Brodifacoum

Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide, but is also used to control larger pests such as possum. Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide, but is also used to control larger pests such as possum. Brodifacoum has an especially long half-life in the body, which ranges to several months, requiring prolonged treatment with antidotal vitamin K for both human and pet poisonings. It has one of the highest risks of secondary poisoning to both mammals and birds. In March 2018, cases of severe coagulopathy and bleeding associated with synthetic cannabinoid use contaminated with brodifacoum were reported in five states of the US. Brodifacoum is a derivative of the 4-hydroxy-coumarin group. Compound 1 is the starting ester needed to synthesize brodifacoum. To obtain this starting compound, a simple Wittig condensation of ethyl chloroacetate with 4’-bromobiphenylcarboxaldehyde is accomplished. Compound 1 is transformed into 2 by consecutive hydrolysis, halogenation to form an acid chloride, and then reacted with the required lithium anion. This is done using KOH and EtOH for hydrolysis, and then adding SOCl2 for chlorination to form the acid chloride which reacts with the addition of lithium anion. Compound 2 is then transformed using organocopper chemistry to yield compound 3 with good regioselectivity of about 98%. Typically, a Friedel-Crafts type cyclization would then be used to obtain the two-ring system portion of compound 4, but this results in low yield. Instead, trifluoromethanesulfonic acid in dry benzene catalyzes the cyclization with good yield. The ketone is then reduced with sodium borohydride yielding a benzyl alcohol. Condensation with 4-hydroxycoumarin under HCl yields compound 5, brodifacoum. Brodifacoum is a 4-hydroxycoumarin anticoagulant, with a similar mode of action to its historical predecessors dicoumarol and warfarin. However, due to very high potency and long duration of action (elimination half-life of 20 – 130 days), it is characterised as a 'second-generation' or 'superwarfarin' anticoagulant. Brodifacoum inhibits the enzyme vitamin K epoxide reductase, which is needed for the reconstitution of the vitamin K in its cycle from vitamin K-epoxide, so brodifacoum steadily decreases the level of active vitamin K in the blood. Vitamin K is required for the synthesis of important substances including prothrombin, which is involved in blood clotting. This disruption becomes increasingly severe until the blood effectively loses any ability to clot. In addition, brodifacoum (as with other anticoagulants in toxic doses) increases permeability of blood capillaries; the blood plasma and blood itself begin to leak from the smallest blood vessels. A poisoned animal suffers progressively worsening internal bleeding, leading to shock, loss of consciousness, and eventually death. Brodifacoum is highly lethal to mammals and birds, and extremely lethal to fish. It is a highly cumulative poison, due to its high lipophilicity and extremely slow elimination. Following are acute LD50 values for a variety of animals: Brodifacoum is marketed under many trade names, including Biosnap, d-CON, Finale, Fologorat, Havoc, Jaguar, Klerat, Matikus, Mouser, Pestoff, Rakan, Ratak+, Rataquill Colombia, Ratshot Red, Rodend, Rodenthor, Ratsak, Talon, Volak, Vertox, and Volid.Plantations in Malaysia are using a rodenticide of this type under the market name of Matikus from Syngenta and Arakus from Advansia.