The Synthesis Process Of Loxoprofen Sodium

Loxoprofen sodium is a kind of minor side effect and high efficacy non-steroidal anti-inflammatory analgesics,its analgesic effect is significantly better than other propionic acid drugs.In order to meet the needs of industrial production,this research project is focus on the improvement of its synthesis route.This paper is that 2-(4-bromomethyl)phenylpropionic acid as raw material,esterification reaction with methanol,and 2-carbethoxycyclopentanone for alkylation,through hydrolysis and decarboxylation and salt formation,then we get loxoprofen sodium.And the reaction conditions of each step is optimized.In the process of esterification reaction,reduced the amount of solvent,and optimize the reaction time.In alkylation reaction step,it is concluded that the optimal reaction conditions as follows:the reaction time is 6 to 7 hours,potassium carbonate as alkali,toluene as reaction solvent,PEG600 as phase transfer catalyst,the molar ratio of 2-Carbethoxycyclopentanone and methyl 2-(4-(bromomethyl)phenyl)propanoate is 1.2:1.It can shorten the reaction time,improved yield and shorten the industrial production cycle.In the process of hydrolysis and decarboxylation,we get a better reaction conditions as follows:40%hydrobromic acid and acetic acid as decarboxylation reagent,reaction temperature is 100?,the molar ratio of hydrobromic acid,acetic acid and the reactant is 6:5:1.And about crystallization of loxoprofen,we use cheap petroleum ether instead of n-hexane,this can save costs for the industry.Through improvement of process,four step total yield can reach 64.5%(literature value of 59.2%).Through the identification of infrared spectroscopy(IR)spectral and nuclear magnetic resonance,we are sure that the structure of the synthesized product is consistent with loxoprofen sodium.In addition this paper we got a pairs of optical isomers enantiomers of loxoprofen which has four optical isomers enantiomers through the cultivation of crystal,and the crystal type of loxoprofen were studied.The crystal is colorless transparent block crystal,belongs to the orthogonal crystal shape,formula for C15H18O3,space group as the pbca,a = 12.341(2)A,b = 10.8493(17)A,c=19.661(3)A,a=90°,? = 90°,?=90°,V = 2632.4(7)A3,Z = 8,p = 1.243 g/mm3.Through study of single crystal,it can further illustrates the structure of loxoprofen,and makes a preliminary exploration for the separation of isomers.