本發(fā)明涉及一種有機化合物及其制備方法，確切講本發(fā)明涉及一種螺吲唑氧化吲哚(spiro[indazole-3,3'-indolin]-2'-one)及其制備方法。

背景技術：

螺氧化吲哚結構單元廣泛存在于天然產物和合成的生物活性分子中，具有廣譜的生物活性，受到化學家和藥物學家的廣泛關注。例如：文獻1列舉的代表性文獻綜述了螺氧化吲哚類天然產物和活性化合物的制備方法，并總結了螺環(huán)氧化吲哚類化合物的結構特征。作為一個例證，文獻2例舉了NITD609抗瘧等活性的報道。

技術實現(xiàn)要素：

本發(fā)明提供一種可能是很好的藥物先導分子化合物，同時提供這種化合物的制備方法。

本發(fā)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為在氧化吲哚的5、6或者7位的取代基，且：當R¹為在氧化吲哚的5位時可以是硝基或氟或氯或溴或甲基或甲氧基的任一種，當R¹為在氧化吲哚的6位或7位時是溴；R²為5,6-二氟或5,6-二甲基或5,6-環(huán)戊基或5,6-二氧環(huán)戊基或7-甲氧基的任一種；R³為任一種供電子基團。作為本發(fā)明優(yōu)選的化合物，其中R³為甲基或芐基。

本發(fā)明的螺吲唑氧化吲哚(化合物Ⅰ)的制備方法如式2所示，

即將通式Ⅱ所示化合物、Ⅲ所示化合物溶于溶有氟試劑的有機溶劑中，反應物Ⅱ消失完，將反應混合物在減壓下除去溶劑，柱層析洗脫得到目標化合物，反應物Ⅱ中：R¹為在吲哚的5、6或者7位的取代基，且：當R¹為在氧化吲哚的5位時可以是硝基或氟或氯或溴或甲基或甲氧基的任一種，當R¹為在氧化吲哚的6位或7位時是溴；R²為5,6-二氟或5,6-二甲基或5,6-環(huán)戊基或5,6-二氧環(huán)戊基或7-甲氧基的任一種；R³為任一種供電子基團。

本發(fā)明優(yōu)選的螺吲唑氧化吲哚的制備方法是，使用TBAT作為氟試劑，以甲苯或四氫呋喃作為溶劑。

本發(fā)明所述的螺吲唑氧化吲哚的制備方法，也可使用氟化銫或氟化鉀作為氟試劑時，以乙腈或者四氫呋喃為溶劑。

進一步，本發(fā)明優(yōu)選的制備方法是：反應時化合物Ⅱ、化合物Ⅲ與氟試劑的摩爾比為Ⅱ：Ⅲ：氟試劑＝1:1.2:2，所用的溶液濃度為0.1M。

更進一步，本發(fā)明優(yōu)選的制備方法在硅膠柱層析時，所用的洗脫液為石油醚與乙酸乙酯的混合溶劑，且體積比V_石油醚:V_乙酸乙酯＝25:1～10:1。

文獻5中綜述了吲唑結構單元在藥物分子中的作用。文獻4中強調了“雜化”概念，也就是把兩種生物活性分子以某種方式連接，可能比原來兩個分子各自的活性更優(yōu)，從而得到新的藥物先導分子。通過已公開的文獻4可知，本發(fā)明公開的化合物，雜化了兩類生物活性分子單元(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，并且兩個骨架以特殊的螺環(huán)方式相連接，這類首次合成得到的化合物很可能是一種很好的藥物先導分子，具有潛在的藥用價值。

現(xiàn)有文獻報道的化合物制備方法主要集中在氧化吲哚螺稠和環(huán)烷烴，咪唑等其它雜環(huán)，螺稠和吲唑氧化吲哚還沒有報道，對于螺吲唑氧化吲哚結構，雖然文獻3中有嘗試，但是沒有成功。本發(fā)明涉及的方法可以很容易制備出螺吲唑氧化吲哚化合物，原料易得，操作簡單，沒有用到金屬試劑，產率普遍較高，且在制備過程中無需惰性氣體保護，反應條件溫和，可在室溫(25℃)順利進行反應。

附圖說明

附圖1至附圖30分別為本發(fā)明實施例所得到的產物Ⅰ-1至Ⅰ-15的核磁譜圖。

具體實施方式

本發(fā)明以下結合具體實施例進行解說。

本發(fā)明的制備方法是將化合物Ⅱ、化合物Ⅲ和氟試劑溶于有機溶劑中進行反應，反應完成后除去溶劑，然后用柱層析得到目標化合物。本發(fā)明的實驗表明，當所用的氟試劑為氟化銫或氟化鉀時，溶劑為乙腈或者四氫呋喃時，其產率稍低，約為72％-91％，而當所用的氟試劑為TBAT，溶劑為甲苯時，反應產物的收率也比較低，約為81％。實驗表明本發(fā)明優(yōu)選的氟試劑為TBAT(四正丁基銨二氟代三苯基硅酸鹽),優(yōu)選的溶液為四氫呋喃，其反應產物的收率為99％，最好的原料摩爾比為化合物Ⅱ：化合物Ⅲ：氟試劑＝1:1.2:2，溶液的最優(yōu)濃度為0.1M。以下是本發(fā)明的一個制備化合物最佳實施例。在以下所有實施例中，核磁譜檢測通過Varian 300,Bruker 400,JEOL 400and Varian 600MHz儀器在CDCl₃或(CD₃)₂CO中獲得。δ值為內標相對值(氯仿定標δ7.26¹H NMR和77.26¹³C NMR；丙酮定標δ2.05¹H NMR和29.84¹³C NMR)。高分辨質譜(HRMS)通過4G quadrupole time-of-flight(QTof)質譜儀器得到。

實施例1

實施例1的反應式，具體使用的化合物Ⅱ-1和化合物Ⅲ-1以及產物Ⅰ-1結構見式3

其具體的做法是：將125mg,0.500mmol化合物Ⅱ-1、180mg,0.600mmol的化合物Ⅲ-1溶于5mL的四氫呋喃中，加入540mg,1.00mm,2.0當量的TBAT(四正丁基銨二氟代三苯基硅酸鹽)，于25℃反應。薄層色譜監(jiān)測反應物Ⅱ-1消失完，將反應混合物在水泵減壓下旋轉蒸發(fā)除去溶劑四氫呋喃。殘留物以200-300目硅膠，洗脫液(體積比V_石油醚:V_乙酸乙酯＝25:1～10:1)柱層析得到Ⅰ-1所示化合物，其產物經過核磁(氫譜、碳譜)、高分辨質譜鑒定，并且Ⅰ-1由單晶進一步確定其結構。

產物Ⅰ-1為黃色固體；熔點：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.單晶結構存于劍橋晶體數(shù)據(jù)庫，單晶存儲號：CCDC 1527592

制備本發(fā)明的其它化合物(化合物Ⅰ-2至化合物Ⅰ-15)的實施例所用的方法與實施例1相同，反應條件如下：化合物Ⅱ0.500mmol、化合物Ⅲ1.2當量溶于5mL的四氫呋喃中，加入TBAT量為540mg,1.00mm,2.0當量，室溫25℃反應。反應物的具體結構及產率參見下表。

所得各產物的核磁譜見附圖3至附圖30，各產物數(shù)據(jù)表征如下：

Ⅰ-2(123mg,Y＝98％,Rf＝0.28(PE:EA＝2:1))為黃色固體；熔點：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))為黃色固體；熔點：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))為灰色固體；熔點：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))為黃色固體；熔點：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))為黃色固體；熔點：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))為灰色固體；熔點：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))為黃色固體；熔點：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))為白色固體；熔點：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))為紅色固體；熔點：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))為白色固體；熔點：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))為黃色固體；熔點：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))為白色固體；熔點：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))為白色固體；熔點：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))為黃色固體；熔點：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.。

本發(fā)明所公開的化合物具有氧化吲哚和吲唑兩個活性分子單元，結構上以獨特的螺環(huán)方式相連接，可能是很好的藥物先導分子。其制備方法簡單，原料易得，沒有用到金屬試劑，產率普遍較高，并且在制備過程中無需惰性氣體保護，反應條件溫和，在室溫(25℃)即可順利進行反應。

本發(fā)明得到國家自然科學基金NSFC(21472072；21302077；21290183),教育部長江學者創(chuàng)新團隊(PCSIRT:IRT_15R28)以及中央高?；究蒲袠I(yè)務費(lzujbky-2016-ct02)的經費資助。

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