Study On The Synthesis Of Azoxystrobin And Intermediate Compounds

In this paper, the synthesis of azoxystrobin and related intermediates including 4,6-dichloropyrimidine, methyl 2-hydroxyphenyl acetate,2-hydroxybenzonitrile were studied.Reaction of methyl malonate and formamide at 60℃for 3 hours gave 4.6-dihydroxypyrimide in 72% yield. Chlorination of 4,6-dihydroxypyrimidine with phosphorus oxychloride in the presence of triethylamine gave 4,6-dichloropyrimidine in 94% yield.2-Hydroxybenzonitrile were prepared in 92% yield in a direct one-pot process by heating salicyladehyde with hydroxylamine hydrochloride in N-methylpyrrolidone (NMP) at 115℃for 5h. The solvent NMP could be recycled.Methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-meth-oxyacrylate (azoxystrobin) was prepared via a known synthetic route in 6 steps. The reaction parameters were optimized and coupling catalyst was used to improve the reaction. The overall yield was 45%, compared with the literature value of 28%.A 4 step synthetic route of azoxystrobin starting from 2-hydroxyphenyl acetic acid was also develop in this paper. Esterification of 2-hydroxyphenyl acetic acid with methanol in the present of thionyl chloride gave methyl 2-hydroxyphenyl acetate. Coupling of the methyl ester obtained with 4,6-dichloropyrimidine gave intermediate methyl 2-(6-chloropyrimidine-4-yloxy)phenyl acetate, which was transformed to methyl (E)-2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-methoxyacrylate by reacting with NaH, methyl formate and CH3I. Coupling of methyl (E)-2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-methoxyacrylate with 2-hydroxybenzonitrile gave the final product azoxystrobin in 50% overall yield.