CN114057760B - 一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物、制备方法及其用途 - Google Patents

一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物、制备方法及其用途 Download PDF

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CN114057760B
CN114057760B CN202111348720.3A CN202111348720A CN114057760B CN 114057760 B CN114057760 B CN 114057760B CN 202111348720 A CN202111348720 A CN 202111348720A CN 114057760 B CN114057760 B CN 114057760B
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朱红萍
邹文林
漆婷
李青竹
张翔
戴青松
曾荣
凡洋
徐鹏帅
代海渝
刘万聪
王亚鹏
黄茂林
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Abstract

本发明涉及一种吲哚并喹唑啉酮螺1,3‑二氧戊环化合物、制备方法及其用途，本发明涉及通式I所示化合物及其盐，本发明还涉及该类化合物的制备方法及含有它们的药物制剂，本发明提供的该类新的化合物，其具有良好的抗菌效果，化合物的制备方法简便、反应温和、收率高，具有广阔的市场应用前景。

Description

一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物、制备方法及其 用途
技术领域
本发明涉及药物化学技术领域，具体说是一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物、制备方法及其用途。
背景技术
吲哚并喹唑啉酮螺1,3-二氧戊环骨架广泛存在于天然产物、合成药物中，相关研究表明含有该骨架的化合物具有多种重要的生物活性和药物活性，对此类化合物的取代基修饰、结构类似物的衍生化以及进一步生物学活性再评价成为了研究热点。
如何简便的制备收率高的吲哚并喹唑啉酮螺1,3-二氧戊环衍生物是目前的研究难点。
发明内容
针对现有技术中的问题，本发明提供了一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物、制备方法及其用途。
本发明解决其技术问题所采用的技术方案是：一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物或其药学上可接受的盐，所述化合物的通式如式I所示：
其中，R1独立选自H、卤素、烷基、烷氧基；
R2独立选自H、卤素；
R3独立选自H、卤素；
R4独立选自H、卤素、烷基；
R5独立选自H、卤素、烷基；
R6独立选自H、烷基；
R7独立选自苯基、取代的苯基、萘基、苯乙基、H；
R8独立选自乙烯基、
优选的，R1、R2、R3、R4、R5所述卤素，优选的为F、Cl、Br；
R1、R4、R5、R6所述烷基，优选的为甲基；
R1所述烷氧基，优选的为甲氧基；
R7所述烷氧基，优选的为2-萘基。
优选的，所述化合物选自如下结构式之一：
一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物的制备方法，包括以下步骤：将1.0eq的底物1和5mol％的Pd(PPh3)4加入反应封管中，在氩气保护下加入干燥的1.5eq的二氯甲烷及碳酸酯2，混合物在常温下反应8小时，反应完成后浓缩纯化得到目标产物3；
制备化合物的技术路线如下所示：
优选的，底物的制备方法，具体包括以下步骤：
步骤一：将1.0eq的苯乙酮、2.0eq的三氟醋酸碘苯投入500ml的干燥圆底烧瓶中，另外量取50mL：10mL的乙腈-水溶液(50mL:10mL)加入作为溶剂，再加入三氟醋酸，放入干净的搅拌子，将烧瓶置于油浴锅内，在80℃下回流反应2h，TLC检测反应完毕后，蒸除乙腈，再将反应液用二氯甲烷萃取，收集有机层，干燥浓缩，柱层析分离纯化，得到羟基苯乙酮类化合物；
步骤二：称取1eq的上述羟基苯乙酮类化合物于圆底烧瓶中，氩气保护下，以THF为反应溶剂，在冰浴条件下缓慢滴加2.5eq的烯基格氏试剂，滴加完毕后，室温反应3h，TLC检测反应完成，反应液用饱和氯化铵溶液淬灭，乙酸乙酯萃取，收集有机层，干燥浓缩，柱层析分离纯化，得到烯基二醇类化合物；
步骤三：准确称量1.0eq的烯基二醇类化合物，0.5eq的三光气于圆底烧瓶中，在氩气保护下，以DCM为反应溶剂，冰浴条件下缓慢滴加4.0eq的吡啶，滴加完毕后，室温反应2h，TLC检测反应完成，反应液用饱和氯化铵溶液淬灭，乙酸乙酯萃取，收集有机层，干燥浓缩，柱层析分离纯化，得到烯基环状碳酸酯类底物，
制备底物的技术路线如下所示：
一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物的双羟基化的制备方法，将0.1mmol的8-溴-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮、1mol％的K2OsO4和0.13mmol的NMO加入反应封管，在氩气保护下加入4:1的乙腈-水做溶剂，在60℃下反应12h，使用薄层色谱监测反应，待反应完成后，将反应液旋干，使用柱层析纯化，使用石油醚：乙酸乙酯＝1：1分离得到产物，
优选的，一种吲哚并喹唑啉酮螺1,3-二氧戊环化合物或其药学上可接受的盐在制备抗菌药物中的用途。
一种药物组合物，包括所述吲哚并喹唑啉酮螺1,3-二氧戊环化合物或其药学上可接受的盐为活性成分，以及加上药学上可接受的辅料制备而成的制剂。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
卤素为氟、氯、溴。
本发明中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与碱金属形成的盐。适合形成盐的碱金属包括但并不限于：锂、钠，钾、钙、镁等。
本发明提供了一类新的化合物，其具有良好的抗菌效果，化合物的制备方法简便、反应温和、收率高，具有广阔的市场应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
附图说明
图1实施例18产物的单晶结构图。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施方式，进一步阐述本发明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
除特别标注外，本发明所用试剂和测试设备均为常规的市售试剂和设备。
实施例1
4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮)
黄色固体，产率96％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.54(d,J＝8.4Hz,1H),8.41(d,J＝7.8Hz,1H),7.83(d,J＝8.4Hz,1H),7.78(t,J＝7.2Hz,1H),7.60–7.53(m,3H),7.50(t,J＝7.8Hz,1H),7.48–7.44(m,2H),7.40(t,J＝7.2Hz,1H),7.22(t,J＝7.8Hz,1H),7.07(d,J＝7.6Hz,1H),6.58(dd,J＝17.4,10.8Hz,1H),5.34(d,J＝10.8Hz,1H),5.19(d,J＝8.4Hz,1H),5.11(d,J＝17.4Hz,1H),4.88(d,J＝8.4Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.2,156.5,147.4,141.6,140.2,140.0,134.3,132.1,128.5,128.2,127.9,127.8,127.1,127.0,126.8,126.7,125.6,122.6,118.4,117.1,107.3,87.3,75.4.
实施例2
8-氟-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.50(dd,J＝9.0,4.2Hz,1H),8.39(d,J＝8.4Hz,1H),7.82(d,J＝8.4Hz,1H),7.78(t,J＝7.8Hz,1H),7.58–7.52(m,3H),7.51–7.45(m,2H),7.42(t,J＝7.2Hz,1H),7.17(td,J＝9.0,2.4Hz,1H),6.68(dd,J＝7.8,3.0Hz,1H),6.55(dd,J＝16.8,10.2Hz,1H),5.35(d,J＝10.8Hz,1H),5.14(d,J＝8.4Hz,1H),5.11(d,J＝18.0Hz,1H),4.88(d,J＝7.8Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):161.1(J＝248.5Hz),159.0,156.4,147.3,141.3,139.8,135.9(J＝2.9Hz),134.4,129.3(J＝8.6Hz),128.5,128.3,128.1,127.9,127.0,126.6,122.5,118.8,118.6(J＝3.0Hz),,118.5,113.1(J＝26.0Hz),106.7,87.6,75.3.
19F NMR(564MHz,CDCl3,40℃)δ(ppm):-113.5.
实施例3
8-氯-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.46(d,J＝9.0Hz,1H),8.39(d,J＝7.2Hz,1H),7.83(d,J＝7.2Hz,1H),7.79(t,J＝7.8Hz,1H),7.58–7.52(m,3H),7.51–7.47(m,2H),7.47–7.41(m,2H),6.92(d,J＝1.8Hz,1H),6.55(dd,J＝17.4,10.2Hz,1H),5.35(d,J＝10.2Hz,1H),5.13(d,J＝3.0Hz,1H),5.11(d,J＝12.6Hz,1H),4.88(d,J＝9.0Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.1,156.1,147.3,141.2,139.8,138.3,134.5,132.3,132.0,129.0,128.6,128.4,128.1,128.0,127.0,126.7,126.0,122.5,118.7,118.2,106.7,87.6,75.3.
实施例4
8-溴-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
黄色固体，产率92％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.40(d,J＝7.8Hz,1H),8.38(d,J＝8.4Hz,1H),7.82(d,J＝7.8Hz,1H),7.79(t,J＝7.8Hz,1H),7.61(dd,J＝8.4,2.4Hz,1H),7.58–7.52(m,3H),7.52–7.46(m,2H),7.43(t,J＝7.2Hz,1H),7.05(d,J＝2.4Hz,1H),6.54(dd,J＝16.8,10.2Hz,1H),5.35(d,J＝10.2Hz,1H),5.12(d,J＝3.6Hz,1H),5.10(d,J＝4.8Hz,1H),4.88(d,J＝9.0Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.1,155.9,147.4,141.2,139.7,138.8,134.9,134.5,129.2,129.0,128.6,128.4,128.2,128.0,127.1,126.7,122.5,119.9,118.7,118.6,106.7,87.6,75.3.
实施例5
8-甲基-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
黄色固体，产率50％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.43-8.36(m,2H),7.83(d,J＝7.2Hz,1H),7.77(t,J＝8.4Hz,1H),7.58(d,J＝7.8Hz,2H),7.54(t,J＝7.2Hz,1H),7.51–7.44(m,2H),7.41(t,J＝7.8Hz,1H),7.29(d,J＝8.4Hz,1H),6.82(s,1H),6.58(dd,J＝16.8,10.8Hz,1H),5.34(d,J＝10.8Hz,1H),5.17(d,J＝9.0Hz,1H),5.11(d,J＝17.4Hz,1H),4.88(d,J＝9.0Hz,1H),2.28(s,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.1,156.7,147.5,141.6,140.1,137.7,136.8,134.2,132.6,128.5,128.2,127.9,127.7,127.02,126.95,126.8,126.1,122.7,118.4,116.9,107.4,87.3,75.4,21.2.
实施例6
8-甲氧基-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.41(d,J＝8.4Hz,1H),8.39(d,J＝7.2Hz,1H),7.82(d,J＝7.8Hz,1H),7.77(t,J＝7.8Hz,1H),7.59(d,J＝7.6Hz,2H),7.54(t,J＝7.2Hz,1H),7.50–7.44(m,2H),7.39(t,J＝7.2Hz,1H),7.00(dd,J＝9.0,2.4Hz,1H),6.54(dd,J＝16.8,10.2Hz,1H),6.50(d,J＝3.0Hz,1H),5.35(d,J＝10.2Hz,1H),5.17–5.10(m,2H),4.90(d,J＝8.4Hz,1H),3.65(s,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):158.9,158.6,156.8,147.4,141.6,139.8,134.1,133.3,128.50,128.47,128.2,128.0,127.7,126.91,126.87,122.7,118.6,118.2,118.0,110.4,107.2,87.4,75.2,55.5.
实施例7
9-氯-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.58(d,J＝2.4Hz,1H),8.39(d,J＝8.4Hz,1H),7.82(d,J＝6.6Hz,1H),7.79(t,J＝7.8Hz,1H),7.58–7.51(m,3H),7.49–7.43(m,2H),7.40(t,J＝7.2Hz,1H),7.18(dd,J＝8.4,1.8Hz,1H),6.92(d,J＝7.2Hz,1H),6.54(dd,J＝17.4,10.8Hz,1H),5.34(d,J＝10.8Hz,1H),5.14(d,J＝8.4Hz,1H),5.10(d,J＝16.8Hz,1H),4.87(d,J＝8.4Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.1,156.2,147.3,141.4,140.6,139.9,137.9,134.6,128.6,128.3,128.0,127.1,126.9,126.7,126.5,125.5,122.4,118.6,117.6,106.8,87.4,75.3.
实施例8
2-氟-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.51(d,J＝8.4Hz,1H),8.03(dd,J＝8.4,3.0Hz,1H),7.83(dd,J＝8.4,4.8Hz,1H),7.55(d,J＝8.4Hz,2H),7.53–7.44(m,4H),7.40(t,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),7.06(d,J＝7.8Hz,1H),6.55(dd,J＝18.0,10.8Hz,1H),5.34(d,J＝10.8Hz,1H),5.14(d,J＝8.4Hz,1H),5.10(d,J＝17.4Hz,1H),4.88(d,J＝9.0Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):161.6(J＝250.1Hz),158.4,156.0,144.0,141.5,140.1,140.0,132.1,130.7(J＝8.8Hz),128.3,127.9,127.2,127.0,126.7,125.6,124.1(J＝8.8Hz),122.6(J＝24.5Hz),118.4,117.2,112.3(J＝24.6Hz),107.2,87.4,75.3.
19F NMR(564MHz,CDCl3,40℃)δ(ppm):-111.2.
实施例9
2-氯-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.50(d,J＝7.8Hz,1H),8.36(d,J＝1.8Hz,1H),7.76(d,J＝9.0Hz,1H),7.71(dd,J＝9.0,3.0Hz,1H),7.55(d,J＝6.6Hz,2H),7.50(t,J＝7.8Hz,1H),7.48–7.44(m,2H),7.40(t,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),7.05(d,J＝9.0Hz,1H),6.54(dd,J＝17.4,10.8Hz,1H),5.34(d,J＝11.4Hz,1H),5.14(d,J＝8.4Hz,1H),5.10(d,J＝16.8Hz,1H),4.87(d,J＝8.4Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):158.1,156.9,145.9,141.5,140.0,139.6,134.7,133.8,132.1,130.0,128.3,127.9,127.0,126.7,126.5,125.6,123.8,118.4,117.2,107.2,87.4,75.4.
实施例10
2-溴-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.52(d,J＝1.8Hz,1H),8.50(d,J＝8.4Hz,1H),7.86(dd,J＝9.0,3.0Hz,1H),7.69(d,J＝7.8Hz,1H),7.55(d,J＝7.2Hz,2H),7.50(t,J＝7.8Hz,1H),7.48–7.43(m,2H),7.41(t,J＝7.2Hz,1H),7.22(t,J＝7.8Hz,1H),7.05(d,J＝7.2Hz,1H),6.54(dd,J＝17.4,10.8Hz,1H),5.34(d,J＝10.8Hz,1H),5.14(d,J＝8.4Hz,1H),5.10(d,J＝17.4Hz,1H),4.87(d,J＝9.0Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):157.9,157.0,146.3,141.5,140.0,139.7,137.5,132.2,130.1,129.7,128.3,127.9,127.1,126.7,125.6,124.1,121.6,118.4,117.2,107.3,87.4,75.4.
实施例11
2-甲基-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.54(d,J＝7.8Hz,1H),8.19(s,1H),7.72(d,J＝8.4Hz,1H),7.59(dd,J＝8.4,2.4Hz,1H),7.56(d,J＝7.2Hz,2H),7.52–7.44(m,3H),7.40(t,J＝7.2Hz,1H),7.21(t,J＝7.2Hz,1H),7.07(d,J＝6.6Hz,1H),6.58(dd,J＝17.4,10.2Hz,1H),5.34(d,J＝10.8Hz,1H),5.18(d,J＝8.4Hz,1H),5.10(d,J＝17.4Hz,1H),4.87(d,J＝8.4Hz,1H),2.53(s,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,155.7,145.4,141.7,140.2,140.0,138.1,135.6,132.0,128.3,128.2,127.8,127.1,126.71,126.67,126.6,125.5,122.3,118.3,117.1,107.3,87.3,75.4,21.3.
实施例12
3-氯-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
淡黄色固体，产率80％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.49(d,J＝8.4Hz,1H),8.32(d,J＝8.4Hz,1H),7.83(d,J＝2.4Hz,1H),7.55(d,J＝7.2Hz,2H),7.53–7.48(m,2H),7.48–7.44(m,2H),7.40(t,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),7.06(d,J＝7.8Hz,1H),6.54(dd,J＝16.8,10.8Hz,1H),5.35(d,J＝9.6Hz,1H),5.14(d,J＝8.4Hz,1H),5.10(d,J＝17.4Hz,1H),4.88(d,J＝9.0Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):158.6,158.0,148.4,141.5,140.6,140.0,139.7,132.2,128.4,128.31,128.26,128.1,127.9,127.0,126.9,126.7,125.7,121.1,118.5,117.1,107.2,87.4,75.4.
实施例13
1-氯-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.56(d,J＝7.8Hz,1H),7.73(dd,J＝8.4,1.8Hz,1H),7.63(t,J＝8.4Hz,1H),7.58–7.52(m,3H),7.51–7.44(m,3H),7.40(t,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),7.06(d,J＝7.8Hz,1H),6.54(dd,J＝16.8,10.8Hz,1H),5.33(d,J＝10.2Hz,1H),5.13(d,J＝8.4Hz,1H),5.10(d,J＝18.0Hz,1H),4.87(d,J＝8.4Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):157.4,157.2,149.9,141.5,140.0,139.8,135.0,133.7,132.2,130.8,128.3,127.9,127.8,126.94,126.90,126.7,125.6,119.7,118.4,117.4,107.2,87.4,75.4.
实施例14
3,4-二甲基-4'-苯基-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用苯乙酮).
黄色固体，产率94％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.53(d,J＝8.4Hz,1H),8.16(d,J＝7.8Hz,1H),7.59(d,J＝7.8Hz,2H),7.53–7.45(m,3H),7.40(t,J＝7.2Hz,1H),7.34(d,J＝8.4Hz,1H),7.22(t,J＝7.2Hz,1H),7.14(d,J＝7.2Hz,1H),6.57(dd,J＝17.4,10.8Hz,1H),5.34(d,J＝10.2Hz,1H),5.23(d,J＝9.0Hz,1H),5.18(d,J＝16.8Hz,1H),4.89(d,J＝9.0Hz,1H),2.63(s,3H),2.47(s,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.7,155.1,145.7,143.7,141.9,140.1,134.8,132.1,129.6,128.3,127.8,127.0,126.6,125.6,123.9,120.5,117.9,117.1,107.3,87.2,75.5,20.9,13.4.
实施例15
4'-(4-溴苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用4-溴苯乙酮).
淡黄色固体，产率72％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.53(d,J＝7.2Hz,1H),8.40(d,J＝8.4Hz,1H),7.82(d,J＝7.8Hz,1H),7.79(t,J＝7.2Hz,1H),7.60(d,J＝8.4Hz,2H),7.56(t,J＝7.2Hz,1H),7.53(t,J＝7.8Hz,1H),7.44(d,J＝8.4Hz,2H),7.29–7.23(m,1H),7.09(d,J＝7.8Hz,1H),6.55(dd,J＝16.8,10.2Hz,1H),5.35(d,J＝11.4Hz,1H),5.20(d,J＝8.4Hz,1H),5.05(d,J＝18.0Hz,1H),4.80(d,J＝8.4Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.2,156.3,147.2,140.7,139.9,139.6,134.4,132.3,131.4,128.51,128.46,127.9,127.0,126.9,126.6,125.4,122.5,122.0,118.9,117.2,107.3,86.9,75.3.
实施例16
4'-(4-甲基苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物使用4-甲基苯乙酮)
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.53(d,J＝7.8Hz,1H),8.41(d,J＝8.4Hz,1H),7.83(d,J＝8.4Hz,1H),7.78(t,J＝8.4Hz,1H),7.55(t,J＝7.8Hz,1H),7.50(t,J＝7.8Hz,1H),7.44(d,J＝7.8Hz,2H),7.27(d,J＝7.2Hz,2H),7.22(t,J＝7.8Hz,1H),7.10(d,J＝7.8Hz,1H),6.57(dd,J＝18.0,11.4Hz,1H),5.33(d,J＝10.2Hz,1H),5.16(d,J＝8.4Hz,1H),5.11(d,J＝16.8Hz,1H),4.85(d,J＝7.8Hz,1H),2.43(s,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,156.5,147.3,140.2,139.9,138.4,137.5,134.3,132.1,128.9,128.5,127.8,127.01,126.96,126.8,126.6,125.6,122.5,118.4,117.1,107.2,87.3,75.4,21.1.
实施例17
4'-(4-乙基苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物使用4-乙基苯乙酮)
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.54(d,J＝7.8Hz,1H),8.41(d,J＝7.8Hz,1H),7.83(d,J＝7.8Hz,1H),7.78(t,J＝7.8Hz,1H),7.55(t,J＝7.8Hz,1H),7.50(t,J＝7.8Hz,1H),7.47(d,J＝7.8Hz,2H),7.29(d,J＝7.8Hz,2H),7.22(t,J＝7.8Hz,1H),7.10(d,J＝7.8Hz,1H),6.58(dd,J＝17.4,10.8Hz,1H),5.33(d,J＝11.4Hz,1H),5.17(d,J＝9.0Hz,1H),5.13(d,J＝16.8Hz,1H),4.86(d,J＝8.4Hz,1H),2.74(q,J＝7.8Hz,2H),1.31(t,J＝7.8Hz,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,156.6,147.5,143.9,140.3,140.0,138.9,134.3,132.0,128.5,127.8,127.7,127.2,127.0,126.8,126.7,125.7,122.6,118.2,117.1,107.3,87.3,75.5,28.5,15.4.
实施例18
4'-(4-正丙基苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物使用4-正丙基苯乙酮)
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.53(d,J＝7.8Hz,1H),8.41(d,J＝7.2Hz,1H),7.83(d,J＝7.8Hz,1H),7.78(t,J＝7.8Hz,1H),7.55(t,J＝7.8Hz,1H),7.50(t,J＝8.4Hz,1H),7.46(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.21(t,J＝7.2Hz,1H),7.06(d,J＝7.8Hz,1H),6.57(dd,J＝16.8,10.8Hz,1H),5.34(d,J＝10.2Hz,1H),5.16(d,J＝8.4Hz,1H),5.12(d,J＝17.4Hz,1H),4.86(d,J＝8.4Hz,1H),2.67(t,J＝7.8Hz,2H),1.77–1.68(m,2H),1.00(t,J＝7.2Hz,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,156.6,147.4,142.4,140.2,139.9,138.8,134.3,132.0,128.5,128.3,127.7,127.2,127.0,126.7,126.6,125.6,122.6,118.2,117.1,107.2,87.3,75.4,37.8,24.4,13.8.
实施例18产物的单晶数据(参见图1和下表)：
实施例19
4'-(4-甲氧基苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物使用4-甲氧基苯乙酮)
淡黄色固体，产率86％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.53(d,J＝7.8Hz,1H),8.40(dd,J＝7.8,1.8Hz,1H),7.83(d,J＝8.4Hz,1H),7.78(t,J＝7.8Hz,1H),7.55(t,J＝7.8Hz,1H),7.52–7.46(m,3H),7.22(t,J＝8.4Hz,1H),7.06(d,J＝7.8Hz,1H),6.99(d,J＝8.4Hz,2H),6.56(dd,J＝16.8,10.2Hz,1H),5.33(d,J＝11.4Hz,1H),5.14(d,J＝9.0Hz,1H),5.10(d,J＝17.4Hz,1H),4.84(d,J＝8.4Hz,1H),3.88(s,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,159.2,156.6,147.4,140.4,139.9,134.3,133.6,132.0,128.5,128.0,127.7,127.2,127.0,126.8,125.6,122.6,118.2,117.1,113.6,107.3,87.1,75.2,55.3.
实施例20
4'-(3-氟苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物使用3-氟苯乙酮)
黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.54(d,J＝8.4Hz,1H),8.41(d,J＝7.6Hz,1H),7.82(d,J＝6.6Hz,1H),7.78(t,J＝7.8Hz,1H),7.55(t,J＝7.8Hz,1H),7.51(t,J＝7.8Hz,1H),7.46–7.41(m,1H),7.34–7.29(m,2H),7.27–7.23(m,1H),7.13–7.07(m,2H),6.55(dd,J＝17.4,10.2Hz,1H),5.36(d,J＝10.2Hz,1H),5.22(d,J＝9.0Hz,1H),5.13(d,J＝16.8Hz,1H),4.82(d,J＝8.4Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):162.9(J＝245.8Hz),159.2,156.4,147.4,144.7(J＝7.2Hz),140.1,139.6,134.3,132.2,129.8(J＝7.2Hz),128.5,127.8,127.1,126.9,126.8,125.5,122.7,122.3,118.5,117.2,114.8(J＝21.7Hz),114.1(J＝23.1Hz),107.5,86.9,75.5.
19F NMR(564MHz,CDCl3,40℃)δ(ppm):-112.3.
实施例21
4'-(3-溴苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物使用3-溴苯乙酮)
黄色固体，产率92％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.54(d,J＝8.4Hz,1H),8.41(d,J＝7.8Hz,1H),7.83(d,J＝6.6Hz,1H),7.78(t,J＝7.8Hz,1H),7.74(s,1H),7.57–7.51(m,3H),7.49(d,J＝7.8Hz,1H),7.34(t,J＝7.8Hz,1H),7.28–7.25(m,1H),7.12(d,J＝7.8Hz,1H),6.53(dd,J＝17.4,10.8Hz,1H),5.36(d,J＝10.8Hz,1H),5.21(d,J＝8.4Hz,1H),5.13(d,J＝16.8Hz,1H),4.81(d,J＝9.0Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.2,156.3,147.3,144.2,140.0,139.5,134.4,132.3,131.0,129.9,129.8,128.5,127.9,127.0,126.9,126.6,125.44,125.38,122.6,122.5,118.7,117.2,107.4,86.7,75.5.
实施例22
4'-(2-氟苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用2-氟苯乙酮)
黄色固体，产率93％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.57(d,J＝7.8Hz,1H),8.41(dd,J＝7.8,1.8Hz,1H),7.83(d,J＝8.4Hz,1H),7.81–7.75(m,2H),7.58–7.52(m,2H),7.43–7.38(m,1H),7.32–7.25(m,3H),7.16(dd,J＝11.4,9.0Hz,1H),6.66(dd,J＝16.8,10.2Hz,1H),5.33(d,J＝10.2Hz,1H),5.26(d,J＝7.8Hz,1H),5.15(d,J＝16.8Hz,1H),4.91(dd,J＝9.0,1.8Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.25,159.21(J＝245.8Hz),156.3,147.3,140.0,138.4,134.4,132.3,129.9(J＝8.6Hz),129.4(J＝11.5Hz),128.64(J＝2.9Hz),128.5,127.9,127.0,126.9,126.8,125.4,124.1(J＝2.9Hz),122.6,117.7,117.3,115.9,115.8,107.3,85.2,75.8(J＝5.7Hz).
19F NMR(564MHz,CDCl3,40℃)δ(ppm):-112.2.
实施例23
4'-(4-苯基苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用4-苯基苯乙酮)
黄色固体，产率95％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.55(d,J＝7.2Hz,1H),8.42(d,J＝8.4Hz,1H),7.85(d,J＝7.8Hz,1H),7.79(t,J＝7.8Hz,1H),7.71(d,J＝8.4Hz,2H),7.68(d,J＝6.6Hz,2H),7.64(d,J＝8.4Hz,2H),7.56(t,J＝7.8Hz,1H),7.53–7.46(m,3H),7.39(t,J＝7.8Hz,1H),7.23(t,J＝7.8Hz,1H),7.16(d,J＝7.2Hz,1H),6.62(dd,J＝17.4,10.8Hz,1H),5.38(d,J＝10.2Hz,1H),5.23(d,J＝7.8Hz,1H),5.19(d,J＝17.4Hz,1H),4.91(d,J＝9.0Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,156.5,147.4,140.8,140.7,140.6,140.1,140.0,134.3,132.1,128.9,128.5,127.8,127.5,127.2,127.1,127.0,126.9,126.8,125.6,122.6,118.4,117.2,107.4,87.3,75.5.
实施例24
4'-(3,4-二甲基苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用3,4-二甲基苯乙酮)
淡黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.54(d,J＝8.4Hz,1H),8.41(d,J＝8.4Hz,1H),7.83(d,J＝6.6Hz,1H),7.78(t,J＝7.8Hz,1H),7.55(t,J＝7.8Hz,1H),7.50(t,J＝7.8Hz,1H),7.33–7.27(m,2H),7.25–7.20(m,2H),7.13(d,J＝7.2Hz,1H),6.56(dd,J＝17.4,10.2Hz,1H),5.33(d,J＝12.0Hz,1H),5.17(d,J＝9.0Hz,1H),5.14(s,1H),4.85(d,J＝8.4Hz,1H),2.34(s,6H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,156.6,147.4,140.3,139.9,139.1,136.3,136.1,134.3,132.0,129.5,128.5,127.9,127.7,127.2,127.0,126.7,125.7,124.1,122.6,118.0,117.1,107.2,87.3,75.5,19.9,19.4.
实施例25
4'-(3,4-二甲氧基苯基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用3,4-二甲氧基苯乙酮)
黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.53(d,J＝8.4Hz,1H),8.40(d,J＝8.4Hz,1H),7.82(d,J＝7.8Hz,1H),7.77(t,J＝7.8Hz,1H),7.54(t,J＝7.8Hz,1H),7.50(t,J＝7.8Hz,1H),7.21(t,J＝7.8Hz,1H),7.12(d,J＝1.8Hz,1H),7.09(d,J＝7.2Hz,1H),7.06(dd,J＝8.4,2.4Hz,1H),6.95(d,J＝8.4Hz,1H),6.53(dd,J＝16.8,10.2Hz,1H),5.33(d,J＝10.2Hz,1H),5.15(d,J＝9.0Hz,1H),5.13(s,1H),4.85(d,J＝8.4Hz,1H),3.95(s,3H),3.86(s,3H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.2,156.5,148.8,148.7,147.4,140.1,140.0,134.3,134.2,132.1,128.5,127.8,127.2,127.0,126.7,125.6,122.6,118.6,118.3,118.2,110.83,110.78,107.2,87.2,75.4,56.00,55.96.
实施例26
4'-(2-萘基)-4'-乙烯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮(合成底物时使用2-萘苯乙酮)
黄色固体，产率99％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.55(d,J＝8.4Hz,1H),8.42(dd,J＝8.4,1.8Hz,1H),8.09(s,1H),7.98–7.89(m,3H),7.86(d,J＝8.4Hz,1H),7.80(t,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,1H),7.59–7.53(m,3H),7.50(t,J＝8.4Hz,1H),7.17(t,J＝7.8Hz,1H),7.06(d,J＝7.2Hz,1H),6.65(dd,J＝17.4,10.2Hz,1H),5.37(d,J＝10.2Hz,1H),5.28(d,J＝8.4Hz,1H),5.14(d,J＝17.4Hz,1H),5.01(d,J＝7.8Hz,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):159.3,156.6,147.4,140.1,140.0,139.0,134.3,133.0,132.1,128.5,128.3,128.1,127.8,127.7,127.0,126.8,126.5,126.4,125.6,125.3,125.1,122.7,118.7,117.2,107.4,87.5,75.4.
实施例27
实施例4的双羟基化：
将实施例4(0.1mmol)、K2OsO4(1mol％)和NMO(0.13mmol)加入反应封管，在氩气保护下加入乙腈-水(4:1)做溶剂，在60℃下反应12h，使用薄层色谱监测反应，待反应完成后，将反应液旋干，使用柱层析纯化，使用石油醚：乙酸乙酯＝1：1分离得到产物。
8-溴-4'-(1,2-二羟基乙基)-4'-苯基-12H-螺[吲哚[2,1-b]喹唑啉-6,2'-[1,3]二氧戊环]-12-酮
淡黄色固体，产率92％
1H NMR(600MHz,CDCl3,40℃)δ(ppm):8.33(d,J＝9.0Hz,1H),8.28(d,J＝7.2Hz,1H),7.94(t,J＝7.8Hz,1H),7.82–7.77(m,2H),7.67(t,J＝7.8Hz,1H),7.58(d,J＝8.4Hz,2H),7.48–7.41(m,3H),6.88(s,1H),5.39(s,1H),5.15(d,J＝9.0Hz,1H),4.88(d,J＝9.0Hz,1H),4.46(t,J＝5.4Hz,1H),4.31–4.27(m,1H),3.52–3.46(m,1H),2.83–2.77(m,1H).
13C NMR(151MHz,CDCl3,40℃)δ(ppm):158.8,156.3,147.0,140.8,138.9,135.6,135.5,130.2,128.9,128.6,128.5,128.4,128.2,127.3,127.2,122.6,119.3,106.1,88.9,76.7,74.4,62.8.
以下通过试验例来具体说明本发明的有益效果。
吲哚并喹唑啉酮螺1,3-二氧戊环衍生物抑菌活性测试
1.实验目的：
采用琼脂平皿二倍稀释法，测定受试化合物27对近2-3年成都地区医院收集的临床分离致病菌(包括耐甲氧西林金黄色葡萄球菌(MRSA)、甲氧西林敏感金黄色葡萄球菌(MSSA)、耐甲氧西林表皮葡萄球菌(MRSE)、甲氧西林敏感表皮葡萄球菌(MSSE)革兰阳性菌以及肺炎克雷伯(ESBLs+)、肺炎克雷伯(ESBLs-)、大肠埃希菌(ESBLs+)、大肠埃希菌(ESBLs-)等革兰阴性菌各4株左右，共计36株左右)的MIC值。
2.实验依据：
采取美国国家临床实验室标准化委员会(Clinical and Laboratory StandardsInstitute CLSI)推荐的琼脂二倍稀释法，进行最低抑菌浓度(MIC)的测定。
3.实验方法：
于无菌平皿内加入1ml供试药液，再加入融化的50℃MHA培养基14ml，混匀，使其每皿内所含药物终浓度依次为128、64、32、16、8、4、2、1、0.5、μg/ml；待冷却后用多点接种仪接种细菌，接种菌量约为104CFU/ml，盖上皿盖，放在培养箱中，36±1℃，孵育20-24h。培养结束后，进行肉眼观察，平皿内未见细菌生长的最低样品浓度即为其最低抑菌浓度(MIC)。同时设立不加任何样品的空白菌对照。
4.实验结果：
通过观察图片，化合物27对耐甲氧西林金黄色葡萄球菌(MRSA)MIC值为16ug/ml；对敏感金黄色葡萄球菌(MSSA)MIC值为32ug/ml；对耐甲氧西林表面葡萄球菌(MMRSE)MIC值为2ug/ml；对敏感表面葡萄球菌(MSSE)MIC值为8ug/ml。对上述细菌显示活性。
本发明制得的化合物能够有效抑制金黄色葡萄球菌及表面葡萄球菌，具有良好的抗菌活性。

Claims (5)

1.一种吲哚并喹唑啉酮螺1，3-二氧戊环化合物或其药学上可接受的盐，其特征在于：所述化合物的结构式为：
2.根据权利要求1所述的一种吲哚并喹唑啉酮螺1，3-二氧戊环化合物的制备方法，其特征在于：包括以下步骤：将1.0eq的底物1和5mol％的Pd(PPh3)4加入反应封管中，在氩气保护下加入碳酸酯2和干燥的二氯甲烷，碳酸酯2的用量是底物1的1.5倍用量，混合物在常温下反应8小时，反应完成后浓缩纯化得到目标产物3；
制备化合物的路线如下所示：
其中R1-R7为权利要求1所述的一种吲哚并喹唑啉酮螺1，3-二氧戊环化合物中相应的基团。
3.根据权利要求2所述的一种吲哚并喹唑啉酮螺1，3-二氧戊环化合物的制备方法，其特征在于：还包括以下步骤：
步骤一：将1.0eq的苯乙酮4、2.0eq的三氟醋酸碘苯投入500ml的干燥圆底烧瓶中，另外量取50mL：10mL的乙腈-水溶液的加入作为溶剂，再加入三氟醋酸，放入干净的搅拌子，将烧瓶置于油浴锅内，在80℃下回流反应2h，TLC检测反应完毕后，蒸除乙腈，再将反应液用二氯甲烷萃取，收集有机层，干燥浓缩，柱层析分离纯化，得到羟基苯乙酮类化合物；
步骤二：称取1eq的上述羟基苯乙酮类化合物于圆底烧瓶中，氩气保护下，以THF为反应溶剂，在冰浴条件下缓慢滴加2.5eq的烯基格氏试剂，滴加完毕后，室温反应3h，TLC检测反应完成，反应液用饱和氯化铵溶液淬灭，乙酸乙酯萃取，收集有机层，干燥浓缩，柱层析分离纯化，得到烯基二醇类化合物5；
步骤三：准确称量1.0eq的烯基二醇类化合物5，0.5eq的三光气于圆底烧瓶中，在氩气保护下，以DCM为反应溶剂，冰浴条件下缓慢滴加4.0eq的吡啶，滴加完毕后，室温反应2h，TLC检测反应完成，反应液用饱和氯化铵溶液淬灭，乙酸乙酯萃取，收集有机层，干燥浓缩，柱层析分离纯化，得到烯基环状碳酸酯类底物6，
反应路线如下所示：
其中R为氢。
4.根据权利要求1所述的一种吲哚并喹唑啉酮螺1，3-二氧戊环化合物的双羟基化的制备方法，其特征在于：将0.1mmol的8-溴-4′-苯基-4′-乙烯基-12H-螺[吲哚[2，1-b]喹唑啉-6,2′-[1，3]二氧戊环]-12-酮、1mol％的K2OsO4和0.13mmol的NMO加入反应封管，在氩气保护下加入4∶1的乙腈-水做溶剂，在60℃下反应12h，使用薄层色谱监测反应，待反应完成后，将反应液旋干，使用柱层析纯化，使用石油醚∶乙酸乙酯＝1∶1分离得到产物，
5.根据权利要求1所述的一种吲哚并喹唑啉酮螺1，3-二氧戊环化合物或其药学上可接受的盐在制备抗菌药物中的用途。
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