Study On The Synthetic Method And Pilot Development Of Ethyl Difluoroacetate

Ethyl difluoroacetate is mainly used for preparing fluorinated pesticides and pharmaceutical products,such as penoxsulam,pyrazolamide bactericide,new nicotinic insecticides,chloramphenicol derivatives,pyrazole and thiazine drugs and other products,as an important fluorine-containing fine chemicals intermediates.In recent years,due to their excellent effects,the sales of pyrazolamide bactericides is increasing rapidly.Therefore,it is very promising to develop a new synthesis route of ethyl difluoroacetate with commercial production value.After investigation of related patents and literature reports,the following route was selected for production of ethyl difluoroacetate:N-methyl-N-isopropyl-2,2-dichloroacetamide was obtained by amidation reaction of dichloroacetyl chloride with N-methyl isopropylamine,which was then fluorinated by potassium fluoride to give N-methyl-N-isopropyl-2,2-difluoroacetamide.Finally ethyl difluoroacetate was obtained by esterification reaction with ethanol.After investigating a series of process parameters,such as process operation,catalyst selection and ratio,solvent selection and dosage,reaction temperature,stirring speed and other parameters,the best technological conditions are obtained:Dichloroacetyl chloride was used as the main raw material for amidation reaction,with 2 mole equivalent N-methyl isopropylamine as the reactant and acid-binding agent,4 times the weight of toluene as the solvent.The reaction was carried out at 20-30 ℃ for 1.5 hours to give 99.0% yield with 99.0% purity.The amidation reaction was carried out in the pipeline reactor at 20-40 ℃ and the purity was 99.3%.The reaction temperature was wider and the purity of the product was higher.For fluoridation reaction 95.0% yield with 99.5% purity was obtained when the reaction was carried out at 90-100℃ for 5 hours,with 3.8 weight times of N,N-dimethylformamide as solvent and 2.3 molar equivalent potassium fluoride as fluoride reagent.For esterification reaction the reaction was conducted at 90-100 ℃for 3 hours to afford 95.0% yield and more than 99.5% purity.2 mole equivalent sulfuric acid was used as solvent and catalyst and 1.05 mole equivalent ethanol was used as reactant.After the process optimization,the total yield reached 89.3%,which was higher than that in the literature.The thermal stability data and reaction exothermic data of products and their intermediates were studied to provide safety data support for pilot production.The optimized process was verified in pilot scale production.Continuous pipeline reactor and continuous working up are adopted the scaling up of amidation step,including continuous extraction and continuous distillation,which improves production capacity and avoided the use of large-volume reaction kettle.The production of fluorination and esterification reactions were done by traditional kettle reactor,which give the same results as lab data.Finally 2097.0 kg of ethyl difluoroacetate was obtained in the pilot production,with 83.0% total yield(base on dichloroacetyl chloride)and more than 99.5% purity.The product quality meets the specifications of pilot test.It is proved that the process meets the requirements of industrial production and can be used for mass production.