【作者】 李林；

【导师】 张雷； 杨凤智；

【作者基本信息】 华南理工大学 ， 药学（专业学位）， 2020， 硕士

【摘要】 随着我国饲养宠物的人越来越多,宠物药研究与开发越来越重要。非罗考昔是一种非甾体抗炎药,通过选择性抑制环氧合酶-2(COX-2)介导的前列腺素合成。非罗考昔为新一代抗炎止痛药,原研厂家为法国梅里亚公司,用于治疗狗的骨关节炎相关的疼痛和炎症反应,非罗考昔对COX-2的选择性是对COX-1的选择性的380倍左右。目前已在中国、美国和欧洲等国家和地区上市,商品名为Previcox。本论文对非罗考昔合成路线进行了研究,考察和优化了合成路线,确定了优化的合成工艺:以氯乙酸钠和环丙基甲醇为原料经亲核取代(氯乙酸钠:环丙基甲醇:叔丁醇钾=1:2:2)得到关键羧酸中间体2-(环丙基甲氧基)乙酸,以市场上廉价易得的苯甲硫醚和异丁酰氯为起始物料,经傅克反应(苯甲硫醚:异丁酰氯:三氯化铝=1:1.3:1.3)、溴代(2-甲基-1-(4-(甲硫基)苯基)丙-1-酮:氢溴酸:DMSO=1:1.1:1.1)、水解(2-溴-2-甲基-1-(4-(甲硫基)苯基)丙-1-酮:氢氧化钠=1:1.4)、氧化(2-羟基-2-甲基-1-(4-(甲硫基)苯基)丙-1-酮:Oxone=1:1.4)制得中间体2-羟基-2-甲基-1-(4-(甲基磺酰基)苯基)丙-1-酮,将中间体2-羟基-2-甲基-1-(4-(甲基磺酰基)苯基)丙-1-酮和中间体2-(环丙基甲氧基)乙酸经酯化(2-羟基-2-甲基-1-(4-(甲基磺酰基)苯基)丙-1-酮:2-(环丙基甲氧基)乙酸:氯化亚砜:DMF:DMAP:三乙胺=1:2:2:0.15:0.3:4)和关环反应(2-甲基-1-(4-(甲基磺酰基)苯基)-1-氧丙烷-2-基-2-(环丙基甲氧基)乙酸酯:三氟乙酸异丙酯:DBU=1:1.4:1.8)得到目标产物非罗考昔,并放大至公斤级,总产率43%。非罗考昔通过LC-MS、H-NMR和C-NMR进行结构确证,纯度经HPLC测定为99.83%。该工艺既适合工业放大生产又经济环保,实现了非罗考昔的高效绿色化的工业制造。更多还原

【Abstract】 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.更多还原