The Synthesis Of Loxoprofen Sodium Of Antipyretic And Analgesic Drugs

Loxoprofen sodium is a novel non-steroidal aryl propionic acid antipyretic analgesic and anti-inflammatory drug.It was first developed and marketed by Japan Sankyo Corporation in 1986.It has the advantages of small oral dose,high efficacy,and few side effects.It has been widely used.In recent years,there has been an increasing demand for such drugs in both domestic and foreign markets.However,due to defects in synthetic technology and lack of competitive advantages,many manufacturers was forced to stop production,a large number of operations have been started,resulting in idle equipment,waste of resources.Therefore,high-quality,high-yield,and low-pollution production of aryl isopropanoic acid drugs with greater economic benefits have become the expectations of many companies.The synthesis route of loxoprofen sodium were reported in a large number of documents,and most of the synthetic routes are synthesized by the key intermediate2-(4-halomethylphenyl)propionic acid.In this paper,under the requirements of industrialization background,reference was made to the relevant literature and some processes were adjusted:The first part is the esterification of methyl lactate and p-toluene chloride to synthesize 2-p-toluenesulfonyloxy methyl propionate;2-Phenylphenylsulfonyloxypropionic acid methyl ester is then subjected to Friedel-Crafts reaction with benzene under the catalysis of trichloride aluminum to synthesize 2-phenylpropionic acid.The two-step synthesis reaction is the innovation point of this thesis.There is no literature about the synthesis of 2-phenylpropionic acid.Subsequent synthesis steps refer to the more mature methods in the literature.In this paper,the process conditions are studied on the basis of the access route,and a process route is obtained,which is cheap,easy to obtain,simple,and easy to operate.It has a relatively good practical significance and research value.The route is based on cheap and easily available methyl lactate 2and p-toluene chloride 3as raw materials under the catalysis of triethylamine.2-(p-methylphenyl sulfonyloxy)propionic acid methyl ester 4 is prepared by esterification reaction,followed by Friedel-Crafts alkylation reaction with benzene,to obtain 2-phenyl propionic acid 5 after hydrolysis,and then with paraformaldehyde Reaction with potassium bromide under acidic conditions to prepare intermediate 2-(4-bromomethyl phenyl)propionic acid 6 and the 6 was esterificated to give methyl 2-(4-bro momethylphenyl)propanoate 7.Which is then condensed with 2-methoxy carbonyl cyclopentanone under basic conditions to obtain 2-[4-(1-Methoxycarbonyl-2-oxo-1-cyclopentylmethyl)phenyl]propionic acid methyl ester 8.finally decarboxylated,and salted to give the target product,loxoprofen sodium 1.The chemical structures of the target products and intermediates were confirmed by ~1H NMR,MS and IR.