Research On The Synthesis Of Metofluthrin

Metofluthrin (Chemical name:(2,3,5,6-Tetrafluoro-4-methoxy methylphenyl) methyl-2,2-dimethyl-3-(1-propenyl) cyclopropanecarboxylate) is an important active ingredient of a new kind of pyrethroid, with low toxicity and low residue. While, there exists some weakporins such as low yield, complex operations, high cost and pollution to the environment in the current synthesis methods. Therefore, it is of great significance to improve the synthesis technic of metofluthrin.Synthesis of metofluthrin and the intermediates was summarized in this thesis, and a series of improvements were proposed. Metofluthrin was prepared from chrysanthemic acid. Firstly, chrysanthemic acid methyl ester was prepared from chrysanthemic acid via esterification with methanol. Secondly, methyl-3-formyl-2,2-dimethylcyclopropanecarboxylate was produced from chrysanthemic acid methyl ester via ozonization and reduction with H2-Pd/C. And then,2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid was prepared by Wittig reaction and hydrolysis. Finally, the final product metofluthrin was prepared via esterification with (2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl)methanol, with the yield of 65.5% from chrysanthemic acid.The reaction conditions of each step are as follows:(1) The esterification of chrysanthemic acid (33.6g,0.2mol) with methanol was catalyzed by concentrated sulfuric acid at refluxing temperature (65℃). The ozonization reaction in methanol was carried out without the separation and purification of chrysanthemic acid methyl ester after the catalyst was removed. The temperature of ozonization was 0℃, and the reaction period was 1.5h. And then methyl-3-formyl-2,2-dimethylcyclopropanecarboxylate was produced via the reduction reaction with H2 (2.5L/h) catalyzed by Pd/C at 25℃over 3h, with the yield of 84.9% and the purity of 94.7%.(2) (Ethyl)triphenylphosphonium bromide was achieved through the reaction of triphenyl phosphine and bromoethane at 40℃for 20h. 2,2-Dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid methyl ester was produced via Wittig reaction of methyl-3-formyl-2,2-dimethylcyclopropanecarboxylate, (ethyl)triphenylphosphonium bromide and sodium methoxide in THF at 10℃for 3h. Then 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid was achieved by hydrolysis at 100℃after adding sodium hydroxide solution and removing THF. And then the pure product was obtained by steam distillation. The proper mole ratio of the materials was methyl-3-formyl-2,2-dimethylcyclopropanecarboxylate: (ethyl)triphenylphosphonium bromide:sodium methoxide:additional sodium methoxide=1:1.2:1.44:1. The yield of the two steps was 83.4%, with the purity of 97.0%. And recycle coefficient of triphenylphosphine oxide was 61.1%, mp:155.1-156.3℃.(3) 2,2-Dimethyl-3-(1-propenyl)cyclopropanecarbonyl chloride was prepared at 25℃via acyl chlorination of 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid with phosphorus trichloride. The mole ratio of the material was 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid:phosphorus trichloride=2.8:1. And then metofluthrin was produced via the esterification between 2,2-dimethyl-3-(1-propenyl)cyclopropanecarbonyl chloride and (2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl)methanol at 25℃with sodium carbonate as acid-binding agent. The mole ratio of the material was 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid: (2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl)methanol:sodium carbonate=1.2:1:1.5. When the reaction was over, the reaction mixture was filtered and pH of the filtrate was adjusted to 10. The aqueous phase was separated and the pH was adjusted to 5. Then the superfluous 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid was recycled by extraction with toluene. Metofluthrin was obtained after removing the solvent of the organic phase, with the yield of 92.5% and the purity of 97.0%. And the total yield was 65.5% from chrysanthemic acid.The structure of the products in every step was confirmed by'H-NMR and 13C-NMR. In the thesis, the following improvements for the traditional process were proposed.(1) The product of esterification by methanol joined the ozonization reaction without separatation and purification, which saved the cost of material and operation and increased the yield. In the ozonization reaction, hydrogenation reduction catalyzed by Pd/C was adopted, which was a clean method, avoiding the polution resulted by Zn-CH3COOH or dimethyl sulphide.(2) The experiment operation was simplified by "one pot reaction" of the Wittig reaction of methyl-3-formyl-2,2-dimethylcyclopropanecarboxylate and the hydrolysis of 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid methyl ester. The sodium hydroxide transformed from superfluous sodium methoxide could be used as the catalyst in the hydrolysis of 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylic acid methyl ester. What's more, the purified by-product triphenylphosphine oxide could be recycled by recrystallization, which reduced the discharge.(3) In the esterification of 2,2-Dimethyl-3-(1-propenyl)cyclopropanecarbonyl chloride and (2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl)methanol, the method of extraction and separation was used in the post treatment to avoid the complicated seperation method of column chromatography, simplify the operation and increace the yield of metofluthrin. What's more, sodium carbonate was used as acid-binding agent, to simplify the operation and reduce the cost and discharge.