes, lettuce, peanuts, pistachios, potatoes, stone fruit, strawberries, tree nuts, Brassica vegetables (subgroups 5A and 5B), cucurbit vegetables, mint, edible peas, certain root vegetables, and sunflower. Pristine™ is intended for berries, bulb vegetables, carrots, grapes, pistachios, stone fruit, strawberries, and tree nuts. Application is via multiple foliar broadcast sprays at a seasonal rate of ca 0.9-1.8 lbs ai/A, depending on crop and target disease. Typically, retreatment intervals are 1-3 weeks, and minimum PHIs are 0-30 days.

References

[1] Kaidi Cui. “Development of Boscalid Resistance in Botrytis cinerea and an Efficient Strategy for Resistance Management.” Plant disease 105 4 (2021): 1042–1047.

[2] WO2018024145A1 - Process for preparing boscalid - Google Patents https://patents.google.com/patent/WO2018024145A1/en

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