Synthesis And Quality Research Of Febuxostat API

Febuxostat has high selectivity and stronger activity when it was compared with other non-purine XOR enzyme inhibitors.And the efficacy is better than allopurinol which was the standard of anti-gout agents.Febuxostat is a novel non-purine XOR enzyme inhibitor,which is highly selective for XOR and has a significant inhibitory effect on oxidized and reduced XOR.Unlike allopurinol,Febuxostat does not inhibit other enzymes including purine or pyridine metabolites.Those inhibitors play an important role in reducing uric acid in serum of patients with gout.Febuxostat was used to reduce gout-patients’ blood uric acid in clinical,which show fast effect that and mild adverse reactions.In view of the clinical efficacy,better tolerance and safety of Febuxostat tablets,research and development "Febuxostat tablets" can not only reduce the pain torture of gout-patients,but help the enterprise to get some economic benefits.1.Synthetic technology of FebuxostatWe selected a simple to synthesize route,which does not use KCN,to get Febuxostat.We used the 4-hydroxybenzaldehyde as the material,and we finally get Febuxostat by recrystallization after seven steps.4-hydroxybenzaldehyde was used as a starting material to produce 4-hydroxy-nitrobenzonitrile in the presence of hydroxylamine and sodium formate,and then 4-hydroxy-nitro-thiobenzamide was formed with thioacetamide.Ethyl 4-chloro-3-oxobutanoate was added under reflux with ethanol to give ethyl-2-(4-hydroxy-3-nitrobenzene)-5-methylthiazole-4-carboxylate,which was then reacted with 1-Bromo-2-methylpropane,and the resulting compound is Febuxostat which is subjected to hydrogenation,diazotization and basic hydrolysis.In this paper,the methods used in the small test and pilot production.In addition the third and fourth step reaction efficiency is low,the rest of the reaction efficiency is greater than 80%.All the solvents used in the reaction including ethanol and butyl acetate can be recycled,and the process does not produce exhaust gas.Therefore,through analysis and comparison,we used a simple route to synthesis Febuxostat,a new non-purine XOR enzyme inhibitor.What’s more,the small and moderate validations have been done.2.Quality research of FebuxostatWe used the method mentioned above to synthesis pure Febuxostat,and then we studied the quality of the synthesized product by elemental analysis,IR,NMR,mass spectrometry,thermogravimetric analysis and differential scanning calorimetry.By comparing with the standard sample,we analysis the composite data of the final product,and its structure and purity have been confirmed.The results of elemental analysis showed that the measured values of the elements C,H,N,S were in agreement with the theoretical values(molecular formula Ci6H,6N2O3S).The results of mass spectrometry showed that an excimer ion peak m/z 315 was existed in the ESI-MS(negative ion mode)spectrum,which was[M-H]-peak,consistent with the molecular weight,and the dissociation peak was also consistent with the dissociation mode of Febuxostat.The infrared spectra show that there are functional groups such as cyano,carboxylic acid,isopropyl,benzene ring and ether.The UV absorption spectrum shows that the thiazolylcarboxylic acid and the benzene ring forms a strong absorption and this is consistent with the group of Febuxostat.The results of 1H-NMR,carbon spectrum(13C-NMR,DEPT),1H-1H COSY,HMQC,HMBC and other related spectra can be used to determine the structure of the product is consistent with Febuxostat.The results of thermogravimetric analysis(TGA)showed that there is no significant weight loss before 150℃,demonstrating that the sample doesn’t contain crystal water;the DSC spectrum showed spikes at 209.3℃and was consistent with the melting point of Febuxostat.After confirming the structure,we studied the difference of crystal form of Febuxostat under different crystallization conditions,and determined the crystallization process conditions and crystal form.At the same time,we investigated the effects of grinding,pulverization and pressure on the crystal form,and tested the relationship between the crystal form and the solubility of the sample.Based on these studies,in order to control the quality of the sample better,the X-ray powder diffraction identification of the sample was added to the quality standard identification.