本发明涉及药物化合物，具体提供了一种小白菊内酯-苯磺酰基呋咱衍生物及其盐，并涉及小白菊内酯-苯磺酰基呋咱衍生物及其盐的制备及其在制备抗癌药物中的用途。
背景技术：
：小白菊内酯(parthenolide)是从木兰科观光木属植物观光木、菊科植物野甘菊中提取分离出来的倍半萜烯内酯化合物，作为草药可能有助于癌症，白血病和偏头痛的治疗。其活性基团c环上的α，β-不饱和内酯，能够选择性的杀死白血病细胞，但是其水溶性、血浆稳定性较差，而且活性也较低，有人研究试图通过对其进行结构修饰来进一步提高其活性、水溶性以及血浆稳定性[q.zhang,y.lu,etl.y.chen,guaianolidesesquiterpenelactones,asourcetodiscoveragentsthatselectivelyinhibitacutemyelogenousleukemiasternandprogenitorcells,j.med.chem.,55(2012)8757-8769.]。近几十年，一氧化氮供体是常被人们用以阐明许多过去未能解释的生理现象，迅速成为近年来研究的热点。一氧化氮自由基是一种寿命较短的自由基，半衰期仅数秒钟，因为其分子小且具有亲脂性，所以很容易透过细胞膜[huertas,chilkas,bonavidab,nitricoxidedonors:novelcancertherapeutics(review).internationaljournalofoncology,2008,33(5):909-927.]。一氧化氮在体内由l-精氨酸和氧分子在一氧化氮合酶(nos)催化下生成。在哺乳动物生理和病理生理反应中发挥着非常重要的作用，如参与维持微血管和大血管的动态平衡、神经信号传导、免疫炎症的调节、肿瘤发生与转移等多种生理病理过程[thomasdd,ridnourla,isenbergjs,etal,thechemicalbiologyofnitricoxide:implicationsincellularsignaling.freeradicalbiologyandmedicine,2008,45(1):18-31；kiechlefl,malinskit,nitricoxide.biochemistry,pathophysiology,anddetection.americanjournalofclinicalpathology,1993,100(5):567-575.]。体内no缺乏常与多种疾病的形成密切相关，因此外源性no对于这些疾病的预防和治疗有着重要意义。所以，no供体药物成为了热门的新型药物研究对象，苯磺酰基呋咱是一种常见的no供体单元。本发明提供了此类小白菊内酯-苯磺酰呋咱衍生物或其盐的制备，以其为有效成分的治疗癌症或辅助治疗癌症的药物组合物，以及该药物化合物和组合物在制备抗癌或辅助抗癌药物中的应用。技术实现要素：本发明提供了式(ⅰ)所示的小白菊内酯-苯磺酰基呋咱衍生物及其盐，并涉及如式(ⅰ)所示的小白菊内酯-苯磺酰基呋咱衍生物及其盐在制备抗癌药物中的应用。如式(ⅰ)所示的小白菊内酯-苯磺酰基呋咱衍生物，式(ⅰ)中x为氧原子或氮原子；并且r1为如下结构之一：式(ⅰ)中，r5可以存在也可以不存在，当r5不存在时，r3、r4共同构成单键；或当r3和r5为氢时，r4为-nr6r7；其中r6和r7可以相同或不同，分别为氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；r6、r7和n原子形成环状结构。本发明的另一优选方案是，在上述方案的基础上，r6、r7和n原子形成环状结构为3–9元环，环状结构上可以被一个或多个取代基取代，取代基包括氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基。本发明的另一优选方案是，在上述方案的基础上，所述小白菊内酯-苯磺酰基呋咱衍生物与无机酸或有机酸形成的在药学上可接受的盐。本发明的另一优选方案是，在上述方案的基础上，所述无机酸为氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸，硼酸、亚硒酸、磷钼酸、亚磷酸或亚硫酸。本发明的另一优选方案是，在上述方案的基础上，所述有机酸为柠檬酸、马来酸、d-苹果酸、l-苹果酸、dl-苹果酸、l-乳酸、d-乳酸、dl-乳酸、草酸、甲磺酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、酒石酸、丙二酸、丁二酸、富马酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸或取代苯甲酸。本发明的另一优选方案是，在上述方案的基础上，包括所述小白菊内酯-苯磺酰基呋咱衍生物与r8z形成的季铵盐，z为氟、氯、溴、碘、对甲苯磺酸酯基、甲磺酸酯基、苯磺酸酯基或三氟甲基磺酸酯基；r8为烃基、环烷基、羟基取代烷基、烯基、炔基、芳基、杂环基、芳基取代烷基、芳基烯基、芳基炔基、氰基取代甲基、烷氧基取代烷基或芳氧取代烷基。本发明的另一优选方案是，在上述方案的基础上，还提供如式(ⅱ)–(ⅷ)任意一项化学式所示的小白菊内酯-苯磺酰基呋咱衍生物，(ⅷ)中r4为-nr6r7；其中r6和r7可以相同或不同，分别为氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；r6、r7和n原子形成环状结构，环优选为3–9元环，环状结构上可以被一个或多个取代基取代，包括氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基；及式(ⅱ)–(ⅷ)所示化合物与无机酸或有机酸形成的在药学上可接受的盐，包括与r8z形成的季铵盐，z为氟、氯、溴、碘、对甲苯磺酸酯基、甲磺酸酯基、苯磺酸酯基或三氟甲基磺酸酯基；r8为烃基、环烷基、羟基取代烷基、烯基、炔基、芳基、杂环基、芳基取代烷基、芳基烯基、芳基炔基、氰基取代甲基、烷氧基取代烷基或芳氧取代烷基；无机酸或有机酸为氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸，硼酸、亚硒酸、磷钼酸、亚磷酸、亚硫酸、柠檬酸、马来酸、d-苹果酸、l-苹果酸、dl-苹果酸、l-乳酸、d-乳酸、dl-乳酸、草酸、甲磺酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、酒石酸、丙二酸、丁二酸、富马酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸或取代苯甲酸。本发明还提供所述小白菊内酯-苯磺酰基呋咱衍生物或其盐在制备抗癌药物或制备辅助抗癌药物中的用途，其中癌症为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子宫颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。本发明还提供所述小白菊内酯-苯磺酰基呋咱衍生物或其盐与药学上可接受的载体或与其他抗癌药物形成的组合物。具体实施方式为了理解本发明，下面结合实施例进一步说明本发明，但本发明的保护范围并不仅限于这些实施例。实施例1：式(ⅰ)所示的小白菊内酯-苯磺酰基呋咱衍生物及其盐的合成化合物1为实施例中各化合物具体合成路线1-8以及化合物的化学式如下：其中，化合物6-16按路线1合成，化合物20-22和31-38按路线2合成，化合物47-54按路线3合成，化合物57a-57b和60按路线4合成，化合物62a-62e,65a-65b和66按路线5合成，化合物67-71按路线6合成，化合物72a-72i按路线7合成，化合物73-74按路线8合成。化合物2的合成将化合物1(6.0g，35.67mmol)溶于冰乙酸(30.0ml)中，加入30％的过氧化氢溶液(h2o2)(12.0ml),反应体系在室温下搅拌3小时,在0℃下，缓慢的将发烟硝酸(16ml)滴加到上述体系中，90℃下搅拌4小时，冷却至室温，加入少量水，0℃下搅拌30min，产生白色固体，过滤干燥得化合物2(白色固体，3600.0mg，产率50.5％)。1hnmr(400mhz,cdcl3)δ8.15(dd,j＝12.8,7.5hz,2h),7.89–7.73(m,1h),7.65(dt,j＝15.5,7.9hz,2h)；13cnmr(100mhz,cdcl3)δ155.7,137.1,136.3,136.2,136.0,130.3,130.0,129.7,129.2,115.2；hrms(esi)计算值c14h10n2nao6s2[m+na]+388.9872,测量值388.9878.化合物4的合成依次取化合物3(30g，121mmol)和二氧化硒(7.6g，68mmol)于反应瓶中，加入二氯甲烷(563ml)，室温下开始搅拌，将预先用无水硫酸镁和无水硫酸钠干燥的过氧化氢叔丁醇(27g，304mmol)加入到上述体系中，反应体系在室温下反应4天，通过tlc检测反应完全后，加过量的饱和硫代硫酸钠，搅拌10分钟，分离有机相，用二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至2:1)得到化合物4(白色无定型固体，20g，产率：62.5％)。1hnmr(400mhz,cdcl3)δ6.15(d,j＝3.5hz,1h),5.60(t,j＝8.2hz,1h),5.52(d,j＝3.2hz,1h),4.05(dd,j＝32.1,12.9hz,2h),3.81(t,j＝9.4hz,1h),2.86–2.76(m,2h),2.48–2.39(m,1h),2.37–2.31(m,3h),2.29–2.20(m,1h),2.20–2.13(m,1h),2.12–2.05(m,1h),1.65–1.55(m,1h),1.49(s,3h),1.03(t,j＝12.4hz,1h).13cnmr(100mhz,cdcl3)δ169.9,139.5,138.8,126.8,120.4,81.4,65.4,63.3,60.4,42.7,36.8,25.5,24.0,23.6,18.0.hrms(esi)计算值c15h20nao4[m+na]+287.1254,测量值287.1258.化合物5的合成依次取化合物4(10g，3.78mmol)和丁二酸酐(0.45g，4.54mmol)，4-二甲氨基吡啶(0.46g，3.78mmol)于反应瓶中，加入二氯甲烷(50ml)，室温下搅拌8小时，通过tlc检测反应完全后，加1n的盐酸调ph到3，分离有机相，用二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物5(白色无定型固体，11.2g，产率：78.5％)。1hnmr(400mhz,cdcl3)δ9.40(s,1h),6.12(d,j＝3.4hz,1h),5.60(t,j＝7.5hz,1h),5.50(d,j＝2.8hz,1h),4.60(d,j＝12.5hz,1h),4.40(d,j＝12.5hz,1h),3.79(t,j＝9.3hz,1h),2.81(dd,j＝22.9,9.2hz,2h),2.67–2.49(m,4h),2.41–2.01(m,6h),1.61(dd,j＝17.7,8.0hz,1h),1.46(s,3h),1.01(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ177.0,171.8,169.5,138.5,134.4,130.3,120.2,81.0,80.9,66.9,63.0,60.1,60.0,42.3,36.2,29.3,28.6,28.5,28.2,25.3,24.1,23.5,17.6,16.9.hrms(esi)计算值c19h24nao7[m+na]+387.1414,测量值387.1418.化合物6的合成在0℃下，将乙二醇(67.8mg，1.09mmol)溶于重蒸的thf(3.0ml)中，加入25％naoh溶液(0.1ml)，搅拌1–2min后，加入苯磺酰基呋咱(2)(100.0mg，0.273mmol)，室温下搅拌8h，用tlc检测反应完全，用饱和氯化铵淬灭反应，乙酸乙酯萃取三次，用无水硫酸镁干燥有机相，过滤，减压浓缩，简单纯化得化合物6a(白色无定型固体，51.0mg，产率65.3％)。将化合物5(100mg，0.27mmol)溶于二氯甲烷(5.0ml)中，依次加入化合物6a(51.48mg，0.18mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐edci(52.3mg，0.27mmol)，4-二甲氨基吡啶dmap(2.2mg，0.018mmol)，三乙胺(38μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物6(白色无定型固体，95.3mg，产率：83.8％)。1hnmr(400mhz,cdcl3)δ8.06(d,j＝7.7hz,2h),7.76(t,j＝7.3hz,1h),7.63(t,j＝7.6hz,2h),6.23(d,j＝2.9hz,1h),5.69(t,j＝7.5hz,1h),5.56(d,j＝2.1hz,1h),4.68(d,j＝12.5hz,1h),4.63(d,j＝4.0hz,2h),4.57–4.42(m,3h),2.91(t,j＝9.3hz,1h),2.85(d,j＝9.4hz,1h),2.76–2.58(m,4h),2.50–2.09(m,6h),1.72–1.62(m,1h),1.54(s,3h),1.10(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ172.0,171.9,169.4,158.6,138.8,137.9,135.7,134.7,130.7,129.7,128.6,120.3,81.0,68.8,67.1,63.2,61.4,59.9,42.6,36.6,29.7,28.8,28.8,25.7,24.5,23.8,18.0.hrms(esi)计算值c29h36n3o12s[m+nh4]+650.2014,测量值650.2023.化合物7的合成步骤同上，得到化合物7(白色无定型固体，87.6mg，产率：75.2％)。1hnmr(400mhz,cdcl3)δ8.03(d,j＝8.0hz,2h),7.75(t,j＝7.4hz,1h),7.61(t,j＝7.7hz,2h),6.21(d,j＝3.2hz,1h),5.67(t,j＝7.9hz,1h),5.56(d,j＝2.8hz,1h),4.63(d,j＝12.5hz,1h),4.49(t,j＝6.0hz,2h),4.44(d,j＝12.5hz,1h),4.28(t,j＝6.0hz,2h),2.95–2.86(m,1h),2.83(d,j＝9.4hz,1h),2.68–2.54(m,4h),2.49–2.09(m,8h),1.66(dd,j＝17.0,8.1hz,1h),1.52(s,2h),1.08(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ172.1,171.9,169.3,158.7,138.7,137.8,135.6,134.6,130.6,129.6,129.3,128.4,120.1,110.4,80.9,67.9,67.0,63.1,60.5,59.9,42.5,36.5,28.8,28.7,27.8,25.6,24.4,23.7,17.9.hrms(esi)计算值c30h38n3o12s[m+nh4]+664.2171测量值664.2171.化合物8的合成步骤同上，得到化合物8(白色无定型固体，82.3mg，产率：69.2％)。1hnmr(400mhz,cdcl3)δ8.03(d,j＝7.8hz,2h),7.75(t,j＝7.5hz,1h),7.69–7.53(m,2h),6.21(d,j＝3.4hz,1h),5.67(t,j＝8.1hz,1h),5.56(d,j＝3.0hz,1h),4.66(d,j＝12.5hz,1h),4.45(m,3h),4.16(t,j＝6.3hz,2h),3.84(t,j＝9.3hz,1h),2.96–2.87(m,1h),2.84(d,j＝9.4hz,1h),2.66–2.59(m,4h),2.48–2.09(m,6h),1.99–1.90(m,2h),1.81(dt,j＝12.8,6.2hz,2h),1.66(t,j＝10.6hz,1h),1.52(s,3h),1.08(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ172.2,172.0,169.4,158.8,138.7,137.8,135.6,134.6,130.6,129.6,128.4,120.2,110.4,80.9,70.9,67.0,63.9,63.1,59.9,42.5,36.5,28.8,28.8,25.6,25.1,24.8,24.4,23.7,17.9.hrms(esi)计算值c31h40n3o12s[m+nh4]+678.2327,测量值678.2328.化合物9的合成步骤同上，得到化合物9(白色无定型固体，74.9mg，产率：61.7％)。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.8hz,2h),7.76(t,j＝7.3hz,1h),7.62(t,j＝7.5hz,2h),6.22(s,1h),5.68(t,j＝7.8hz,1h),5.56(s,1h),4.66(d,j＝12.5hz,1h),4.47(d,j＝12.6hz,1h),4.42(t,j＝6.1hz,2h),4.12(t,j＝6.2hz,2h),3.84(t,j＝9.3hz,1h),2.92(t,j＝9.7hz,1h),2.84(d,j＝9.4hz,1h),2.62(s,4h),2.47–2.09(m,6h),1.89(dd,j＝13.7,6.7hz,2h),1.78–1.62(m,4h),1.53(s,4h),1.09(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ172.4,172.2,169.5,159.1,138.9,138.1,135.8,134.8,130.7,129.8,128.6,120.4,110.6,81.1,71.3,67.2,64.4,63.3,60.0,42.7,36.6,29.0,29.0,28.1,28.1,25.8,24.6,23.9,22.2,18.1.hrms(esi)计算值c32h42n3o12s[m+nh4]+692.2484,测量值692.2492.化合物10的合成步骤同上，得到化合物10(白色无定型固体，84.5mg，产率：68.1％)。1hnmr(400mhz,cdcl3)δ8.05(d,j＝7.9hz,2h),7.76(t,j＝7.5hz,1h),7.62(t,j＝7.8hz,2h),6.23(d,j＝3.4hz,1h),5.69(t,j＝8.0hz,1h),5.57(d,j＝3.0hz,1h),4.67(d,j＝12.5hz,1h),4.48(d,j＝12.5hz,1h),4.42(t,j＝6.4hz,1h),4.10(t,j＝6.6hz,2h),3.85(t,j＝9.3hz,2h),2.93(dd,j＝14.9,5.9hz,1h),2.85(d,j＝9.4hz,1h),2.66–2.57(m,4h),2.46–2.13(m,6h),1.92–1.84(m,2h),1.71–1.62(m,3h),1.54(s,3h),1.45(m,4h),1.10(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ172.3,172.1,169.4,158.9,138.7,137.9,135.6,134.7,130.6,129.6,128.5,120.3,110.4,80.9,71.4,67.0,64.6,63.2,59.9,42.5,36.5,28.9,28.8,28.4,28.2,25.6,25.4,25.2,24.4,23.7,17.9.hrms(esi)计算值c31h40n3o12s[m+nh4]+678.2327,测量值678.2328.化合物11的合成步骤同上，得到化合物11(白色无定型固体，91.0mg，产率：71.9％)。1hnmr(400mhz,cdcl3)δ8.02(d,j＝7.5hz,2h),7.75(t,j＝7.5hz,1h),7.65–7.56(m,2h),6.21(d,j＝3.3hz,1h),5.67(t,j＝8.0hz,1h),5.56(d,j＝2.9hz,1h),4.66(d,j＝12.5hz,1h),4.46(d,j＝12.5hz,1h),4.39(t,j＝6.5hz,2h),4.07(t,j＝6.6hz,2h),3.83(t,j＝9.3hz,1h),2.90(t,j＝8.8hz,1h),2.83(d,j＝9.4hz,1h),2.61(s,4h),2.48–2.09(m,6h),1.91–1.79(m,2h),1.64(dd,j＝14.6,7.5hz,3h),1.52(s,3h),1.48–1.25(m,6h),1.08(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ172.2,172.0,169.3,158.9,138.7,137.9,135.5,134.6,130.5,129.5,128.4,120.1,110.3,80.9,71.4,66.9,64.7,63.1,59.8,42.5,36.5,28.9,28.8,28.6,28.3,28.2,25.6,25.6,25.4,24.4,23.7,17.9.hrms(esi)计算值c34h46n3o12s[m+nh4]+720.2797,测量值720.2806.化合物12的合成步骤同上，得到化合物12(白色无定型固体，77.1mg，产率：59.7％)。1hnmr(400mhz,cdcl3)δ8.05(d,j＝7.6hz,2h),7.76(t,j＝7.5hz,1h),7.62(t,j＝7.8hz,2h),6.24(d,j＝3.4hz,1h),5.69(t,j＝8.1hz,1h),5.57(d,j＝3.0hz,1h),4.68(d,j＝12.5hz,1h),4.48(d,j＝12.5hz,1h),4.41(t,j＝6.5hz,2h),4.08(t,j＝6.7hz,2h),3.85(t,j＝9.3hz,1h),2.97–2.87(m,1h),2.85(d,j＝9.4hz,1h),2.69–2.57(m,4h),2.47–2.11(m,6h),1.92–1.81(m,2h),1.68–1.59(m,3h),1.54(s,3h),1.44(d,j＝12.1hz,2h),1.36(s,6h),1.11(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ172.3,172.1,169.4,159.0,138.7,138.1,135.6,134.7,130.6,129.6,128.5,120.2,110.4,81.0,71.5,67.1,64.8,63.2,59.9,42.6,36.5,29.6,29.0,28.9,28.9,28.5,28.3,25.7,25.7,25.5,24.5,23.8,17.9.hrms(esi)计算值c35h48n3o12s[m+nh4]+734.2953,测量值734.2958.化合物13的合成：步骤同上，得到化合物13(白色无定型固体，171.7mg，产率：87％)。1hnmr(400mhz,cdcl3)δ8.02(d,j＝8.2hz,2h),7.75(t,j＝7.4hz,1h),7.60(t,j＝7.7hz,2h),6.21(d,j＝3.2hz,1h),5.66(t,j＝8.1hz,1h),5.56(d,j＝2.7hz,1h),4.66(d,j＝12.4hz,1h),4.46(d,j＝12.5hz,2h),4.38(t,j＝6.5hz,2h),4.05(t,j＝6.7hz,1h),3.83(t,j＝9.3hz,1h),2.89(t,j＝10.1hz,1h),2.83(d,j＝9.4hz,1h),2.60(s,4h),2.47–2.09(m,6h),1.89–1.79(m,2h),1.69–1.56(m,3h),1.52(s,3h),1.41(d,j＝7.2hz,2h),1.31(s,8h),1.08(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ172.4,172.2,169.5,159.1,138.8,138.1,135.7,134.8,130.7,129.7,128.5,120.4,110.5,81.1,71.7,67.2,65.0,63.3,60.0,42.7,36.6,29.4,29.2,29.0,29.0,28.6,28.4,25.9,25.7,25.6,24.5,23.9,18.0.hrms(esi)c36h46n2nao12s[m+na]+计算值：753.2664，实验值：753.2667。化合物14的合成：步骤同上，得到化合物14(白色无定型固体，产率：83％)。1hnmr(400mhz,cdcl3)δ8.05(d,j＝7.9hz,2h),7.76(t,j＝7.5hz,1h),7.61(t,j＝7.8hz,2h),6.24(d,j＝3.4hz,1h),5.68(t,j＝8.1hz,1h),5.57(d,j＝3.1hz,1h),4.68(d,j＝12.4hz,1h),4.47(d,j＝12.5hz,1h),4.40(t,j＝6.6hz,2h),4.07(t,j＝6.8hz,2h),3.85(t,j＝9.3hz,1h),2.96–2.87(m,1h),2.85(d,j＝9.4hz,1h),2.67–2.57(m,4h),2.46–2.11(m,6h),1.90–1.81(m,2h),1.68–1.57(m,3h),1.54(s,3h),1.50–1.40(m,2h),1.31(s,10h),1.10(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ172.5,172.3,169.6,159.2,138.9,138.2,135.7,134.9,130.8,129.8,128.7,120.5,110.6,81.2,71.8,67.2,65.1,63.4,60.1,42.8,36.7,29.5,29.3,29.2,29.1,29.1,28.7,28.5,26.0,25.8,25.7,24.6,23.9,18.1.hrms(esi)c37h48n2nao12s[m+na]+计算值：767.2820，实验值：767.2825。化合物15的合成：化合物15的合成方法同化合物6的合成步骤相同，只是将反应物3a替换为10a，经过简单的后处理和纯化可以得到白色固体化合物15(产率：89％)。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.7hz,2h),7.75(t,j＝7.5hz,1h),7.61(t,j＝7.8hz,2h),6.22(d,j＝3.4hz,1h),5.68(t,j＝8.0hz,1h),5.57(d,j＝3.0hz,1h),4.67(d,j＝12.4hz,1h),4.46(d,j＝12.5hz,1h),4.39(t,j＝6.5hz,2h),4.06(t,j＝6.7hz,2h),3.84(t,j＝9.3hz,1h),2.94–2.86(m,1h),2.84(d,j＝9.5hz,1h),2.67–2.55(m,4h),2.45–2.11(m,6h),1.90–1.80(m,2h),1.67–1.56(m,3h),1.53(s,3h),1.48–1.38(m,2h),1.28(s,12h),1.09(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ172.5,172.3,169.5,159.1,138.8,138.1,135.7,134.9,130.8,129.7,128.6,120.5,110.5,81.1,71.7,67.2,65.1,63.3,60.1,42.7,36.7,29.6,29.5,29.3,29.2,29.1,29.0,28.6,28.5,26.0,25.8,25.6,24.5,23.9,18.1.hrms(esi)c38h50n2nao12s[m+na]+计算值：781.2977，实验值：781.2973。化合物16的合成：化合物16的合成方法同化合物6的合成步骤相同，只是将反应物3a替换为11a，经过简单的后处理和纯化可以得到白色固体化合物16(产率：77％)。1hnmr(400mhz,cdcl3)δ8.04(d,j＝8.2hz,2h),7.75(t,j＝7.4hz,1h),7.61(t,j＝7.6hz,2h),6.23(d,j＝3.2hz,1h),5.68(t,j＝8.0hz,1h),5.57(d,j＝2.6hz,1h),4.68(d,j＝12.4hz,1h),4.46(d,j＝12.4hz,1h),4.39(t,j＝6.5hz,2h),4.05(t,j＝6.7hz,2h),3.84(t,j＝9.3hz,1h),2.90(d,j＝9.2hz,1h),2.84(d,j＝9.5hz,1h),2.71–2.53(m,4h),2.48–2.10(m,6h),1.92–1.80(m,2h),1.71–1.57(m,3h),1.53(s,3h),1.47–1.38(m,2h),1.27(s,14h),1.09(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ172.5,172.3,169.5,159.1,138.8,138.2,135.7,134.9,130.8,129.7,128.6,120.5,110.5,81.1,71.8,67.2,65.1,63.4,60.1,42.7,36.7,29.6,29.6,29.6,29.3,29.2,29.1,29.0,28.6,28.5,26.0,25.8,25.7,24.5,23.9,18.1.hrms(esi)c39h52n2nao12s[m+na]+计算值：795.3133，实验值：795.3137。化合物20的合成步骤同上，得到化合物20(白色无定型固体，69.1mg，产率：58.3％)1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.7hz,2h),7.75(t,j＝7.5hz,1h),7.61(t,j＝7.8hz,2h),6.21(d,j＝3.4hz,1h),5.89(q,j＝5.2hz,2h),5.68(t,j＝8.0hz,1h),5.55(d,j＝3.1hz,1h),5.04(d,j＝5.2hz,2h),4.73(d,j＝5.1hz,2h),4.67(d,j＝12.5hz,1h),4.47(d,j＝12.5hz,1h),3.84(t,j＝9.3hz,1h),2.97–2.87(m,1h),2.83(d,j＝9.4hz,1h),2.71–2.56(m,4h),2.48–2.10(m,6h),1.76–1.61(m,1h),1.52(s,3h),1.09(t,j＝12.5hz,1h)13cnmr(100mhz,cdcl3)δ171.9,171.9,169.3,158.4,138.7,137.8,135.6,134.6,130.7,130.1,129.6,128.5,125.8,120.2,110.5,80.9,67.1,66.5,63.2,60.2,59.9,42.6,36.5,28.8,28.7,25.7,24.5,23.7,17.9.hrms(esi)计算值c31h38n3o12s[m+nh4]+676.2171,测量值676.2169.化合物21的合成步骤同上，得到化合物21(白色无定型固体，77.2mg，产率：65.4％)1hnmr(400mhz,cdcl3)δ8.07(d,j＝7.8hz,2h),7.76(d,j＝7.4hz,1h),7.64(t,j＝7.8hz,2h),6.25(d,j＝3.4hz,1h),5.70(t,j＝8.1hz,1h),5.57(d,j＝3.1hz,1h),5.10(s,2h),4.76(s,2h),4.69(d,j＝12.5hz,1h),4.50(d,j＝12.5hz,1h),3.85(t,j＝9.3hz,1h),2.98–2.89(m,1h),2.85(d,j＝9.4hz,1h),2.74–2.60(m,4h),2.51–2.12(m,6h),1.74–1.63(m,1h),1.55(s,3h),1.11(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ171.8,171.4,169.3,157.9,138.8,137.7,135.7,134.6,130.8,129.7,128.6,120.2,83.6,81.0,78.7,67.2,63.2,59.9,58.5,52.2,42.6,36.6,28.8,28.7,25.7,24.5,23.8,17.9.hrms(esi)计算值c31h36n3o12s[m+nh4]+674.2014,测量值674.2006.化合物22的合成步骤同上，得到化合物22(白色无定型固体，88.1mg，产率：81.9％)1hnmr(400mhz,cdcl3)δ8.01(d,j＝7.7hz,2h),7.74(t,j＝7.4hz,1h),7.60(t,j＝7.7hz,2h),6.20(d,j＝3.3hz,1h),5.64(t,j＝7.9hz,1h),5.55(d,j＝2.9hz,1h),4.56(d,j＝12.5hz,1h),4.38(d,j＝12.5hz,1h),4.15(s,2h),4.03(s,2h),3.82(t,j＝9.3hz,1h),2.92–2.84(m,1h),2.82(d,j＝9.4hz,1h),2.60(s,4h),2.47–2.08(m,6h),1.65(dd,j＝17.1,8.2hz,1h),1.51(s,3h),1.14–1.01(m,7h).13cnmr(100mhz,cdcl3)δ171.9,171.8,169.3,158.9,138.6,137.9,135.6,134.5,130.5,129.6,128.3,120.1,110.3,80.9,75.4,68.6,66.9,63.1,59.8,42.5,36.5,35.2,28.8,28.70,25.5,24.3,23.7,21.3,17.8.hrms(esi)计算值c32h42n3o12s[m+nh4]+692.2484,测量值692.2484.化合物23的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入二乙二醇(85.86mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4–二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物23(白色无定型固体，178.4mg，产率：71.8％)化合物24的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入三乙二醇(121.58mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4-二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物24(白色无定型固体，124.9mg，产率：45.8％)化合物25的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入2-甲基-2-丙基-1,3-丙二醇(107.08mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4-二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物25(白色无定型固体，144.8mg，产率：55.1％)化合物26的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入对苯二甲醇(111.78mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4-二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物26(白色无定型固体，141.2mg，产率：53.0％)化合物27的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入间苯二甲醇(111.78mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4-二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物27(白色无定型固体，155.9mg，产率：58.5％)化合物28的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入间羟基苯甲醇(100.44mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4-二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物28(白色无定型固体，132.7mg，产率：51.4％)化合物29的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入2-(3-羟基苯基)乙醇(111.78mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4-二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物29(白色无定型固体，169.2mg，产率：63.6％)化合物30的合成将化合物5(200mg，0.54mmol)溶于二氯甲烷(10.0ml)中，依次加入3-氨基-1-丙醇(60.75mg，0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156.9mg，0.81mmol)，4-二甲氨基吡啶(6.6mg，0.054mmol)，三乙胺(114μl)室温下搅拌12小时，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到化合物30(白色无定型固体，122.5mg，产率：53.0％)化合物31的合成在0℃下，将化合物23(180.8mg，0.40mmol)溶于重蒸的thf(3.0ml)中，加入25％naoh溶液(0.1ml)，搅拌1–2min后，加入苯磺酰基呋咱(2)(75.0mg，0.20mmol)，室温下搅拌8h，用tlc检测反应完全，用饱和氯化铵淬灭反应，乙酸乙酯萃取三次，用无水硫酸镁干燥有机相，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得化合物31(白色无定型固体，111.2mg，产率79.3％)。1hnmr(400mhz,cdcl3)δ8.11–7.95(m,2h),7.75(t,j＝7.5hz,1h),7.61(dd,j＝10.2,5.4hz,2h),6.21(d,j＝3.4hz,1h),5.66(t,j＝8.0hz,1h),5.56(d,j＝3.1hz,1h),4.65(d,j＝12.5hz,1h),4.61–4.49(m,2h),4.46(d,j＝12.5hz,1h),4.26(dd,j＝10.6,5.9hz,2h),3.89(dd,j＝9.0,4.7hz,2h),3.83(t,j＝9.3hz,1h),3.77(dd,j＝10.8,6.2hz,2h),2.92(d,j＝9.0hz,1h),2.84(d,j＝9.4hz,1h),2.70–2.63(m,2h),2.63–2.55(m,2h),2.44–2.10(m,6h),1.65(t,j＝11.6hz,1h),1.52(s,3h),1.08(t,j＝12.4hz,1h).13cnmr(100mhz,cdcl3)δ172.4,172.1,169.5,158.9,138.8,138.0,135.7,134.7,130.6,129.7,128.6,120.3,81.1,70.6,69.4,68.4,67.2,63.8,63.3,60.1,42.7,36.6,28.9,28.9,25.7,24.5,23.9,18.1.hrms(esi)计算值c31h36n2nao13s[m+na]+699.1836,测量值699.1835.化合物31的合成步骤同上，得化合物31(白色无定型固体，81.7mg，产率55.4％)。1hnmr(400mhz,cdcl3)δ8.07(d,j＝7.6hz,2h),7.77(t,j＝7.5hz,1h),7.63(t,j＝7.8hz,2h),6.24(d,j＝3.3hz,1h),5.69(t,j＝7.9hz,1h),5.58(d,j＝2.9hz,1h),4.68(d,j＝12.4hz,1h),4.62–4.53(m,2h),4.48(d,j＝12.5hz,1h),4.35–4.19(m,2h),4.00–3.90(m,2h),3.85(t,j＝9.3hz,1h),3.79–3.65(m,6h),2.93(t,j＝8.8hz,1h),2.86(d,j＝9.4hz,1h),2.71–2.57(m,4h),2.48–2.11(m,6h),1.75–1.62(m,1h),1.55(s,3h),1.11(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ172.4,172.2,169.6,159.0,138.8,138.1,135.7,134.8,130.7,129.8,128.7,120.5,81.2,71.0,70.8,69.2,68.6,67.2,64.0,63.4,60.1,42.7,36.7,29.8,29.0,28.9,25.8,24.6,23.9,18.1.hrms(esi)计算值c33h40n2nao14s[m+na]+743.2092,测量值743.2098.化合物32的合成步骤同上，得化合物32(白色无定型固体，90.4mg，产率62.8％)。1hnmr(400mhz,cdcl3)δ8.03(d,j＝8.1hz,2h),7.75(t,j＝7.4hz,1h),7.62(t,j＝7.7hz,2h),6.23(d,j＝3.1hz,1h),5.66(t,j＝7.9hz,1h),5.57(s,1h),4.56(d,j＝12.5hz,1h),4.38(d,j＝12.5hz,1h),4.25–4.15(m,2h),4.11–4.03(m,2h),3.84(t,j＝9.2hz,1h),2.90-2.83(m,2h),2.61(s,4h),2.49–2.11(m,6h),1.66(t,j＝12.2hz,1h),1.53(s,3h),1.46–1.29(m,4h),1.11(d,j＝11.9hz,1h),1.05(s,3h),0.95(t,j＝6.7hz,3h).13cnmr(100mhz,cdcl3)δ172.0,171.9,169.4,159.1,138.7,138.0,135.6,134.6,130.6,130.5,129.6,128.4,120.3,110.4,80.9,74.2,67.5,66.9,63.2,59.9,42.6,37.9,36.5,28.9,28.8,25.6,24.5,23.7,18.7,17.9,16.3,14.8.hrms(esi)计算值c34h42n2nao12s[m+na]+725.2351,测量值725.2355.化合物33的合成步骤同上，得化合物33(白色无定型固体，102.1mg，产率70.4％)。1hnmr(400mhz,cdcl3)δ8.00(d,j＝7.3hz,2h),7.73(d,j＝6.9hz,1h),7.58(d,j＝6.7hz,2h),7.52–7.41(m,2h),7.41–7.30(m,2h),6.20(s,1h),5.68(s,1h),5.54(s,1h),5.43(s,2h),5.14(s,2h),4.67(d,j＝11.9hz,1h),4.47(d,j＝12.4hz,1h),3.84(t,j＝9.2hz,1h),2.91(s,1h),2.84(d,j＝9.3hz,1h),2.66(d,j＝20.0hz,4h),2.49–2.08(m,6h),1.74–1.59(m,1h),1.53(s,3h),1.08(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ172.1,169.5,158.6,138.8,137.9,136.8,135.7,134.7,133.8,130.7,129.7,128.5,128.5,120.3,110.6,81.1,72.2,67.2,66.1,63.2,60.0,42.6,36.6,29.7,29.0,25.7,24.5,23.8,18.0.hrms(esi)计算值c35h36n2nao12s[m+na]+731.1881,测量值731.1885.化合物34的合成步骤同上，得化合物34(白色无定型固体，87.5mg，产率60.3％)。1hnmr(400mhz,cdcl3)δ8.01(d,j＝8.1hz,2h),7.74(t,j＝7.1hz,1h),7.58(t,j＝7.5hz,2h),7.44-7.37(m,4h),6.20(d,j＝2.4hz,1h),5.67(t,j＝7.7hz,1h),5.54(d,j＝1.7hz,1h),5.44(s,2h),5.16(s,2h),4.67(d,j＝12.4hz,1h),4.46(d,j＝12.5hz,1h),3.84(t,j＝9.2hz,1h),2.91(t,j＝9.1hz,1h),2.84(d,j＝9.4hz,1h),2.70(d,j＝6.3hz,2h),2.64(d,j＝5.8hz,2h),2.48–2.11(m,6h),1.69–1.60(m,1h),1.53(s,3h),1.08(t,j＝12.6hz,2h).13cnmr(100mhz,cdcl3)δ172.0,171.9,169.4,158.5,138.7,137.8,136.4,135.6,134.6,134.1,130.6,129.6,129.0,128.6,128.4,127.9,127.6,120.2,110.4,80.9,72.2,67.0,66.0,63.1,59.9,42.5,36.4,28.8,25.6,24.4,23.7,17.9.hrms(esi)计算值c35h36n2nao12s[m+na]+731.1881,测量值731.1885.化合物35的合成步骤同上，得化合物35(白色无定型固体，74.6mg，产率52.5％)。1hnmr(400mhz,cdcl3)δ8.09(d,j＝7.5hz,2h),7.80(t,j＝7.5hz,1h),7.66(t,j＝7.8hz,2h),7.44(t,j＝7.9hz,1h),7.33(s,1h),7.29(d,j＝7.6hz,2h),6.21(d,j＝3.5hz,1h),5.69(t,j＝8.0hz,1h),5.54(d,j＝3.1hz,1h),5.16(s,2h),4.68(d,j＝12.4hz,1h),4.46(d,j＝12.5hz,1h),3.84(t,j＝9.3hz,1h),2.99–2.82(m,2h),2.71(dd,j＝9.4,4.0hz,2h),2.64(dt,j＝7.0,3.8hz,2h),2.47–2.09(m,6h),1.65(dd,j＝14.3,12.2hz,1h),1.54(s,3h),1.10(t,j＝12.4hz,1h).13cnmr(100mhz,cdcl3)δ172.1,172.1,169.5,158.5,152.7,138.8,138.6,137.9,136.0,134.8,131.0,130.3,129.9,128.8,126.2,120.4,119.7,119.3,110.9,81.1,67.3,65.5,63.3,60.0,42.7,36.6,29.0,25.8,24.5,23.9,18.1,1.1.hrms(esi)计算值c34h34n2nao12s[m+na]+717.1725,测量值717.1729.化合物36的合成步骤同上，得化合物36(白色无定型固体，84.1mg，产率57.9％)。1hnmr(400mhz,cdcl3)δ7.92(d,j＝7.7hz,2h),7.72(t,j＝7.4hz,1h),7.56(t,j＝7.8hz,2h),7.33(d,j＝8.3hz,2h),7.06(d,j＝8.3hz,2h),6.19(d,j＝3.2hz,1h),5.68(t,j＝7.8hz,1h),5.52(d,j＝2.8hz,1h),4.70(d,j＝12.4hz,1h),4.59(t,j＝6.3hz,2h),4.50(d,j＝12.5hz,1h),3.83(t,j＝9.3hz,1h),3.17(t,j＝6.3hz,2h),2.96–2.85(m,3h),2.82(d,j＝9.4hz,1h),2.78–2.66(m,2h),2.42–2.07(m,6h),1.67–1.57(m,1h),1.52(s,3h),1.06(t,j＝12.7hz,1h).13cnmr(101mhz,cdcl3)δ172.0,171.1,169.5,158.9,149.7,138.8,138.0,135.7,134.7,134.6,130.8,130.3,129.8,128.4,121.7,120.5,110.5,81.1,71.6,67.3,63.3,60.0,42.7,36.6,34.3,29.3,29.1,25.7,24.4,23.8,18.0.hrms(esi)计算值c35h36n2nao12s[m+na]+731.1881,测量值731.1889.化合物37的合成步骤同上，得化合物37(白色无定型固体，107.3mg，产率81.2％)。1hnmr(400mhz,cdcl3)δ8.08(t,j＝8.8hz,2h),7.78(t,j＝7.5hz,1h),7.65(t,j＝7.6hz,2h),6.49(s,1h),6.23(d,j＝3.2hz,1h),5.73–5.54(m,2h),4.62(d,j＝12.6hz,1h),4.54(dd,j＝11.3,5.7hz,2h),4.48(d,j＝12.6hz,1h),3.84(t,j＝9.3hz,1h),3.56(dd,j＝11.3,5.7hz,2h),2.95(t,j＝9.1hz,1h),2.86(d,j＝9.4hz,1h),2.71–2.60(m,2h),2.60–2.49(m,2h),2.41(t,j＝9.1hz,1h),2.35–2.08(m,6h),1.72–1.60(m,1h),1.54(d,j＝6.0hz,3h),1.10(t,j＝12.8hz,1h).13cnmr(100mhz,cdcl3)δ172.9,171.8,169.6,138.9,137.6,136.0,134.9,130.4,129.9,128.7,120.5,110.5,81.2,71.4,67.0,63.3,60.1,42.7,37.6,36.7,30.5,29.8,29.4,28.5,25.8,24.6,23.9,18.1.hrms(esi)计算值c30h35n3nao11s[m+na]+668.1885,测量值668.1886.化合物47的合成依次取化合物4(10g，3.78mmol)和戊二酸酐(0.52g，4.54mmol)，4-二甲氨基吡啶(0.46g，3.78mmol)于反应瓶中，加入二氯甲烷(50ml)，室温下搅拌8小时，通过tlc检测反应完全后，加1n的盐酸调ph到2-3，分离有机相，用二氯甲烷萃取水相三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至1:1)得到白色固体化合物39，直接投下一步。在25ml圆底烧瓶中依次加入化合物10a(123.8mg,0.3mmol)，化合物39(170mg,0.45mmol)，edci(86.3mg,0.45mmol)和damp(0.36mg,0.003mmol)，加入无水二氯甲烷5ml,最后加入三乙胺(62ul,0.45mmol)。反应过夜，点板反应基本法完毕，加饱和碳酸氢钠淬灭反应，二氯甲烷萃取三次，合并有机相干燥旋干过柱(pe:ea＝1：1)，得到白色固体化合物47(192mg,83％)，1hnmr(400mhz,cdcl3)δ8.03(dd,j＝8.4,1.1hz,2h),7.73(d,j＝7.5hz,1h),7.60(t,j＝7.9hz,2h),6.22(d,j＝3.5hz,1h),5.66(t,j＝8.0hz,1h),5.53(d,j＝3.2hz,1h),4.63(d,j＝12.5hz,1h),4.45(d,j＝12.5hz,1h),4.39(t,j＝6.6hz,2h),4.04(t,j＝6.8hz,2h),3.83(t,j＝9.3hz,1h),2.93–2.79(m,2h),2.48–2.09(m,10h),1.93(p,j＝7.4hz,2h),1.88–1.79(m,2h),1.71–1.55(m,3h),1.52(s,3h),1.41(dd,j＝13.9,6.2hz,2h),1.28(s,12h),1.08(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ173.0,172.7,169.4,159.1,138.9,138.2,135.7,134.9,130.7,129.7,128.6,128.5,120.3,110.5,81.1,71.7,66.7,64.7,63.3,60.0,42.7,36.7,33.3,29.5,29.5,29.3,29.1,28.7,28.5,26.0,25.8,25.6,24.5,23.9,20.2,18.1.化合物48的合成步骤同上，得化合物47(白色无定型固体，114mg，产率85％)。1hnmr(400mhz,cdcl3)δ8.08–8.03(m,2h),7.78–7.72(m,1h),7.61(dd,j＝10.8,5.0hz,2h),6.25(d,j＝3.5hz,1h),5.68(t,j＝8.0hz,1h),5.55(d,j＝3.2hz,1h),4.65(d,j＝12.5hz,1h),4.46(d,j＝12.5hz,1h),4.41(t,j＝6.6hz,2h),4.05(t,j＝6.8hz,2h),3.84(t,j＝9.3hz,1h),2.93–2.80(m,2h),2.52–2.11(m,10h),1.92–1.80(m,2h),1.69–1.57(m,7h),1.54(s,3h),1.44(dd,j＝15.0,7.1hz,2h),1.30(s,12h),1.10(t,j＝12.4hz,1h).13cnmr(100mhz,cdcl3)δ173.5,173.1,169.4,159.2,138.9,138.3,135.7,135.1,130.8,129.8,128.7,120.4,110.6,81.1,71.8,66.7,64.7,63.4,60.0,42.8,36.8,34.0,29.6,29.6,29.4,29.2,28.8,28.6,26.0,25.9,25.7,24.6,24.5,24.0,18.1.化合物49的合成步骤同上，得化合物47(白色无定型固体，75mg，产率63％)。1hnmr(400mhz,cdcl3)δ8.04(dd,j＝8.4,1.1hz,2h),7.80–7.72(m,1h),7.61(t,j＝7.9hz,2h),6.23(d,j＝3.5hz,1h),5.71(t,j＝8.0hz,1h),5.55(d,j＝3.2hz,1h),4.75(d,j＝12.3hz,1h),4.53(d,j＝12.3hz,1h),4.40(t,j＝6.6hz,2h),4.24(d,j＝2.5hz,2h),4.20(d,j＝3.3hz,2h),4.14(t,j＝6.8hz,2h),3.84(t,j＝9.3hz,1h),2.91–2.79(m,2h),2.51–2.11(m,6h),1.90–1.79(m,2h),1.68–1.60(m,3h),1.53(s,3h),1.43(dd,j＝14.9,7.0hz,2h),1.29(s,12h),1.10(t,j＝12.4hz,1h).13cnmr(100mhz,cdcl3)δ169.8,169.6,169.4,159.2,138.8,138.3,135.7,134.6,131.7,129.7,128.6,120.4,,110.6,81.1,71.8,68.3,68.2,67.3,65.4,63.4,60.0,42.7,36.7,29.5,29.3,29.2,28.6,28.5,25.9,25.8,25.7,24.5,24.0,18.1.化合物50的合成步骤同上，得化合物47(白色无定型固体，133mg，产率90％)。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.5hz,2h),7.75(t,j＝7.4hz,1h),7.61(t,j＝7.6hz,2h),6.23(s,1h),5.67(t,j＝7.7hz,1h),5.54(s,1h),4.63(d,j＝12.5hz,1h),4.41(dd,j＝15.9,9.5hz,3h),4.03(t,j＝6.5hz,2h),3.83(d,j＝9.3hz,1h),2.85(t,j＝8.7hz,2h),2.51–2.10(m,10h),1.91–1.79(m,2h),1.71–1.56(m,3h),1.53(s,3h),1.42(d,j＝6.0hz,2h),1.28(s,12h),1.07(d,j＝17.7hz,7h).13cnmr(100mhz,cdcl3)δ172.0,171.6,169.5,159.1,138.8,138.2,135.7,135.0,130.6,129.7,128.6,120.4,110.5,81.1,71.7,66.4,64.4,63.4,60.0,45.2,45.0,42.7,36.7,32.7,29.6,29.5,29.3,29.2,28.7,28.5,27.8,27.8,26.0,25.8,25.7,24.5,23.9,18.1.化合物51的合成步骤同上，得化合物47(白色无定型固体，107mg，产率86％)。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.5hz,2h),7.75(t,j＝7.4hz,1h),7.61(t,j＝7.4hz,2h),6.23(s,1h),5.66(t,j＝7.5hz,1h),5.55(s,1h),4.63(d,j＝12.4hz,1h),4.41(dd,j＝13.8,9.3hz,3h),4.02(t,j＝6.2hz,2h),3.84(t,j＝9.2hz,1h),2.87(dd,j＝19.8,9.6hz,2h),2.61–2.46(m,4h),2.45–2.10(m,6h),1.90–1.80(m,2h),1.63(t,j＝17.2hz,11h),1.53(s,3h),1.42(d,j＝5.8hz,2h),1.26(d,j＝19.3hz,12h),1.08(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ172.4,172.0,169.5,159.2,138.9,138.2,135.7,135.1,130.4,129.7,128.6,120.4,110.6,81.1,71.8,66.4,64.4,63.4,60.1,43.1,42.7,42.2,38.2,38.1,36.7,29.6,29.5,29.3,29.2,28.7,28.5,26.0,25.8,25.7,24.5,24.1,23.9,18.1.化合物52的合成步骤同上，得化合物47(白色无定型固体，93mg，产率77％)。1hnmr(400mhz,cdcl3)δ8.03(d,j＝7.7hz,2h),7.75(t,j＝7.4hz,1h),7.60(t,j＝7.5hz,2h),6.21(s,1h),5.66(t,j＝7.6hz,1h),5.54(s,1h),4.62(d,j＝12.5hz,1h),4.39(t,j＝10.3hz,3h),4.01(t,j＝6.2hz,2h),3.83(t,j＝9.2hz,1h),2.86(dd,j＝24.1,10.1hz,2h),2.59–2.45(m,4h),2.26(ddt,j＝28.9,17.2,9.0hz,6h),1.89–1.78(m,2h),1.70–1.54(m,3h),1.52(s,3h),1.49–1.37(m,12h),1.28(s,12h),1.07(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ172.2,171.8,169.5,159.1,138.9,138.2,135.7,135.1,130.4,129.7,128.6,120.3,110.5,81.1,71.7,66.3,64.3,63.3,60.0,42.7,41.2,36.7,35.9,35.4,29.6,29.5,29.3,29.2,28.7,28.5,26.0,25.8,25.7,25.6,24.5,23.9,21.5,18.1.化合物53的合成步骤同上，得化合物47(113mg，产率72％)。1hnmr(400mhz,cdcl3)δ8.05(d,j＝8.1hz,2h),7.75(t,j＝7.1hz,2h),7.63(dt,j＝16.2,5.9hz,3h),7.54(dd,j＝5.1,3.5hz,2h),6.14(d,j＝3.1hz,1h),5.78(t,j＝8.0hz,1h),5.48(d,j＝2.6hz,1h),4.93(d,j＝12.3hz,1h),4.67(d,j＝12.3hz,1h),4.41(t,j＝6.5hz,2h),4.35–4.19(m,2h),3.84(t,j＝9.3hz,1h),2.89(t,j＝10.8hz,2h),2.55–2.10(m,6h),1.91–1.81(m,2h),1.78–1.69(m,2h),1.63(dd,j＝19.7,7.7hz,1h),1.55(s,3h),1.41(dd,j＝14.3,7.7hz,4h),1.31(s,10h),1.13(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ169.5,167.8,167.3,159.2,138.7,138.3,135.7,135.0,132.5,131.8,131.4,131.2,129.8,129.2,128.7,120.4,110.6,81.1,71.8,68.4,66.0,63.5,60.0,42.8,36.8,29.8,29.6,29.6,29.4,29.2,28.7,28.5,26.1,25.9,25.7,24.7,24.0,18.1.化合物54的合成步骤同上，得化合物47(104mg，产率81％)。1hnmr(400mhz,cdcl3)δ8.28(s,1h),8.17(s,1h),8.05(d,j＝8.1hz,2h),7.99–7.86(m,2h),7.75(t,j＝7.3hz,1h),7.68–7.56(m,4h),6.12(d,j＝3.2hz,1h),5.81(t,j＝8.1hz,1h),5.50(d,j＝2.7hz,1h),4.98(d,j＝12.3hz,1h),4.72(d,j＝12.3hz,1h),4.40(t,j＝6.5hz,2h),4.33(dd,j＝14.6,7.2hz,2h),3.86(t,j＝9.3hz,1h),2.93(dd,j＝19.0,9.3hz,2h),2.60–2.11(m,6h),1.92–1.73(m,4h),1.68(dd,j＝20.4,10.4hz,1h),1.56(s,3h),1.44(s,4h),1.33(s,10h),1.15(t,j＝12.9hz,1h).13cnmr(101mhz,cdcl3)δ169.5,167.9,167.5,159.2,138.7,138.3,135.7,135.1,133.5,133.4,131.3,130.5,129.9,129.8,128.9,128.9,128.8,128.7,128.7,128.4,120.5,110.6,81.2,71.8,68.4,66.0,63.5,60.0,42.9,36.8,29.6,29.6,29.4,29.2,28.8,28.5,26.1,25.9,25.7,24.7,24.1,18.1.化合物56a的合成：将间苯二甲酸55a(1.0g,6.0mmol)溶于10ml无水dmf中，冰水浴下搅拌，分批加入nah(240mg,6mmol),搅拌五分钟后，加入sem-cl(1.17ml,6mmol),继续搅拌4h后，tlc检测反应，基本反应完毕。用1n的盐酸溶液调节ph到2–3，乙酸乙酯萃取三次，饱和食盐水洗三次，无水硫酸钠干燥，过滤，旋干，简单纯化直接投下一步。将mmb(300mg,1.14mmol)和上一步的酸(673mg,2.27mmol)共同溶于10ml无水dcm中，依次加入dmap(13.9mg,0.11mmol)和dic(0.35ml,2.27mmol),室温下反应过夜，加饱和碳酸氢钠溶液淬灭反应，dcm萃取三次，无水硫酸钠干燥，过滤，旋干，过硅胶柱纯化[pe/ea＝3:1-2:1],得到白色固体化合物56a(378mg,产率61％)。1hnmr(400mhz,cdcl3)δ8.66(s,1h),8.21(dd,j＝15.1,7.7hz,2h),7.53(t,j＝7.7hz,1h),6.17(d,j＝3.0hz,1h),5.76(t,j＝8.1hz,1h),5.51(d,j＝6.2hz,3h),4.91(d,j＝12.5hz,1h),4.72(d,j＝12.5hz,1h),3.92–3.68(m,3h),2.91(t,j＝9.2hz,1h),2.85(d,j＝9.4hz,1h),2.56–2.09(m,6h),1.69(t,j＝11.9hz,1h),1.52(s,3h),1.08(q,j＝10.1hz,1h),1.01–0.92(m,2h),-0.02(s,9h).13cnmr(100mhz,cdcl3)δ169.3,165.4,165.2,138.7,134.7,134.2,134.0,131.0,130.9,130.7,130.4,128.9,120.4,89.9,81.0,68.2,67.4,63.3,60.0,42.7,36.6,25.7,24.4,23.9,18.1,18.0,-1.4.化合物56b的合成：化合物56b的合成方法同化合物56a的合成步骤相同，只是将间苯二酸替换为5–甲基间苯二酸，经过简单的后处理和纯化可以得到白色固体化合物56b(产率：54％)。1hnmr(400mhz,cdcl3)δ8.49(s,1h),8.05(d,j＝21.7hz,2h),6.21(d,j＝3.2hz,1h),5.79(t,j＝8.3hz,1h),5.60–5.48(m,3h),4.94(d,j＝12.5hz,1h),4.71(d,j＝12.5hz,1h),3.86(t,j＝9.5hz,1h),3.84–3.77(m,2h),2.99–2.91(m,1h),2.88(d,j＝9.4hz,1h),2.59–2.13(m,9h),1.75–1.66(m,1h),1.55(s,3h),1.12(t,j＝12.9hz,1h),1.04–0.96(m,2h),0.02(s,9h).13cnmr(100mhz,cdcl3)δ169.4,165.7,165.5,139.1,138.7,134.9,134.9,134.7,131.2,130.7,130.4,128.3,120.5,90.0,81.1,68.3,67.4,63.4,60.0,42.8,36.7,25.8,24.5,24.0,21.3,18.2,18.1,-1.3.化合物57a的合成：将化合物56a(514mg,0.947mmol)溶解于9.4ml无水dcm中，冰水浴中搅拌，加入溴化镁乙醚(733.7mg,2.84mmol)，反应4h后点板，反应基本完毕。使用1n盐酸溶液调节ph到2–3，dcm萃取三次，无水硫酸钠干燥，过滤，旋干，过硅胶柱纯化(dcm/meoh＝50:1),得无色油状物直接投下一步。取上步纯化的酸(111.4mg，0.27mmol)溶于无水二氯甲烷(5.0ml)中，依次加入化合物，10a(468mg,1.13mmol),edci(216.6mg,1.13mmol)和dmap(11.6mg，0.095mmol)，三乙胺(157μl,1.13mmol)室温下搅拌过夜，通过tlc检测反应完全后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，并用无水硫酸镁干燥，减压浓缩，残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1至5:1至3:1)得到白色固体化合物57a(405mg，产率：53％)。1hnmr(400mhz,cdcl3)δ8.67(s,1h),8.22(dd,j＝15.6,7.8hz,2h),8.05(d,j＝8.1hz,2h),7.75(t,j＝7.4hz,1h),7.61(t,j＝7.7hz,2h),7.54(t,j＝7.8hz,1h),6.22(d,j＝3.3hz,1h),5.80(s,1h),5.53(d,j＝2.9hz,1h),4.93(d,j＝12.5hz,1h),4.76(d,j＝12.5hz,1h),4.40(t,j＝6.5hz,2h),4.35(t,j＝6.7hz,2h),3.87(t,j＝9.3hz,1h),3.00–2.85(m,2h),2.58–2.12(m,6h),1.91–1.74(m,4h),1.73–1.66(m,1h),1.56(s,3h),1.49–1.40(m,4h),1.40–1.29(m,10h),1.13(t,j＝12.8hz,1h).13cnmr(100mhz,cdcl3)δ169.4,165.8,165.6,159.2,138.7,138.3,135.7,134.9,134.2,133.8,131.3,131.1,130.9,130.4,129.8,128.9,128.7,120.5,110.6,81.1,71.8,67.4,65.7,63.4,60.1,42.8,36.8,29.8,29.6,29.6,29.4,29.2,28.8,28.5,26.1,25.9,25.7,24.6,24.0,18.1.hrms(esi)c42h50n2nao12s[m+na]+计算值：829.2977，实验值：829.2981。化合物57b的合成：化合物57b的合成方法同化合物57a的合成步骤相同，只是将化合物56a替换为化合物56b，经过简单的后处理和纯化可以得到白色固体化合物57b(产率：34％)。1hnmr(400mhz,cdcl3)δ8.47(s,1h),8.03(t,j＝12.5hz,4h),7.75(t,j＝7.4hz,1h),7.61(t,j＝7.8hz,2h),6.22(d,j＝3.3hz,1h),5.79(t,j＝8.3hz,1h),5.52(d,j＝3.0hz,1h),4.93(d,j＝12.5hz,1h),4.73(d,j＝12.5hz,1h),4.37(dt,j＝28.9,6.6hz,4h),3.87(t,j＝9.3hz,1h),2.96(t,j＝9.1hz,1h),2.89(d,j＝9.4hz,1h),2.57–2.14(m,9h),1.89-1.11(m,5h),1.56(s,3h),1.49–1.40(m,4h),1.32(s,10h),1.13(t,j＝12.8hz,1h).13cnmr(100mhz,cdcl3)δ169.4,166.0,165.8,159.2,139.0,138.8,138.3,135.7,134.9,134.8,134.4,131.2,131.1,130.3,129.8,128.7,128.1,120.5,81.1,71.8,67.4,65.7,63.5,60.1,42.9,36.8,29.8,29.6,29.6,29.6,29.4,29.2,28.8,28.6,26.1,25.9,25.7,24.6,24.0,21.3,18.1.hrms(esi)c43h52n2nao12s[m+na]+计算值：843.3133，实验值：843.3136。化合物59的合成：化合物59的合成方法同化合物56a的合成步骤相同，只是将间苯二酸替换为对苯二酸，经过简单的后处理和纯化可以得到白色固体化合物59(产率：36％)。1hnmr(400mhz,cdcl3)δ8.07(q,j＝8.6hz,4h),6.17(d,j＝3.4hz,1h),5.76(t,j＝8.3hz,1h),5.51(s,3h),4.89(d,j＝12.5hz,1h),4.72(d,j＝12.6hz,1h),3.84(t,j＝9.3hz,1h),3.80–3.74(m,2h),2.96–2.87(m,1h),2.85(d,j＝9.4hz,1h),2.55–2.07(m,6h),1.76–1.63(m,1h),1.52(s,3h),1.12–1.03(m,1h),1.00–0.90(m,2h),-0.02(s,9h).13cnmr(100mhz,cdcl3)δ169.3,165.4,165.2,138.7,134.7,134.1,133.8,130.9,129.8,129.6,120.3,90.0,81.0,68.2,67.4,63.2,60.0,42.7,36.6,25.6,24.4,23.9,18.1,18.0,-1.4.化合物60的合成：化合物60的合成方法同化合物57a的合成步骤相同，只是将化合物56a替换为化合物59，经过简单的后处理和纯化可以得到白色固体化合物60(产率：41％)。1hnmr(400mhz,cdcl3)δ8.16–7.99(m,6h),7.75(t,j＝7.4hz,1h),7.61(t,j＝7.5hz,2h),6.24(d,j＝2.2hz,1h),5.79(t,j＝8.2hz,1h),5.54(s,1h),4.92(d,j＝12.6hz,1h),4.75(d,j＝12.5hz,1h),4.41(t,j＝6.5hz,2h),4.34(t,j＝6.5hz,2h),3.87(t,j＝9.3hz,1h),2.95(d,j＝10.4hz,1h),2.89(d,j＝9.5hz,1h),2.58–2.14(m,6h),1.91–1.67(m,5h),1.56(s,3h),1.48–1.29(m,14h),1.13(t,j＝13.0hz,1h).13cnmr(100mhz,cdcl3)δ169.4,165.9,165.6,159.2,138.7,138.3,135.7,134.8,134.8,133.6,131.1,129.8,129.7,128.7,120.6,110.6,81.1,71.8,67.5,65.8,63.4,60.1,42.8,36.8,29.6,29.6,29.4,29.2,28.8,28.6,26.1,25.9,25.7,24.6,24.0,18.1.hrms(esi)c42h50n2nao12s[m+na]+计算值：829.2977，实验值：829.2973。化合物61a的合成将mmb(264mg,1.0mmol),pph3(393mg,1.5mmol)和香豆酸(210mg,1.5mmol)放于反应瓶中，置换氩气，加入无水thf(10ml)溶解，冰水浴下搅拌加入diad(0.3ml,1.5mmol)，缓慢升温到室温，室温下搅拌4h，取样点板，反应基本完毕，加饱和氯化铵溶液淬灭反应，ea萃取三次，合并有机相饱和食盐水洗三次，干燥，过滤，浓缩硅胶柱层析纯化的白色固体化合物61a(285mg,产率69％)。1hnmr(400mhz,cdcl3)δ7.62(d,j＝15.9hz,1h),7.38(d,j＝8.5hz,2h),7.13-6.99(m,1h),6.87(d,j＝8.4hz,2h),6.26(d,j＝8.9hz,1h),6.23(d,j＝3.6hz,1h),5.72(t,j＝7.9hz,1h),5.57(d,j＝3.3hz,1h),4.76(d,j＝12.5hz,1h),4.59(d,j＝12.5hz,1h),3.89(t,j＝9.3hz,1h),2.98(t,j＝9.1hz,1h),2.91(d,j＝9.4hz,1h),2.51–2.11(m,6h),1.73–1.64(m,1h),1.55(s,3h),1.12(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ169.9,167.3,158.6,145.7,138.5,134.9,130.6,130.1,126.3,120.8,116.0,114.1,81.2,66.8,63.3,60.3,42.6,36.5,25.8,24.5,23.8,17.9.hrms(esi)calcdforc24h30no6[m+nh4]+428.2068,found428.2067.化合物61b的合成合成方法同化合物61a，白色固体(产率:55％).1hnmr(400mhz,cdcl3)δ7.62(d,j＝15.9hz,1h),7.07(dd,j＝8.2,1.8hz,1h),7.00(d,j＝1.8hz,1h),6.92(d,j＝8.2hz,1h),6.25(dd,j＝9.7,6.2hz,2h),5.88(s,1h),5.75(t,j＝8.3hz,1h),5.56(d,j＝3.2hz,1h),4.78(d,j＝12.4hz,1h),4.60(d,j＝12.5hz,1h),3.94(s,3h),3.88(t,j＝9.3hz,1h),3.09–2.98(m,1h),2.91(d,j＝9.4hz,1h),2.55–2.14(m,6h),1.70(dd,j＝16.9,9.1hz,1h),1.56(s,3h),1.14(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ169.4,166.8,148.2,146.8,145.6,138.8,135.0,130.8,126.6,123.2,120.3,114.7,114.6,109.2,81.0,66.9,63.3,60.0,55.9,42.7,36.6,25.8,24.7,23.8,18.0.hrms(esi)calcdforc25h29o7[m+h]+441.1908,found441.1910.化合物61c的合成合成方法同化合物61a，白色固体(产率:63％)1hnmr(400mhz,cdcl3)δ7.89(d,j＝16.1hz,1h),7.32(d,j＝8.6hz,1h),6.97(s,1h),6.50–6.41(m,2h),6.37(d,j＝16.1hz,1h),6.22(d,j＝3.5hz,1h),5.73(t,j＝8.2hz,1h),5.55(d,j＝3.1hz,1h),4.74(d,j＝12.5hz,1h),4.60(d,j＝12.5hz,1h),3.88(t,j＝9.3hz,1h),3.81(s,3h),3.11–2.99(m,1h),2.92(d,j＝9.4hz,1h),2.50–2.12(m,6h),1.65(dd,j＝22.8,9.8hz,1h),1.55(s,3h),1.12(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ170.1,168.2,160.5,160.2,141.6,138.7,135.3,131.0,130.8,120.9,115.7,114.5,108.2,99.3,81.4,67.0,63.5,60.4,55.6,42.9,36.7,26.1,25.0,24.0,18.1.hrms(esi)calcdforc25h28nao7[m+na]+463.1727,found463.1730.化合物61d的合成合成方法同化合物61a，黄色固体(产率:54％).1hnmr(400mhz,cdcl3)δ7.58(d,j＝15.9hz,1h),6.74(s,2h),6.30–6.21(m,2h),5.80(s,1h),5.75(t,j＝8.2hz,1h),5.55(d,j＝3.2hz,1h),4.77(d,j＝12.5hz,1h),4.60(d,j＝12.5hz,1h),3.92(s,6h),3.88(t,j＝9.3hz,1h),3.05(ddd,j＝12.0,9.1,3.1hz,1h),2.91(d,j＝9.4hz,1h),2.53–2.13(m,6h),1.73–1.66(m,1h),1.56(s,3h),1.14(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ169.5,166.9,147.4,145.9,139.1,137.6,135.3,131.1,125.7,120.4,115.2,105.3,81.2,67.2,63.5,60.1,56.5,43.0,36.8,26.1,25.0,24.0,18.2.hrms(esi)calcdforc26h30nao8[m+na]+493.1833,found483.1838.化合物63a的合成合成方法同化合物61a，白色固体产率:65％。1hnmr(400mhz,cdcl3)δ7.60(d,j＝16.0hz,1h),7.21(t,j＝7.7hz,1h),7.11(s,1h),7.01(d,j＝8.2hz,2h),6.90(d,j＝8.4hz,1h),6.35(d,j＝16.0hz,1h),6.23(d,j＝3.0hz,1h),5.71(t,j＝8.1hz,1h),5.56(d,j＝2.6hz,1h),4.74(d,j＝12.5hz,1h),4.59(d,j＝12.5hz,1h),3.89(s,1h),3.00(t,j＝9.4hz,1h),2.89(d,j＝9.4hz,1h),2.49–2.09(m,6h),1.67(t,j＝10.8hz,1h),1.54(s,3h),1.10(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ170.2,167.0,156.7,145.7,138.7,135.5,134.9,131.0,130.2,120.9,120.6,118.1,117.5,114.6,81.5,67.3,63.4,60.4,42.8,36.6,25.9,24.8,23.9,18.0.hrms(esi)calcdforc24h26nao6[m+na]+433.1622,found433.1625.化合物64的合成合成方法同化合物55a，白色固体产率:68％。1hnmr(400mhz,cdcl3)δ7.96(d,j＝16.1hz,1h),7.42(dd,j＝7.8,1.4hz,1h),7.25–7.19(m,1h),6.90(t,j＝7.5hz,2h),6.85(d,j＝8.0hz,1h),6.59(d,j＝16.1hz,1h),6.22(d,j＝3.5hz,1h),5.75(t,j＝8.1hz,1h),5.55(d,j＝3.2hz,1h),4.76(d,j＝12.4hz,1h),4.62(d,j＝12.4hz,1h),3.89(t,j＝9.3hz,1h),3.16–3.02(m,1h),2.93(d,j＝9.4hz,1h),2.53–2.13(m,6h),1.68(t,j＝12.5hz,1h),1.56(s,3h),1.13(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ170.2,167.8,155.8,141.5,138.8,135.3,131.8,131.3,129.7,121.5,120.8,117.9,116.6,81.4,67.5,63.5,60.3,43.0,36.7,29.8,26.2,25.2,24.0,18.2.hrms(esi)calcdforc24h26nao6[m+na]+433.1622,found433.1625.化合物4b-9b的合成将四溴化碳(265.3mg,0.8mmol)和三苯基膦(209.8mg,0.8mmol)共同放入反应瓶中，置换氩气，加入无水二氯甲烷4ml，冰水浴下将4ml无水二氯甲烷溶解的化合物4a-9a(4mmol)加入到反应瓶中，缓慢升温到室温，反应4小时后加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取三次，干燥，浓缩，过硅胶柱层析纯化直接投下一步。化合物62a的合成将化合物61a(123.3mg,0.3mmol)和化合物5b(339.0mg,0.9mmol)共同溶解于15ml无水dmf中，加入无水碳酸钾(165.8mg,1.2mmol)，40度下搅拌4小时，反应基本完成，加饱和食盐水淬灭反应，ea萃取三次，合并有机相，饱和食盐水洗三次，干燥，过滤浓缩硅胶柱层析纯化得到白色固体化合物62a(154mg,产率73％)。1hnmr(400mhz,cdcl3)δ8.03(dd,j＝8.4,1.1hz,2h),7.74(t,j＝7.5hz,1h),7.68–7.56(m,3h),7.46(d,j＝8.7hz,2h),6.91(d,j＝8.8hz,2h),6.28(d,j＝15.9hz,1h),6.24(d,j＝3.5hz,1h),5.73(t,j＝8.2hz,1h),5.56(d,j＝3.2hz,1h),4.77(d,j＝12.5hz,1h),4.59(d,j＝12.6hz,1h),4.50(t,j＝6.1hz,2h),4.09(t,j＝5.9hz,2h),3.86(d,j＝9.3hz,1h),3.03–2.93(m,1h),2.89(d,j＝9.4hz,1h),2.49–2.12(m,6h),2.12–1.97(m,4h),1.68(dd,j＝13.3,9.0hz,1h),1.55(s,3h),1.11(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ169.5,167.0,160.9,159.0,145.2,138.8,138.0,135.8,135.1,130.6,130.0,129.7,128.5,126.9,120.4,114.9,114.9,110.5,81.1,71.3,67.3,66.8,63.3,60.1,42.7,36.7,25.9,25.6,25.4,24.6,23.9,18.1.化合物62b的合成合成方法同化合物62a，白色固体，产率：66％。1hnmr(400mhz,cdcl3)δ8.11–7.98(m,2h),7.89(d,j＝16.1hz,1h),7.75(t,j＝7.5hz,1h),7.60(t,j＝7.9hz,2h),7.40(d,j＝8.6hz,1h),6.51(dd,j＝8.6,2.2hz,1h),6.46(d,j＝2.2hz,1h),6.40(d,j＝16.1hz,1h),6.22(d,j＝3.5hz,1h),5.73(t,j＝8.1hz,1h),5.54(d,j＝3.2hz,1h),4.75(d,j＝12.4hz,1h),4.59(d,j＝12.5hz,1h),4.51(t,j＝6.1hz,2h),4.11(t,j＝6.0hz,2h),3.93–3.81(m,4h),3.09–2.99(m,1h),2.97–2.85(m,1h),2.50–2.13(m,6h),2.13–1.95(m,4h),1.70–1.62(m,1h),1.55(s,3h),1.13(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ169.6,167.7,162.3,160.2,159.1,141.2,138.8,138.0,135.8,135.4,130.9,130.9,129.8,128.6,120.5,116.4,115.2,110.6,105.9,98.9,81.2,71.4,67.5,67.0,63.4,60.1,55.6,42.9,36.7,26.1,25.8,25.5,25.0,24.0,18.2.化合物62c的合成合成方法同化合物62a，白色固体，产率：77％。1hnmr(400mhz,cdcl3)δ8.04(d,j＝8.0hz,2h),7.74(t,j＝7.4hz,1h),7.61(dd,j＝16.7,9.9hz,3h),7.08(d,j＝8.3hz,1h),7.02(s,1h),6.90(d,j＝8.3hz,1h),6.27(d,j＝15.4hz,2h),5.75(t,j＝8.0hz,1h),5.56(s,1h),4.78(d,j＝12.5hz,1h),4.60(d,j＝12.5hz,1h),4.53(t,j＝5.6hz,2h),4.16(t,j＝5.5hz,2h),3.93–3.81(m,4h),3.02(t,j＝9.9hz,1h),2.91(d,j＝9.4hz,1h),2.58–2.19(m,6h),2.15–2.02(m,4h),1.71(d,j＝8.2hz,1h),1.56(s,3h),1.14(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ169.5,167.0,159.1,150.8,149.7,145.6,139.0,138.2,135.7,135.2,131.0,129.8,128.7,127.4,122.9,120.5,115.2,112.7,110.1,100.1,81.2,71.4,68.4,67.1,63.5,60.1,56.0,42.9,36.8,26.1,25.6,25.6,24.9,24.0,18.2.化合物62d的合成合成方法同化合物62a，白色固体，产率：61％。1hnmr(400mhz,cdcl3)δ8.04(d,j＝8.0hz,2h),7.74(t,j＝7.5hz,1h),7.66–7.55(m,3h),6.74(d,j＝14.3hz,2h),6.31(d,j＝15.9hz,1h),6.23(d,j＝3.3hz,1h),5.74(t,j＝8.2hz,1h),5.55(d,j＝3.0hz,1h),4.77(d,j＝12.5hz,1h),4.60(d,j＝12.5hz,1h),4.53(t,j＝6.4hz,2h),4.07(t,j＝6.0hz,2h),3.92–3.81(m,7h),3.03(t,j＝8.9hz,1h),2.90(d,j＝9.4hz,1h),2.51–2.27(m,4h),2.27–2.09(m,4h),1.91(dt,j＝12.9,6.3hz,2h),1.72–1.66(m,1h),1.55(s,3h),1.12(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ169.5,166.6,159.1,153.7,145.6,139.4,139.0,138.2,135.7,135.1,131.1,129.8,128.6,120.3,116.7,110.6,105.3,81.2,72.5,71.5,67.2,63.4,60.1,56.2,42.9,36.7,29.8,26.3,26.0,25.3,24.9,24.0,18.1.化合物62e的合成合成方法同化合物62a，白色固体，产率：64％。1hnmr(400mhz,cdcl3)δ8.11(d,j＝16.2hz,1h),8.06–8.00(m,2h),7.75(t,j＝7.5hz,1h),7.60(t,j＝7.9hz,2h),6.69(d,j＝16.2hz,1h),6.19(d,j＝3.5hz,1h),6.12(s,2h),5.74(t,j＝8.0hz,1h),5.53(d,j＝3.2hz,1h),4.72(d,j＝12.4hz,1h),4.60(d,j＝12.4hz,1h),4.53(t,j＝6.0hz,2h),4.13(t,j＝5.9hz,2h),3.92–3.80(m,7h),3.19–3.06(m,1h),2.94(d,j＝9.4hz,1h),2.52–2.14(m,6h),2.14–1.98(m,4h),1.70–1.62(m,1h),1.56(s,3h),1.14(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ169.7,168.8,162.4,161.5,159.1,138.8,138.0,136.6,135.8,135.6,131.0,129.8,128.7,120.6,116.3,110.6,105.7,90.9,81.2,71.4,67.4,67.1,63.5,60.2,55.9,42.9,36.8,26.3,25.9,25.5,25.3,24.0,18.2.化合物65a的合成合成方法同化合物56a，白色固体，产率：61％。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.5hz,2h),7.74(t,j＝7.5hz,1h),7.69–7.54(m,3h),7.31(t,j＝7.9hz,1h),7.10(d,j＝7.6hz,1h),7.04(s,1h),6.96(dd,j＝8.2,1.9hz,1h),6.40(d,j＝16.0hz,1h),6.25(d,j＝3.4hz,1h),5.74(t,j＝8.1hz,1h),5.56(d,j＝3.1hz,1h),4.77(d,j＝12.5hz,1h),4.61(d,j＝12.5hz,1h),4.52(t,j＝6.1hz,2h),4.10(t,j＝6.0hz,2h),3.87(t,j＝9.3hz,1h),2.98(d,j＝8.9hz,1h),2.89(d,j＝9.4hz,1h),2.53–2.13(m,6h),2.13–1.94(m,4h),1.73–1.66(m,1h),1.56(s,3h),1.17–1.10(m,1h).13cnmr(100mhz,cdcl3)δ169.5,166.6,159.3,159.1,145.5,139.0,138.2,135.8,135.7,135.1,131.0,130.2,129.8,128.6,121.2,120.4,117.9,117.2,113.5,110.6,81.2,71.4,67.4,67.2,63.4,60.1,42.9,36.8,26.0,25.8,25.5,24.8,24.0,18.1.化合物65b的合成：化合物65b的制备方式同化合物65a的合成步骤相同，只是将化合物63a替换为化合物63b，经过简单的后处理和纯化可以得到无色油状物化合物65b(产率：44％)。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.8hz,2h),7.73(t,j＝7.5hz,1h),7.60(dd,j＝15.4,7.2hz,3h),7.16–7.02(m,2h),6.87(d,j＝8.3hz,1h),6.25(dd,j＝11.6,9.9hz,2h),5.74(t,j＝8.1hz,1h),5.54(d,j＝3.0hz,1h),4.74(d,j＝12.6hz,1h),4.59(d,j＝12.4hz,1h),4.54(t,j＝5.9hz,2h),4.15(t,j＝5.9hz,2h),3.94–3.80(m,4h),3.04(t,j＝8.8hz,1h),2.90(d,j＝9.4hz,1h),2.54–2.17(m,6h),2.10(ddd,j＝19.2,13.5,6.9hz,4h),1.74–1.63(m,1h),1.56(s,3h),1.13(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ169.5,166.9,159.1,151.9,148.7,145.5,139.1,138.2,135.7,135.3,131.1,129.8,128.7,127.2,123.3,120.3,115.2,111.5,111.5,81.2,71.5,68.5,67.2,63.5,60.1,56.1,42.9,36.8,29.8,26.1,25.7,25.6,25.0,24.0,18.2.hrms(esi)c37h40n2nao12s[m+na]+计算值：759.2194，实验值：759.2199。化合物66的合成合成方法同化合物62a，白色固体，产率：58％。1hnmr(400mhz,cdcl3)δ8.10–7.98(m,3h),7.73(t,j＝7.5hz,1h),7.59(t,j＝7.8hz,2h),7.51(d,j＝7.6hz,1h),7.36(t,j＝7.7hz,1h),6.97(dd,j＝12.9,7.9hz,2h),6.48(d,j＝16.1hz,1h),6.22(d,j＝3.3hz,1h),5.73(t,j＝8.0hz,1h),5.55(d,j＝2.9hz,1h),4.72(d,j＝12.5hz,1h),4.61(d,j＝12.6hz,1h),4.52(t,j＝5.7hz,2h),4.15(t,j＝5.6hz,2h),3.86(t,j＝9.3hz,1h),2.99(t,j＝9.0hz,1h),2.89(d,j＝9.4hz,1h),2.54–2.17(m,6h),2.15–2.03(m,4h),1.68(t,j＝12.1hz,1h),1.55(s,3h),1.12(t,j＝12.7hz,1h).13cnmr(100mhz,cdcl3)δ169.6,167.1,159.1,157.6,140.9,138.9,138.1,135.7,135.2,132.0,130.7,129.8,128.8,128.7,123.2,121.1,120.5,117.7,112.3,110.6,81.2,71.3,67.8,66.9,63.4,60.1,42.9,36.8,26.0,25.7,25.6,24.9,24.0,18.1.化合物67的合成将化合物61c(220mg,0.5mmol)和化合物4b(363.2mg,1mmol)共同溶解于5ml无水dmf中，加入无水碳酸钾(276mg,2mmol)，40度下搅拌4小时，反应基本完成，加饱和食盐水淬灭反应，ea萃取三次，合并有机相，饱和食盐水洗三次，干燥，过滤浓缩硅胶柱层析纯化得到白色固体化合物67(249mg,产率69％)。1hnmr(400mhz,cdcl3)δ8.01–7.95(m,2h),7.90(d,j＝16.1hz,1h),7.71(t,j＝7.5hz,1h),7.52(t,j＝7.9hz,2h),7.42(d,j＝8.6hz,1h),6.52(d,j＝8.6hz,1h),6.48(d,j＝2.2hz,1h),6.42(d,j＝16.1hz,1h),6.21(d,j＝3.5hz,1h),5.73(t,j＝8.2hz,1h),5.54(d,j＝3.1hz,1h),4.75(d,j＝12.5hz,1h),4.67–4.55(m,3h),4.21(t,j＝5.8hz,2h),3.91–3.83(m,4h),3.09–2.98(m,1h),2.90(d,j＝9.4hz,1h),2.52–2.10(m,8h),1.71–1.62(m,1h),1.55(s,3h),1.12(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ169.6,167.7,162.0,160.2,159.0,141.0,138.9,138.0,135.8,135.4,130.9,130.8,129.8,128.5,120.4,116.7,115.4,110.6,105.9,99.1,81.2,68.1,66.9,63.8,63.4,60.1,55.7,42.8,36.7,28.5,26.1,25.0,24.0,18.1.化合物68的合成合成方法同化合物67，白色固体，产率：77％。1hnmr(400mhz,cdcl3)δ8.09–8.01(m,2h),7.90(d,j＝16.1hz,1h),7.74(t,j＝7.5hz,1h),7.60(t,j＝7.9hz,2h),7.40(d,j＝8.6hz,1h),6.54–6.44(m,2h),6.40(d,j＝16.1hz,1h),6.23(d,j＝3.5hz,1h),5.74(t,j＝8.2hz,1h),5.55(d,j＝3.2hz,1h),4.76(d,j＝12.4hz,1h),4.60(d,j＝12.5hz,1h),4.47(t,j＝6.4hz,2h),4.05(t,j＝6.2hz,2h),3.92–3.81(m,4h),3.10–2.99(m,1h),2.92(d,j＝9.4hz,1h),2.51–2.14(m,6h),2.02–1.85(m,4h),1.74–1.66(m,3h),1.56(s,3h),1.14(t,j＝12.8hz,1h).13cnmr(100mhz,cdcl3)δ169.6,167.7,162.5,160.2,159.1,141.2,138.9,138.2,135.8,135.5,130.9,130.9,129.8,128.7,120.5,116.4,115.2,110.6,105.9,99.0,81.2,71.5,67.9,67.0,63.5,60.1,55.7,42.9,36.8,28.8,28.3,26.2,25.0,24.0,22.5,18.2.化合物69的合成合成方法同化合物67，白色固体，产率：71％。1hnmr(400mhz,cdcl3)δ8.04(dd,j＝8.4,1.1hz,2h),7.89(d,j＝16.1hz,1h),7.78–7.71(m,1h),7.60(t,j＝7.9hz,2h),7.39(d,j＝8.6hz,1h),6.49(dd,j＝8.6,2.2hz,1h),6.45(d,j＝2.2hz,1h),6.40(d,j＝16.1hz,1h),6.22(d,j＝3.5hz,1h),5.73(t,j＝8.2hz,1h),5.54(d,j＝3.2hz,1h),4.75(d,j＝12.5hz,1h),4.59(d,j＝12.5hz,1h),4.44(t,j＝6.5hz,2h),4.02(t,j＝6.3hz,2h),3.91–3.82(m,4h),3.10–2.99(m,1h),2.91(d,j＝9.4hz,1h),2.53–2.13(m,6h),1.97–1.78(m,4h),1.70–1.62(m,3h),1.55(s,5h),1.13(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ169.6,167.8,162.6,160.2,159.2,141.2,138.9,138.2,135.7,135.4,130.9,130.9,129.8,128.7,120.5,116.3,115.1,110.6,105.9,99.0,81.2,71.6,68.0,67.0,63.5,60.1,55.6,42.9,36.8,29.1,28.5,26.2,25.7,25.5,25.0,24.0,18.2.化合物70的合成合成方法同化合物67，白色固体，产率：76％。1hnmr(400mhz,cdcl3)δ8.05(dd,j＝8.4,1.1hz,2h),7.89(d,j＝16.1hz,1h),7.74(dd,j＝10.7,4.3hz,1h),7.61(t,j＝7.9hz,2h),7.39(d,j＝8.6hz,1h),6.49(dd,j＝8.6,2.2hz,1h),6.45(d,j＝2.2hz,1h),6.40(d,j＝16.1hz,1h),6.22(d,j＝3.5hz,1h),5.73(t,j＝8.2hz,1h),5.54(d,j＝3.2hz,1h),4.75(d,j＝12.5hz,1h),4.59(d,j＝12.5hz,1h),4.42(t,j＝6.5hz,2h),4.00(t,j＝6.4hz,2h),3.91–3.81(m,4h),3.09–2.99(m,1h),2.91(d,j＝9.4hz,1h),2.52–2.11(m,6h),1.85(ddd,j＝29.0,14.0,6.7hz,4h),1.72–1.61(m,3h),1.55(s,3h),1.53–1.47(m,4h),1.13(t,j＝12.6hz,1h).13cnmr(100mhz,cdcl3)δ169.6,167.8,162.6,160.2,159.2,141.3,138.9,138.2,135.7,135.4,130.9,130.9,129.8,128.6,126.0,120.5,116.2,115.0,106.0,99.0,81.2,71.7,68.2,67.0,63.5,60.1,55.6,42.9,36.8,29.2,29.0,28.5,26.2,26.0,25.7,25.0,24.0,18.2.化合物71的合成合成方法同化合物67，白色固体，产率：66％。1hnmr(400mhz,cdcl3)δ8.09–8.02(m,2h),7.90(d,j＝16.1hz,1h),7.75(t,j＝7.5hz,1h),7.61(t,j＝7.9hz,2h),7.40(d,j＝8.6hz,1h),6.49(dd,j＝8.6,2.2hz,1h),6.45(d,j＝2.1hz,1h),6.40(d,j＝16.1hz,1h),6.23(d,j＝3.5hz,1h),5.74(t,j＝8.1hz,1h),5.55(d,j＝3.2hz,1h),4.76(d,j＝12.5hz,1h),4.60(d,j＝12.5hz,1h),4.42(t,j＝6.5hz,2h),4.00(t,j＝6.4hz,2h),3.91–3.83(m,4h),3.12–3.00(m,1h),2.92(d,j＝9.4hz,1h),2.51–2.12(m,6h),1.93–1.77(m,4h),1.72–1.63(m,3h),1.56(s,3h),1.49(d,j＝6.2hz,3h),1.44–1.39(m,3h),1.14(t,j＝12.5hz,1h).13cnmr(100mhz,cdcl3)δ169.6,167.8,162.7,160.2,159.2,141.3,138.9,138.2,135.7,135.5,130.9,130.9,129.8,128.7,120.5,116.2,115.0,106.0,100.1,99.0,81.2,71.7,68.3,67.0,63.5,60.1,55.6,42.9,36.8,29.3,29.3,29.1,28.5,26.2,26.0,25.6,25.0,24.0,18.2.化合物72a的合成：在反应瓶中加入化合物68(105mg,0.14mmol)在冰水浴下加入2n甲胺的四氢呋喃溶液(10ml)。反应液在冰水浴下搅拌1h，tlc检测原料消失后，旋干溶剂，直接过硅胶柱层析(dcm:meoh＝50:1)纯化得到无色油状物72a(101mg,92％)。1hnmr(400mhz,cdcl3)δ8.05(d,j＝7.5hz,2h),7.92(d,j＝16.0hz,1h),7.74(t,j＝7.1hz,1h),7.60(t,j＝7.4hz,2h),7.43(d,j＝8.4hz,1h),6.48(dd,j＝21.3,12.4hz,3h),5.70(t,j＝8.0hz,1h),4.87(d,j＝12.8hz,1h),4.48(dd,j＝17.6,11.4hz,3h),4.05(s,2h),3.94–3.78(m,4h),2.99(d,j＝12.6hz,1h),2.82(t,j＝11.4hz,2h),2.46(s,6h),2.23(d,j＝17.2hz,5h),2.02–1.84(m,6h),1.70(d,j＝6.7hz,2h),1.55(s,3h),1.10(t,j＝13.0hz,1h).13cnmr(100mhz,cdcl3)δ177.4,167.7,162.5,160.2,159.2,141.0,138.2,135.9,135.7,130.8,129.8,129.7,128.7,116.5,115.4,111.8,105.9,99.1,81.6,71.5,67.9,66.2,63.7,60.0,55.7,49.4,46.9,41.5,37.0,36.9,28.8,28.3,26.9,24.6,23.9,22.5,18.1.化合物72b的合成：化合物72b的制备方法与化合物72a的合成方法相同，只是将甲胺替换为二甲胺，其他合成及后处理方法相同，得到无色油状物72b，产率87％。1hnmr(400mhz,cdcl3)δ8.03(d,j＝7.7hz,2h),7.90(d,j＝16.1hz,1h),7.72(t,j＝7.3hz,1h),7.58(t,j＝7.6hz,2h),7.42(d,j＝8.5hz,1h),6.47(dd,j＝20.0,12.2hz,3h),5.64(t,j＝7.9hz,1h),4.83(d,j＝12.8hz,1h),4.64(d,j＝12.9hz,1h),4.45(t,j＝6.1hz,2h),4.03(t,j＝5.8hz,2h),3.85(s,4h),2.80(d,j＝9.3hz,1h),2.73(d,j＝12.0hz,1h),2.61(d,j＝12.4hz,1h),2.50–2.36(m,4h),2.34–2.08(m,11h),2.00–1.84(m,4h),1.72–1.62(m,2h),1.54(s,3h),1.07(s,1h).13cnmr(100mhz,cdcl3)δ177.1,167.5,162.3,160.0,159.1,140.6,138.1,136.2,135.7,130.6,129.7,128.6,128.4,116.4,115.5,110.5,105.8,98.9,81.2,71.4,67.8,66.1,63.9,60.0,58.4,55.6,45.8,44.6,43.1,37.0,28.7,28.2,27.0,24.8,23.8,22.4,18.0.化合物72c的合成：化合物72c的制备方法与化合物72a的合成方法相同，只是将甲胺替换为吡咯烷，其他合成及后处理方法相同，得到无色油状物72c，产率81％。1hnmr(400mhz,cdcl3)δ8.05(d,j＝7.6hz,2h),7.91(d,j＝15.8hz,1h),7.74(t,j＝7.1hz,1h),7.59(t,j＝7.5hz,2h),7.43(d,j＝8.6hz,1h),6.47(dd,j＝22.0,12.9hz,3h),5.65(t,j＝7.9hz,1h),4.85(d,j＝12.6hz,1h),4.61(d,j＝12.8hz,1h),4.47(t,j＝5.9hz,2h),4.04(t,j＝5.4hz,2h),3.92–3.78(m,4h),3.01–2.87(m,2h),2.81(d,j＝9.3hz,1h),2.58(s,4h),2.44(d,j＝9.4hz,3h),2.30(dd,j＝21.4,9.9hz,3h),2.17(dd,j＝23.2,9.9hz,3h),2.01–1.86(m,4h),1.76(s,4h),1.70(d,j＝7.3hz,2h),1.25(s,3h),1.10(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ177.1,167.6,162.4,160.1,159.2,140.6,138.2,136.3,135.8,130.7,129.8,128.7,128.6,116.6,115.6,105.9,99.0,81.4,71.5,67.9,66.2,64.1,60.0,55.7,54.4,53.7,45.4,42.4,37.1,29.8,28.8,28.3,26.9,24.7,23.9,23.8,22.5,18.1.化合物72d的合成：化合物72d的制备方法与化合物72a的合成方法相同，只是将甲胺替换为哌啶，其他合成及后处理方法相同，得到无色油状物72d，产率85％。1hnmr(400mhz,cdcl3)δ8.03(d,j＝5.5hz,2h),7.90(d,j＝16.0hz,1h),7.72(s,1h),7.58(s,2h),7.42(d,j＝7.8hz,1h),6.46(t,j＝16.5hz,3h),5.64(s,1h),4.80(dd,j＝30.4,12.7hz,2h),4.45(s,2h),4.03(s,2h),3.84(s,4h),2.78(t,j＝10.1hz,2h),2.63(s,2h),2.47–2.22(m,9h),2.21–2.07(m,2h),1.92(d,j＝27.4hz,4h),1.67(s,2h),1.54(s,8h),1.38(s,2h),1.08(s,1h).13cnmr(100mhz,cdcl3)δ177.5,167.4,162.3,160.0,159.1,140.5,138.1,136.3,135.7,130.6,129.7,128.6,128.0,116.5,115.6,110.5,105.9,98.9,81.3,71.4,67.8,66.2,64.0,60.0,58.1,55.6,54.8,43.9,43.1,37.0,28.7,28.2,27.2,25.9,24.8,24.3,23.8,22.4,18.0.化合物72e的合成：化合物72e的制备方法与化合物72a的合成方法相同，只是将甲胺替换为吗啉，其他合成及后处理方法相同，得到无色油状物72e，产率77％。1hnmr(400mhz,cdcl3)δ8.05(d,j＝7.5hz,2h),7.91(d,j＝16.1hz,1h),7.74(t,j＝7.5hz,1h),7.60(t,j＝7.8hz,2h),7.43(d,j＝8.5hz,1h),6.55–6.39(m,3h),5.68(t,j＝8.1hz,1h),4.90(d,j＝12.6hz,1h),4.66(d,j＝12.6hz,1h),4.47(t,j＝6.4hz,2h),4.05(t,j＝6.1hz,2h),3.86(s,4h),3.68(t,j＝4.4hz,4h),2.83(dd,j＝17.2,6.5hz,2h),2.72(dd,j＝13.2,5.4hz,1h),2.58–2.39(m,7h),2.36–2.12(m,4h),2.04–1.82(m,4h),1.69(dt,j＝15.3,7.6hz,2h),1.60(s,2h),1.56(s,3h),1.10(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ177.0,167.6,162.4,160.1,140.9,138.2,136.1,135.8,130.8,129.8,128.9,128.7,116.5,115.4,110.6,105.9,100.1,99.0,81.3,71.5,67.9,67.0,66.2,63.9,60.1,57.5,55.7,54.0,44.0,43.0,37.0,28.8,28.3,27.2,24.7,23.9,22.5,18.1.化合物72f的合成：化合物72f的制备方法与化合物72a的合成方法相同，只是将甲胺替换为哌嗪，其他合成及后处理方法相同，得到无色油状物72f，产率71％。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.9hz,2h),7.90(d,j＝16.1hz,1h),7.73(t,j＝7.4hz,1h),7.59(t,j＝7.7hz,2h),7.43(d,j＝8.5hz,1h),6.46(dd,j＝21.1,12.4hz,3h),5.66(t,j＝8.1hz,1h),4.86(d,j＝12.7hz,1h),4.68(d,j＝12.7hz,1h),4.45(t,j＝6.3hz,2h),4.03(t,j＝6.1hz,2h),3.91–3.77(m,4h),2.88(s,4h),2.81(dd,j＝12.6,6.3hz,2h),2.69(dd,j＝13.0,5.8hz,1h),2.61–2.35(m,9h),2.34–2.10(m,4h),2.00–1.84(m,4h),1.69(dd,j＝15.1,8.0hz,2h),1.61–1.50(m,4h),1.09(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ177.2,167.5,162.4,160.0,159.1,140.7,138.1,136.0,135.7,130.7,129.8,128.6,116.4,115.4,110.6,105.8,98.9,81.3,71.4,67.8,66.2,63.9,60.1,57.6,55.6,54.4,45.8,43.9,42.9,37.0,30.1,29.8,28.7,28.2,27.2,24.7,23.8,22.4,18.1.化合物72g的合成：化合物72g的制备方法与化合物72a的合成方法相同，只是将甲胺替换为n-甲基哌嗪，其他合成及后处理方法相同，得到无色油状物72g，产率68％。1hnmr(400mhz,cdcl3)δ8.03(d,j＝7.9hz,2h),7.90(d,j＝16.1hz,1h),7.73(t,j＝7.4hz,1h),7.58(t,j＝7.7hz,2h),7.42(d,j＝8.5hz,1h),6.55–6.36(m,3h),5.66(t,j＝8.1hz,1h),4.82(s,1h),4.71(s,1h),4.45(t,j＝6.3hz,2h),4.03(t,j＝6.0hz,2h),3.93–3.76(m,4h),2.87–2.77(m,2h),2.70(dd,j＝13.0,6.8hz,1h),2.62–2.24(m,14h),2.23(s,3h),2.19–2.07(m,2h),2.00–1.83(m,4h),1.68(dd,j＝15.1,8.0hz,2h),1.54(s,4h),1.08(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ177.1,167.5,162.4,160.0,159.1,140.8,138.1,136.1,135.7,130.7,129.8,128.6,128.5,116.4,115.5,110.6,105.8,98.9,81.2,71.4,67.8,66.3,63.9,60.1,57.,55.6,55.0,53.4,46.0,43.9,43.1,37.0,28.7,28.2,27.2,24.7,23.8,22.4,18.1.化合物72h的合成：化合物72h的制备方法与化合物72a的合成方法相同，只是将甲胺替换为n-boc哌嗪，其他合成及后处理方法相同，得到无色油状物72h，产率77％。1hnmr(400mhz,cdcl3)δ8.03(d,j＝7.8hz,2h),7.89(d,j＝16.1hz,1h),7.72(t,j＝7.4hz,1h),7.58(t,j＝7.8hz,2h),7.41(d,j＝8.5hz,1h),6.53–6.37(m,3h),5.65(t,j＝8.0hz,1h),4.85(d,j＝12.7hz,1h),4.66(d,j＝12.7hz,1h),4.45(t,j＝6.3hz,2h),4.03(t,j＝6.1hz,2h),3.91–3.78(m,4h),3.40(s,4h),2.86–2.67(m,3h),2.54–2.09(m,13h),2.01–1.83(m,4h),1.67(dt,j＝15.0,7.6hz,2h),1.54(s,3h),1.41(s,9h),1.08(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ177.0,167.5,162.4,160.1,159.1,154.8,140.8,138.2,136.0,135.7,130.7,129.7,128.6,128.6,116.4,115.4,110.6,105.9,99.0,81.3,79.6,71.4,67.8,66.1,63.9,60.0,57.2,55.6,53.3,44.1,43.0,37.0,29.8,28.7,28.5,28.2,27.2,24.7,23.8,22.4,18.0.化合物72i的合成：化合物72i的制备方法与化合物72a的合成方法相同，只是将甲胺替换为n-boc哌嗪，其他合成及后处理方法相同，得到无色油状物72i，产率81％。1hnmr(400mhz,cdcl3)δ8.04(d,j＝7.7hz,2h),7.90(d,j＝16.1hz,1h),7.73(t,j＝7.4hz,1h),7.59(t,j＝7.8hz,2h),7.42(d,j＝8.5hz,1h),6.46(td,j＝16.2,7.6hz,3h),5.67(t,j＝8.0hz,1h),4.85(d,j＝12.6hz,1h),4.68(d,j＝12.7hz,1h),4.45(t,j＝6.3hz,2h),4.04(t,j＝6.1hz,2h),3.91–3.75(m,4h),3.54(t,j＝5.1hz,2h),2.87–2.76(m,2h),2.70(dd,j＝12.9,6.9hz,2h),2.60–2.35(m,13h),2.35–2.07(m,6h),1.99–1.85(m,4h),1.68(dt,j＝9.6,7.5hz,2h),1.55(s,3h),1.09(t,j＝12.9hz,1h).13cnmr(100mhz,cdcl3)δ177.1,167.5,162.4,160.0,159.1,140.8,138.1,136.0,135.7,130.6,129.8,128.7,128.6,116.3,115.4,110.6,105.9,98.9,81.2,71.4,67.8,66.4,63.9,60.1,59.2,57.7,57.2,55.6,53.4,52.8,43.9,43.1,37.0,28.7,28.2,27.2,24.7,23.8,22.4,18.1.化合物73的合成5ml圆底烧瓶中，加入化合物68(105mg,0.14mmol)，然后加入2.0m二甲氨基的四氢呋喃置于室温下搅拌2h。使用旋转蒸发仪将溶液浓缩，将浓缩液用硅胶柱纯化得到白色固体103mg，将所得固体溶解于乙酸乙酯中，加入15mg富马酸，搅拌过夜，旋干得到白色固体化合物73(108mg,两步产率95％)。1hnmr(400mhz,meod-d4)δ8.04(dd,j＝8.5,1.2hz,2h),7.94(d,j＝16.1hz,1h),7.80(t,j＝7.5hz,1h),7.66(t,j＝7.9hz,2h),7.52(d,j＝8.3hz,1h),6.71(s,2h),6.62–6.54(m,2h),6.46(d,j＝16.1hz,1h),5.71(t,j＝8.2hz,1h),4.87(d,j＝12.8hz,2h),4.55(d,j＝12.7hz,1h),4.48(t,j＝6.1hz,2h),4.13(dt,j＝12.3,7.8hz,2h),3.88(s,2h),3.39(dd,j＝13.2,9.6hz,1h),3.24(dd,j＝13.3,4.1hz,1h),3.06–2.75(m,7h),2.33–2.10(m,4h),1.99–1.86(m,3h),1.69(dt,j＝14.8,7.3hz,2h),1.58(s,2h),1.07(t,j＝13.0hz,1h).13cnmr(100mhz,meod-d4)δ178.2,169.5,164.3,161.5,160.6,158.7,158.5,142.2,139.6,137.0,136.8,136.0,131.4,130.9,130.6,129.6,115.5,107.6,99.7,83.5,75.3,72.6,69.0,67.4,64.6,61.6,56.2,44.6,43.9,43.1,37.9,36.0,33.7,29.7,29.2,27.8,26.9,25.2,24.6,23.5,21.4,17.9.化合物74的合成合成方法同化合物73的制备，两步产率86％。1hnmr(400mhz,dmso-d6)δ8.01(d,j＝8.1hz,2h),7.87(t,j＝7.4hz,1h),7.80(d,j＝16.1hz,1h),7.72(t,j＝7.6hz,2h),7.65(d,j＝8.5hz,1h),6.66–6.55(m,4h),6.50(d,j＝16.1hz,1h),5.60(t,j＝7.5hz,1h),4.84(d,j＝12.6hz,1h),4.61(d,j＝12.6hz,1h),4.42(t,j＝6.1hz,2h),4.10–3.98(m,3h),3.85(s,3h),3.63–3.57(m,1h),2.78–2.54(m,4h),2.33(dd,j＝24.0,15.1hz,8h),2.18–2.01(m,3h),1.80(td,j＝14.6,7.1hz,5h),1.63(t,j＝10.8hz,1h),1.54(dd,j＝14.9,7.8hz,2h),1.48(s,3h),0.93(t,j＝12.7hz,1h).13cnmr(100mhz,dmso-d6)δ177.3,166.7,166.0,162.2,159.5,158.9,139.5,137.2,136.1,135.9,134.0,130.4,130.0,128.3,128.3,115.1,114.9,110.5,106.6,98.8,80.5,71.4,67.6,66.3,66.0,63.2,59.9,57.3,56.0,55.7,53.5,42.5,36.6,28.1,27.6,25.8,24.2,23.2,21.8,18.6,17.5.实施例2：小白菊内酯-苯磺酰呋咱衍生物及其盐对人胰腺癌细胞系panc-1的抑制作用将待测试细胞配成2×105/ml细胞悬液，加入96孔板圆底细胞培养板内，分别加入待测化合物，每一测试浓度3孔，置37℃、5％co2饱和湿度条件下培养72小时，用mtt法在酶联检测仪570nm波长测得吸光度(a)值，计算出本发明化合物对测试癌细胞的抑制作用。如表1-表4所示，所测试化合物对测试的癌细胞系显示出较强的抗癌活性。表1小白菊内酯–no供体杂合物6-16对胰腺癌细胞系panc-1细胞的抑制作用化合物nic50(μm)ab611.484±0.182722.247±0.837830.611±0.206940.787±0.3781050.535±0.1201160.271±0.1441270.201±0.1061380.125±0.0351490.130±0.07115100.067±0.02416110.104±0.024ptl-4.020±0.113adr-0.780±0.435由上表可见，小白菊内酯–no供体杂合物6-16对胰腺癌细胞系panc-1细胞的抑制作用十分明显。表2.小白菊内酯-苯磺酰基呋咱衍生物对胰腺癌细胞系panc-1的抑制活性(ic50，μm)由上表可以看出，小白菊内酯-苯磺酰基呋咱衍生物能有效地抑制胰腺癌细胞系panc-1的活性表3小白菊内酯–no供体杂合物47-54,57a–57b和60对胰腺癌panc-1细胞的抑制作用a所有数据均为三次独立测试的平均值，表示方法为平均值±标准偏差；bpanc-1:胰腺癌细胞系从表3可以看出，小白菊内酯–no供体杂合物47-54,57a–57b和60对胰腺癌panc-1细胞抑制作用明显。表4小白菊内酯–no供体杂合物对胰腺癌panc-1细胞的抑制作用ab化合物ic50(μm)ab62a0.037±0.01762b0.058±0.02762c0.034±0.01662d0.114±0.01965a0.128±0.09065b0.142±0.112660.180±0.110670.048±0.021680.024±0.011690.386±0.203700.118±0.057710.424±0.10272c0.24±0.0672d0.22±0.0572e0.14±0.0172f0.13±0.0272g0.13±0.0172h0.15±0.0272i0.24±0.03740.19±0.003ptl5.14±0.72adr0.87±0.09a所有数据均为三次独立测试的平均值，表示方法为平均值±标准偏差。bpanc-1:胰腺癌细胞系。从表4可以看出，小白菊内酯–no供体杂合物对胰腺癌panc-1细胞的抑制作用十分明显。上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。当前第1页12