本發(fā)明涉及雜環(huán)化合物和有機(jī)化學(xué)合成領(lǐng)域，具體涉及一種螺[3,5'-吡咯[2,1-a]異喹啉-氧化吲哚]類化合物及其制備方法。

背景技術(shù)：

運(yùn)用簡(jiǎn)單易得的原料合成結(jié)構(gòu)多樣化的含氮雜環(huán)化合物一直是有機(jī)化學(xué)界關(guān)注的焦點(diǎn)。含有吡啶并吡咯環(huán)的吲嗪骨架是構(gòu)成天然生物堿的核心結(jié)構(gòu)單元，含有這種雜環(huán)骨架的化合物往往具有良好的生物活性和潛在的藥物價(jià)值。目前，吲嗪類衍生物的獲得主要通過(guò)從天然產(chǎn)物中提取分離或人工合成的方法實(shí)現(xiàn)。其中，人工合成的方法日益重要，主要包括基于吡咯或異喹啉骨架的分子內(nèi)環(huán)化反應(yīng)、吡咯或不飽和胺的串聯(lián)環(huán)化反應(yīng)等。

然而，現(xiàn)有的人工合成技術(shù)仍存在一定的局限性，如合成的吲嗪類衍生物，除吲嗪基本骨架外，主要是一些支鏈或并環(huán)結(jié)構(gòu)，其結(jié)構(gòu)類型不夠廣泛。對(duì)于空間結(jié)構(gòu)更為復(fù)雜的吲嗪類衍生物，尤其是含螺環(huán)結(jié)構(gòu)的吲嗪類衍生物的合成，仍是一項(xiàng)挑戰(zhàn)性的工作。而且從藥物的設(shè)計(jì)與構(gòu)效關(guān)系的角度考慮，含螺環(huán)結(jié)構(gòu)的化合物由于其獨(dú)特的三維構(gòu)象，在空間上更容易與靶點(diǎn)結(jié)合，往往具有更好的藥物活性。因此，發(fā)展簡(jiǎn)便、高效的合成技術(shù)實(shí)現(xiàn)結(jié)構(gòu)新穎的螺環(huán)吲嗪類衍生物的合成具有重要意義。

技術(shù)實(shí)現(xiàn)要素：

本發(fā)明的目的在于提供一種以金屬鈀催化3-吡咯氧化吲哚和2-溴甲基芳基溴化物的親核取代/C(sp²)-H芳基化一鍋法串聯(lián)反應(yīng)，高產(chǎn)率合成一系列結(jié)構(gòu)新穎且多樣化的螺[3,5'-吡咯[2,1-a]異喹啉-氧化吲哚]類化合物的方法。

本發(fā)明的技術(shù)方案是，一種螺[3,5'-吡咯[2,1-a]異喹啉-氧化吲哚]類化合物，結(jié)構(gòu)通式為，

式中：R¹各自獨(dú)立地選自5-Me、5-OMe、5-F、5-OCF₃、5-Cl、5-Br、7-F、7-Cl、7-CF₃或7-OCF₃；

R²各自獨(dú)立地選自H、Me、Et、ⁿPr、ⁿBu、ⁱPr、allyl、Ph或Bn；

Ar各自獨(dú)立地選自苯基、甲氧基取代苯基、[1,3]二氧戊烷并苯基、氟取代苯基、三氟甲基取代苯基、氯取代苯基、萘基或噻吩基。其中，nPr、nBu、iPr分別表示：正丙基、正丁基和異丙基。

螺[3,5'-吡咯[2,1-a]異喹啉-氧化吲哚]類化合物的制備方法，包括如下步驟制備：將3-吡咯氧化吲哚、2-溴甲基芳基溴化物作為底物，將金屬鈀催化劑、膦配體和無(wú)機(jī)堿依次加入到有機(jī)溶劑中，反應(yīng)完畢后經(jīng)萃取、干燥、柱層析或者重結(jié)晶處理后得到螺[3,5'-吡咯[2,1-a]異喹啉-氧化吲哚]類化合物，合成路線如下 所示：

與現(xiàn)有技術(shù)相比，本發(fā)明具有如下有益效果：本發(fā)明以金屬鈀催化3-吡咯氧化吲哚和2-溴甲基芳基溴化物的親核取代/C(sp²)-H芳基化一鍋法串聯(lián)反應(yīng)，合成結(jié)構(gòu)新穎且多樣化的螺[3,5'-吡咯[2,1-a]異喹啉-氧化吲哚]類化合物，是對(duì)新型吲嗪類衍生物與螺環(huán)氧化吲哚類化合物合成方法的重要補(bǔ)充，對(duì)設(shè)計(jì)3-吡咯氧化吲哚參與的新的串聯(lián)反應(yīng)，用于合成其他新結(jié)構(gòu)的螺雜環(huán)化合物具有重要的啟示作用，而且該技術(shù)具有底物適用范圍廣、操作簡(jiǎn)單、產(chǎn)物較為單一，基本無(wú)副產(chǎn)物生成，易純化等優(yōu)點(diǎn)。

優(yōu)選的，所述的金屬鈀催化劑為零價(jià)鈀催化劑或二價(jià)鈀催化劑，所述零價(jià)鈀催化劑為四(三苯基膦)鈀或三(二亞芐基丙酮)二鈀，所述二價(jià)鈀催化劑為醋酸鈀、三氟乙酸鈀、特戊酸鈀或氯化鈀。選用這些金屬鈀催化劑，產(chǎn)物的產(chǎn)率較高，最高可達(dá)92％。

優(yōu)選的，所述有機(jī)溶劑為甲苯、氯苯、氟苯、三氟甲苯、均三甲苯、二甲基亞砜、特戊醇、N,N-二甲基甲酰胺、1,4-二氧六環(huán)或乙腈，最高可達(dá)92％。

優(yōu)選的，所述無(wú)機(jī)堿為碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫、特戊酸鈉、磷酸鉀、叔丁醇鈉或叔丁醇鉀。選用這些無(wú)機(jī)堿后，產(chǎn)物的產(chǎn)率較高，最高可達(dá)92％。

優(yōu)選的，所述反應(yīng)溫度為120～160℃，反應(yīng)時(shí)間為24～48h。在該反應(yīng)條件下的產(chǎn)物產(chǎn)率最高。

優(yōu)選的，所述膦配體為三苯基膦、1,4-雙二苯基膦丁烷、2,2'-雙-(二苯膦基)-1,1'-聯(lián)萘或者4,5-雙二苯基膦-9,9-二甲基氧雜蒽。

進(jìn)一步優(yōu)選的，所述處理方法為柱層析分離方法。在生成的產(chǎn)物中，部分不是固體，通過(guò)柱層析分離純化，更為實(shí)用。

附圖說(shuō)明

圖1為本發(fā)明手性化合物3a的¹H NMR譜圖；

圖2為本發(fā)明手性化合物3a的¹³C NMR譜圖；

圖3為本發(fā)明手性化合物3b的¹H NMR譜圖；

圖4為本發(fā)明手性化合物3b的¹³C NMR譜圖；

圖5為本發(fā)明手性化合物3c的¹H NMR譜圖；

圖6為本發(fā)明手性化合物3c的¹³C NMR譜圖。

具體實(shí)施方式

下面結(jié)合具體實(shí)施例對(duì)本發(fā)明作進(jìn)一步的解釋說(shuō)明，但具體實(shí)施例并不對(duì)本發(fā)明作任何限定。除非特別說(shuō)明，實(shí)施例中所涉及的試劑、方法均為本領(lǐng)域常用的試劑和方法。

本發(fā)明一種結(jié)構(gòu)新穎的螺[3,5'-吡咯[2,1-a]異喹啉-氧化吲哚]類化合物及其制備方法，合成的化合物3a～x，結(jié)構(gòu)式如下：

制備方法的具體步驟如下：

合成代表性化合物3a的操作步驟：

實(shí)施例1：

稱取3-吡咯氧化吲哚1a(59.4mg,0.3mmol)、2-溴芐溴2a(90.0mg,0.36mmol)、Na₂CO₃(0.75mmol,79.5mg)、Pd(TFA)₂(10mol％,10.0mg)與PPh₃(20mol％,15.7mg)于硬質(zhì)反應(yīng)管中，然后加入2.5mL DMF，反應(yīng)液在140℃下攪拌反應(yīng)24h。TLC監(jiān)測(cè)反應(yīng)進(jìn)行完全后，向反應(yīng)液中加入10.0mL水，并用乙酸乙酯萃取(6×6mL)。合并所得的有機(jī)相用飽和的食鹽水洗滌、無(wú)水硫酸鈉干燥、過(guò)濾和濃縮。最后所得的殘留物經(jīng)柱層析(石油醚/乙酸乙酯＝5:1)分離純化得目標(biāo)化合物3a(yield 72％)。

實(shí)施例2：

稱取3-吡咯氧化吲哚1a(39.6mg,0.2mmol)、2-溴芐溴2a(50.0mg,0.2mmol)、Na₂CO₃(0.5mmol,53.0mg)、Pd₂(dba)₃(10mol％,18.3mg)與PPh₃(20mol％,10.5mg)于硬質(zhì)反應(yīng)管中，然后加入2.0mL DMF，反應(yīng)液在140℃下攪拌反應(yīng)10h。TLC監(jiān)測(cè)反應(yīng)進(jìn)行完全后，向反應(yīng)液中加入10.0mL水，并用乙酸乙酯萃取(6×6mL)。合并所得的有機(jī)相用飽和的食鹽水洗滌、無(wú)水硫酸鈉干燥、過(guò)濾和濃縮。最后所得的殘留物經(jīng)柱層析(石油醚/乙酸乙酯＝5:1)分離純化得目標(biāo)化合物3a(yield 53％)。

實(shí)施例3：

稱取3-吡咯氧化吲哚1a(39.6mg,0.2mmol)、2-溴芐溴2a(50.0mg,0.2mmol)、Na₂CO₃(0.5mmol,53.0mg)、Pd(TFA)₂(10mol％,6.7mg)與PPh₃(20mol％,10.5mg)于硬質(zhì)反應(yīng)管中，然后加入2.0mL DMF，反應(yīng)液在160℃下攪拌反應(yīng)10h。TLC監(jiān)測(cè)反應(yīng)進(jìn)行完全后，向反應(yīng)液中加入10.0mL水，并用乙酸乙酯萃取(6×6mL)。合并所得的有機(jī)相用飽和的食鹽水洗滌、無(wú)水硫酸鈉干燥、過(guò)濾和濃縮。最后所得的殘留物經(jīng)柱層析(石油醚/乙酸乙酯＝5:1)分離純化得目標(biāo)化合物3a(yield 48％)。

實(shí)施例4：

稱取3-吡咯氧化吲哚1a(39.6mg,0.2mmol)、2-溴芐溴2a(50.0mg,0.2mmol)、NaOPiv(0.5mmol,71.1mg)、Pd(TFA)₂(10mol％,6.7mg)與PPh₃(20mol％,10.5mg)于硬質(zhì)反應(yīng)管中，然后加入2.0mL DMF，反應(yīng)液在140℃下攪拌反應(yīng)10h。TLC監(jiān)測(cè)反應(yīng)進(jìn)行完全后，向反應(yīng)液中加入10.0mL水，并用乙酸乙酯萃取(6×6mL)。合并所得的有機(jī)相用飽和的食鹽水洗滌、無(wú)水硫酸鈉干燥、過(guò)濾和濃縮。最后所得的殘留物經(jīng)柱層析(石油醚/乙酸乙酯＝5:1)分離純化得目標(biāo)化合物3a(yield 62％)。

實(shí)施例5：

稱取3-吡咯氧化吲哚1a(39.6mg,0.2mmol)、2-溴芐溴2a(50.0mg,0.2mmol)、Na₂CO₃(0.5mmol,53.0mg)、Pd(TFA)₂(10mol％,6.7mg)與PPh₃(20mol％,10.5mg)于硬質(zhì)反應(yīng)管中，然后加入2.0mL均三甲苯，反應(yīng)液在140℃下攪拌反應(yīng)10h。TLC監(jiān)測(cè)反應(yīng)進(jìn)行完全后，向反應(yīng)液中加入10.0mL水，并用乙酸乙酯萃取(6×6mL)。合并所得的有機(jī)相用飽和的食鹽水洗滌、無(wú)水硫酸鈉干燥、過(guò)濾和濃縮。最后所得的殘留物經(jīng)柱層析(石油醚/乙酸乙酯＝5:1)分離純化得目標(biāo)化合物3a(yield 60％)。

化合物3b～x的制備：使用與實(shí)施例1制備化合物3a相同的反應(yīng)條件，可分別得到化合物3b～x。

抽取化合物3a、3b、3c進(jìn)行譜圖分析，NMR譜圖如圖1～圖6所示。

化合物3a～x的數(shù)據(jù)表征如下：

3a:Yellow solid；61.8mg,yield 72％；mp 260.5-261.5℃；¹H NMR(400MHz,CDCl₃),δ9.17(s,1H),7.68(d,J＝7.6Hz,1H),7.36-7.32(m,1H),7.23-7.19(m,1H),7.15-7.13(m,2H),6.92-6.89(m,1H),6.84-6.79(m,2H),6.72-6.71(m,1H),6.43-6.42(m,1H),6.25-6.23(m,1H),3.51(d,J＝15.6Hz,1H),3.21(d,J＝15.6Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ177.2,139.6,130.4,129.9,129.2,128.6,127.7,127.3,126.0,124.2,123.4, 122.4,119.0,111.1,110.5,105.6,63.6,39.2.HRMS(ESI)calcd.for C₁₉H₁₄N₂NaO[M+Na]⁺:309.0998；found:309.0999.

3b:Light yellow solid；61.3mg,yield68％；mp202.6-204.1℃；¹H NMR(400MHz,CDCl₃),δ8.68(s,1H),7.66(d,J＝7.7Hz,1H),7.35-7.31(m,1H),7.16-7.12(m,2H),7.02(d,J＝7.9Hz,1H),6.74(d,J＝7.9Hz,1H),6.70(d,J＝3.3Hz,1H),6.65(s,1H),6.41(s,1H),6.23(s,1H),3.48(d,J＝15.7Hz,1H),3.20(d,J＝15.7Hz,1H),2.16(s,3H)；¹³C NMR(100MHz,CDCl₃),δ177.0,137.0,133.1,130.4,130.3,130.0,129.1,128.5,127.7,127.3,126.0,124.9,122.4,119.0,110.6,110.5,105.5,63.6,39.2,21.2.HRMS(ESI)calcd.for C₂₀H₁₇N₂O[M+H]⁺:301.1335；found:301.1323.

3c:Light yellow solid；63.6mg,yield67％；mp176.2-177.2℃；¹H NMR(400MHz,CDCl₃),δ8.66(s,1H),7.66(d,J＝7.6Hz,1H),7.34-7.30(m,1H),7.13(d,J＝3.9Hz,2H),6.79-6.73(m,2H),6.70-6.69(m,1H),6.45(s,1H),6.41(s,1H),6.24(s,1H),3.60(s,3H),3.53(d,J＝15.6Hz,1H),3.18(d,J＝15.6Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ176.9,156.2,132.6,131.2,130.3,129.1,128.6,127.8,127.2,126.1,122.4,119.0,114.5,111.3,111.2,110.6,105.6,63.9,55.7,39.3.HRMS(ESI)calcd.for C₂₀H₁₇N₂O₂[M+H]⁺:317.1285；found:317.1301.

3d:Yellow solid；65.7mg,yield72％；mp254.3-255.6℃；¹H NMR(400MHz,CDCl₃),δ8.68(s,1H),7.66(d,J＝7.7Hz,1H),7.36-7.32(m,1H),7.17-7.12(m,2H),6.94-6.90(m,1H),6.81-6.78(m,1H),6.70-6.69(m,1H),6.49(d,J＝7.5Hz,1H),6.43(d,J＝3.3Hz,1H),6.24(s,1H),3.56(d,J＝15.6Hz,1H),3.13(d,J＝15.6Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ176.8,159.3(d,J＝241.3Hz,1C),135.1,131.4(d,J＝7.9Hz,1C),130.2,129.0,128.7,128.0,126.7,126.3,122.5,118.9,116.4(d,J＝23.6Hz,1C),112.3(d,J＝24.9Hz,1C),111.6(d,J＝7.9Hz,1C),110.9,105.8,63.9,39.1.HRMS(ESI)calcd.for C₁₉H₁₄FN₂O[M+H]⁺:305.1085；found:305.1074.

3e:Light yellow solid；67.4mg,yield70％；mp290.6-291.2℃；¹H NMR(400MHz,CDCl₃),δ8.66(s,1H),7.67(d,J＝7.8Hz,1H),7.36-7.33(m,1H),7.22-7.19(m,1H),7.16-7.15(m,2H),6.79-6.77(m,2H),6.70(s,1H),6.41(s,1H),6.25(s,1H),3.51(d,J＝15.7Hz,1H),3.18(d,J＝15.6Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ176.4,137.9,131.5,130.3,130.0,128.9,128.8,128.6,128.0,126.7,126.3,124.8,122.5,118.9,111.9,110.9,105.8,63.6,39.2.HRMS(ESI)calcd.for C₁₉H₁₄ClN₂O[M+H]⁺:321.0789；found:321.0777.

3f:Yellow solid；48.4mg,yield53％；mp203.4-204.6℃；¹H NMR(400MHz,CDCl₃),δ8.32(s,1H),7.66(d,J＝7.8Hz,1H),7.36-7.32(m,1H),7.17-7.13(m,2H),7.05-7.00(m,1H),6.86-6.81(m,1H),6.71-6.70(m,1H),6.55(d,J＝7.5Hz,1H),6.46-6.45(m,1H),6.26-6.24(m,1H),3.60(d,J＝15.5Hz,1H),3.15(d,J＝15.5Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ175.6,147.2(d,J＝243.9Hz,1C),132.5(d,J＝2.6Hz,1C),130.2,129.0,128.6,127.9,126.8,126.5(d,J＝12.6Hz,1C),126.1,124.2(d,J＝5.7Hz,1C),122.5,119.9(d,J＝3.6 Hz,1C),119.0,116.9(d,J＝16.9Hz,1C),110.8,105.7,63.7,39.2.HRMS(ESI)calcd.for C₁₉H₁₄FN₂O[M+H]⁺:305.1085；found:305.1090.

3g:Yellow solid；69.3mg,yield72％；mp222.6-223.4℃；¹H NMR(400MHz,CDCl₃),δ7.77(s,1H),7.66(d,J＝7.7Hz,1H),7.35-7.32(m,1H),7.23(s,1H),7.17-7.13(m,2H),6.86-6.82(m,1H),6.70(d,J＝3.2Hz,1H),6.66(d,J＝7.5Hz,1H),6.44(s,1H),6.26-6.24(m,1H),3.59(d,J＝15.5Hz,1H),3.16(d,J＝15.5Hz,1H)； ¹³C NMR(100MHz,CDCl₃),δ175.1,136.8,131.3,130.2,129.7,129.0,128.6,128.0,126.8,126.2,124.4,122.6,122.5,119.0,115.6,110.8,105.8,64.4,39.3.HRMS(ESI)calcd.for C₁₉H₁₃ClN₂NaO[M+Na]⁺:343.0609；found:343.0604.

3h:Grey solid；80.8mg,yield76％；mp232.6-233.7℃；¹H NMR(400MHz,CDCl₃),δ8.41(s,1H),7.68(d,J＝7.6Hz,1H),7.46(d,J＝7.8Hz,1H),7.37-7.34(m,1H),7.18-7.15(m,2H),6.99-6.95(m,1H),6.91(d,J＝7.4Hz,1H),6.73-6.72(m,1H),6.46(s,1H),6.27(s,1H),3.63(d,J＝15.5Hz,1H),3.15(d,J＝15.5Hz,1H)； ¹³C NMR(100MHz,CDCl₃),δ175.8,136.6,131.5,130.2,129.0,128.7,128.0,127.7,126.6,126.5,126.2,125.1,123.3,122.5,119.0,112.9(q,J＝33.1Hz,1C),110.9,105.9,62.6,39.2.HRMS(ESI)calcd.for C₂₀H₁₃F₃N₂NaO[M+Na]⁺:377.0872；found:377.0870.

3i:Yellow solid；82.2mg,yield74％；mp274.3-275.4℃；¹H NMR(400MHz,CDCl₃),δ8.12(s,1H),7.67-7.65(m,1H),7.36-7.32(m,1H),7.18-7.14(m,3H),6.92-6.88(m,1H),6.71-6.69(m,2H),6.44-6.43(m,1H),6.26-6.24(m,1H),3.60(d,J＝15.5Hz,1H),3.16(d,J＝15.5Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ175.3,132.3,132.2,131.9,130.2,129.0,128.7,128.0,126.7,126.2,124.1,122.9,122.6,122.5,119.0,110.9,105.9,63.7,39.2.HRMS(ESI)calcd.for C₂₀H₁₃F₃N₂NaO₂[M+Na]⁺:393.0821；found:393.0804.

3j:Light yellowsolid；82.9mg,yield92％；mp155.3-157.1℃；¹H NMR(400MHz,CDCl₃),δ7.67(d,J＝5.7Hz,1H),7.33-7.32(m,2H),7.13(s,2H),6.93-6.92(m,2H),6.80(d,J＝5.0Hz,1H),6.69(s,1H),6.36(s,1H),6.22(s,1H),3.55(d,J＝13.9Hz,1H),3.32(s,3H),3.12(d,J＝13.6Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.6,142.2,130.4,129.8,129.6,129.3,128.6,127.7,127.4,126.0,124.0,123.4,122.4,118.9,110.4,108.8,105.5,63.2,39.3,26.8.HRMS(ESI)calcd.for C₂₀H₁₆N₂NaO[M+Na]⁺:323.1155；found:323.1165.

3k:Yellow solid；79.2mg,yield84％；mp156.8-158.2℃；¹H NMR(400MHz,CDCl₃),δ7.65(d,J＝2.0Hz,1H),7.34-7.29(m,2H),7.12(s,2H),6.93(d,J＝7.7Hz,1H),6.90-6.86(m,1H),6.77(d,J＝7.4Hz,1H),6.68(s,1H),6.35(s,1H),6.21(s,1H),3.86(q,J＝6.7Hz,2H),3.57(d,J＝15.5Hz,1H),3.08(d,J＝15.4Hz,1H),1.35(t,J＝6.6Hz,3H)；¹³C NMR(100MHz,CDCl₃),δ174.3,141.2,130.3,129.9,129.7,129.3,128.6,127.7,127.4,126.0,124.2,123.2,122.4,118.7,110.4,108.9,105.5,63.1,39.1,35.3,12.9.HRMS(ESI)calcd.for C₂₁H₁₉N₂O[M+H]⁺:315.1492；found:315.1479.

3l:Yellow solid；77.8mg,yield79％；mp157.4-158.6℃；¹H NMR(400MHz,CDCl₃),δ7.66(d,J＝7.8Hz,1H),7.33-7.28(m,2H),7.15-7.12(m,2H),6.93-6.86(m,2H),6.76(d,J＝7.2Hz,1H),6.68(d,J＝2.2Hz,1H),6.36(s,1H),6.22-6.20(m,1H),3.80-3.75(m,2H),3.57(d,J＝15.5Hz,1H),3.08(d,J＝15.5Hz,1H),1.84-1.75(m,2H),1.01(t,J＝7.4Hz,3H)；¹³C NMR(100MHz,CDCl₃),δ174.7,141.6,130.4,129.8,129.7,129.3,128.6,127.7,127.5,126.0,124.1,123.2,122.4,118.8,110.4,109.1,105.5,63.2,42.0,39.3,20.9,11.5.HRMS(ESI)calcd.for C₂₂H₂₀N₂NaO[M+Na]⁺:351.1468；found:351.1473.

3m:Light yellow solid；61.7mg,yield63％；mp187.6-188.9℃；¹H NMR(400MHz,CDCl₃),δ7.67(d,J＝7.4Hz,1H),7.33-7.28(m,2H),7.13(s,2H),6.92-6.90(m,2H),6.84-6.80(m,1H),6.70(s,1H),6.37(s,1H),6.23(s,1H),5.97-5.87(m,1H),5.29(d,J＝13.5Hz,2H),4.43(s,2H),3.58(d,J＝15.5Hz,1H),3.13(d,J＝15.4Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.4,141.3,131.1,130.4,129.7,129.6,129.2,128.6,127.7,127.4,126.0,124.1,123.4,122.4,118.8,118.1,110.5,109.7,105.6,63.1,42.7,39.3.HRMS(ESI)calcd.for C₂₂H₁₉N₂O[M+H]⁺:327.1492；found:327.1478.

3n:Light yellow solid；84.7mg,yield75％；mp119.6-121.0℃；¹H NMR(400MHz,CDCl₃),δ7.70(d,J＝7.8Hz,1H),7.41-7.32(m,6H),7.23-7.19(m,1H),7.18-7.16(m,2H),6.90-6.87(m,1H),6.83(d,J＝7.7Hz,2H),6.74-6.73(m,1H),6.43-6.41(m,1H),6.27-6.26(m,1H),5.05(d,J＝15.6Hz,1H),4.98(d,J＝15.6Hz,1H),3.64(d,J＝15.5Hz,1H),3.19(d,J＝15.5Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.8,141.2,135.5,130.4,129.7,129.5,129.2,129.1,128.6,128.0,127.7,127.4,127.3,126.0,124.0,123.4,122.4,118.8,110.6,109.8,105.6,63.2,44.2,39.3.HRMS(ESI)calcd.for C₂₆H₂₀N₂NaO[M+Na]⁺:399.1468；found:399.1483.

3o:Light yellow solid；69.6mg,yield64％；mp210.5-211.8℃；¹H NMR(400MHz,CDCl₃),δ7.70(d,J＝7.9Hz,1H),7.59-7.55(m,2H),7.52-7.49(m,2H),7.47-7.43(m,1H),7.37-7.33(m,1H),7.26-7.23(m,1H),7.18-7.16(m,2H),6.97-6.93(m,2H),6.89(d,J＝7.4Hz,1H),6.75-6.73(m,1H),6.53-6.52(m,1H),6.29-6.27(m,1H),3.70(d,J＝15.5Hz,1H),3.29(d,J＝15.5Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.0,142.1,134.0,130.4,129.8,129.7,129.4,129.2,128.6,128.5,127.8,127.2,126.5,126.0,124.3,123.9,122.4,118.8,110.6,110.1,105.6,63.3,39.5.HRMS(ESI)calcd.for C₂₅H₁₈N₂NaO[M+Na]⁺:385.1311；found:385.1322.

3p:Yellow solid；58.5mg,yield59％；mp206.5-207.7℃；¹H NMR(400MHz,CDCl₃),δ7.60-7.57(m,1H),7.33-7.29(m,1H),6.94-6.87(m,3H),6.82(d,J＝7.9Hz,1H),6.67(s,1H),6.57-6.55(m,1H),6.31(s,1H),6.20-6.17(m,1H),3.80(d,J＝3.2Hz,3H),3.52(d,J＝15.4Hz,1H),3.30(d,J＝3.2Hz,3H),3.08(d,J＝15.5Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.7,157.9,142.2,130.5,129.8,129.6,129.0,124.0,123.8,123.5,122.5,118.0,113.9,113.4,110.2,108.7,104.0,63.1,55.4,39.4,26.8.HRMS(ESI)calcd.for C₂₁H₁₈N₂NaO₂[M+Na]⁺:353.1260；found:353.1276.

3q:Yellow solid；50.6mg,yield49％；mp206.5-207.7℃；¹H NMR(400MHz,CDCl₃),δ7.34-7.30(m,1H),7.13(s,1H),6.96-6.86(m,3H),6.59(s,1H),6.53(s,1H),6.30(s,1H),6.18(s,1H),5.98(s,1H),5.94(s,1H),3.44(d,J＝15.5Hz,1H),3.30(s,3H),3.02(d,J＝15.4Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.7,147.4,146.0,142.2,130.6,129.9,129.5,124.1,123.5,121.0,118.4,110.2,109.0,108.8,104.6,103.3,101.1,63.2,39.4,26.8.HRMS(ESI)calcd.for C₂₁H₁₇N₂O₃[M+H]⁺:345.1234；found:345.1216.

3r:Yellow solid；74.5mg,yield78％；mp198.5-199.5℃；¹H NMR(400MHz,CDCl₃),δ7.45(d,J＝7.8Hz,1H),7.37-7.33(m,1H),7.30-7.25(m,1H),7.00-6.96(m,1H),6.94-6.91(m,2H),6.89-6.84(m,1H),6.72-6.71(m,1H),6.36(s,1H),6.23-6.21(m,1H),3.45(d,J＝16.3Hz,1H),3.29(s,3H),3.27(d,J＝16.3Hz,1H)；¹H NMR(400MHz,CDCl₃),δ174.3,160.7(d,J＝243.1Hz,1C),142.4,131.3,130.1,129.7,129.2,128.6(d,J＝8.7Hz,1C),123.8(d,J＝33.5Hz,1C),119.5,118.0,117.9,114.4(d,J＝17.8Hz,1C),112.4(d,J＝21.8Hz,1C),110.6,108.9,106.7,62.4,31.6,26.8.HRMS(ESI)calcd.for C₂₀H₁₅FN₂NaO[M+Na]⁺:341.1061；found:341.1074.

3s:Light yellow solid；68.8mg,yield72％；mp266.5-267.2℃；¹H NMR(400MHz,CDCl₃),δ7.36-7.32(m,1H),7.15(d,J＝8.2Hz,1H),7.03-6.99(m,2H),6.92(d,J＝7.4Hz,1H),6.83-6.78(m,2H),6.66-6.62(m,1H),6.22(s,2H),3.87(d,J＝14.0Hz,1H),3.64(d,J＝14.0Hz,1H),3.17(s,3H)；¹³C NMR(100MHz,CDCl₃),δ174.4,162.6(d,J＝242.3Hz,1C),142.3,130.9,130.2,129.9,129.7,129.2,124.0,123.5,123.1,119.5,112.7(d,J＝22.0Hz,1C),110.6,109.1(d,J＝23.4Hz,1C),108.9,106.5,63.1,38.7,26.8.HRMS(ESI)calcd.for C₂₀H₁₅FN₂NaO[M+Na]⁺:341.1061；found:341.1068.

3t:Light yellow solid；72.6mg,yield76％；mp198.5-199.6℃；¹H NMR(400MHz,CDCl₃),δ7.63-7.60(m,1H),7.36-7.32(m,1H),7.05-7.00(m,1H),6.97(d,J＝7.5Hz,1H),6.92(d,J＝8.0Hz,1H),6.87-6.84(m,2H),6.62(d,J＝3.1Hz,1H),6.32(s,1H),6.20-6.19(m,1H),3.48(d,J＝15.7Hz,1H),3.29(s,3H),3.14(d,J＝15.7Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.4,161.1(d,J＝244.0Hz,1C),142.3,130.1,129.8,129.5(d,J＝7.6Hz,1C),129.2,125.7,124.0,123.9,123.6,118.7,115.4(d,J＝22.1Hz,1C),114.8(d,J＝21.8Hz,1C),110.4,108.9,105.2,62.9,39.2,26.8.HRMS(ESI)calcd.for C₂₀H₁₆FN₂O[M+H]⁺:319.1241；found:319.1248.

3u:Yellow solid；75.3mg,yield75％；mp206.5-207.7℃；¹H NMR(400MHz,CDCl₃),δ7.58(d,J＝8.3Hz,1H),7.37-7.33(m,1H),7.30-7.27(m,1H),7.11(s,1H),6.99-6.95(m,1H),6.93(d,J＝7.8Hz,1H),6.88-6.86(m,1H),6.68-6.66(m,1H),6.35-6.34(m,1H),6.22-6.20(m,1H),3.46(d,J＝15.7Hz,1H),3.29(s,3H),3.13(d,J＝15.7Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.3,142.3,131.1,130.1,129.6,129.1,129.0,128.4,127.9,127.8,124.0,123.6,123.5,119.2,110.6,108.9,106.0,62.9,38.9,26.8.HRMS(ESI)calcd.for C₂₀H₁₆ClN₂O[M+H]⁺:335.0946；found:335.0931.

3v:Light yellow solid；91.7mg,yield 83％；mp 142.5-143.6℃；¹H NMR(400MHz,CDCl₃),δ7.73(d,J＝8.1Hz,1H),7.55(d,J＝8.2Hz,1H),7.38-7.35(m,2H),7.01-6.97(m,1H),6.94(d,J＝7.8Hz,1H),6.88(d,J＝7.5Hz,1H),6.79-6.78(m,1H),6.39(d,J＝1.4Hz,1H),6.25-6.24(m,1H),3.49(d,J＝15.8Hz,1H),3.30-3.29(m,3H),3.24(d,J＝15.9Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.1,142.5,132.4,130.3,129.3,128.9,127.7,127.6,127.3,125.4(q,J＝3.8Hz,1C),124.8(q,J＝3.8Hz,1C),124.0,123.7,122.4,120.1,111.0,109.0,107.6,62.9,39.0,26.8.HRMS(ESI)calcd.for C₂₁H₁₆F₃N₂O[M+H]⁺:369.1209；found:369.1222.

3w:Orange solid；91.5mg,yield 87％；mp 298.3-299.7℃；¹H NMR(400MHz,CDCl₃),δ8.81(d,J＝8.6Hz,1H),7.89(d,J＝8.1Hz,1H),7.67(d,J＝8.2Hz,1H),7.63-7.59(m,1H),7.55-7.51(m,1H),7.29(s,1H),7.24(s,1H),7.05(d,J＝3.7Hz,1H),6.92(d,J＝7.8Hz,1H),6.79-6.75(m,1H),6.63(d,J＝7.5Hz,1H),6.55-6.54(m,1H),6.36-6.34(m,1H),3.78(d,J＝15.5Hz,1H),3.36(s,3H),3.14(d,J＝15.6Hz,1H)；¹³C NMR(100MHz,CDCl₃),δ174.7,142.1,134.0,129.7,129.3,128.9,128.8,128.3,127.0,126.9,126.8,126.6,126.1,125.7,125.5,124.3,123.4,119.0,110.9,109.5,108.8,62.3,41.0,27.0.HRMS(ESI)calcd.for C₂₄H₁₈N₂NaO[M+Na]⁺:373.1311；found:373.1318.

3x:Light yellow solid；75.4mg,yield 82％；mp 157.7-158.5℃；¹H NMR(400MHz,CDCl₃),δ7.34-7.29(m,1H),7.11-7.09(m,1H),6.96-6.90(m,2H),6.86-6.84(m,2H),6.41-6.40(m,1H),6.32-6.31(m,1H),6.16-6.14(m,1H),3.48(d,J＝13.9Hz,1H),3.32-3.31(m,3H),3.12-3.07(m,1H)；¹³C NMR(100MHz,CDCl₃),δ174.8,141.8,129.9,129.8,127.4,127.3,127.2,123.7,123.5,121.7,118.6,110.2,110.1,108.8,105.2,64.0,35.5,26.8.HRMS(ESI)calcd.for C₁₈H₁₅N₂OS[M+H]⁺:307.0900；found:307.0905.

以上所述的僅是本發(fā)明的實(shí)施例，方案中公知的具體結(jié)構(gòu)及特性等常識(shí)在此未作過(guò)多描述。應(yīng)當(dāng)指出，對(duì)于本領(lǐng)域的技術(shù)人員來(lái)說(shuō)，在不脫離本發(fā)明結(jié)構(gòu)的前提下，還可以作出若干變形和改進(jìn)，這些也應(yīng)該視為本發(fā)明的保護(hù)范圍，這些都不會(huì)影響本發(fā)明實(shí)施的效果和專利的實(shí)用性。本申請(qǐng)要求的保護(hù)范圍應(yīng)當(dāng)以其權(quán)利要求的內(nèi)容為準(zhǔn)，說(shuō)明書中的具體實(shí)施方式等記載可以用于解釋權(quán)利要求的內(nèi)容。