Study On The Synthesis Process Of Firocoxib

As more and more people keep pets in China,the research and development of pet medicine is becoming more and more important.Firocoxib is a non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2?COX-2?mediated prostaglandin synthesis.Firocoxib is a new generation of anti-inflammatory and analgesic drugs.The original manufacturer is the French company Melia,which is used to treat pain and inflammation associated with osteoarthritis in dogs,the selectivity of firocoxib for COX-2 is about 380 times that of COX-1.It has been listed in China,the United States and Europe and other countries and regions.In this paper,the synthetic route of Firocoxib is studied,the synthetic route is investigated and optimized,and the optimized synthetic process is determined:the key carboxylic acid intermediate 2-?cyclopropylmethoxy?acetic acid was obtained by nucleophilic substitution reaction?sodium 2-chloroacetate:cyclopropylmethanol:t-Bu OK=1:2:2?with sodium 2-chloroacetate and cyclopropylmethanol as raw materials.The intermediate 2-hydroxy-2-methyl-1-?4-?methylsulfonyl?phenyl?propan-1-one was prepared from cheap and readily available methyl?phenyl?sulfane and isobutyryl chloride by Friedel Crafts reaction?methyl?phenyl?sulfane:isobutyryl chloride:ACl₃=1:1.3:1.3?,bromination?2-methyl-1-?4-?methylthio?phenyl?propan-1-one:HBr:DMSO=1:1.1:1.1?,hydrolysis?2-bromo-2-methyl-1-?4-?methylthio?phenyl?propan-1-one:Na OH=1:1.4?and oxidation?2-hydroxy-2-methyl-1-?4-?methylthio?phenyl?propan-1-one:Oxone=1:1.4?.The intermediate 2-hydroxy-2-methyl-1-?4-?methylsulfonyl?phenyl?propan-1-one and intermediate 2-?cyclopropylmethoxy?acetic acid wereesterified?2-hydroxy-2-methyl-1-?4-?methylsulfonyl?phenyl?propan-1-one:2-?cyclopropylmethoxy?acetic acid:SOCl₂:DMF:DMAP:triethylamine=1:2:2:0.15:0.3:4?and ring-closed?2-methyl-1-?4-?methylsulfonyl?phenyl?-1-oxopropan-2-yl2-?cyclopropylmethoxy?acetate:isopropyl trifluoroacetate:DBU=1:1.4:1.8?to obtain the target product Firocoxib,and scaled up to the kilogram level,the total yield is 43%.Firocoxib was confirmed by LC-MS,H-NMR and C-NMR,and the purity was 99.83%determined by HPLC.The process is suitable for industrial scale-up production and is economical and environmentally friendly,and achieves high-efficiency and green industrial manufacturing of Firocoxib.