螺吲唑氧化吲哚及其制备方法与流程

本发明涉及一种有机化合物及其制备方法，确切讲本发明涉及一种螺吲唑氧化吲哚(spiro[indazole-3,3'-indolin]-2'-one)及其制备方法。

背景技术：

螺氧化吲哚结构单元广泛存在于天然产物和合成的生物活性分子中，具有广谱的生物活性，受到化学家和药物学家的广泛关注。例如：文献1列举的代表性文献综述了螺氧化吲哚类天然产物和活性化合物的制备方法，并总结了螺环氧化吲哚类化合物的结构特征。作为一个例证，文献2例举了NITD609抗疟等活性的报道。

技术实现要素：

本发明提供一种可能是很好的药物先导分子化合物，同时提供这种化合物的制备方法。

本发明所述的化合物是如式1中Ⅰ所示的化合物—螺吲唑氧化吲哚(spiro[indazole-3,3'-indolin]-2'-one)，

其中：R¹为在氧化吲哚的5、6或者7位的取代基，且：当R¹为在氧化吲哚的5位时可以是硝基或氟或氯或溴或甲基或甲氧基的任一种，当R¹为在氧化吲哚的6位或7位时是溴；R²为5,6-二氟或5,6-二甲基或5,6-环戊基或5,6-二氧环戊基或7-甲氧基的任一种；R³为任一种供电子基团。作为本发明优选的化合物，其中R³为甲基或芐基。

本发明的螺吲唑氧化吲哚(化合物Ⅰ)的制备方法如式2所示，

即将通式Ⅱ所示化合物、Ⅲ所示化合物溶于溶有氟试剂的有机溶剂中，反应物Ⅱ消失完，将反应混合物在减压下除去溶剂，柱层析洗脱得到目标化合物，反应物Ⅱ中：R¹为在吲哚的5、6或者7位的取代基，且：当R¹为在氧化吲哚的5位时可以是硝基或氟或氯或溴或甲基或甲氧基的任一种，当R¹为在氧化吲哚的6位或7位时是溴；R²为5,6-二氟或5,6-二甲基或5,6-环戊基或5,6-二氧环戊基或7-甲氧基的任一种；R³为任一种供电子基团。

本发明优选的螺吲唑氧化吲哚的制备方法是，使用TBAT作为氟试剂，以甲苯或四氢呋喃作为溶剂。

本发明所述的螺吲唑氧化吲哚的制备方法，也可使用氟化铯或氟化钾作为氟试剂时，以乙腈或者四氢呋喃为溶剂。

进一步，本发明优选的制备方法是：反应时化合物Ⅱ、化合物Ⅲ与氟试剂的摩尔比为Ⅱ：Ⅲ：氟试剂＝1:1.2:2，所用的溶液浓度为0.1M。

更进一步，本发明优选的制备方法在硅胶柱层析时，所用的洗脱液为石油醚与乙酸乙酯的混合溶剂，且体积比V_石油醚:V_乙酸乙酯＝25:1～10:1。

文献5中综述了吲唑结构单元在药物分子中的作用。文献4中强调了“杂化”概念，也就是把两种生物活性分子以某种方式连接，可能比原来两个分子各自的活性更优，从而得到新的药物先导分子。通过已公开的文献4可知，本发明公开的化合物，杂化了两类生物活性分子单元(氧化吲哚和吲唑)，例如本合成加和了氧化吲哚骨架和吲唑骨架，并且两个骨架以特殊的螺环方式相连接，这类首次合成得到的化合物很可能是一种很好的药物先导分子，具有潜在的药用价值。

现有文献报道的化合物制备方法主要集中在氧化吲哚螺稠和环烷烃，咪唑等其它杂环，螺稠和吲唑氧化吲哚还没有报道，对于螺吲唑氧化吲哚结构，虽然文献3中有尝试，但是没有成功。本发明涉及的方法可以很容易制备出螺吲唑氧化吲哚化合物，原料易得，操作简单，没有用到金属试剂，产率普遍较高，且在制备过程中无需惰性气体保护，反应条件温和，可在室温(25℃)顺利进行反应。

附图说明

附图1至附图30分别为本发明实施例所得到的产物Ⅰ-1至Ⅰ-15的核磁谱图。

具体实施方式

本发明以下结合具体实施例进行解说。

本发明的制备方法是将化合物Ⅱ、化合物Ⅲ和氟试剂溶于有机溶剂中进行反应，反应完成后除去溶剂，然后用柱层析得到目标化合物。本发明的实验表明，当所用的氟试剂为氟化铯或氟化钾时，溶剂为乙腈或者四氢呋喃时，其产率稍低，约为72％-91％，而当所用的氟试剂为TBAT，溶剂为甲苯时，反应产物的收率也比较低，约为81％。实验表明本发明优选的氟试剂为TBAT(四正丁基铵二氟代三苯基硅酸盐),优选的溶液为四氢呋喃，其反应产物的收率为99％，最好的原料摩尔比为化合物Ⅱ：化合物Ⅲ：氟试剂＝1:1.2:2，溶液的最优浓度为0.1M。以下是本发明的一个制备化合物最佳实施例。在以下所有实施例中，核磁谱检测通过Varian 300,Bruker 400,JEOL 400and Varian 600MHz仪器在CDCl₃或(CD₃)₂CO中获得。δ值为内标相对值(氯仿定标δ7.26¹H NMR和77.26¹³C NMR；丙酮定标δ2.05¹H NMR和29.84¹³C NMR)。高分辨质谱(HRMS)通过4G quadrupole time-of-flight(QTof)质谱仪器得到。

实施例1

实施例1的反应式，具体使用的化合物Ⅱ-1和化合物Ⅲ-1以及产物Ⅰ-1结构见式3

其具体的做法是：将125mg,0.500mmol化合物Ⅱ-1、180mg,0.600mmol的化合物Ⅲ-1溶于5mL的四氢呋喃中，加入540mg,1.00mm,2.0当量的TBAT(四正丁基铵二氟代三苯基硅酸盐)，于25℃反应。薄层色谱监测反应物Ⅱ-1消失完，将反应混合物在水泵减压下旋转蒸发除去溶剂四氢呋喃。残留物以200-300目硅胶，洗脱液(体积比V_石油醚:V_乙酸乙酯＝25:1～10:1)柱层析得到Ⅰ-1所示化合物，其产物经过核磁(氢谱、碳谱)、高分辨质谱鉴定，并且Ⅰ-1由单晶进一步确定其结构。

产物Ⅰ-1为黄色固体；熔点：127-128℃。¹H NMR(300MHz,CDCl₃)δ8.28(d,J＝7.8Hz,1H),7.66(td,J＝7.6,0.9Hz,1H),7.54(td,J＝7.5,0.9Hz,1H),7.48-7.28(m,7H),7.02-6.94(m,2H),6.58(dt,J＝7.5,0.6Hz,1H),6.08(s,2H)；¹³C NMR(100MHz,CDCl₃)δ167.1,160.5,143.7,137.6,134.8,131.4,130.8,130.6,129.3,129.2,128.3,127.4,124.8,123.5,122.8,122.5,111.4,99.2,45.2；ESI-HRMS m/z Calcd.for C₂₁H₁₆N₃O[M+H]⁺:326.1288,found 326.1287.单晶结构存于剑桥晶体数据库，单晶存储号：CCDC 1527592

制备本发明的其它化合物(化合物Ⅰ-2至化合物Ⅰ-15)的实施例所用的方法与实施例1相同，反应条件如下：化合物Ⅱ0.500mmol、化合物Ⅲ1.2当量溶于5mL的四氢呋喃中，加入TBAT量为540mg,1.00mm,2.0当量，室温25℃反应。反应物的具体结构及产率参见下表。

所得各产物的核磁谱见附图3至附图30，各产物数据表征如下：

Ⅰ-2(123mg,Y＝98％,Rf＝0.28(PE:EA＝2:1))为黄色固体；熔点：177-178℃.¹H NMR(300MHz,CDCl₃)δ8.22(d,J＝7.8Hz,1H),7.61(td,J＝7.5,1.2Hz,1H),7.51-7.41(m,2H),7.34(d,J＝7.5Hz,1H),7.06-6.98(m,2H),6.54(d,J＝7.5Hz,1H),3.36(s,3H)；¹³C NMR(75MHz,CDCl₃)δ167.2,160.3,146.1,138.1,131.0,131.0,130.2,124.3,123.6,122.8,122.1,121.7,109.4,99.6,27.5；ESI-HRMS m/z Calcd.for C₁₅H₁₂N₃O[M+H]⁺:250.0975,found 250.0974.。

Ⅰ-3(160mg,Y＝86％,Rf＝0.20(PE:EA＝2:1))为黄色固体；熔点：106-107℃.¹H NMR(300MHz,CDCl₃)δ8.27-8.20(m,2H),7.69-7.64(t,J＝7.6Hz,1H),7.57-7.52(t,J＝7.5Hz,1H),7.44(d,J＝2.1Hz,1H),7.38-7.30(m,6H),7.02(d,J＝8.7Hz,1H),5.12(d,J＝15.8Hz,1H),5.05(d,J＝15.8Hz,1H)；¹³C NMR(75MHz,CDCl₃)δ167.5,160.6,150.5,144.0,136.6,134.0,131.6,130.9,129.3,128.5,127.6,127.3,122.7,122.6,120.1,110.1,98.4.45.2,(1C missing)；ESI-HRMS m/z Calcd.for C₂₁H₁₅N₄O₃[M+H]⁺:371.1139,found 371.1140.。

Ⅰ-4(155mg,Y＝90％,Rf＝0.41(PE:EA＝5:1))为灰色固体；熔点：123-124℃.¹H NMR(400MHz,(CD₃)₂CO)δ8.30(d,J＝7.6Hz,1H),7.74(td,J＝7.6,1.2Hz,1H),7.63(td,J＝7.6,1.2Hz,1H),7.55(d,J＝7.6Hz,1H),7.48(d,J＝7.6Hz,2H),7.42-7.39(m,2H),7.32(t,J＝7.4Hz,1H),7.19-7.16(m,2H),6.61-6.58(m,1H),5.17(d,J＝15.8Hz,1H),5.08(d,J＝15.8Hz,1H)；¹³C NMR(100MHz,(CD₃)₂CO)δ167.6,161.2,160.1(d,J＝239.3Hz),142.2,138.7,136.5,132.0,131.2,129.7,128.6,128.1,124.3(d,J＝8.9Hz),123.6,122.5,117.7(d,J＝23.3Hz),112.9(d,J＝25.4Hz),112.1(d,J＝8.2Hz),110.2,45.0；ESI-HRMS m/z Calcd.for C₂₁H₁₅FN₃O[M+H]⁺:344.1194,found 344.1193.。

Ⅰ-5(178mg,Y＝99％,Rf＝0.38(PE:EA＝5:1))为黄色固体；熔点：149-150℃.¹H NMR(400MHz,(CD₃)₂CO)δ8.31(d,J＝7.6Hz,1H),7.76(t,J＝7.6Hz,1H),7.65(t,J＝7.2Hz,1H),7.57(d,J＝7.6Hz,1H),7.49-7.31(m,6H),7.20(d,J＝8.4Hz,1H),6.76(d,J＝2.0Hz,1H),5.18(d,J＝16.0Hz,1H),5.09(d,J＝16.0Hz,1H)；¹³C NMR(100MHz,(CD₃)₂CO)δ167.6,161.3,145.0,138.6,136.4,132.1,131.4,131.3,129.8,129.0,128.7,128.1,125.2,124.6,123.7,122.6,112.5,100.0,45.1；ESI-HRMS m/z Calcd.for C₂₁H₁₅ClN₃O[M+H]⁺:360.0898,found 360.0900.。

Ⅰ-6(199mg,Y＝98％,Rf＝0.48(PE:EA＝5:1))为黄色固体；熔点：178-179℃.¹H NMR(400MHz,(CD₃)₂CO)δ8.31(d,J＝8.0Hz,1H),7.76(td,J＝7.6,1.2Hz,1H),7.65(td,J＝7.2,0.8Hz,1H),7.60-7.57(m,2H),7.48-7.39(m,4H),7.35-7.31(m,1H),7.15(d,J＝8.4Hz,1H),6.88(d,J＝2.0Hz,1H),5.18(d,J＝15.8Hz,1H).5.09(d,J＝15.8Hz,1H)；¹³C NMR(100MHz,(CD₃)₂CO)δ167.5,161.3,145.4,138.6,136.4,134.3,132.1,131.3,129.8,128.7,128.1,127.9,124.9,123.7,122.6,116.1,113.0,99.9,45.1；ESI-HRMS m/z Calcd.for C₂₁H₁₅BrN₃O[M+H]⁺:404.0393,found404.0393.。

Ⅰ-7(176mg,Y＝87％,Rf＝0.31(PE:EA＝5:1))为灰色固体；熔点：75-76℃.¹H NMR(300MHz,(CD₃)₂CO)δ8.30(d,J＝7.8Hz,1H),7.33(t,J＝7.5Hz,1H),7.64-7.55(m,2H),7.51-7.30(m,6H),7.20(dd,J＝8.1,1.5Hz,1H),6.60(d,J＝8.1Hz,1H),5.20(d,J＝15.9Hz,1H),5.11(d,J＝15.9Hz,1H)；¹³C NMR(75MHz,(CD₃)₂CO)δ167.8,161.1,147.5,138.6,136.2,132.0,131.2,129.7,128.6,128.0,127.0,126.4,124.7,123.6,122.5,121.8,114.3,99.8,44.9；ESI-HRMS m/z Calcd.for C₂₁H₁₅BrN₃O[M+H]⁺:404.0393,found404.0392.。

Ⅰ-8(193mg,Y＝95％,Rf＝0.46(PE:EA＝5:1))为黄色固体；熔点：66-67℃.¹H NMR(300MHz,(CD₃)₂CO)δ8.30(d,J＝7.5Hz,1H),7.76-7.71(m,1H),7.65-7.62(m,2H),7.57(d,J＝8.1Hz,1H),7.40-7.36(m,4H),7.31-7.29(m,1H),6.96(t,J＝7.8Hz,1H),6.60(d,J＝7.2Hz,1H),5.54(s,2H)；¹³C NMR(75MHz,(CD₃)₂CO)δ168.6,161.2,143.4,138.7,137.8,137.2,132.1,131.2,129.5,128.0,126.9,125.7,125.6,124.3,123.7,122.5,103.5,99.8,46.2；ESI-HRMS m/z Calcd.for C₂₁H₁₅BrN₃O[M+H]⁺:404.0393,found404.0392.。

Ⅰ-9(154mg,Y＝91％,Rf＝0.30(PE:EA＝5:1))为白色固体；熔点：158-159℃.¹H NMR(400MHz,CDCl₃)δ8.29(d,J＝7.6Hz,1H),7.67(t,J＝8.0Hz,1H),7.56(t,J＝7.4Hz,1H),7.43-7.29(m,6H),7.15(d,J＝8.0Hz,1H),6.88(d,J＝8.0Hz,1H),6.43(s,1H),5.08(s,2H),2.22(s,3H)；¹³C NMR(100MHz,CDCl₃)δ167.3,160.2,142.7,138.4,135.3,133.4,131.0,130.1,129.0,128.0,127.4,125.0,122.6,122.0,121.7,110.1,99.8,44.9,20.9,(1C missing)；ESI-HRMS m/z Calcd.for C₂₂H₁₈N₃O[M+H]⁺:340.1444,found 340.1445.。

Ⅰ-10(149mg,Y＝84％,Rf＝0.20(PE:EA＝5:1))为红色固体；熔点：157-158℃.¹H NMR(400MHz,CDCl₃)δ8.15(d,J＝7.6Hz,1H),7.55(t,J＝7.2Hz,1H),7.42(t,J＝7.6Hz,1H),7.31-7.20(m,6H),6.72(br s,2H),6.04(s,1H),4.92(s,2H),3.50(s,3H)；¹³C NMR(100MHz,CDCl₃)δ167.1,160.2,156.6,138.4,138.2,135.2,131.2,130.3,129.1,128.1,127.4,122.8,122.7,122.2,115.6,111.1,111.0,99.8,55.9,45.0；ESI-HRMS m/z Calcd.for C₂₂H₁₈N₃O₂[M+H]⁺:356.1394,found 356.1394.。

Ⅰ-11(145mg,Y＝80％,Rf＝0.38(PE:Acetone＝10:1))为白色固体；熔点：147-148℃.¹H NMR(400MHz,(CD₃)₂CO)δ8.35(dd,J＝9.2,0.8Hz,1H),7.65(dd,J＝8.8,6.8Hz,1H),7.50-7.48(m,2H),7.44-7.38(m,3H),7.34-7.30(m,1H),7.18(d,J＝7.6Hz,1H),7.04(td,J＝7.2,0.8Hz,1H),6.74(dd,J＝7.6,0.8Hz,1H),5.19(d,J＝15.8Hz,1H),5.05(d,J＝15.8Hz,1H)；¹³C NMR(100MHz,(CD₃)₂CO)δ167.0,156.7(dd,J＝7.4,2.0Hz),154.1(dd,J＝97.7,14.7Hz),151.6(dd,J＝94.0,14.8Hz),146.2,136.6,135.8(dd,J＝8.3,2.8Hz),131.9,129.7,128.6,128.1,125.1,124.4,121.7,112.9(d,J＝21.6Hz),111.5(d,J＝19.8Hz),111.4,101.2(d,J＝1.4Hz),45.1；ESI-HRMS m/z Calcd.for C₂₁H₁₄F₂N₃O[M+H]⁺:362.1099,found362.1098.。

Ⅰ-12(167mg,Y＝94％,Rf＝0.25(PE:EA＝5:1))为黄色固体；熔点：163-164℃.¹H NMR(300MHz,(CD₃)₂CO)δ8.05(s,1H),7.50-7.47(m,2H),7.43-7.32(m,4H),7.25(s,1H),7.16(d,J＝7.8Hz,1H),7.01(t,J＝7.5Hz,1H),6.60(d,J＝7.5Hz,1H),5.16(d,J＝15.8Hz,1H),5.08(d,J＝15.8Hz,1H),2.45(s,3H),2.34(s,3H)；¹³C NMR(100MHz,(CD₃)₂CO)δ168.3,160.3,146.1,141.6,140.0,137.2,136.9,131.4,129.7,128.6,128.1,124.8,124.2,124.1,123.2,122.8,111.1,99.8,44.9,20.2,20.2；ESI-HRMS m/z Calcd.for C₂₃H₂₀N₃O[M+H]⁺:354.1601,found 354.1601.。

Ⅰ-13(161mg,Y＝88％,Rf＝0.22(PE:EA＝5:1))为白色固体；熔点：182-183℃.¹H NMR(400MHz,(CD₃)₂CO)δ8.06(s,1H),7.48(d,J＝7.2Hz,2H),7.42-7.30(m,4H),7.26(s,1H),7.15(d,J＝8.0Hz,1H),7.01(t,J＝7.6Hz,1H),6.61(d,J＝7.6Hz,1H),5.15(d,J＝16.0Hz,1H),5.09(d,J＝16.0Hz,1H),3.07(t,J＝7.4Hz,2H),2.97-2.93(m,2H),2.21-2.14(m,2H)；¹³C NMR(100MHz,(CD₃)₂CO)δ168.4,161.0,149.5,147.9,146.2,138.4,136.9,131.4,129.7,128.6,128.2,124.8,124.2,123.4,119.2,118.0,111.2,99.3,44.9,33.2,33.1,26.7；ESI-HRMS m/z Calcd.for C₂₄H₂₀N₃O[M+H]⁺:366.1601,found 366.1600.。

Ⅰ-14(167mg,Y＝90％,Rf＝0.34(PE:EA＝5:1))为白色固体；熔点：200-201℃.¹H NMR(400MHz,CDCl₃)δ7.61(s,1H),7.37-7.27(m,6H),6.96(t,J＝7.4Hz,1H),6.90(d,J＝7.6Hz,1H),6.72(s,1H),6.59(d,J＝7.6Hz,1H),6.09(d,J＝8.8Hz,2H),5.02(s,2H)；¹³C NMR(100MHz,CDCl₃)δ167.5,155.4,151.5,149.9,145.1,135.2,133.9,130.8,129.2,128.1,127.4,124.4,123.7,121.8,110.4,103.1,102.8,102.4,98.7,45.0；ESI-HRMS m/z Calcd.for C₂₂H₁₆N₃O[M+H]⁺:370.1186,found 370.1185.。

Ⅰ-15(153mg,Y＝86％,Rf＝0.35(PE:EA＝5:1))为黄色固体；熔点：160-161℃.¹H NMR(400MHz,CDCl₃)δ7.41-7.28(m,7H),7.08(d,J＝7.6Hz,1H),6.95(t,J＝7.4Hz,1H),6.90-6.86(m,2H),6.56(d,J＝7.2Hz,1H),5.03(s,2H),4.23(s,3H)；¹³C NMR(100MHz,CDCl₃)δ167.5,153.0,148.9,145.1,141.0,135.2,133.1,130.8,129.2,128.1,127.4,124.5,123.7,122.1,114.5,114.4,110.4,99.2,57.7,44.9；ESI-HRMS m/z Calcd.for C₂₂H₁₈N₃O₂[M+H]⁺:356.1394,found 356.1394.。

本发明所公开的化合物具有氧化吲哚和吲唑两个活性分子单元，结构上以独特的螺环方式相连接，可能是很好的药物先导分子。其制备方法简单，原料易得，没有用到金属试剂，产率普遍较高，并且在制备过程中无需惰性气体保护，反应条件温和，在室温(25℃)即可顺利进行反应。

本发明得到国家自然科学基金NSFC(21472072；21302077；21290183),教育部长江学者创新团队(PCSIRT:IRT_15R28)以及中央高校基本科研业务费(lzujbky-2016-ct02)的经费资助。

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