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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。
OBJECTIVE To explore the synthetic method of 5 related substances of ethacryl to prepare a control sample for the study of the quality of Methods 2-Amino-3-pyridinecarbaldehyde was used as starting material to prepare 6-chloro-2- (6-methylpyridin-3-yl) -3- [4- Acyl) phenyl] -1,8-naphthyridine (1). The coupling reaction of ethaoxal and dimethylamine hydrochloride under the catalysis of palladium acetate / Xantphos to prepare the impurity N, N, Chloroperbenzoic acid (molar ratio of substance to substance) (2) Methyl-3- [4- (methylsulfonyl) phenyl] 1: 1.1) was prepared by oxidation at room temperature to prepare an impurity 5-chloro-6’-methyl-3- [4- (methylsulfonyl) phenyl] ). The oxidation of 5-chloro-6’-methyl-3- [4- (methylsulfonyl) Phenyl] -1,1’-dioxo-2,3’-bipyridine (4); 1- (6-methylpyridin-3-yl) -2- [4- (methylsulfonyl) benzene (E) -N- (2-chloro-3- (dimethylamino) allylene) -N-methylmethanamine hexafluoro Phosphate was condensed and then heated and cyclized in a 7.2 mol·L -1 hydroxylamine hydrochloride solution to prepare an impurity 5-chloro-6’-methyl-3- [4- (methylsulfonyl) phenyl] -1 Oxo-2,3’-bipyridine (5). RESULTS AND CONCLUSIONS In this paper, five related substances based on Cox-2 were synthesized and their chemical structures were confirmed by MS and 1H-NM R. The method of synthesis of impurities studied laid the foundation for the mass preparation of impurities reference substance and the quality study of ethacryx.