依托考昔(etoricoxib)有关物质的合成研究

Synthesis of related substances of etoricoxib

目的探索依托考昔5个有关物质的合成方法,制备对照样品,用于依托考昔质量研究。方法以2-氨基-3-吡啶甲醛为原料,经氯化、微波催化环合制备杂质6-氯-2-(6-甲基吡啶-3-基)-3-[4-(甲基磺酰基)苯基]-1,8-二氮杂萘(1);在醋酸钯/Xantphos催化下,依托考昔与二甲胺盐酸盐经偶联反应制备杂质N,N,6'-三甲基-3-[4-(甲基磺酰基)苯基]-(2,3'-联吡啶)-5-胺(2);依托考昔与间氯过氧苯甲酸(物质的量比为1∶1.1)经室温下氧化制备杂质5-氯-6'-甲基-3-[4-(甲磺酰基)苯基]-1'-氧代-2,3'-联吡啶(3);依托考昔与间氯过氧苯甲酸(物质的量比为1∶3.0)经室温下氧化制备双氧化杂质5-氯-6'-甲基-3-[4-(甲磺酰基)苯基]-1,1'-二氧代-2,3'-联吡啶(4);以1-(6-甲基吡啶-3-基)-2-[4-(甲磺酰基)苯基]乙酮为原料,经叔丁醇钾去质子化,与(E)-N-(2-氯-3-(二甲基氨基)亚烯丙基)-N-甲基甲胺六氟磷酸盐缩合,然后在7.2 mol·L^(-1)盐酸羟胺溶液中加热环合,制备杂质5-氯-6'-甲基-3-[4-(甲磺酰基)苯基]-1-氧代-2,3'-联吡啶(5)。结果与结论本文定向合成了5个依托考昔的有关物质,其化学结构经MS、1H-NM R确证。所研究的杂质合成方法为杂质对照品的大量制备和依托考昔的质量研究奠定了基础。

Etoricoxib is a novel selective COX-2 inhibitor as non-steroidal anti-inflammatory drug.The main process and degradation impurities of etoricoxib play an important role in its quality research and control.To perform the quality control of etoricoxib,five related substances were prepared.Using 2-aminonicotinaldehyde as a starting material,the impurity 6-chloro-2-（6-methylpyridin-3-yl）-3-（4-（methylsulfonyl） phenyl）-1,8-naphthyridine（1） was prepared by two steps of chlorination and microwave irradiated cyclization.The impurity N,N,6＇-trimethyl-3-（4-（methylsulfonyl） phenyl）-[2,3＇-bipyridine]-5-amine（2） was prepared by palladium acetate/Xantphos catalyzed coupling reaction of dimethylamine hydrochloride and etoricoxib.Through the oxidation reactions of 3-chloroperbenzoic acid（1.0 or 3.0 molar equivalents） and etoricoxib at room temperature,the impurity 3 and 4 were prepared separately.Synthetic methods of above impurities（1,2,4） have not been reported.In addition,the synthesis of 5-chloro-6＇-methyl-3-（4-（methylsulfonyl） phenyl）-[2,3＇-bipyridine]1-oxide（5） was accomplished from 1-（6-methylpyridin-3-yl）-2-（4-methylsulfonyl）phenyl） ethanone as starting material,through two steps of condensation and cyclization.The structures of five impurities of etoricoxib were confirmed by MS and1H-NMR.The five specified impurities can be used as the control samples in the quality research and control of etoricoxib.