苯並咪唑類苦參鹼衍生物、製備方法及其應用

2024-04-16 05:48:05

1.本發明涉及製藥技術領域，特別是涉及一種苯並咪唑類苦參鹼衍生物、製備方法及其應用。


背景技術：

2.苦參鹼(matrine)是一種具有四環骨架的天然生物鹼，化學分子式為c
15h24n2o
，相對分子質量為248.58。苦參鹼的分子具有2個手性氮原子和4個手性碳原子，具有6個手性中心，手性碳的絕對構型已經確定為5s、6s、11r。苦參鹼分子由四個六元環組成，由兩個雙稠環哌啶駢合而成，屬於內醯胺結構，內醯胺結構在強鹼性條件下可以水解開環生成苦參酸或羧酸的衍生物。其有如下結構式：
[0003][0004]
苦參鹼具有廣泛的藥理作用，已有研究證實，苦參鹼可在消化系統、心腦血管等患病部位發病時發揮作用，並且在抗癌、抗炎、抗病毒中發揮效能。它可以用來治療脂多糖引起的肝損傷，還能調節免疫力，對於心腦血管，可以使血壓降低；此外，還有鎮靜、肌力、解熱、抗B肝病毒、抗纖維化、抗過敏、止瀉和止痛。對於腫瘤細胞，可抑制腫瘤細胞增殖與轉移，有抗癌作用，但可能由於其廣泛的結合點與低特異性使本身抗癌作用不夠強。
[0005]
苯並咪唑從結構來看，是一種雙環化合物，由苯和咪唑併合形成具有雜環和芳香的性質，是最早一批被發現的含氮化合物。其有如下結構式：
[0006][0007]
研究還表明，含有苯並咪唑這種骨架結構的化合物具有廣譜活性，如抗炎、抗凝血、抗腫瘤等。但是並非所有含有苯並咪唑結構的化合物均具有抗炎、抗凝血、抗腫瘤活性。


技術實現要素：

[0008]
本發明的目的在於克服現有技術的不足，提供一種苯並咪唑類苦參鹼衍生物、製備方法及其應用，所述苯並咪唑類苦參鹼衍生物具備較強抗腫瘤活性。
[0009]
為實現上述目的，本發明提供了如下方案：
[0010]
一種苯並咪唑類苦參鹼衍生物，具有如通式ⅰ、通式ⅱ或通式ⅲ所示的結構：
[0019][0020]
通式ⅲ[0021][0022]
一種所述苯並咪唑類苦參鹼衍生物的製備方法，當製備具有通式ⅰ和通式ⅱ結構的苯並咪唑類苦參鹼衍生物時，以苦參鹼為起始原料，經過苦參鹼d環醯胺鍵水解得到苦參酸鈉鹽，再與鄰苯二胺衍生物脫水得到第一中間體，再脫去氯化氫得到第二中間體，再與醯氯類衍生物脫氯化氫反應，得到具備較強的抗腫瘤活性的具有通式ⅰ結構的苯並咪唑類苦參鹼衍生物，其化學反應式為：
[0023][0024]
包括以下步驟：
[0025]
(1)將苦參鹼與氫氧化鈉和水混合，攪拌回流，反應結束後冷卻至室溫，抽濾，乾燥得到白色固體，即為苦參酸鈉鹽，無須純化直接用於下一步反應，所述苦參酸鈉鹽的結構式
如下：
[0026]
(2)取1.2～1.5g的苦參酸鈉鹽，用1n(1n＝1mol/l)鹽酸調節ph至6～7，得到苦參酸鈉鹽溶液，在4～5eq的鄰苯二胺衍生物中加入20～25ml 6n的鹽酸，加入所述苦參酸鈉鹽溶液，攪拌回流，反應結束後冷卻至室溫，濃縮得第一中間體，無需純化直接用於下一步反應；所述第一中間體的結構式如下：r3＝h、滷素、硝基或三氟甲基，r4＝h或滷素；
[0027]
(3)取1～1.2eq所述第一中間體加水溶解，用10wt％～15wt％的naoh溶液調節ph至6～7，析出固體，抽濾，乾燥，用meoh(甲醇):dcm(二氯甲烷)＝1:20(v:v)洗脫劑過柱得第二中間體，所述第二中間體的結構式如下：
[0028]
r3＝h、滷素、硝基或三氟甲基，r4＝h或滷素；
[0029]
(4)在1～1.2eq的所述第二中間體中加入2～3g碳酸鉀和20～25ml乙腈，再加入2.4～4.8eq的醯氯衍生物，過夜攪拌，tlc監測反應完全後，二氯甲烷萃取，濃縮，用ea(乙酸乙酯):pe(石油醚)＝2:1(v:v)洗脫劑過柱，得具有通式ⅰ結構的苯並咪唑類苦參鹼衍生物，當製備qg-b1～qg-b7和qg-c23、qg-c24時，步驟(4)中碳酸鉀的用量為1～1.5g，醯氯衍生物的用量為1.2～1.4eq；
[0030]
當製備具有通式ⅲ結構的苯並咪唑類苦參鹼衍生物時，以苦參鹼為起始原料，經過苦參鹼d環醯胺鍵水解得到苦參鹼鈉鹽，再與醯氯衍生物脫氯化氫得第三中間體12n取代的苦參酸，再與氨基苯並咪唑類衍生物縮合得具有通式ⅲ結構的苯並咪唑類苦參鹼衍生物，其化學反應式為：
[0031][0032]
包括以下步驟：
[0033]
(1)將苦參鹼與氫氧化鈉和水混合，攪拌回流，反應結束後冷卻至室溫，抽濾，乾燥得到白色固體，即為苦參酸鈉鹽，無須純化直接用於下一步反應，所述苦參酸鈉鹽的結構式如下：
[0034]
(2)將1～1.2eq苦參酸鈉鹽用水溶解，用1n hcl溶液調節ph至7～8，加入10ml 10wt％na2co3溶液攪拌溶解，得到混合液，接著稱取1.2eq醯氯，用等體積的1,4-二氧六環溶解，在冰浴條件下，滴加到上述的混合液中，保溫繼續攪拌4h，然後轉移至室溫攪拌8～10h，tlc監測反應，反應結束後加水(h2o)，用1n hcl溶液調節ph至6～7，用dcm萃取三次，減壓蒸
餾，濃縮，用meoh:dcm＝1:40的洗脫劑過柱得第三中間體12n取代的苦參酸，所述第三中間體的結構式如下：
[0035]
r1＝9-芴甲氧羰基。
[0036]
(3)氮氣保護下，在1～1.2eq所述第三中間體中加入1.2～1.5eq的二氯亞碸，於55～60℃下回流1h，然後減壓濃縮，用無水二氯甲烷溶解、濃縮，重複三到四次，除去殘留的二氯亞碸，然後加入1.2～1.5eq的氨基苯並咪唑衍生物，加入20ml的乙腈溶解，滴加1.2ml的三乙胺，室溫過夜攪拌，tlc監測反應，反應完成後，加水，用二氯甲烷萃取三到四次，減壓濃縮，用dcm:meoh比例為30:1～40:1(體積比)的洗脫劑過矽膠柱純化，得具有通式ⅲ結構的苯並咪唑類苦參鹼衍生物。
[0037]
優選的，在具有通式ⅰ結構的苯並咪唑類苦參鹼衍生物的製備方法中，步驟(1)中苦參鹼與氫氧化鈉和水的料液比為10～15g:25～30g:100～120ml；攪拌回流溫度為110℃～130℃，時間為10～12h。
[0038]
優選的，在具有通式ⅰ結構的苯並咪唑類苦參鹼衍生物的製備方法中，步驟(2)中攪拌回流溫度為100℃～120℃，時間為10～12h。
[0039]
優選的，在具有通式ⅰ結構的苯並咪唑類苦參鹼衍生物的製備方法中，步驟
[0040]
(4)中洗脫時用的洗脫劑為乙酸乙酯和石油醚，體積比為2:1。
[0041]
優選的，在具有通式ⅲ結構的苯並咪唑類苦參鹼衍生物的製備方法中，步驟(1)中苦參鹼與氫氧化鈉和水的料液比為10～15g:25～30g:100～120ml；攪拌回流溫度為110℃～130℃，時間為10～12h。
[0042]
優選的，在具有通式ⅲ結構的苯並咪唑類苦參鹼衍生物的製備方法中，步驟(2)中洗脫時用的洗脫劑為甲醇和二氯甲烷，體積比為1:40。
[0043]
優選的，在具有通式ⅲ結構的苯並咪唑類苦參鹼衍生物的製備方法中，步驟(3)中洗脫時用的洗脫劑為二氯甲烷和甲醇，體積比為30:1～40:1。
[0044]
所述苯並咪唑類苦參鹼衍生物在製備抗腫瘤藥物中的應用。
[0045]
所述苯並咪唑類苦參鹼衍生物在製備治療宮頸癌或肺癌藥物中的應用。
[0046]
本發明公開了以下技術效果：
[0047]
本發明苯並咪唑類苦參鹼衍生物的製備方法，原料易得、操作簡單、精簡了合成步驟、反應條件溫和、產物收率高。通過實驗表明本發明的苯並咪唑類苦參鹼衍生物對多種癌細胞增殖具有較強的抑制作用，該類化合物可使用於臨床上腫瘤的治療。
具體實施方式
[0048]
現詳細說明本發明的多種示例性實施方式，該詳細說明不應認為是對本發明的限制，而應理解為是對本發明的某些方面、特性和實施方案的更詳細的描述。
[0049]
應理解本發明中所述的術語僅僅是為描述特別的實施方式，並非用於限制本發明。另外，對於本發明中的數值範圍，應理解為還具體公開了該範圍的上限和下限之間的每個中間值。在任何陳述值或陳述範圍內的中間值以及任何其他陳述值或在所述範圍內的中間值之間的每個較小的範圍也包括在本發明內。這些較小範圍的上限和下限可獨立地包括
或排除在範圍內。
[0050]
除非另有說明，否則本文使用的所有技術和科學術語具有本發明所述領域的常規技術人員通常理解的相同含義。雖然本發明僅描述了優選的方法和材料，但是在本發明的實施或測試中也可以使用與本文所述相似或等同的任何方法和材料。本說明書中提到的所有文獻通過引用併入，用以公開和描述與所述文獻相關的方法和/或材料。在與任何併入的文獻衝突時，以本說明書的內容為準。
[0051]
在不背離本發明的範圍或精神的情況下，可對本發明說明書的具體實施方式做多種改進和變化，這對本領域技術人員而言是顯而易見的。由本發明的說明書得到的其他實施方式對技術人員而言是顯而易見得的。本發明說明書和實施例僅是示例性的。
[0052]
關於本文中所使用的「包含」、「包括」、「具有」、「含有」等等，均為開放性的用語，即意指包含但不限於。
[0053]
本發明的室溫指的是25
±
2℃。
[0054]
實施例1
[0055]
一、qg-b1的製備：
[0056][0057]
(1)取10g(10mmol)苦參鹼置於250ml燒瓶中，加入25g氫氧化鈉和100ml水，於110℃下攪拌回流12h，反應結束後冷卻至室溫，抽濾，乾燥得到白色固體，即為苦參酸鈉鹽，無須純化直接用於下一步反應。
[0058]
(2)取1.4g(5mmol)的苦參酸鈉鹽，用1n鹽酸調節ph至6～7待用。取2.2g的鄰苯二胺置於與100ml三口瓶中，加入20ml 6n的鹽酸,將製備好的苦參酸鈉鹽溶液注射進入三口瓶中，於120℃下攪拌回流12h，反應結束後冷卻至室溫，濃縮得第一間體，無需純化直接用於下一步反應。
[0059]
(3)取1.9g(5mmol)ⅲ加水溶解，用10wt％的naoh溶液調節ph6～7，析出大量固體，抽濾，乾燥。用meoh:dcm＝1:20(v:v)洗脫劑過柱得第二中間體。
[0060]
(4)取1.7g(5mmol)第二中間體置於100ml燒瓶中，加入1g碳酸鉀和20ml乙腈，取1.9g(7.5mmol)的芴甲氧羰醯氯加入燒瓶中，過夜攪拌。tlc監測反應完全後，用dcm萃取三次，濃縮。用ea:pe＝2:1(v:v)洗脫劑過柱得1.87g黃色油狀物12n-9芴甲氧羰基-15-苯並咪唑苦參丙烷(qg-b1)，收率77％。1h nmr(500mhz,chloroform-d)δ10.81(s,1h),7.76(dd,j＝7.5,5.0hz,2h),7.58(dt,j＝17.8,7.4hz,4h),7.39(q,j＝7.2hz,2h),7.33
–
7.26(m,2h),7.21(dd,j＝6.0,3.1hz,2h),4.69(dt,j＝16.2,8.1hz,2h),4.24(t,j＝5.4hz,1h),3.75(s,1h),3.45
–
3.21(m,2h),3.12
–
2.72(m,4h),2.01
–
1.94(m,1h),1.88(t,j＝11.0hz,3h),1.73
–
1.58(m,3h),1.46
–
1.27(m,9h),0.87(s,1h).；
13
c nmr(126mhz,cdcl3)δ156.35,155.12,144.13,143.91,141.52,141.45,127.65,127.07,127.04,124.66,121.72,119.96,65.97,63.82,56.92,56.86,55.78,47.64,46.81,40.15,35.55,30.13,29.71,28.19,27.37,23.67,21.09,20.81.m/z：561.74(m+1)
[0061]
參考化合物qg-b1的實驗方法製備化合物qg-b2～qg-b7,qg-c23～qg-c24,化合物qg-b2～qg-b7,qg-c23～qg-c24的結構鑑定數據如下：
[0062]
化合物qg-b2:12n-9芴甲氧羰基-15-[(6-溴)苯並咪唑]苦參丙烷，淡黃色粉末，收
率：78％，熔點107.2℃～108.4℃。1h nmr(500mhz,chloroform-d)δ10.98(s,1h),7.77(t,j＝6.8hz,2h),7.60(dd,j＝7.9,3.5hz,2h),7.54(d,j＝8.2hz,1h),7.39(q,j＝7.1hz,2h),7.31(t,j＝7.5hz,4h),4.69(d,j＝38.2hz,2h),4.26(s,1h),3.75(s,1h),3.32(s,2h),3.07(s,1h),2.91(s,1h),2.75(s,2h),1.88(s,6h),1.39(dd,j＝9.4,4.3hz,6h),1.28(s,1h)；
13
c nmr(126mhz,cdcl3)δ156.40,156.30,144.05,143.82,141.50,141.43,127.67,127.08,127.05,124.79,124.60,119.98,66.03,63.78,56.90,56.84,55.81,47.60,46.95,40.14,35.60,29.97,29.71,28.10,27.33,23.53,21.11,20.80.m/z：640.62(m+1)。
[0063]
化合物qg-b3:12n-9芴甲氧羰基-15-[(6-氯)苯並咪唑]苦參丙烷，淡黃色粉末，收率75％，熔點96.5℃～97℃。1h nmr(500mhz,chloroform-d)δ11.04(s,1h),7.79
–
7.74(m,2h),7.60(dd,j＝7.5,4.0hz,3h),7.42
–
7.36(m,2h),7.30(td,j＝7.3,1.1hz,3h),7.16(d,j＝8.2hz,1h),4.68(d,j＝33.9hz,2h),4.25(t,j＝5.5hz,1h),3.40
–
3.25(m,2h),2.98(d,j＝76.1hz,2h),2.74(s,2h),2.11(s,2h),1.42
–
1.37(m,4h)；
13
c nmr(126mhz,cdcl3)δ156.45,156.38,144.06,143.81,141.51,141.42,128.74,127.67,127.07,127.05,124.60,122.16,121.00,120.01,119.99,119.74,107.78,66.09,63.71,56.94,56.86,56.00,47.60,46.94,40.28,35.66,30.20,28.22,27.45,23.45,21.19,20.92.m/z:596.28(m+1)。
[0064]
化合物qg-b4:12n-9芴甲氧羰基-15-[(5，6-二氯)苯並咪唑]苦參丙烷,棕紅色粉末,收率65％，熔點124.5℃～125.7℃；1h nmr(500mhz,chloroform-d)δ11.16(s,1h),7.79
–
7.70(m,3h),7.60(d,j＝7.4hz,2h),7.42
–
7.36(m,3h),7.31(tdd,j＝7.4,3.4,1.0hz,2h),4.74(dd,j＝10.7,5.8hz,1h),4.65(s,1h),4.26(t,j＝5.5hz,1h),3.37
–
3.26(m,2h),2.90(s,1h),2.78
–
2.69(m,2h),2.02
–
1.87(m,5h),1.44
–
1.32(m,8h),0.87(s,1h).；
13
cnmr(126mhz,cdcl3)δ169.72,162.56,144.44,140.14,138.02,134.71,129.09,128.74,127.05,125.38,124.33,121.00,120.32,119.74,107.78,77.29,66.17,63.21,57.13,57.04,54.82,50.89,44.59,36.50,29.71,28.46,27.51,26.52,22.27,20.92,20.59..m/z:629.24(m+1)。
[0065]
化合物qg-b5:12n-9芴甲氧羰基-15-[(6-三氟甲基)苯並咪唑]苦參丙烷，棕黃色油狀物，收率75％；1h nmr(500mhz,chloroform-d)δ11.43(s,1h),8.05
–
7.69(m,4h),7.59(dd,j＝7.6,3.9hz,2h),7.49
–
7.29(m,5h),4.74(t,j＝7.8hz,1h),4.70
–
4.63(m,1h),4.25(t,j＝5.4hz,1h),3.77(s,1h),3.34(s,2h),3.11(s,1h),2.95(s,1h),2.76(s,2h),2.41(s,1h),1.95(d,j＝38.2hz,3h),1.39(q,j＝15.2,12.3hz,7h),1.26(d,j＝17.3hz,2h).；
13
c nmr(126mhz,cdcl3)δ171.73,156.44,144.04,144.01,143.79,141.50,141.43,141.33,127.69,127.17,127.09,127.07,125.20,124.58,123.98,120.04,119.98,118.69,66.03,63.97,56.86,56.83,55.87,47.62,40.10,35.65,29.71,28.05,27.90,27.13,23.36,20.98,20.64..m/z:629.31(m+1)。
[0066]
化合物qg-b6:12n-9芴甲氧羰基-15-[(4，5-二溴)苯並咪唑]苦參丙烷，黃淡色粉末，收率62％，熔點115.4℃～116.6℃；1h nmr(500mhz,chloroform-d)δ11.74(s,0h),7.73(q,j＝10.4,7.1hz,3h),7.63
–
7.51(m,3h),7.35(q,j＝7.0hz,2h),7.26(dt,j＝7.6,4.0hz,2h),4.70
–
4.51(m,2h),4.20(t,j＝5.5hz,1h),3.70(s,1h),3.46
–
3.16(m,2h),2.92(d,j＝66.3hz,2h),2.71(t,j＝7.4hz,2h),1.96
–
1.78(m,4h),1.59(s,3h),1.50
–
1.10(m,10h).；
13
c nmr(126mhz,cdcl3)δ157.48,156.42,144.01,143.36,141.51,141.40,140.15,
138.03,128.75,127.71,127.09,127.06,124.60,124.57,121.02,120.07,119.75,116.65,107.79,66.21,63.68,56.94,56.86,56.15,47.59,47.02,40.38,35.73,30.23,28.23,27.43,26.87,23.20,21.21,20.96.m/z:719.14(m+1)。
[0067]
化合物qg-b7:12n-(9芴甲氧羰基)-15-[(1-甲基-4-硝基)苯並咪唑]苦參丙烷，黑褐色粉末，收率65％，熔點78℃～78.9℃；1h nmr(500mhz,chloroform-d)δ8.59(d,j＝2.1hz,1h),8.19(dd,j＝8.9,2.1hz,1h),7.80
–
7.71(m,2h),7.58(ddd,j＝7.5,4.6,1.0hz,2h),7.38(t,j＝7.6hz,2h),7.34
–
7.25(m,3h),4.58(dd,j＝10.2,5.5hz,2h),4.19(t,j＝5.3hz,1h),3.71(s,3h),3.34(qd,j＝13.5,8.0hz,2h),2.95
–
2.52(m,4h),1.94
–
1.89(m,1h),1.84(d,j＝8.8hz,7h),1.77
–
1.06(m,6h),0.87(s,1h).；
13
c nmr(126mhz,cdcl3)δ170.10,159.25,144.16,143.42,141.78,141.50,139.96,127.57,127.55,126.99,124.67,124.61,119.92,119.89,118.01,115.70,108.67,77.29,65.79,63.71,56.89,56.82,55.40,47.62,39.94,35.42,30.20,29.71,28.32,27.57,24.01,21.13,21.01,20.96..m/z：620.33(m+1)。
[0068]
化合物qg-c23:12n-(2-萘甲醯基)-15-[(6-氟)苯並咪唑]苦參丙烷，淡黃色粉末，收率67％，熔點126.6℃～127.4℃；1h nmr(500mhz,chloroform-d)δ12.07(s,1h),7.92(s,2h),7.84(q,j＝11.4,9.1hz,3h),7.53(dt,j＝14.8,7.4hz,3h),6.89
–
6.75(m,1h),4.41(s,1h),3.43(d,j＝103.4hz,2h),2.95(d,j＝35.4hz,2h),2.80(dd,j＝32.5,11.1hz,2h),2.08
–
1.93(m,3h),1.90
–
1.70(m,6h),1.40(ddd,j＝25.3,11.9,6.2hz,4h),1.34
–
1.28(m,4h),0.89(dt,j＝9.1,5.4hz,1h).
13
c nmr(126mhz,cdcl3)δ172.73,159.99,158.11,156.47,134.63,133.63,132.69,128.42,128.34,127.85,127.06,126.76,126.30,124.16,109.73,109.53,105.91,62.75,56.65,56.54,48.10,39.95,35.46,28.54,26.98,24.67,23.57,21.85,21.08,20.83.m/z:511.28(m+1)。
[0069]
化合物qg-c24:12n-(2-萘甲醯基)-15-[(6-溴)苯並咪唑]苦參丙烷，淡黃色油狀物，收率67％；1h nmr(500mhz,chloroform-d)δ11.75(s,1h),7.93(s,1h),7.91
–
7.80(m,3h),7.76
–
7.38(m,4h),7.23(t,j＝30.3hz,3h),4.42(s,1h),3.59(s,1h),3.38(s,1h),3.00(d,j＝57.0hz,2h),2.84(dd,j＝32.8,10.9hz,2h),2.51(s,1h),2.28
–
1.96(m,3h),1.85(d,j＝53.3hz,4h),1.51
–
1.40(m,3h),1.39
–
1.25(m,4h).
13
c nmr(126mhz,cdcl3)δ172.81,156.29,134.53,133.68,132.70,128.50,128.38,127.89,127.13,126.83,126.35,124.66,124.12,122.05,114.57,62.87,56.66,56.57,53.72,39.96,35.59,31.68,29.71,29.67,28.42,24.40,21.07,20.80.m/z:573.20(m+1)。
[0070]
二、化合物qg-b8的製備：
[0071]
化合物qg-b8的製備方法如上，步驟(4)中碳酸鉀的量為2eq，醯氯的量為2.4eq，得到化合物qg-b8:12n-9芴甲氧羰基-15-[[1-(9芴甲氧羰基)]苯並咪唑]苦參丙烷。淡黃色固體，收率87％，熔點：99.7℃-99.9℃。1h nmr(500mhz,chloroform-d)δ7.82(d,j＝7.6hz,2h),7.74(d,j＝7.5hz,2h),7.65
–
7.55(m,5h),7.44(t,j＝7.5hz,2h),7.37
–
7.32(m,4h),7.28
–
7.19(m,4h),7.10
–
7.05(m,1h),5.01(d,j＝4.9hz,2h),4.53(m,2h),4.43(t,j＝4.8hz,1h),4.21(t,1h),3.66(s,1h),3.43
–
3.26(m,2h),3.01
–
2.88(m,2h),2.74
–
2.64(m,2h),1.95(s,2h),1.88(s,1h),1.85
–
1.78(m,2h),1.67
–
1.59(m,3h),1.45(m,3h),1.37(m,3h),1.30(m,3h).
13
c nmr(126mhz,cdcl3)δ156.65,150.40,144.33,144.31,143.01,
142.99,142.06,141.58,141.43,132.58,128.14,127.46,127.43,126.98,126.93,124.86,124.76,124.53,124.23,124.14,120.29,119.82,119.79,119.33,114.79,68.62,65.77,63.72,56.96,56.87,56.83,47.67,46.80,39.92,39.89,35.24,30.73,29.71,28.45,27.84,23.89,21.17.m/z:783.39(m+1)。
[0072]
參考化合物qg-b8的實驗方法製備化合物qg-b9、qg-c1～qg-c22,化合物qg-b9、qg-c1～qg-c22的結構鑑定數據如下：
[0073]
化合物qg-b9:12n-9芴甲氧羰基-15-[[1-(9芴甲氧羰基)-6-(三氟甲基)]苯並咪唑]苦參丙烷。黃色固體，收率71％，熔點：91.5℃-92.6℃。1h nmr(500mhz,chloroform-d)δ7.92(s,1h),7.85
–
7.72(m,4h),7.70(d,j＝8.3hz,1h),7.64
–
7.52(m,5h),7.42(q,j＝6.2,4.9hz,2h),7.35(m,4h),7.30
–
7.24(m,3h),5.02(d,j＝5.2hz,2h),4.55(m,2h),4.40(t,j＝5.0hz,1h),4.21(t,j＝5.4hz,1h),3.69
–
3.58(m,1h),3.34(m,2h),2.89(s,2h),2.68(t,j＝9.0hz,2h),1.87
–
1.75(m,5h),1.59(m,4h),1.47
–
1.26(m,9h).
13
c nmr(126mhz,cdcl3)δ159.20,158.47,156.07,150.02,141.59,141.44,141.40,132.42,128.27,128.19,127.55,127.48,127.42,124.81,124.72,124.36,121.44,121.00,120.47,120.36,119.86,119.70,115.06,69.10,68.75,65.83,56.97,56.85,55.75,47.65,46.78,39.95,35.36,30.88,30.71,28.42,27.79,23.67,21.19,21.05.m/z:851.38(m+1)。
[0074]
化合物qg-c1:12n-[(4-叔丁基苯磺醯基)-15-[[1-(4-叔丁基苯磺醯基)-5-氯]苯並咪唑]苦參丙烷。白色固體，收率63％，熔點：83.0℃-84.0℃。1h nmr(500mhz,chloroform-d)δ7.99(d,j＝8.8hz,1h),7.85(d,j＝8.7hz,2h),7.80
–
7.75(m,2h),7.63(d,j＝2.1hz,1h),7.53(d,j＝8.7hz,2h),7.45(d,j＝8.5hz,2h),7.32(dd,j＝8.8,2.1hz,1h),3.67
–
3.59(m,1h),3.57(dd,j＝12.4,5.4hz,1h),3.28(dd,j＝12.4,11.1hz,1h),3.20
–
3.00(m,2h),2.71
–
2.55(m,2h),2.11
–
1.91(m,7h),1.87(dt,j＝6.8,3.0hz,5h),1.72(s,1h),1.63
–
1.23(m,27h).
13
c nmr(126mhz,cdcl3)δ159.03,156.38,155.78,142.96,137.43,135.08,131.77,130.07,127.37,126.84,126.74,125.64,124.87,119.66,114.41,63.27,57.57,56.85,56.80,47.84,39.40,35.40,35.01,34.85,31.04,30.90,30.56,29.76,27.97,23.04,20.87.m/z:765.32(m+1)。
[0075]
化合物qg-c2:12n-[(4-叔丁基苯磺醯基)-15-[[1-(4-叔丁基苯磺醯基)-6-氯]苯並咪唑]苦參丙烷。黃色固體，收率77％，熔點：93.5℃-94.9℃。1h nmr(500mhz,chloroform-d)δ8.10(d,j＝1.9hz,1h),7.88(d,j＝8.7hz,2h),7.78(d,j＝8.5hz,2h),7.56(d,j＝8.7hz,3h),7.45(d,j＝8.5hz,2h),7.31(dd,j＝8.5,2.0hz,1h),3.63(ddd,j＝10.0,6.2,4.2hz,1h),3.57(dd,j＝12.4,5.4hz,1h),3.28(dd,j＝12.4,11.1hz,1h),3.20
–
2.97(m,2h),2.71
–
2.56(m,2h),2.18
–
1.81(m,10h),1.68(s,1h),1.61
–
1.33(m,8h),1.31(s,9h),1.28(s,9h),0.97
–
0.80(m,1h).
13
c nmr(126mhz,cdcl3)δ159.03,156.38,155.78,142.96,137.43,135.08,131.77,130.07,127.37,126.84,126.74,125.64,124.87,119.66,114.41,63.27,57.57,56.85,56.80,47.84,39.40,35.40,35.01,34.85,31.04,30.90,30.56,29.76,27.97,23.04,20.87.m/z:765.32(m+1)。
[0076]
化合物qg-c3:12n-[(4-氯苯磺醯基)-15-[[1-(4-氯苯磺醯基)-5-氯]苯並咪唑]苦參丙烷。淺紅色固體，收率78％,熔點：78.9℃-79.2℃。1h nmr(500mhz,chloroform-d)δ7.94(d,j＝8.7hz,1h),7.92
–
7.84(m,2h),7.83
–
7.77(m,2h),7.65(d,j＝2.0hz,1h),7.61
–
7.48(m,2h),7.43(dq,j＝9.2,2.5hz,2h),7.34(dd,j＝8.8,2.1hz,1h),3.65
–
3.56(m,1h),3.52(dd,j＝12.4,5.7hz,1h),3.24(dd,j＝12.4,11.0hz,1h),3.21
–
3.00(m,2h),2.71
–
2.52(m,2h),2.08
–
1.79(m,11h),1.70
–
1.60(m,2h),1.51
–
1.35(m,4h).
13
cnmr(126mhz,cdcl3)δ141.75,140.60,138.61,136.45,133.51,130.76,130.24,129.00,128.93,128.32,125.47,120.66,113.74,62.90,57.39,56.66,47.42,39.36,34.49,30.95,29.70,29.64,27.91,23.04,20.83,20.76.m/z:723.12(m+1)。
[0077]
化合物qg-c4:12n-[(4-氯苯磺醯基)-15-[[1-(4-氯苯磺醯基)-6-氯]苯並咪唑]苦參丙烷。黃褐色固體，收率69％,熔點：92.2℃-92.3℃。1h nmr(500mhz,chloroform-d)δ7.94(d,j＝8.8hz,1h),7.90
–
7.85(m,2h),7.83
–
7.77(m,2h),7.65(d,j＝2.0hz,1h),7.54
–
7.48(m,2h),7.46
–
7.41(m,2h),7.34(dd,j＝8.8,2.1hz,1h),3.61(dt,j＝8.8,5.4hz,1h),3.52(dd,j＝12.3,5.8hz,1h),3.24(dd,j＝12.4,10.9hz,1h),3.20
–
3.02(m,2h),2.71
–
2.50(m,2h),2.03
–
1.79(m,9h),1.51
–
1.35(m,6h).
13
c nmr(126mhz,cdcl3)δ156.05,142.97,141.71,138.61,136.48,130.49,130.19,129.00,128.94,128.26,125.20,119.91,114.26,62.92,57.42,56.66,56.63,47.44,39.37,34.49,30.94,29.71,28.07,27.90,23.09,20.85,20.75.m/z:723.12(m+1)。
[0078]
化合物qg-c5:12n-[(4-溴苯磺醯基)-15-[[1-(4-溴苯磺醯基)-5-氯]苯並咪唑]苦參丙烷。黃色固體，收率66％。熔點：78.9℃-79.9℃。1h nmr(500mhz,cdcl3)δ8.04(d,j＝2.0hz,1h),7.85
–
7.79(m,2h),7.75
–
7.67(m,4h),7.61
–
7.56(m,3h),7.34(dd,j＝8.5,2.0hz,1h),3.60(ddd,j＝9.0,6.3,4.6hz,1h),3.52(dd,j＝12.4,5.7hz,1h),3.28
–
3.19(m,1h),3.19
–
2.98(m,2h),2.69
–
2.57(m,2h),2.02
–
1.97(m,2h),1.94
–
1.79(m,6h),1.59
–
1.34(m,8h),0.93
–
0.87(m,1h).
13
c nmr(126mhz,cdcl3)δ155.31,140.60,139.17,137.01,133.52,133.23,131.92,130.79,130.38,129.10,128.30,127.05,125.50,120.68,113.76,62.93,57.45,56.68,47.49,34.55,30.89,29.71,29.64,28.07,27.91,23.04,20.83,20.77.m/z:811.02(m+1)。
[0079]
化合物qg-c6:12n-[(4-溴苯磺醯基)-15-[[1-(4-溴苯磺醯基)-6-氯]苯並咪唑]苦參丙烷。白色固體，收率75％。熔點：93.4℃-94.8℃。1h nmr(500mhz,chloroform-d)δ7.94(d,j＝8.8hz,1h),7.81
–
7.77(m,2h),7.75
–
7.70(m,2h),7.70
–
7.64(m,3h),7.60(d,j＝8.6hz,2h),7.34(dd,j＝8.8,2.1hz,1h),3.60(ddd,j＝8.9,6.1,4.5hz,1h),3.52(dd,j＝12.4,5.7hz,1h),3.24(dd,j＝12.4,11.0hz,1h),3.19
–
3.01(m,2h),2.69
–
2.56(m,2h),2.03
–
1.79(m,9h),1.70(s,2h),1.59
–
1.33(m,6h).
13
c nmr(126mhz,cdcl3)δ156.04,142.97,139.19,139.17,137.02,133.18,131.93,131.55,130.50,130.33,129.09,128.25,127.06,125.21,119.93,114.26,62.92,57.46,56.67,56.62,47.48,39.38,34.53,30.90,29.68,28.07,27.90,23.08,20.82,20.77.m/z:811.02(m+1)。
[0080]
化合物qg-c7:12n-[(4-三氟甲基)苯磺醯基]-15-[[1-(4-三氟甲基)苯磺醯基-5-氯]苯並咪唑]苦參丙烷。白色固體，收率60％，熔點：67.2℃-68.2℃。1h nmr(500mhz,chloroform-d)δ8.09(d,j＝8.3hz,2h),8.06(d,j＝2.0hz,1h),8.00(d,j＝8.2hz,2h),7.83(d,j＝8.4hz,2h),7.73(d,j＝8.3hz,2h),7.58(d,j＝8.5hz,1h),7.35(dd,j＝8.5,2.0hz,1h),3.71
–
3.59(m,1h),3.53(dd,j＝12.5,6.1hz,1h),3.30
–
3.21(m,1h),3.21
–
3.00(m,2h),2.56(dd,j＝33.4,11.3hz,2h),2.02
–
1.75(m,8h),1.58
–
1.33(m,7h).
13
cnmr
(126mhz,cdcl3)δ155.20,143.62,141.45,140.59,136.51,136.24,136.12,135.97,133.47,131.00,128.06,127.46,127.20,127.14,127.11,127.08,127.05,125.79,125.75,125.72,123.81,122.22,120.78,113.72,62.68,57.35,56.57,56.55,47.00,39.52,34.33,31.54,29.67,28.22,27.87,23.18,20.80,20.64.m/z:789.17(m+1)。
[0081]
化合物qg-c8:12n-[(4-三氟甲基)苯磺醯基]-15-[[1-(4-三氟甲基)苯磺醯基-6-氯]苯並咪唑]苦參丙烷。淡黃色固體，收率76％，熔點：131.6℃～132.5℃。1h nmr(500mhz,chloroform-d)δ8.07(d,j＝8.3hz,2h),8.00(d,j＝8.2hz,2h),7.95(d,j＝8.8hz,1h),7.81(d,j＝8.5hz,2h),7.74(d,j＝8.2hz,2h),7.66(d,j＝2.0hz,1h),7.36(dd,j＝8.8,2.0hz,1h),3.66(dt,j＝8.6,5.5hz,1h),3.57
–
3.50(m,1h),3.26(dd,j＝12.5,10.7hz,1h),3.22
–
3.03(m,2h),2.75
–
2.42(m,2h),2.02
–
1.89(m,5h),1.86
–
1.77(m,4h),1.64(s,2h),1.57
–
1.37(m,6h).
13
c nmr(126mhz,cdcl3)δ155.95,142.97,131.50,131.48,130.76,130.75,128.06,127.42,127.09,127.06,127.05,127.03,127.00,125.80,125.76,125.73,125.41,120.03,114.21,62.68,57.37,56.56,56.53,47.00,39.51,34.33,29.71,28.21,28.20,27.86,23.22,20.79,20.63.789.17(m+1)。
[0082]
化合物qg-c9:12n-[(4-甲基苯磺醯基)-15-[[1-(4-甲基苯磺醯基)-5-硝基]苯並咪唑]苦參丙烷。黃色固體，收率63％。熔點：165.8℃-166.6℃。1h nmr(500mhz,chloroform-d)δ8.27(dd,j＝8.8,2.2hz,1h),7.94
–
7.88(m,2h),7.73(d,j＝8.5hz,3h),7.37(d,j＝8.1hz,2h),7.25(d,j＝8.0hz,2h),3.57(ddd,j＝14.8,8.3,4.6hz,2h),3.28
–
3.19(m,2h),3.13(ddd,j＝16.5,8.8,5.7hz,1h),2.72
–
2.60(m,2h),2.42(s,3h),2.36(s,3h),2.04
–
1.81(m,7h),1.60
–
1.26(m,10h).
13
c nmr(126mhz,cdcl3)δ159.95,146.81,146.37,144.84,137.12,134.64,132.62,129.37,127.55,127.22,120.30,119.77,110.23,63.29,57.53,56.88,56.81,48.21,39.21,34.84,30.05,29.91,27.94,27.80,22.68,21.75,21.45,20.93,20.86.m/z:692.25(m+1)。
[0083]
化合物qg-c10:12n-[(4-甲基苯磺醯基)-15-[[1-(4-甲基苯磺醯基)-6-硝基]苯並咪唑]苦參丙烷。白色固體，收率67％，熔點：87.5℃～88.8℃。1h nmr(500mhz,chloroform-d)δ8.54(d,j＝2.2hz,1h),8.28(dd,j＝9.0,2.3hz,1h),8.17(d,j＝9.0hz,1h),7.87(d,j＝8.4hz,2h),7.73(d,j＝8.4hz,2h),7.36(d,j＝8.1hz,2h),7.25(d,j＝8.0hz,2h),3.57(ddd,j＝12.1,8.9,5.6hz,2h),3.28
–
3.06(m,3h),2.72
–
2.59(m,2h),2.42(s,3h),2.36(s,3h),2.06
–
1.98(m,2h),1.95
–
1.84(m,5h),1.69(s,2h),1.59
–
1.34(m,8h),0.91
–
0.87(m,1h).
13
c nmr(126mhz,cdcl3)δ158.37,146.80,145.09,142.90,141.88,137.26,137.13,134.73,130.60,129.37,127.54,127.08,120.01,115.86,113.67,63.28,57.55,56.88,56.81,48.19,39.22,34.83,30.03,29.79,27.94,27.81,22.54,21.75,21.45,20.94,20.88.m/z:692.25(m+1)。
[0084]
化合物qg-c11:12n-(4-叔丁基苯磺醯基)-15-[[1-(4-叔丁基苯磺醯基)-5-硝基]苯並咪唑]苦參丙烷。白色固體，收率79％，熔點：168.7℃-169.4℃。1h nmr(500mhz,chloroform-d)δ8.99(d,j＝2.1hz,1h),8.27(dd,j＝8.8,2.2hz,1h),7.99
–
7.91(m,2h),7.81
–
7.76(m,2h),7.73(d,j＝8.8hz,1h),7.61
–
7.56(m,2h),7.49
–
7.43(m,2h),3.62(m,1h),3.57(dd,j＝12.3,5.4hz,1h),3.31
–
3.11(m,3h),2.59(m,2h),2.07
–
1.84(m,9h),1.59
–
1.33(m,8h),1.30(d,j＝7.1hz,17h).
13
c nmr(126mhz,cdcl3)δ159.94,159.65,
155.85,146.36,144.84,137.12,134.50,132.66,127.43,127.06,125.66,120.27,119.78,110.25,63.20,57.40,56.83,56.77,47.83,39.34,35.48,35.02,34.78,31.05,30.87,30.51,29.96,27.94,27.93,22.74,20.87,20.86.m/z:776.35(m+1)。
[0085]
化合物qg-c12:12n-(4-叔丁基苯磺醯基)-15-[[1-(4-叔丁基苯磺醯基)-6-硝基]苯並咪唑]苦參丙烷。白色固體，收率74％，熔點：110.3℃-111.6℃。1h nmr(500mhz,chloroform-d)δ8.54(d,j＝2.2hz,1h),8.29(dd,j＝9.1,2.2hz,1h),8.19(d,j＝9.1hz,1h),7.91(m,2h),7.77(m,2h),7.60
–
7.55(m,2h),7.50
–
7.45(m,2h),3.63(m,1h),3.57(dd,j＝12.3,5.4hz,1h),3.50(q,j＝7.0hz,1h),3.30
–
3.10(m,3h),2.64(m,2h),2.09
–
2.07(m,1h),2.06
–
2.00(m,2h),2.00
–
1.84(m,5h),1.67(s,2h),1.60
–
1.44(m,4h),1.37(mz,3h),1.30(d,j＝3.5hz,17h).
13
c nmr(126mhz,cdcl3)δ159.64,158.38,155.87,145.07,141.87,137.30,137.12,134.59,127.43,127.07,126.94,125.67,115.86,113.70,63.21,57.43,56.84,56.78,47.83,39.35,35.49,35.03,34.78,31.06,30.98,30.87,30.48,29.86,27.94,27.92,22.63,20.88,20.86.m/z:776.35(m+1)。
[0086]
化合物qg-c13:12n-[(4-三氟甲基)苯磺醯基]-15-[[1-(4-三氟甲基)苯磺醯基-5-溴]苯並咪唑]苦參丙烷。黑色固體，收率71％，熔點：85.4℃-86.7℃。1h nmr(500mhz,chloroform-d)δ8.23
–
8.04(m,3h),8.00(m,2h),7.85
–
7.77(m,2h),7.73(m,2h),7.62
–
7.52(m,1h),7.51
–
7.32(m,1h),3.74
–
3.60(m,1h),3.53(dd,j＝12.5,6.1hz,1h),3.29
–
3.21(m,1h),3.21
–
3.01(m,2h),2.52(m,2h),2.05
–
1.77(m,10h),1.66(s,1h),1.58
–
1.35(m,7h).
13
c nmr(126mhz,cdcl3)δ155.10,140.98,140.59,128.47,128.05,127.47,127.12,127.09,125.73,125.71,121.18,120.77,116.54,113.71,62.68,57.36,56.56,56.53,39.50,34.33,31.51,29.64,28.21,27.85,23.15,20.79,20.62.m/z:835.12(m+1)。
[0087]
化合物qg-c14:12n-[(4-三氟甲基)苯磺醯基]-15-[[1-(4-三氟甲基)苯磺醯基-6-溴]苯並咪唑]苦參丙烷。白色固體，收率80％，熔點：79.8℃-80.8℃。1h nmr(500mhz,chloroform-d)δ8.07(t,2h),8.00(d,j＝8.2hz,2h),7.93(m,1h),7.87
–
7.64(m,5h),7.43(m,1h),3.66(m,1h),3.53(dd,j＝12.5,6.1hz,1h),3.30
–
3.22(m,1h),3.22
–
3.03(m,2h),2.61(m,2h),2.05
–
1.91(m,6h),1.82(m,4h),1.66(s,1h),1.58
–
1.30(m,9h),0.94
–
0.81(m,1h).
13
c nmr(126mhz,cdcl3)δ155.95,155.80,143.63,143.33,142.96,141.45,128.10,128.06,127.41,127.06,127.03,125.75,125.42,123.07,120.03,118.15,114.62,114.22,62.67,57.35,56.56,56.54,46.98,39.51,34.31,31.55,29.70,28.22,27.86,23.22,20.79,20.63.m/z:835.12(m+1)。
[0088]
化合物qg-c15:12n-(4-甲基苯磺醯基)-15-[[1-(4-甲基苯磺醯基)-5-溴]苯並咪唑]苦參丙烷，白色粉末，收率86％，熔點86.5℃～87.6℃；1h nmr(600mhz,chloroform-d)δ7.93(dd,j＝28.1,8.7hz,1h),7.83
–
7.78(m,2h),7.77(d,j＝2.0hz,1h),7.71(d,j＝8.0hz,2h),7.44(dd,j＝8.7,2.0hz,1h),7.30(d,j＝8.2hz,2h),7.20(d,j＝7.9hz,2h),3.56(ddd,j＝21.2,11.2,4.7hz,2h),3.26(t,j＝11.8hz,1h),3.13(ddd,j＝14.4,9.0,5.6hz,1h),3.07
–
2.97(m,1h),2.63(dd,j＝22.1,7.2hz,2h),2.38(s,3h),2.31(s,3h),2.06
–
1.96(m,4h),1.91(dtd,j＝9.4,6.4,3.0hz,2h),1.88
–
1.80(m,4h),1.58
–
1.38(m,5h),1.38
–
1.30(m,3h),1.30
–
1.23(m,1h).
13
c nmr(151mhz,cdcl3)δ156.21,146.21,143.34,142.79,137.46,135.15,132.14,130.38,129.31,127.54,127.46,126.87,122.67,
117.51,114.79,63.30,57.65,56.88,56.82,48.12,39.27,34.88,30.12,29.67,27.96,27.88,22.96,21.68,21.41,20.93,20.86.m/z:725.18(m+1)。
[0089]
化合物qg-c16:12n-(4-甲基苯磺醯基)-15-[[1-(4-甲基苯磺醯基)-6-溴]苯並咪唑]苦參丙烷。淡黃色色粉末，收率78％，熔點78.5℃～79.6℃；1h nmr(600mhz,chloroform-d)δ7.84(d,j＝8.1hz,2h),7.72(d,j＝8.0hz,2h),7.51(d,j＝8.5hz,1h),7.45(dd,j＝8.5,1.7hz,1h),7.34(d,j＝8.1hz,2h),7.22(d,j＝7.9hz,2h),3.57(ddd,j＝17.9,11.4,5.5hz,2h),3.27(t,j＝11.9hz,1h),3.11(ddd,j＝14.9,9.2,5.5hz,1h),3.01(ddt,j＝15.5,8.9,5.4hz,1h),2.66(dd,j＝25.5,11.5hz,2h),2.42(s,3h),2.33(s,3h),2.07(s,1h),2.04
–
1.99(m,2h),1.96
–
1.83(m,6h),1.74(s,3h),1.50(dddd,j＝53.7,30.0,15.1,11.6hz,5h),1.39
–
1.27(m,4h).
13
c nmr(151mhz,cdcl3)δ155.57,146.26,142.80,140.99,137.45,135.15,134.07,129.31,127.85,127.46,126.92,120.85,116.66,113.59,63.32,57.65,56.88,56.82,48.14,39.26,34.90,30.11,29.63,27.96,27.88,22.90,21.71,21.41,20.94,20.85.m/z:725.18(m+1)。
[0090]
化合物qg-c17:12n-[(4-甲基)苯磺醯基)-15-[[1-(4-甲基苯磺醯基)]苯並咪唑]苦參丙烷。白色固體，收率80％熔點：79.7℃～80.9℃。1h nmr(500mhz,cdcl3)δ8.08
–
8.01(m,1h),7.86
–
7.80(m,2h),7.77
–
7.70(m,2h),7.68
–
7.63(m,1h),7.38
–
7.29(m,4h),7.21(d,j＝8.2hz,2h),3.65
–
3.58(m,1h),3.56(dd,j＝12.4,5.3hz,1h),3.29(t,j＝11.9hz,1h),3.22
–
2.93(m,2h),2.78
–
2.54(m,2h),2.39(s,3h),2.31(s,3h),2.09
–
1.82(m,10h),1.61
–
1.30(m,8h).
13
c nmr(126mhz,cdcl3)δ154.94,145.85,142.76,142.01,137.65,135.53,133.11,130.25,129.30,127.44,126.86,124.61,124.48,119.73,113.60,63.38,57.77,56.91,56.85,48.15,39.32,34.96,30.20,29.73,27.98,27.93,23.20,21.66,21.37,20.95,20.86.m/z:647.27(m+1)。
[0091]
化合物qg-c18:12n-[(4-三氟甲基)苯磺醯基]-15-[[1-(4-三氟甲基)苯磺醯基-5-氟]苯並咪唑]苦參丙烷。白色固體，收率73％，熔點：65.1℃～66.0℃。1h nmr(500mhz,chloroform-d)δ8.08(d,j＝8.3hz,2h),8.00(d,j＝8.2hz,2h),7.85
–
7.68(m,5h),7.59(dd,j＝8.8,4.9hz,1h),7.10(td,j＝9.0,2.4hz,1h),3.65(s,1h),3.51(s,1h),3.28(s,1h),3.15(s,1h),3.05(s,1h).
13
c nmr(126mhz,chloroform-d)δ154.90,128.03,127.47,127.03,125.74,113.18,57.37,56.53,56.51,46.97,39.51,34.35,31.56,29.68,28.21,23.26,20.75,20.61.m/z：773.20(m+1)。
[0092]
化合物qg-c19:12n-[(4-三氟甲基)苯磺醯基]-15-[[1-(4-三氟甲基)苯磺醯基-6-氟]苯並咪唑]苦參丙烷。白色固體，收率67％，熔點：128.3℃～129.4℃。1h nmr(500mhz,chloroform-d)δ8.06(d,j＝8.3hz,2h),8.00(d,j＝8.2hz,2h),7.96(dd,j＝9.0,4.5hz,1h),7.79(d,j＝8.3hz,2h),7.72(d,j＝8.1hz,2h),7.33(dd,j＝8.5,2.4hz,1h),7.11(td,j＝9.0,2.3hz,1h),3.66(s,1h),3.53(dd,j＝12.6,6.1hz,1h),3.26(t,j＝11.6hz,1h),3.18(ddd,j＝14.1,8.3,5.5hz,1h),3.09(dt,j＝15.8,6.9hz,1h),2.54(dd,j＝33.3,11.2hz,2h),2.04
–
1.87(m,6h),1.86
–
1.76(m,4h),1.41(dt,j＝36.3,14.7hz,6h).
13
c nmr(126mhz,cdcl3)δ161.45,159.53,156.26,142.92,142.82,141.47,136.09,133.70,128.02,127.41,126.98,125.76,123.81,121.64,114.11,114.04,113.05,112.85,106.49,106.30,62.66,57.38,56.53,56.51,46.96,39.51,34.35,31.62,29.76,28.19,27.83,
23.30,20.74,20.58.m/z：773.20(m+1)。
[0093]
化合物qg-c20:12n-[1-萘磺醯基]-15-[[1-(1-萘磺醯基)-5-氟]苯並咪唑]苦參丙烷。黃色固體，收率70％，熔點：145.3℃～146.4℃。
11
h nmr(500mhz,chloroform-d)δ8.57(d,j＝1.9hz,1h),8.42(d,j＝1.6hz,1h),8.07
–
7.98(m,2h),7.94
–
7.47(m,11h),7.26(dd,j＝8.7,2.6hz,1h),7.11(td,j＝9.1,2.6hz,1h),3.68(dt,j＝9.4,5.4hz,1h),3.62(dd,j＝12.5,5.5hz,1h),3.36(dd,j＝12.5,10.8hz,1h),3.10(dddd,j＝57.4,16.5,8.6,5.5hz,2h),2.64
–
2.49(m,2h),2.07
–
1.90(m,6h),1.88
–
1.76(m,4h),1.71(s,2h),1.61
–
1.25(m,9h).
13
c nmr(126mhz,cdcl3)δ161.20,159.28,156.39,142.76,142.67,135.53,134.94,134.55,132.03,131.84,130.30,129.92,129.73,129.16,128.86,128.35,128.15,127.98,127.64,127.22,121.01,114.15,114.08,112.55,112.36,106.16,105.97,77.29,63.21,57.85,56.70,47.91,39.44,34.92,30.56,29.71,27.99,27.90,23.19,20.80,20.69.m/z:737.26(m+1)。
[0094]
化合物qg-c21:12n-[1-萘磺醯基]-15-[[1-(1-萘磺醯基)-6-氟]苯並咪唑]苦參丙烷。淡黃色粉末，收率67％，熔點：70.6℃～71.8℃。1h nmr(500mhz,chloroform-d)δ8.58(d,j＝1.9hz,1h),8.42(d,j＝1.5hz,1h),8.04(d,j＝8.2hz,1h),7.94
–
7.49(m,13h),7.06(td,j＝9.0,2.5hz,1h),3.68(dt,j＝10.2,5.4hz,1h),3.62(dd,j＝12.4,5.5hz,1h),3.35(dd,j＝12.5,10.8hz,1h),3.09(dddd,j＝56.9,16.5,8.7,5.5hz,2h),2.64
–
2.52(m,2h),2.06
–
1.90(m,6h),1.81(ddd,j＝11.5,7.5,3.5hz,4h),1.72(s,2h),1.61
–
1.30(m,7h).
13
c nmr(126mhz,cdcl3)δ171.17,161.36,159.44,155.16,155.13,138.20,137.60,135.55,134.92,134.52,132.04,131.84,130.34,129.96,129.76,129.13,128.92,128.83,128.31,128.18,127.98,127.63,127.19,123.10,121.01,120.42,120.34,112.61,112.41,101.28,101.05,57.78,56.76,56.72,47.87,39.47,34.89,30.62,29.67,28.08,27.95,23.09,20.82,20.78.m/z:737.26(m+1)。
[0095]
化合物qg-22：12n-(4-叔丁基苯磺醯基)-15-[[1-(4-叔丁基苯磺醯基)]苯並咪唑]苦參丙烷。淡黃色固體，收率81％，熔點：162℃～163℃。1h nmr(500mhz,chloroform-d)δ8.11
–
8.04(m,1h),7.91
–
7.84(m,2h),7.81
–
7.75(m,2h),7.68
–
7.63(m,1h),7.54
–
7.49(m,2h),7.47
–
7.42(m,2h),7.38
–
7.30(m,2h),3.69
–
3.61(m,1h),3.57(dd,j＝12.4,5.5hz,1h),3.38
–
3.26(m,1h),3.22
–
3.00(m,2h),2.71
–
2.54(m,2h),2.07
–
1.93(m,6h),1.91
–
1.81(m,4h),1.76(s,1h),1.60
–
1.31(m,8h),1.30(s,9h),1.27(s,9h).
13
cnmr(126mhz,cdcl3)δ158.71,155.72,154.95,141.99,137.57,135.42,133.16,126.72,125.61,124.61,124.45,119.73,113.63,63.30,57.63,56.86,56.82,47.81,39.43,35.35,34.99,34.87,31.04,30.91,30.66,29.79,28.03,27.98,23.24,20.89,20.86.m/z:731.37(m+1)。
[0096]
三、化合物qg-a1的製備：
[0097][0098]
具體包括以下步驟：
[0099]
(1)取10g(0.1mol)苦參鹼置於250ml燒瓶中，加入25g氫氧化鈉和100ml水，於110
℃下攪拌回流12h，反應結束後冷卻至室溫，抽濾，乾燥得到白色固體，即為苦參酸鈉鹽，無須純化直接用於下一步反應。
[0100]
(2)稱取1.4g(5mmol)苦參酸鈉鹽於250ml燒瓶中，加入少量水溶解，用1n hcl溶液調節ph至7～8，加入10ml 10wt％na2co3溶液攪拌溶解，接著稱取1.5g芴甲氧羰醯氯，用等體積的1,4-二氧六環溶解，在冰浴條件下，滴加到上述的混合液中，保溫繼續攪拌4h，然後轉移至室溫攪拌10h，tlc監測反應，反應結束後加h2o，用1nhcl溶液調節ph至6～7，用dcm萃取三次，減壓蒸餾，濃縮，用meoh：dcm＝1：40(v:v)的洗脫劑過柱得12n-fmoc苦參酸。
[0101]
(3)取2.4g(5mmol)12n-fmoc苦參酸於100ml的三口圓底燒瓶中，氮氣保護，用注射器加入1.3eq的二氯亞碸，於58℃下回流1h，後減壓旋蒸,用無水二氯甲烷溶解、濃縮，重複三到四次，除去殘留的二氯亞碸。後加入1g(7mmol)的2-氨基苯並咪唑置於100ml的圓底燒瓶中，加入20ml的乙腈溶解，滴加1.2ml的三乙胺。將新製備的12n-fmoc苦參醯氯用適量的無水的乙腈溶解，的滴加到氨基苯並咪唑衍生物中，室溫過夜攪拌。tlc監測反應，反應完成後，加水，用二氯甲烷萃取三到四次，減壓濃縮，用dcm:meoh比例為30:1～40:1(v:v)的洗脫劑過矽膠柱純化，得化合物qg-a1，即12n-9芴甲氧羧基-15-苯並咪唑苦參丙醯胺，油狀物，收率70％。1h nmr(500mhz,cdcl3)δ11.84(s,1h),11.17(s,1h),7.80
–
7.70(m,2h),7.61(d,j＝7.5hz,2h),7.49(s,1h),7.37(td,j＝7.6,2.7hz,2h),7.34
–
7.26(m,3h),7.22(m,1h),4.76
–
4.54(m,2h),4.42(dd,j＝11.9,4.4hz,1h),4.23(t,j＝5.3hz,1h),3.84(td,j＝9.3,5.7hz,1h),3.68(s,1h),3.47
–
3.23(m,2h),3.07(t,j＝12.7hz,1h),2.91
–
2.78(m,2h),2.76
–
2.40(m,4h),2.27(ddd,j＝17.1,10.9,5.5hz,1h),2.10(tdt,j＝8.9,6.0,3.0hz,2h),2.03
–
1.95(m,3h),1.78
–
1.75(m,1h),1.70
–
1.63(m,3h),1.55(dt,j＝13.6,5.0hz,2h),1.45
–
1.41(m,4h),0.88
–
0.82(m,1h).
13
c nmr(126mhz,cdcl3)δ174.07,169.47,147.82,144.29,144.28,141.48,141.45,127.52,127.49,126.99,126.96,124.77,124.72,119.86,119.84,65.94,63.80,57.30,57.22,53.20,47.62,43.22,41.46,35.33,32.85,27.16,26.45,21.17,20.76,18.98.m/z:604.32(m+1)。
[0102]
參考化合物qg-a1的實驗方法製備化合物qg-a2～qg-a5,化合物qg-a2～qg-a5的結構鑑定數據如下：
[0103]
化合物a2:12n-9芴甲氧羧基-15-(2-丙基-3-三氟甲基)苯並咪唑苦參丙醯胺，白色固體，收率50％熔點：104.3℃-105.9℃。1h nmr(500mhz,cdcl3)δ12.38(s,1h),7.89(d,j＝15.6hz,1h),7.76(d,j＝7.5hz,2h),7.64(d,j＝7.6hz,1h),7.60
–
7.55(m,2h),7.45(dd,j＝8.4,1.8hz,1h),7.40(td,j＝7.3,3.4hz,2h),7.32(td,j＝8.0,4.5hz,2h),4.65(s,2h),4.21(t,j＝5.1hz,1h),3.80
–
3.63(m,1h),3.43
–
3.31(m,3h),3.27(m,1h),2.91(q,j＝5.4hz,2h),2.84(s,1h),2.39
–
2.17(m,2h),1.92(h,j＝5.3hz,4h),1.68(s,3h),1.58
–
1.31(m,8h),1.32
–
1.21(m,3h).
13
c nmr(126mhz,cdcl3)δ174.97,157.15,144.01,143.90,141.50,141.45,128.28,127.66,127.63,127.12,127.09,126.12,124.11,123.96,123.85,121.80,119.88,119.86,118.76,65.49,64.64,56.55,47.65,47.24,39.20,37.75,35.30,35.02,29.69,28.53,27.15,25.55,21.58,19.89.m/z:714.36(m+1)。
[0104]
化合物a3:12n-9芴甲氧羧基-15-(1甲基-2-丙基-5-硝基)苯並咪唑苦參丙醯胺。熔點：61.5℃-62.6℃。1h nmr(500mhz,cdcl3)δ8.54(d,j＝2.1hz,1h),8.19(dd,j＝8.8,2.1hz,1h),7.73(d,j＝7.5hz,2h),7.57(dd,j＝7.5,3.8hz,2h),7.40
–
7.36(m,2h),7.33
–
7.29(m,2h),7.27(d,j＝3.4hz,1h),6.75(s,1h),4.55(s,2h),4.19(t,j＝5.6hz,1h),3.73(s,3h),3.65(s,1h),3.45
–
3.26(m,5h),2.92(t,j＝7.1hz,2h),2.71(d,j＝9.9hz,2h),2.15
–
2.11(m,6h),1.94
–
1.82(m,4h),1.63(d,3h),1.45
–
1.38(m,5h),1.30
–
1.24(m,2h),1.18
–
1.06(m,1h).
13
c nmr(126mhz,cdcl3)δ173.38,158.54,144.19,143.50,141.62,141.44,139.87,127.56,127.55,126.99,124.69,124.66,119.88,118.16,115.64,108.80,65.97,63.65,56.92,56.85,47.55,40.05,38.66,36.18,35.40,30.55,30.20,28.38,27.69,26.64,25.03,22.34,21.17,21.01.m/z:705.37(m+1)。
[0105]
化合物a4:12n-9芴甲氧羧基-15-(2-丙基)苯並咪唑苦參丙醯胺，黃色固體，收率60％。熔點：61.5℃-62.6℃。1h nmr(500mhz,chloroform-d)δ7.76(d,j＝7.5hz,2h),7.58(dd,j＝7.7,5.2hz,4h),7.40(td,j＝7.5,2.8hz,2h),7.32(tdd,j＝7.4,3.6,1.2hz,2h),7.23
–
7.16(m,2h),4.68
–
4.62(m,1h),4.21(t,j＝5.1hz,1h),3.70(s,1h),3.37(qd,j＝12.8,11.6,7.6hz,3h),3.27(dd,j＝13.2,7.1hz,1h),2.96
–
2.80(m,4h),2.18
–
1.87(m,6h),1.72(s,3h),1.55
–
1.23(m,13h).
13
c nmr(126mhz,cdcl3)δ174.76,154.65,144.08,141.51,141.46,127.65,127.63,127.11,127.07,124.64,124.60,121.80,119.92,119.91,65.69,64.29,56.78,56.74,47.63,47.07,46.03,39.57,37.75,35.42,29.67,28.81,27.67,26.90,25.47,21.88,20.67,20.38.m/z:646.29(m+1)。
[0106]
化合物a5:12n-9芴甲氧羧基-15-(2-丙基-6-氟)苯並咪唑苦參丙醯胺，黃色油狀物，收率55％。1h nmr(500mhz,chloroform-d)δ7.75(d,j＝7.6hz,2h),7.58(t,j＝6.6hz,2h),7.47(dd,j＝8.9,4.8hz,1h),7.40(ddd,j＝8.0,5.3,1.8hz,2h),7.33(t,j＝7.7hz,2h),7.25(dd,j＝9.5,2.6hz,1h),6.94(td,j＝9.2,2.5hz,1h),4.75(s,1h),4.19(s,1h),3.80(s,1h),3.48(t,j＝12.5hz,1h),3.37(ddd,j＝13.7,9.3,5.5hz,1h),3.26
–
3.12(m,2h),2.87(t,j＝6.4hz,2h),2.31(s,4h),1.93(tdd,j＝14.6,9.7,2.8hz,3h),1.58(d,j＝14.4hz,4h),1.53
–
1.38(m,5h),1.37
–
1.20(m,7h),0.97(t,j＝7.5hz,1h).
13
cnmr(126mhz,cdcl3)δ174.90,165.97,160.06,158.18,155.96,143.98,141.51,129.48,127.70,127.62,127.24,127.13,127.06,124.63,124.54,121.00,119.83,119.78,109.88,109.69,67.78,65.14,56.66,56.39,47.77,38.90,37.55,35.20,30.57,29.70,28.98,28.76,25.47,23.98,22.97,22.69.m/z:664.29(m+1)。
[0107]
表1給出了苯並咪唑類苦參鹼衍生物的結構式。
[0108]
表1
[0109]
[0110]
[0111]
[0112]
[0113]
[0114]
[0115][0116]
實施例2
[0117]
研究製備的苯並咪唑類苦參鹼衍生物的體外抗腫瘤活性，腫瘤細胞為宮頸癌細胞hela，肺癌細胞a549，均通過購買得到。
[0118]
實驗方法：所有細胞養在含10％fbs和1％青黴素-鏈黴素的mccoy5a培養基中，並置於37℃，5％co2的細胞培養箱中。用mtt法進行測試，將苯並咪唑類苦參鹼衍生物用二甲基亞碸(dmso)溶解稀釋成所需溶液濃度。取生長狀態良好的細胞一皿，加入胰蛋白酶消化製成每毫升含2
×
104～4
×
104個細胞懸液。取細胞懸液接種於96孔板中設空白組、對照組以及給藥組(150μl)，每組設3個平行孔。置於37℃，5％co2的細胞培養箱中，24h後加入不同濃度的藥物，繼續培養48h後，每個孔加入15μl，5mg/ml mtt，培養箱孵育4h,棄上清液，加入150μl dmso，振蕩混勻，用酶標儀在490nm處測試每孔的吸收度，計算細胞抑制率。
[0119][0120]
上述實驗重複3次，並且blies法計算出ic
50
值。
[0121]
實驗結果：
[0122]
表2目標化合物對hela細胞和a549細胞增殖的抑制
[0123]
[0124][0125]
實驗數據表明，合成的系列苦參鹼衍生物大部分具有良好的抗腫瘤活性，在以苦參鹼為對照藥，與合成的目標化合物給藥的情況下，對比它們的抑制率發現，化合物中的qg-15、qg-c16、qg-c17對hela細胞和a549細胞有較強的抑制作用，具有高效的抗腫瘤抑制活性。
[0126]
以上所述的實施例僅是對本發明的優選方式進行描述，並非對本發明的範圍進行限定，在不脫離本發明設計精神的前提下，本領域普通技術人員對本發明的技術方案做出的各種變形和改進，均應落入本發明權利要求書確定的保護範圍內。