Patent Watch

April 16, 2012

Use less catalyst to make a commercial fungicide. Azoxystrobin (3) belongs to a group of fungicides known as strobilurins that, ironically, are found in the wood-rotting fungus Strobilurus tenacellus. A published method for preparing 3 uses as much as 20% DABCO (diazabicyclo[2.2.2]octane) as the catalyst. Inventors A. J. Whitton, E.C. Boyd, and J. Vass note that this reagent is expensive and that an improved process would be desirable.

The inventors describe a process that produces 3 by coupling o-cyanophenol (1) and pyrimidine derivative 2 with <2% DABCO catalyst. K2CO3 is also present in the reaction mixture to form the potassium salt of 1. The preferred solvent is DMF, but other solvents—such as methyl isobutyl ketone, cyclohexanone, i-PrOAc, and EtN-i-Pr2—are also usable. The yield of product 3, as a 43.6 wt% solution in toluene, is 98.7%; the inventors do not disclose the details for recovering the pure material. The authors obtained pyrimidine 2 by using a process described in WO 92/08703 (1992), but there are no details in the current patent.

The inventors give examples that show the effect of DABCO concentration on reaction time and the recovered yield of 3. Without DABCO, the yield is 86.6%; it increases to 98.7% with 1% DABCO catalyst, and it falls slightly to 97.5% with 2% DABCO. The reaction time is 8 h without DABCO and decreases to 1 h with 1 or 2% DABCO. Experiments to assess the effect of order of addition of the reagents showed that the yield improves if DABCO is the last component added.

The inventors report that 3 can also be prepared by the reaction of 1 with acetal 4, as shown in Figure 2. This example actually describes a reaction between 1 and a mixture of 2 and 4 that produces a mixture of 3 and azoxystrobin derivative 5. The proportion of 3 in the mixture is higher than might be expected from the relative amounts of 2 and 4 because 5 loses MeOH to form 3. From a mixture of 2 and 4 that contains 12.4% 4, the product is a cyclohexanone solution that contains 27% 3 and 73% 5. MeOH can be eliminated from 5 to give 3 by treating it with methanesulfonic acid (MsOH) and Ac2O, but the inventors give few details.

Another option for preparing 3 is the reaction of cyanophenoxypyrimidine 6 and phenol derivative 7 shown in Figure 3. Unfortunately, no examples in the patent describe this procedure. The inventors do, however, describe the preparation of 7, also shown in Figure 3.

The starting material for 7 is 8, which the inventors prepared by a method reported in GB Patent 2,291,874 (1996), but they do not include any details in the current patent. The first step in preparing 7 is protecting the hydroxyl group in 8 with BnBr to give compound 9, recovered in 57% yield. Treating 9 with Ac2O in the presence of methanesulfonic acid (MsOH) eliminates MeOH to produce compound 10. Mixing the product mixture with toluene isolates the product; evaporating the toluene leaves crystalline 10 in 44% yield.

In the final step, catalytic hydrogenation over Pd/C removes the benzyl protecting group. The product is an oil that crystallizes on standing; its yield is not reported. The inventors provide 1H NMR data for compounds 5, 7, 9, and 10. (Syngenta [Guildford, UK]. US Patent 8,124,761, Feb. 28, 2012; Keith Turner)

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