7-氟-6′-羟基-5′-(噻吩-2-羰基)-6′-三氟甲基-5′,6′-二氢-1′H-螺环[吲哚-3,4′-嘧啶]-2,2′(3′H)-二酮的绿色合成与晶体结构解析  

Green synthesis of 7-fluoro-6′-hydroxy-5′-(thiophene-2-carbonyl)-6′-trifluoroomethyl-5′,6′- dihydro-1′H-spiro[indole-3,4′-pyrimidine]-2,2′(3′H)-dione and X-ray analysis

作　　者：闫宇辰 张雅姗 陶香敏 李文文 刘轩滔 朱晓彤 YAN Yuchen;ZHANG Yashan;TAO Xiangmin;LI Wenwen;LIU Xuantao;ZHU Xiaotong(First School of Clinical Medicine,Xuzhou Medical University,Xuzhou,Jiangsu 221004,China;School of Pharmacy,Xuzhou Medical University)

机构地区：[1]徐州医科大学第一临床医学院,江苏徐州221004 [2]徐州医科大学药学院

出　　处：《徐州医科大学学报》2022年第4期279-283,共5页Journal of Xuzhou Medical University

基　　金：江苏省自然科学基金(BK 20171175);徐州市科技发展计划项目(KC19042);江苏省高等学校大学生创新创业训练计划项目(201910313096H)。

摘　　要：目的 用一种绿色、简便和高效的方法构建嘧啶-2-酮类骨架分子,为此类分子的抗肿瘤活性研究提供物质基础。方法 以7-氟吲哚啉-2,3-二酮、尿素、4,4,4-三氟-1-(噻吩-2-基)丁烷-1,3-二酮为原料,对甲基苯磺酸为催化剂,无溶剂条件下经Biginelli反应多组分一锅法合成目标化合物。核磁共振谱、红外光谱、高分辨质谱和X射线单晶衍射确证目标分子的结构。结果 在无溶剂条件下,通过Biginelli反应,以92%分离收率制备得到7-氟-6′-羟基-5′-(噻吩-2-羰基)-6′-(三氟甲基)-5′,6′-二氢-1′H-螺环[吲哚-3,4′-嘧啶]-2,2′(3′H)-二酮杂环化合物,产物结构经核磁共振谱、红外光谱和高分辨质谱表征,并通过X射线衍射分析进一步确证产物结构。该产物的晶体结构属正交晶系,P2_(1)/n空间群,晶胞参数:a=18.691?,b=6.052?,c=20.084?,α=90.00°,β=108.8570(10)°,γ=90.00°。全矩阵最小二乘法修正的原子参数显示,最终的偏离因子R=0.3967,wR_(2)=0.8133。结论 通过无溶剂Biginelli反应一锅法成功构建嘧啶-2-酮骨架分子,方法绿色环保,后处理仅需重结晶即可获得纯品。Objective To develop a green,simple and efficient method to construct pyrimidine-2-ketone skeleton molecules,so as to provide evidence for investigating antitumor activity of these molecules.Methods 7-Fluoroindoline-2,3-dione,urea and 4,4,4-trifluoro-1-(thiophene-2-yl) butane-1,3-dione were used as raw materials,while p-methylbenzene sulfonic acid as the catalyst.The target compound was synthesized through Biginelli reaction using a multi-component one pot method without solvent.The crystal structure was verified by ^(1)H NMR,^(13)C NMR,IR,HRMS and X-ray diffraction.Results The target compound,7-fluoro-6′-hydroxy-5′-(thiophene-2-carbonyl)-6′-(trifluoroomethyl)-5′,6′-dihydro-1′H-spiro[indole-3,4′-pyrimidine]-2,2′(3′ H)-dione was obtained through Biginelli reaction under solvent free conditions,with a yield of 92%.The resultant product was characterized by NMR,IR and HRMS,and further confirmed by X-ray diffraction.According to X-ray diffraction,the crystal structure belonged to the orthorhombic system,and the space group was P2_(1)/n.Lattice parameters:a=18.691?,b=6.052?,c=20.084?,α=90.00°,β=108.8570(10)°,γ=90.00°.According to atomic parameters corrected by the full matrix least square method,the final deviation factor was R=0.3967,wR_(2)=0.8133.Conclusions Pyrimidine-2-one skeleton molecule is successfully constructed via a multi-component Biginelli reaction under solvent-free conditions.The method is green and environment-friendly and the pure product can be obtained only by recrystallization.

关 键 词：嘧啶-2-酮 多组分反应 晶体结构 绿色合成 药物分子 

分 类 号：O626.32[理学—有机化学]