CN102964320A - 19-羧基穿心莲内酯衍生物、制备方法及其医药用途 - Google Patents
19-羧基穿心莲内酯衍生物、制备方法及其医药用途 Download PDFInfo
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Abstract
本发明公开了一种19-羧基穿心莲内酯衍生物、制备方法及其医药用途,属于药物化学领域。本发明的19-羧基穿心莲内酯衍生物的结构通式如(1)所示:R1为取代或未取代C1~8脂肪族酰基、取代或未取代的苯甲酰基;R2为氢、取代或未取代C1~8脂肪族酰基、取代或未取代的苯甲酰基;R3为氢、取代或未取代C1~8烷基、取代或未取代的苯基。本发明还公开了本发明的19-羧基穿心莲内酯衍生物的制备方法及其在制备抗肿瘤药物中的应用。
Description
技术领域
本发明涉及穿心莲内酯衍生物的合成方法及医药用途,具体是指19-羧基穿心莲内酯衍生物的合成方法及在制备抗肿瘤药物中的用途,属于药物化学领域。
背景技术
恶性肿瘤的发病率呈逐年上升趋势,已成为严重危害人类健康的常见疾病。尽管目前已上市的抗肿瘤药物品类繁多,但仍不能满足临床需求,因此开发疗效确切、副作用小的新型抗肿瘤药物则显得尤为迫切。
穿心莲内酯(Andrographolide)系爵床科植物穿心莲Andrographis paniculata(Burm.f.)Nees中提取得到的二萜内酯类化合物,是穿心莲的主要有效成分之一。现代药理学研究表明穿心莲内酯具有抗菌、抗病毒、抗肿瘤、免疫调节以及抗HIV等作用。[S.Nanduri,et al.WO2001085709;J.X.Chen,et al.Biol.Pharm.Bull.2009,8:1385-1391;H.Y.Chung,et al.Planta.2005,71:1106-1111;S.Rajagopal,et al.J.Exp.Ther.Oncol.2003,3:147-158;T.G.Kim,et al.In Vivo.2005,19(3):551-557;R.Ajaya.Kumar,et al.J.Ethnopharmacol.2004,92:291-295;C.G.Jiang,etal.Anticancer Res.2007,27:2439-2447;Y.C.Lee,et al.Eur.J.Pharmaol.2010,63:23-32;Y.Ding,et al.J.Exp.Cell Res.2008,314(3):590-602]
鉴于穿心莲内酯在抗肿瘤方面的诱人潜力,许多研究者对其结构进行了改造,以期得到抗肿瘤活性更好的化合物。印度研究人员Nanduri等首次考查了穿心莲内酯的抗肿瘤构效关系,发现完整的内酯环结构对其抗肿瘤活性有重要作用,而8,17双键环氧化后对其活性无明显影响。在此基础上该研究小组合成了一系列3,14,19-OH酯化的衍生物,药理实验证明这些化合物在体外对多种人癌细胞,如乳腺癌细胞MCF-7、中枢神经癌细胞U251、结肠癌细胞SW 620、肺癌细胞H 522、卵巢癌细胞SK OV3、前列腺癌细胞DU145、肾癌细胞A 498等有明显抑制作用。[S.Nanduri,et al.Bioorg Med Chem Lett.2004,14:4711-4717]Chowdhury和Saeeng等两个研究小组在保留穿心莲内酯完整内酯环的基础上也分别合成了一系列3,14,19-OH酯化的衍生物,体外细胞毒试验显示部分改造后的化合物抗肿瘤活性有明显增强。[C.Chowdhury,et al.Bioorg Med Chem Lett.2010,20:6947-6950;R.Saeeng,et al.Bioorg MedChem Lett.2012,22:49-52]此外,武汉大学何祥久等研究小组利用生物转化的方法得到了一系列3,19-OH被氧化的穿心莲内酯衍生物,体外细胞毒测试显示部分衍生物有较好的抗肿瘤活性。[X.J.He,et al.Journal of Molecular Catalysis B:Enzymatic.2010,62:242-247;X.J.He,et al. Journal of Molecular Catalysis B:Enzymatic.2011,68:89-93]
由于穿心莲内酯不稳定的理化性质,在针对其抗肿瘤的结构改造中,已有的研究工作要么改动很小,只对3,14,19-OH进行酰化,要么有较大变化但破坏了完整的内酯环结构。本发明将两者结合起来,既保留对抗肿瘤有重要作用的完整内酯环结构,又将19-OH氧化为羧基,以便开发新型的19-羧基穿心莲内酯抗肿瘤衍生物。
发明内容
本发明的目的在于提供一种新的有药用价值的19-羧基穿心莲内酯衍生物。
本发明的目的还在于提供一种新的有药用价值的19-羧基穿心莲内酯衍生物的制备方法。
本发明的目的还在于提供一种新的有药用价值的19-羧基穿心莲内酯衍生物在制备抗肿瘤药物中的应用。
本发明的目的通过以下技术方案实现:
一种19-羧基穿心莲内酯衍生物,具有如通式(1)所示的结构:
其中,R1为取代或未取代C1~8脂肪族酰基、取代或未取代的苯甲酰基;R2为氢、取代或未取代C1~8脂肪族酰基、取代或未取代的苯甲酰基;R3为氢、取代或未取代C1~8烷基、取代或未取代的苯基。
本发明较佳的实施例中所述的脂肪族酰基的取代基为1~8个碳的直链或支链式胺基、1~8个碳的直链或支链式烷氧基、取代或未取代的芳香基。
本发明更佳的实施例中所述的烷基的取代基为1~8个碳的直链或支链式胺基、1~8个碳的直链或支链式烷氧基、取代或未取代的芳香基。
以上所有描述中苯甲酰基、苯基及芳香基的取代基为氟、氯、溴、胺基、乙酰胺基、羟基、甲氧基。
本发明的最佳实施例中,所述的19-羧基穿心莲内酯衍生物为:
I1:14-O-乙酰基-19-羧基穿心莲内酯;
I2:3-O-乙酰基-14-O-乙酰基-19-羧基穿心莲内酯;
I3:3-O-乙酰基-14-O-乙酰基-19-甲氧羰基穿心莲内酯;
I4:3-O-乙酰基-14-O-乙酰基-19-苄氧羰基穿心莲内酯;
II1:14-O-苯甲酰基-19-羧基穿心莲内酯;
II2:3-O-乙酰基-14-O-苯甲酰基-19-羧基穿心莲内酯;
II3:3-O-乙酰基-14-O-苯甲酰基-19-甲氧羰基穿心莲内酯;
II4:3-O-乙酰基-14-O-苯甲酰基-19-苄氧羰基穿心莲内酯;
III1:14-O-(4-甲氧基)肉桂酰基-19-羧基穿心莲内酯;
III2:3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-羧基穿心莲内酯;
III3:3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-甲氧羰基穿心莲内酯;
III4:3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-苄氧羰基穿心莲内酯。
通式(1)化合物制备方法,方法如下:
穿心莲内酯1在甲苯/二甲亚砜溶剂中与2,2二甲氧基丙烷在加热条件下反应得到化合物2,化合物2成酯得到化合物3,然后在乙酸/水条件下脱保护得到化合物4,化合物4被2,2,6,6-四甲基哌啶-氮-氧化物/氮-氯代琥珀酰亚胺在弱碱性条件下选择性氧化为化合物5,化合物5酰化得化合物6,化合物6再被亚氯酸钠氧化为羧基化合物7,或者化合物5不经酰化直接氧化为羧基化合物7,化合物7成酯或者不成酯得到目的物(1)。
其中化合物4的制备可参考:WO0157026A1、WO0185710A1、WO2009018780、US20110077295A1。
通过药理实验,详细说明19-羧基穿心莲内酯衍生物对肿瘤细胞株的增殖抑制作用:
I.材料和方法
1.1表一.材料与仪器
1.2方法
1.2.1细胞培养:分别以McCoy′5A+10%FBS+1%P/S,DMEM+10%FBS+1%P/S培养液对HCT-116细胞以及MCF-7细胞在37℃,5%CO2培养箱中进行培养。
1.2.2细胞处理:取处于指数生长期,状态良好的细胞,加入适量胰酶消化细胞,收集细胞离心,弃上清。用含血清的培养液重新混悬细胞,然后计数,并将细胞密度稀释至3×104个/ml密度。
1.2.3细胞接种:取细胞悬液接种于96孔板上,100μl/well(3000个细胞/孔),将培养板转入37℃,5%CO2培养箱中培养24小时。
1.2.4化合物配置:将化合物以DMSO配置成1000×的9个浓度梯度,分别为100、33.33、11.11、3.7、1.23、0.41、0.14、0.045、0.015(mM),然后每个浓度取1μL对应加入1mL的细胞培养液中,得到终浓度为100、33.33、11.11、3.7、1.23、0.41、0.14、0.045、0.015(μM)的化合物梯度稀释液。
1.2.5给药:弃去各孔细胞培养液,每孔加入100μL配置好的含有药物的培养液,每个浓度设置3个复孔,其中对照组加入含0.1%的DMSO的培养液;继续将培养板放在37℃,5%CO2培养箱中培养72h。
1.2.6加MTS:到达作用时间后,每孔加入10μL MTS溶液,继续将培养板放在37℃,5%CO2培养箱中孵育2.5h。
1.2.7检测:于Infinite M200酶标仪上检测各孔OD492nM值。
II.药理活性数据
表二.19-羧基穿心莲内酯衍生物对肿瘤细胞株的增殖抑制作用
通过以上化合物的活性筛选,对两种肿瘤细胞株均有较好抑制作用的化合物为I4、II4、I3、II3、III4,其中I4、II4的抑制作用特别强,有进一步改造的潜力。
具体实施方式
实施例1
3,19-异丙氧基-穿心莲内酯的制备:
将穿心莲内酯(10.00g,28.54mmol)溶于干燥的甲苯/DMSO(200ml/27ml)中,加入2,2-二甲氧基丙烷(14ml)、对甲苯磺酸(催化量),80℃下搅拌约1.5小时至反应完全,冷却至室温,加三乙胺(7ml)淬灭催化剂,反应液加甲苯(150ml)稀释并水洗(3X300ml),分离有机层,无水硫酸钠干燥。将干燥的有机相浓缩,加乙醚(30ml)搅拌,抽滤烘干得白色固体颗粒(10.36g,26.53mmol,产率93%)。1H-NMR(300MHz,CDCl3,ppm)δ:6.96(1H,t,J=6.4Hz,H-12),5.03(1H,d,J=5.9Hz,H-14),4.91(1H,s,H-17a),4.63(1H,s,H-17b),4.48-4.43(1H,dd,J=10.4Hz,6.1Hz,H-15a),4.28-4.24(1H,dd,J=1.9Hz,10.4Hz,H-15b),3.97(1H,d,J=5.8Hz,H-19a),3.52-3.48(1H,dd,J=3.4Hz,8.4Hz,H-3),3.2(dd,1H,H-19b),2.64-2.40(4H,m),2.05-1.97(2H,m),1.85-1.72(4H,m),1.32-1.25(3H,m),1.42(3H,s),1.37(3H,s),1.20(3H,s,H-18),0.96(3H,s,H-20).
实施例2
14-O-乙酰基-穿心莲内酯的制备:
将3,19-异丙氧基-穿心莲内酯(7.00g,17.93mmol)、Ac2O(60ml)在142℃下回流约1.5小时至反应完全,冷却至室温,加少量的水及适量碳酸氢钠粉末搅拌至无气泡溢出,反应液加二氯甲烷(100ml)稀释,分离有机层并依次用饱和碳酸氢钠溶液(3X120ml)、饱和食盐水(3X120ml)洗涤。有机相不经干燥直接浓缩,再将浓缩的粗产品3,19-异丙氧基-14-乙酰基-穿心莲内酯在室温下溶解于乙酸的水溶液(乙酸∶水=28ml∶12ml),反应完成后,加碳酸氢钠粉末搅拌至无气泡溢出,反应液加二氯甲烷(80ml)稀释,分离有机层并依次用饱和碳酸氢钠溶液(3X100ml)、饱和食盐水(3X100ml)洗涤,无水硫酸钠干燥。将干燥的有机相浓缩,乙酸乙酯-石油醚结晶,最终得干燥的白色针簇状结晶(5.21g,15.21mmol,产率85%)。mp:160-161℃.1H-NMR(300MHz,CDCl3,ppm)δ:7.01(1H,td,J=6.9,1.5Hz,H-12),5.92(1H,d,J=6.0Hz,H-14),4.88(1H,s,H-17b),4.57-4.51(2H,m,H-15b and H-17a),4.24(1H,dd,J=11.2,1.9Hz,H-15a),4.18(1H,d,J=11.1Hz,H-19b),3.49(1H,t,J=16.0Hz,H-3),3.33(1H,d,JJ=11.1Hz,H-19a),2.45-2.37(3H,m),2.31(2H,s),2.12(3H,s,CH3CO),2.01-1.92(1H,m),1.83-1.72(5H,m),1.25(3H,s,H-18),1.33-1.20(3H,m),0.67(3H,s,H-20).
实施例3
14-O-乙酰基-19-醛基-穿心莲内酯的制备:
将14-O-乙酰基-穿心莲内酯(5.00g,12.74mmol)溶于二氯甲烷(130ml)中,冰浴下依次加入TEMPO(0.10g,064mmol)、pH约为9的碳酸钾-碳酸氢钠缓冲溶液(130ml)、TBAI(0.24g,0.65mmol)及NCS(2.40g,17.97mmol),剧烈搅拌约9小时至反应完全。反应完全后分离有机层,二氯甲烷(2X100ml)萃取水层,饱和食盐水(2X300ml)洗涤有机层,无水硫酸钠干燥。将干燥的有机相浓缩,柱层析分离(石油醚∶乙酸乙酯=2∶1),最终得干燥的淡黄色泡沫状物质(4.52g,11.57mmol,产率91%)。mp:60-61℃.1H-NMR(300MHz,CDCl3,ppm)δ:9.77(1H,s,H-19),7.01(1H,t,J=6.8Hz,,H-12),5.92(1H,d,J=5.8Hz,H-14),4.95(1H,s,H-17b),4.57-4.52(2H,m,H-15b and H-17a),4.24(1H,dd,J=11.2,1.7Hz,H-15a),3.26-3.23(1H,m,H-3),2.77(1H,s),2.54-2.38(3H,m),2.12(3H,s,CH3CO),2.07-1.79(9H,m),1.67-1.62(1H,m),1.42-1.37(1H,m),1.30(3H,s,H-18),1.28-1.26(2H,m),0.66(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:207.5(C-19),170.5(CH3CO),168.9(C-16),150.0(C-12),146.1(C-8),124.1(C-13),109.4(C-17),77.5(C-3),71.6(C-15),67.8(C-14),55.5(C-9),54.6(C-5),52.8(C-4),39.4(C-10),37.6(C-7),37.1(C-1),28.5(C-2),25.3(C-6),23.8(C-11),20.7(CH3CO),19.4(C-18),13.7(C-20).
实施例4
3-O-乙酰基-14-O-乙酰基-19-醛基-穿心莲内酯的制备:
将14-O-乙酰基-19-醛基-穿心莲内酯(4.36g,11.17mmol)、Ac2O(50ml)在142℃下回流约1.5小时至反应完全,冷却至室温,加少量的水及适量碳酸氢钠粉末搅拌至无气泡溢出,反应液加二氯甲烷(80ml)稀释,分离有机层并依次用饱和碳酸氢钠溶液(3X100ml)、饱和食盐水(3X100ml)洗涤,无水硫酸钠干燥。将干燥的有机相浓缩,柱层析分离(石油醚∶乙酸乙酯=3∶1),最终得干燥的淡黄色泡沫状物质(3.78g,8.73mmol,产率78%)。mp:176-179℃. 1H-NMR(300MHz,CDCl3,ppm)δ:10.05(1H,s,H-19),7.01(1H,t,J=6.6Hz,H-12),5.93(1H,d,J=5.3Hz,H-14),4.92(1H,s,H-17b),4.76-4.70(1H,m,H-15b),4.57-4.52(2H,m,H-15b andH-17a),4.25(1H,dd,J=11.2,1.7Hz,H-15a),2.77(1H,s),2.55-2.27(3H,m),2.12(3H,s,CH3CO),2.06(3H,s,CH3CO),2.06-2.02(1H,m),2.02-1.86(4H,m),1.55-1.24(4H,m),1.11(3H,s,H-18),0.66(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:204.1(C-19),170.4(CH3CO),170.3(CH3CO),168.9(C-16),149.7(C-12),146.0(C-8),124.1(C-13),109.3(C-17),78.1(C-3),71.5(C-15),67.7(C-14),56.4(C-9),54.4(C-5),52.0(C-4),39.0(C-10),37.3(C-7),36.3(C-1),25.4(C-2),24.6(C-6),23.9(C-11),21.0(CH3CO),20.9(C-18),20.7(CH3CO),15.1(C-20).
实施例5
3-O-乙酰基-14-O-乙酰基-19-羧基-穿心莲内酯(I2)的制备:
将3,14-O-乙酰基-19-醛基-穿心莲内酯(2.16g,5.00mmol)、二甲亚砜(2ml)及异戊烯(3.50ml,30.58mmol)加入t-BuOH(20ml)中,冰浴下滴加新鲜制备的NaClO2-NaH2PO4缓冲液(1.13g/1.38g,40mlH2O),半小时后升至室温,48小时后停止反应。反应液加乙酸乙酯(30ml)稀释,分离有机层,乙酸乙酯(2X30ml)萃取水层,合并有机层并用饱和食盐水(2X80ml)洗涤,无水硫酸钠干燥。将干燥的有机相浓缩,柱层析纯化(石油醚∶乙酸乙酯=3∶1),再用乙酸乙酯-石油醚结晶,最终得干燥的白色颗粒状结晶(1.70g,3.81mmol,产率76%)。mp:186-188℃.1H-NMR(300MHz,DMSO-d6,ppm)δ:12.34(1H,s,H-19),6.84(1H,t,J=6.5Hz,H-12),5.95(1H,d,J=5.4Hz,H-14),4.87(1H,s,H-17b),4.59-4.45(3H,m,H-3,H-15b andH-17a),4.30-4.27(1H,d,J=11.0Hz,H-15a),2.42-2.27(4H,m),2.09-1.99(8H,m,CH3CO),1.93-1.76(2H,m),1.63-1.60(1H,m),1.52-1.31(3H,m),1.15(3H,s,H-18),0.68(3H,s,H-20). 13C-NMR(75MHz,CDCl3,ppm)δ:179.3(C-19),170.8(CH3CO),170.4(CH3CO),169.0(C-16),150.1(C-12),146.3(C-8),124.1(C-13),109.0(C-17),78.7(C-3),71.6(C-15),67.8(C-14),55.6(C-9),55.3(C-5),52.8(C-4),39.4(C-10),37.6(C-7),37.1(C-1),25.2(C-2),25.1(C-6),24.5(C-11),24.1(C-18),21.2(CH3CO),20.7(CH3CO),12.5(C-20).
实施例6
14-O-乙酰基-19-羧基-穿心莲内酯(I1)的制备:
参照实施例5的制备方法,由14-O-乙酰基-19-醛基-穿心莲内酯制得,产率42%。mp:168-172℃.1H-NMR(300MHz,DMSO-d6,ppm)δ:12.31(1H,s),6.83(1H,t,J=6.3Hz,H-12),5.92(1H,d,J=5.3Hz,H-14),4.86(1H,s,H-17b),4.59-4.52(2H,m,H-15b and H-17a),4.38(1H,bs,3-OH),4.29-4.26(1H,d,J=11.0Hz,H-15a),3.09(1H,d,H-3),2.50-2.32(2H,m),2.121.91(8H,m),1.81-1.59(m,3H),1.32-1.20(5H,m),0.63(3H,s,H-20)13C-NMR(75MHz,CDCl3,ppm)δ:181.4(C-19),170.5(CH3CO),169.1(C-16),150.3(C-12),146.6(C-8),124.0(C-13),108.7(C-17),77.7(C-3),71.6(C-15),67.8(C-14),55.5(C-9),55.3(C-5),49.4(C-4),39.8(C-10),37.9(C-7),37.7(C-1),28.5(C-2),25.4(C-6),25.3(C-11),24.1(C-18),20.7(CH3CO),12.8(C-20).
实施例7
3-O-乙酰基-14-O-乙酰基-19-甲氧酰基-穿心莲内酯(I3)的制备:
将3,14-O-乙酰基-19-羧基-穿心莲内酯(0.3g,0.67mmol)溶于DMF(10ml)中,加入K2CO3(0.10g,0.07mmol),室温搅拌下缓慢滴加碘甲烷(0.05ml,0.80mmol),1小时后停止反应。 反应液加乙酸乙酯(25ml)稀释并依次用水(3X30ml)、饱和食盐水(2X30ml)洗涤,分离有机层,无水硫酸钠干燥。将干燥的有机相浓缩,柱层析分离(石油醚∶乙酸乙酯=6∶1),最终得干燥的白色固体(0.19g,0.41mmol,产率61%)。mp:148-149℃.1H-NMR(300MHz,CDCl3,ppm)δ:7.01(1H,t,J=6.5Hz,H-12),5.92(1H,d,J=5.8Hz,H-14),4.96(1H,s,H-17b),4.61-4.52(3H,m,H-3,H-15b and H-17a),4.27-4.23(1H,d,J=11.2Hz,H-15a),3.66(3H,s,COOCH3),2.52-2.29(4H,m),2.12(3H,s,CH3CO),2.07(3H,s,CH3CO),2.01-1.94(1H,m),1.86-1.80(3H,m),1.60-1.30(4H,m),1.25(3H,s,H-18),0.65(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:173.8(C-19),170.9(CH3CO),170.4(CH3CO),169.0(C-16),150.1(C-12),146.4(C-8),124.0(C-13),109.0(C-17),79.0(C-3),71.5(C-15),67.8(C-14),55.6(C-9),55.3(C-5),51.1(COOCH3),48.4(C-4),39.3(C-10),37.6(C-7),37.1(C-1),25.2(C-2),25.2(C-6),24.5(C-11),24.0(C-18),21.2(CH3CO),20.6(CH3CO),12.4(C-20).
实施例8
3-O-乙酰基-14-O-乙酰基-19-苄氧酰基-穿心莲内酯(I4)的制备:
将3,14-O-乙酰基-19-羧基-穿心莲内酯(0.3g,0.67mmol)溶于DMF(10ml)中,加入K2CO3(0.10g,0.07mmol),室温搅拌下缓慢滴加苄溴(0.10ml,0.84mmol),1小时后停止反应。反应液加乙酸乙酯(25ml)稀释并依次用水(3X30ml)、饱和食盐水2X30ml)洗涤,分离有机层,无水硫酸钠干燥。将干燥的有机相浓缩,柱层析分离(石油醚∶乙酸乙酯=6∶1),最终得干燥的白色固体(0.20g,0.37mmol,产率55%)。mp:50-52℃.1H-NMR(300MHz,CDCl3,ppm)δ:7.35-7.31(5H,m,PhCH2),7.00(1H,t,J=6.6Hz,H-12),5.91(1H,d,J=5.8Hz,H-14),5.12(2H,q,J=12.0Hz,PhCH2),4.88(1H,s,H-17b),4.62-4.50(3H,m,H-3,H-15b and H-17a),4.26-4.22(1H,d,J=11.2Hz,H-15a),2.50-2.30(4H,m),2.11(3H,s,CH3CO),2.04(3H,s,CH3CO),2.00-1.90(2H,m),1.82-1.79(3H,m),1.61-1.32(4H,m),1.29(3H,s,H-18),0.60(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:173.1(C-19),170.8(CH3CO),170.4(CH3CO),169.0(C-16),150.1(C-12),146.4(C-8),135.8(PhCH2),128.5(PhCH2),128.2(PhCH2),128.1(PhCH2),124.0(C-13),109.0(C-17),79.0(C-3),71.5(C-15),67.8(C-14),66.1(PhCH2),55.5(C-9),55.4(C-5),48.5(C-4),39.3(C-10),37.6(C-7),37.0(C-1),25.2(C-2),25.2(C-6),24.6(C-11),24.3(C-18),21.2(CH3CO),20.7(CH3CO),12.5(C-20).
实施例9
14-O-苯甲酰基-穿心莲内酯的制备:
将3,19-异丙氧基-穿心莲内酯(6.00g,15.36mmol)溶于无水二氯甲烷(130ml)中,室温下依次加入三乙胺(2.58ml,18.44mmol)、DMAP(催化量)、苯甲酰氯(2.16ml,18.44mmol)。 4小时后停止反应,反应液加二氯甲烷(100ml)稀释,再依次用饱和碳酸氢钠溶液(3X150ml)、饱和食盐水(3X150ml)洗涤。有机相不经干燥直接浓缩,将浓缩的粗产品3,19-异丙氧基-14-苯甲酰基-穿心莲内酯在室温下溶解于乙酸的水溶液(乙酸∶水=42ml∶18ml),反应完成后,加碳酸氢钠粉末搅拌至无气泡溢出,反应液加二氯甲烷(80ml)稀释,分离有机层并依次用饱和碳酸氢钠溶液(3X100ml)、饱和食盐水(3X100ml)洗涤,无水硫酸钠干燥。将干燥的有机相浓缩,柱层析纯化(石油醚∶乙酸乙酯=2∶1),最终得干燥的白色泡沫状物质(6.03g,13.25mmol,产率85%)。mp:88-90℃.1H-NMR(300MHz,CDCl3,ppm)δ:8.02(2H,d,J=1.4Hz,PhCO),7.62(1H,t,J=7.4Hz,PhCO),7.47(2H,t,J=7.7Hz,PhCO),7.10(1H,td,J=6.8,1.4Hz,H-12),6.17(1H,d,J=5.9Hz,H-14),4.85(1H,s,H-17b),4.67(1H,dd,J=11.3,6.2Hz,H-15b),4.51(1H,s,H-17a),4.37(1H,dd,J=11.3,1.9Hz,H-15a),4.14(1H,d,J=11.2,H-19b),3.46(1H,t,J=16.0Hz,H-3),3.29(1H,d,J=11.2Hz,H-19a),2.57-2.37(3H,m),2.02-1.95(4H,m),1.90-1.68(5H,m),1.23(3H,s,H-18),1.34-1.14(2H,m),0.59(3H,s,H-20).
实施例10
14-O-苯甲酰基-19-醛基-穿心莲内酯的制备:
参照实施例3的制备方法,由14-O-苯甲酰基-穿心莲内酯制得,产率83%。mp:98-102℃. 1H-NMR(300MHz,CDCl3,ppm)δ:9.72(1H,s,H-19),8.03(2H,d,J=7.2Hz,PhCO),7.62(1H,t,J=7.5Hz,PhCO),7.47(2H,t,J=7.7Hz,PhCO),7.10(1H,td,J=6.8,1.4Hz,H-12),6.18(1H,d,J=6.3Hz,H-14),4.91(1H,s,H-17b),4.67(1H,dd,J=11.3,6.2Hz,H-15b),4.56(1H,s,H-17a),4.38(1H,dd,J=11.3,1.9Hz,H-15a),3.23-3.19(1H,m),2.77(1H,s),2.56-2.44(3H,m),2.05-1.90(3H,m),1.83-1.75(2H,m),1.67-1.54(2H,m),1.28(3H,s,H-18),1.39-1.21(2H,m),0.58(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:207.5(C-19),169.1(C-16),166.1(PhCO),150.3(C-12),146.1(C-8),133.8(PhCO),129.8(PhCO),128.8(PhCO),128.7(PhCO),124.1(C-13),109.5(C-17),77.5(C-3),71.7(C-15),68.3(C-14),55.5(C-9),54.5(C-5),52.8(C-4),39.4(C-10),37.5(C-7),37.0(C-1),28.5(C-2),25.4(C-6),23.7(C-11),19.4(C-18),13.7(C-20).
实施例11
3-O-乙酰基-14-O-苯甲酰基-19-醛基-穿心莲内酯的制备:
参照实施例4的制备方法,由14-O-苯甲酰基-19-醛基-穿心莲内酯制得,产率60%。mp:145-146℃.1H-NMR(300MHz,CDCl3,ppm)δ:10.01(1H,s,H-19),8.03(2H,d,J=7.2Hz,PhCO),7.62(1H,t,J=7.5Hz,PhCO),7.47(2H,t,J=7.6Hz,PhCO),7.09(1H,td,J=6.8,1.4Hz,H-12),6.18(1H,d,J=5.8Hz,H-14),4.88(1H,s,H-17b),4.73-4.65(2H,m,H-3and H-15b),4.53(1H,s,H-17a),4.38(1H,dd,J=11.3,1.9Hz,H-15a),2.56-2.39(4H,m),2.05(3H,s,CH3CO), 2.13-1.82(6H,m),1.49-1.34(3H,m),1.08(3H,s,H-18),0.58(3H,s,H-20).13C-NMR 75MHz,CDCl3,ppm)δ:204.0(C-19),170.3(CH3CO),169.0(C-16),166.1(PhCO),150.1(C-12),146.0(C-8),133.9(PhCO),129.8(PhCO),128.8(PhCO),128.7(PhCO),124.2(C-13),107.5(C-17),78.1(C-3),71.6(C-15),68.3(C-14),56.4(C-9),54.4(C-5),52.0(C-4),39.0(C-10),37.2(C-7),36.3(C-1),25.4(C-2),24.6(C-6),23.9(C-11),21.0(CH3CO),20.9(C-18),15.1(C-20).
实施例12
3-O-乙酰基-14-O-苯甲酰基-19-羧基-穿心莲内酯(II2)的制备:
参照实施例5的制备方法,由3-O-乙酰基-14-O-苯甲酰基-19-醛基-穿心莲内酯制得,产率50%。mp:109-111℃.1H-NMR(300MHz,DMSO-d6,ppm)δ:12.29(1H,s,H-19),7.96(2H,d,J=7.4Hz,PhCO),7.69(1H,t,J=7.2Hz,PhCO),7.54(2H,t,J=7.7Hz,PhCO),6.92(1H,t,J=6.3Hz,H-12),6.23(1H,d,J=5.6Hz,H-14),4.81(1H,s,H-17b),4.69(1H,dd,J=11.0,6.1Hz,H-15b),4.52-4.44(3H,m,H-17a,H-3,H-15a),2.45-2.30(3H,m),1.99(3H,s,CH3CO),2.05-1.71(4H,m),1.58-1.34(5H,m),1.06(3H,s,H-18),0.59(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:178.9(C-19),170.8(CH3CO),169.2(C-16),166.0(PhCO),150.4(C-12),146.2(C-8),133.8(PhCO),129.8(PhCO),128.8(PhCO),128.7(PhCO),124.2(C-13),109.1(C-17),78.7(C-3),71.7(C-15),68.3(C-14),55.5(C-9),55.3(C-5),48.2(C-4),39.5(C-10),37.5(C-7),37.1(C-1),25.3(C-2),25.0(C-6),24.4(C-11),24.1(C-18),21.2(CH3CO),12.5(C-20).
实施例13
14-O-苯甲酰基-19-羧基-穿心莲内酯(II1)的制备:
参照实施例5的制备方法,由14-O-苯甲酰基-19-醛基-穿心莲内酯制得,产率51%。mp:164-165℃.1H-NMR(300MHz,DMSO-d6,ppm)δ:12.29(1H,s,H-19),7.97(2H,d,J=7.3Hz,PhCO),7.69(1H,t,J=7.2Hz,PhCO),7.55(2H,t,J=7.7Hz,PhCO),6.92(1H,t,J=6.2,Hz,H-12),6.22(1H,d,J=5.7Hz,H-14),4.80(1H,s,H-17b),4.69(1H,dd,J=11.1,6.2Hz,H-15b),4.50(1H,s,H-17a),4.45(1H,dd,J=11.1,1.9Hz,H-15a),4.35(1H,s,3-OH),3.08-3.05(1H,m,H-3),2.62-2.39(3H,m),2.36-1.85(4H,m),1.71-1.53(3H,m),1.25(3H,s,H-18),1.29-1.18(2H,m),0.58(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:181.6(C-19),169.3(C-16),166.1(PhCO),150.7(C-12),146.5(C-8),133.8(PhCO),129.8(PhCO),128.8(PhCO),128.7(PhCO),124.0(C-13),108.8(C-17),77.7(C-3),71.7(C-15),68.3(C-14),55.5(C-9),55.2(C-5),49.3(C-4),39.8(C-10),37.8(C-7),37.7(C-1),28.4(C-2),25.3(C-6),25.3(C-11),24.0(C-18),12.7(C-20).
实施例14
3-O-乙酰基-14-O-苯甲酰基-19-甲氧酰基-穿心莲内酯(II3)的制备:
参照实施例7的制备方法,由3-O-乙酰基-14-O-苯甲酰基-19-羧基-穿心莲内酯制得,产率62%。mp:68-71℃.1H-NMR(300MHz,CDCl3,ppm)δ:8.01(2H,d,J=7.2Hz,PhCO),7.62(1H,t,J=7.4Hz,PhCO),7.47(2H,t,J=7.6Hz,PhCO),7.10(1H,t,J=6.1Hz,H-12),6.17(1H,d,J=5.8Hz,H-14),4.88(1H,s,H-17b),4.67(1H,dd,J=11.3,6.2Hz,H-15b),4.58-4.52(2H,m,H-3,H-17a),4.38(1H,dd,J=11.3,1.8Hz,H-15a),3.63(3H,s,COOCH3),2.60-2.33(4H,m),2.06(3H,s,CH3CO),1.99-1.74(5H,m),1.47-1.23(3H,m),1.16(3H,s,H-18),0.57(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:173.8(C-19),170.9(CH3CO),169.1(C-16),166.1(PhCO),150.5(C-12),146.4(C-8),133.8(PhCO),129.8(PhCO),128.8(PhCO),128.7(PhCO),124.1(C-13),109.1(C-17),79.0(C-3),71.7(C-15),68.3(C-14),55.5(C-9),55.3(C-5),51.1(COOCH3),48.4(C-4),39.3(C-10),37.5(C-7),37.1(C-1),25.3(C-2),25.2(C-6),24.5(C-11),24.0(C-18),21.3(CH3CO),12.4(C-20).
实施例15
3-O-乙酰基-14-O-苯甲酰基-19-苄氧酰基-穿心莲内酯(II4)的制备:
参照实施例8的制备方法,由3-O-乙酰基-14-O-苯甲酰基-19-羧基-穿心莲内酯制得,产率49%。mp:64-67℃.1H-NMR(300MHz,CDCl3,ppm)δ:8.02(2H,d,J=7.5Hz,PhCO),7.62(1H,t,J=7.4Hz,PhCO),7.47(2H,t,J=7.6Hz,PhCO),7.33(5H,s,PhCH2),7.09(1H,t,J=6.5Hz,H-12),6.16(1H,d,J=5.8Hz,H-14),5.09(2H,q,J=12.5Hz,PhCH2),4.86(1H,s,H-17b),4.67(1H,dd,J=12.2,6.1Hz,H-15b),4.57(1H,dd,J=12.1,3.9Hz,H-3),4.51(1H,s,H-17a),4.38(1H,dd,J=11.2,6.2Hz,H-15a),2.58-2.33(4H,m),2.03(3H,s,CH3CO),1.98-1.76(4H,m),1.51-1.31(4H,m),1.27(3H,s,H-18),0.53(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:173.1(C-19),170.8(CH3CO),170.8(CH3CO),169.1(C-16),166.0(PhCO),150.6(C-12),146.3(C-8),135.8(PhCH2),133.8(PhCO),129.8(PhCO),128.8(PhCO),128.7(PhCO),128.4(PhCH2),128.0(PhCH2),128.0(PhCH2),124.0(C-13),109.1(C-17),79.0(C-3),71.7(C-15),68.4(C-14),66.1(PhCH2),55.4(C-9),55.3(C-5),48.5(C-4),39.3(C-10),37.5(C-7),37.0(C-1),25.3(C-2),25.1(C-6),24.6(C-11),24.3(C-18),21.2(CH3CO),12.5(C-20).
实施例16
14-O-(4-甲氧基)肉桂酰基-穿心莲内酯的制备:
冰浴及氮气保护条件下,向溶有4-甲氧基肉桂酸(3.00g,16.83mmol)的二氯甲烷/三乙胺(150ml/7ml)溶液中缓慢加入三氟甲磺酸酐(3.3ml,19.49mmol),15分钟后将溶有3,19-异丙氧基-穿心莲内酯(5.25g,13.44mmol)的二氯甲烷(50ml)溶液缓慢加入到上述反应瓶中,1小时后升至室温,4天后停止反应。反应液加二氯甲烷(100ml)稀释,再依次用饱和碳 酸氢钠溶液(2X300ml)、饱和食盐水(2X300ml)洗涤。有机相不经干燥直接浓缩,将浓缩物在室温下溶解于乙酸的水溶液(乙酸∶水=42ml∶18ml),反应完成后,加碳酸氢钠粉末搅拌至无气泡溢出,反应液加二氯甲烷(120ml)稀释,分离有机层并依次用饱和碳酸氢钠溶液(3X120ml)、饱和食盐水(3X120ml)洗涤,无水硫酸钠干燥。将干燥的有机相浓缩,柱层析分离(石油醚∶乙酸乙酯=2∶1),最终得干燥的白色泡沫状物质(2.91g,5.70mmol,产率42%)。mp:89-91℃.1H-NMR(300MHz,CDCl3,ppm)δ:7.69(1H,d,J=16.0Hz CH=CHCO),7.49(2H,d,J=8.7Hz CH3OPh),7.05(1H,t,J=6.7Hz,H-12),6.93(2H,d,J=8.7Hz CH3OPh),6.29(1H,d,J=16.0Hz CH=CHCO),6.05(1H,d,J=5.7Hz,H-14),4.88(1H,s,H-17b),4.61(1H,dd,J=12.3,6.2Hz,H-15b),4.55(1H,s,H-17a),4.31(1H,dd,J=11.1,1.8Hz,H-15a),4.15(1H,d,J=11.1Hz,H-19b),3.85(3H,s,CH3OPh),3.48(1H,t,J=7.8Hz,H-3),3.31(1H,d,J=11.2Hz,H-19a),2.54-2.39(3H,m),1.95-1.72(9H,m),1.24(3H,s,H-18),1.34-1.16(2H,m),0.64(3H,s,H-20).
实施例17
14-O-(4-甲氧基)肉桂酰基-19-醛基-穿心莲内酯的制备:
参照实施例3的制备方法,由14-O-(4-甲氧基)-肉桂酰基-穿心莲内酯制得,产率85%。mp:76-78℃.1H-NMR(300MHz,CDCl3,ppm)δ:9.74(1H,s,H-19),7.69(1H,d,J=16.0HzCH=CHCO),7.48(2H,d,J=8.7Hz CH3OPh),7.05(1H,t,J=6.6Hz,H-12),6.92(2H,d,J=8.6Hz CH3OPh),6.28(1H,d,J=16.0Hz CH=CHCO),6.06(1H,d,J=5.6Hz,H-14),4.95(1H,s,H-17b),4.64-4.59(2H,m,H-15b,H-17a),4.32(1H,dd,J=11.2,1.8Hz,H-15a),3.85(3H,s,CH3OPh),3.26-3.22(1H,m,H-3),2.54-2.43(3H,m),2.05-1.80(9H,m),1.67-1.55(2H,m),1.29(3H,s,H-18),1.42-1.23(2H,m),0.63(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:207.5(C-19),169.2(C-16),166.1(CH=CHCO),162.0(CH3OPh),149.9(C-12),146.5(C-8),146.0(CH=CHCO),130.0(CH3OPh),126.6(CH3OPh),124.4(C-13),114.5(CH=CHCO),113.7(CH3OPh),109.5(C-17),77.5(C-3),71.8(C-15),67.5(C-14),55.5(C-9),55.4(CH3OPh),54.7(C-5),52.8(C-4),39.5(C-10),37.6(C-7),37.1(C-1),28.6(C-2),25.3(C-6),23.8(C-11),19.4(C-18),13.7(C-20).
实施例18
3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-醛基-穿心莲内酯的制备:
参照实施例4的制备方法,由14-O-(4-甲氧基)-肉桂酰基-19-醛基-穿心莲内酯制得,产率76%。mp:83-86℃.1H-NMR(300MHz,CDCl3,ppm)δ:10.02(1H,s,H-19),7.69(1H,d,J=16.0Hz CH=CHCO),7.50(2H,d,J=8.7Hz CH3OPh),7.04(1H,t,J=6.0Hz,H-12),6.92(2H,d, J=8.7Hz CH3OPh),6.28(1H,d,J=16.0Hz CH=CHCO),6.06(1H,d,J=5.5Hz,H-14),4.92(1H,s,H-17b),4.72(1H,dd,J=10.6,6.5Hz,H-3),4.64-4.57(2H,m,H-15b,H-17a),4.32(1H,dd,J=11.2,1.8Hz,H-15a),3.85(3H,s,CH3OPh),2.59-2.40(3H,m),2.05(3H,s,CH3CO),2.13-1.83(5H,m),1.56-1.26(4H,m),1.09(3H,s,H-18),0.63(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:204.0(C-19),170.3(CH3CO),169.1(C-16),166.6(CH=CHCO),161.9(CH3OPh),149.8(C-12),146.4(C-8),146.0(CH=CHCO),130.0(CH3OPh),126.6(CH3OPh),124.4(C-13),114.5(CH=CHCO),113.7(CH3OPh),109.5(C-17),78.2(C-3),71.7(C-15),67.5(C-14),56.4(C-9),55.4(CH3OPh),54.5(C-5),52.0(C-4),39.0(C-10),37.3(C-7),36.3(C-1),25.4(C-2),24.6(C-6),23.9(C-11),21.0(CH3CO),20.9(C-18),15.2(C-20).
实施例19
3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-羧基-穿心莲内酯(III2)的制备:
参照实施例5的制备方法,由3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-醛基-穿心莲内酯制得,产率63%。mp:121-124℃.1H-NMR(300MHz,DMSO-d6,ppm)δ:12.29(1H,s,H-19),7.71-7.64(3H,m,CH=CHCO,CH3OPh),6.95(2H,d,J=9.2Hz CH3OPh),6.88(1H,t,J=6.6Hz,H-12),6.52(1H,d,J=16.0Hz CH=CHCO),6.11(1H,d,J=5.6Hz,H-14),4.87(1H,s,H-17b),4.63(1H,dd,J=11.0,6.0Hz,H-15b),4.56(1H,s,H-17a),4.47(1H,dd,J=12.0,4.2Hz,H-3),4.34(1H,dd,J=11.2,1.8Hz,H-15a),3.80(3H,s,CH3OPh),2.44-2.32(3H,m),2.00(3H,s,CH3CO),2.03-1.75(5H,m),1.62-1.33(4H,m),1.14(3H,s,H-18),0.64(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:178.8(C-19),170.9(CH3CO),169.2(C-16),166.6(CH=CHCO),161.9(CH3OPh),150.1(C-12),146.4(C-8),146.3(CH=CHCO),130.0(CH3OPh),126.6(CH3OPh),124.3(C-13),114.5(CH=CHCO),113.7(CH3OPh),109.1(C-17),78.7(C-3),71.8(C-15),67.6(C-14),55.6(C-9),55.4(CH3OPh),55.3(C-5),48.2(C-4),39.5(C-10),37.6(C-7),37.0(C-1),25.2(C-2),25.1(C-6),24.5(C-11),24.1(C-18),21.2(CH3CO),15.2(C-20).
实施例20
14-O-(4-甲氧基)肉桂酰基-19-羧基-穿心莲内酯(III1)的制备:
参照实施例5的制备方法,由14-O-(4-甲氧基)肉桂酰基-19-醛基-穿心莲内酯制得,产率59%。mp:129-130℃.1H-NMR(300MHz,DMSO-d6ppm)δ:12.31(1H,s,H-19),7.71-7.64(3H,m,CH3OPh,CH=CHCO),6.98(2H,d,J=8.5Hz,CH3OPh),6.87(1H,t,J=6.4Hz,H-12),6.52(2H,d,J=16.0Hz CH=CHCO),6.09(1H,d,J=4.8Hz,H-14),4.85(1H,s,H-17b),4.63(1H,dd,J=10.9,6.0Hz,H-15b),4.54(1H,s,H-17a),4.33(1H,dd,J=10.8,1.8Hz,H-15a),3.80(3H,s,CH3OPh),3.09-3.06(1H,m,H-3),2.44-2.31(2H,m),2.14-1.85(5H,m),1.76-1.57(3H,m),1.26 (3H,s,H-18),1.31-1.51(3H,m),0.59(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:181.2(C-19),169.2(C-16),166.7(CH=CHCO),161.9(CH3OPh),150.4(C-12),146.5(C-8),146.5(CH=CHCO),130.0(CH3OPh),126.6(CH3OPh),124.2(C-13),114.5(CH=CHCO),113.7(CH3OPh),108.8(C-17),77.8(C-3),71.8(C-15),67.6(C-14),55.5(C-9),55.4(CH3OPh),55.3(C-5),49.3(C-4),39.8(C-10),37.9(C-7),37.7(C-1),28.5(C-2),25.4(C-6),25.3(C-11),24.0(C-18),13.8(C-20).
实施例21
3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-甲氧酰基-穿心莲内酯(III3)的制备:
参照实施例7的制备方法,由3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-羧基-穿心莲内酯制得,产率60%。mp:84-88℃.1H-NMR(300MHz,CDCl3,ppm)δ:7.69(1H,d,J=16.0HzCH=CHCO),7.49(2H,d,J=8.7Hz CH3OPh),7.05(1H,t,J=6.0Hz,H-12),6.92(2H,d,J=8.7Hz,CH3OPh),6.28(1H,d,J=16.0Hz,CH=CHCO),6.05(1H,d,J=5.7Hz,H-14),4.91(1H,s,H-17b),4.69-4.52(3H,m,H-3,H-15b,H-17a),4.32(1H,dd,J=11.2,1.7Hz,H-15a),3.85(3H,s,CH3OPh),3.63(3H,s,COCH3),2.58-2.40(4H,m),2.07(3H,s,CH3CO),1.99-1.77(5H,m),1.60-1.29(3H,m),1.24(3H,s,H-18),0.62(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:173.9(C-19),170.9(CH3CO),169.3(C-16),166.6(CH=CHCO),161.9(CH3OPh),150.2(C-12),146.4(C-8),146.4(CH=CHCO),130.1(CH3OPh),126.6(CH3OPh),124.3(C-13),114.5(CH=CHCO),113.8(CH3OPh),109.1(C-17),79.0(C-3),71.8(C-15),67.6(C-14),55.6(C-9),55.4(CH3OPh),55.3(C-5),51.1(COOCH3),48.4(C-4),39.4(C-10),37.6(C-7),37.1(C-1),25.2(C-2),25.2(C-6),24.5(C-11),24.0(C-18),21.3(CH3CO),12.4(C-20).
实施例22
3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-苄氧酰基-穿心莲内酯(III4)的制备:
参照实施例8的制备方法,由3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-羧基-穿心莲内酯制得,产率51%。mp:69-71℃.1H-NMR(300MHz,CDCl3,ppm)δ:7.69(1H,d,J=16.0HzCH=CHCO),7.49(2H,d,J=8.6Hz CH3OPh),7.3(5H,s,PhCH2),7.04(1H,t,J=6.1Hz,H-12),6.93(2H,d,J=8.7Hz,CH3OPh),6.28(1H,d,J=16.0Hz,CH=CHCO),6.04(1H,d,J=5.7Hz,H-14),5.09(2H,q,J=12.8Hz,PhCH2),4.89(1H,s,H-17b),4.63-4.54(3H,m,H-3,H-15b,H-17a),4.32(1H,dd,J=11.1,1.7Hz,H-15a),3.85(3H,s,CH3OPh),2.47-2.30(4H,m),2.03(3H,s,CH3CO),1.99-1.80(5H,m),1.63-1.29(4H,m),1.28(3H,s,H-18),0.57(3H,s,H-20).13C-NMR(75MHz,CDCl3,ppm)δ:173.2(C-19),170.8(CH3CO),169.1(C-16),166.6(CH=CHCO),161.9(CH3OPh),150.2(C-12),146.4(C-8),146.4(CH=CHCO),135.8(PhCH2),130.0(CH3OPh),128.4 (PhCH2),128.1(PhCH2),126.6(CH3OPh),124.3(C-13),121.3(PhCH2),114.5(CH=CHCO),113.8(CH3OPh),109.1(C-17),79.1(C-3),71.8(C-15),67.6(C-14),66.1(PhCH2),55.6(C-9),55.4(CH3OPh),55.3(C-5),48.5(C-4),39.4(C-10),37.6(C-7),37.0(C-1),25.2(C-2),25.2(C-6),24.6(C-11),24.4(C-18),21.2(CH3CO),12.5(C-20)。
Claims (6)
2.根据权利要求1所述的一种19-羧基穿心莲内酯衍生物,其特征在于:所述的脂肪族酰基的取代基为1~8个碳的直链或支链式胺基、1~8个碳的直链或支链式烷氧基、取代或未取代的芳香基。
3.根据权利要求1所述的一种19-羧基穿心莲内酯衍生物,其特征在于:所述的烷基的取代基为1~8个碳的直链或支链式胺基、1~8个碳的直链或支链式烷氧基、取代或未取代的芳香基。
4.根据权利要求1、2或3所述的一种19-羧基穿心莲内酯衍生物,其特征在于:所述的苯甲酰基、苯基及芳香基的取代基为氟、氯、溴、胺基、乙酰胺基、羟基、甲氧基。
5.根据权利要求1至4所述的一种19-羧基穿心莲内酯衍生物,其特征在于:所述的优选化合物为:
14-O-乙酰基-19-羧基穿心莲内酯;
3-O-乙酰基-14-O-乙酰基-19-羧基穿心莲内酯;
3-O-乙酰基-14-O-乙酰基-19-甲氧羰基穿心莲内酯;
3-O-乙酰基-14-O-乙酰基-19-苄氧羰基穿心莲内酯;
14-O-苯甲酰基-19-羧基穿心莲内酯;
3-O-乙酰基-14-O-苯甲酰基-19-羧基穿心莲内酯;
3-O-乙酰基-14-O-苯甲酰基-19-甲氧羰基穿心莲内酯;
3-O-乙酰基-14-O-苯甲酰基-19-苄氧羰基穿心莲内酯;
14-O-(4-甲氧基)肉桂酰基-19-羧基穿心莲内酯;
3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-羧基穿心莲内酯;
3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-甲氧羰基穿心莲内酯;
3-O-乙酰基-14-O-(4-甲氧基)肉桂酰基-19-苄氧羰基穿心莲内酯。
6.根据权利要求1所述的一种19-羧基穿心莲内酯衍生物在制备抗肿瘤药物中的用途。
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