Research On The Synthesis Of 2,3,4,5-tetrefluorobenzoic Acid As The Key Intermediates Of Fluoroquinolones

2,3,4,5-tetrefluorobenzoic acid is the key intermediate of the new generation of antibiotics-fluoroquinolones,with large domestic and external demand.The main problems of reported processes are complexity of process,using varieties of solvents,the large dosage of fluridizer,poor product quality,the low recovery rate of solvents and high cost in production.Besides,the improvement of process is going on slowly because it lacks the understanding of reaction mechanisms.It is significant to look through the reaction mechanisms and combine principles of the green chemistry and the methods of chemical process intensification.Hence,exploring an economic,environmental,efficient,suitable industrial production process of 2,3,4,5-tetrefluorobenzoic acid is very important.In this paper,we used the available tetrachlorophthalic anhydride as starting materials.Imidization,fluorination,hydrolyzation and decarboxylation provided 2,3,4,5-tetrefluorobenzoic acid in overall yield of 68.8%.Based on experiments,we speculated the mechanism of fluoridation,expanded the substrates and obtained the data of quantum chemical calculation.Research on process:Explore the recycling of mother solution of process of synthesis of tetrachloro-N-phenylphthalimide,using 95%acetic acid and 1.2 moles of aniline.Imidization produced a mole of water and the concentration of acetic acid would decrease.Thus,we added some acetic acid and aniline to the mother liquor for recycling use.After ten times of recycling process,the yield of product could not decrease.The new process effectively reduces the amount of acetic acid,cost of production and waste emissions.Under the optimized condition,the yield is 96%.Study the process of composite catalysts catalyzing fluorination of tetrachloro-N-phenylphthalimide,using new method to prepare KF,Ph4PBr and PEG-6000 as the catalysts and the sulfolane as solvent.The new process solved the problems of large dosage of KF,the long time of pretreatment and the low of conversion and selectivity The molar ratio of KF and substrate fell to 6:1 from 12:1 in the past and the time of pretreatment fell to 4h from 48h.The yield of tetrafluoro-N-phenylphthalimide was 83.2%,exceeding the yield of 74%in the literatureImprove the process of hydrolysis of tetrafluoro-N-phenylphthalimide in alkaline condition.Used 15%NaOH instead of sulfuric acid to reduce waste water.The time of improved process was 2 hours and the yield of 3,4,5,6-tetrafluorophthalic acid was 93%under optimized process conditions.Study the process of decarboxylation of 3,4,5,6-tetrafluorophthalic acid in high temperature liquid water.Used the water at high temperature instead of DMSO,tributylamine and H2SO4.The process was simplified and economic.This process was subjected to further studies and an optimized process with the yield of 92.7%is described.The structures of products were confirmed by 1H-NMR and 13C-NMR.Research on the mechanism,development of substrates and the data of quantum chemical calculation:In this dissertation,the mechanism of fluoridation was studied.The reaction pathway was speculated as follow:The chlorine atom farther from carbanyl group was firstly substituted.Then ortho chlorine atoms were substituted until all the fluorine atoms were added to the benzene ring.We used Material Studio software to calculate the function of Fukui and verify the mechanism.Moreover,we developed the substrates for the fluoridation.Five kinds of N-substituted imides were synthesized.The effects of different N-substituted on fluoridation reaction were studied.The activity of substrates follows the order of 3-pentyl>phenyl>butyl>ethyl>methyl.Based on the results of the experiment and analysis of reaction process,using the butyl amine could obtained good yield and high recovery.Thus,butyl amine is used as the material of the industrial production process in the future.