7-甲基-4-苯氨基喹啉类化合物的设计与合成
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摘要
结合已经上市的具有喹唑啉、喹啉结构的蛋白酪氨酸激酶抑制剂构效关系,设计并合成8个4-苯氨基喹啉化合物.以间甲基苯胺与乙氧基亚甲基丙二酸二乙酯(Diethyl Ethoxymethylene-malonate,EM ME)为起始原料,经缩合、Gould-Jacobs高温环合、水解、脱羧、氯化制得4-氯-7-甲基喹啉,总收率为37. 57%(以间甲基苯胺计),再以4-氯-7-甲基喹啉为原料与苯胺或取代苯胺反应得目标化合物(Ⅰ～Ⅷ),其结构经ESI-MS确证.
According to the structure-activity relationship of quinazoline and quinoline tyrosine kinase inhibitors,eight 4-anilinoquinoline compounds were designed and synthesized. 4-chlorine-7-methyl quinoline(5) was prepared from m-methylaniline and EMME through the condensation reaction,Gould-Jacobs cyclization,hydrolysis,decarboxylation and chlorination reaction,and the total yield was 37. 57 %( m/m). Target compounds( Ⅰ-Ⅷ) was obtained by the reaction of 4-chlorine-7-methylquinoline with aniline or substituted anilines. The structure of target compounds was confirmed by ESI-MS.
According to the structure-activity relationship of quinazoline and quinoline tyrosine kinase inhibitors,eight 4-anilinoquinoline compounds were designed and synthesized. 4-chlorine-7-methyl quinoline(5) was prepared from m-methylaniline and EMME through the condensation reaction,Gould-Jacobs cyclization,hydrolysis,decarboxylation and chlorination reaction,and the total yield was 37. 57 %( m/m). Target compounds( Ⅰ-Ⅷ) was obtained by the reaction of 4-chlorine-7-methylquinoline with aniline or substituted anilines. The structure of target compounds was confirmed by ESI-MS.
引文
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[2]刘宝,尤启冬,李志裕.3-氰基-7-喹啉酰胺衍生物的合成和生物活性研究[J].药学学报,2009,44(8):879-884.
[3]PAWAR V G,SOS M L,RODE H B,et al.Synthesis and Biological Evaluation of 4-Anilinoquinolines as Potent Inhibitors of Epidermal Growth Factor Receptor[J].Journal of Medicinal Chemistry,2010,53(7):2892-2901.
[4]姜梦,刘丹,兰帅鹏.喹啉类蛋白酪氨酸激酶抑制剂的研究进展[J].化学试剂,2013,35(4):333-336.
[5]LIU D,LUAN T,KONG J,et al.Synthesis and AntiTumor Activities of 4-Anilinoquinoline Derivatives[J].Molecules,2015,21(1),21-28.
[6]SHEWCHUK L,HASSELL A,WISELY B.Binding Mode of the 4-Anilinoquinazoline Class of Protein Kinase Inhibitor:X-ray Crystallographic Studies of4-Anilinoquinazolines Bound to Cyclin-Dependent Kinase 2 and p38 Kinase[J].Journal of Medicinal Chemistry,2000,43(1):133-138.
[7]CHANG S H,ZHANG L W,XU S L,et al.Design,Synthesis,and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine790→Methionine790Mutant[J].Journal of Medicinal Chemistry,2012,55(6):2711-2723.
[8]刘丹,朱秀杰,姜梦,等.3-[(4-吗啉基)-羰基或乙氧羰基]-4-苯氨基喹啉化合物的合成及抗肿瘤活性[J].高等学校化学学报,2012,33(10):2249-2255.
[9]张淑兰,祝丽君,刘文东,等.4-(甲基苯胺基)-3-氰基喹啉类衍生物的合成及抗肿瘤活性[J].中国药物化学杂志,2010,20(4):269-274.