CN111825631B - Be-43547衍生物及其盐,制备方法及其在制备抗癌药物中的用途 - Google Patents
Be-43547衍生物及其盐,制备方法及其在制备抗癌药物中的用途 Download PDFInfo
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Abstract
本发明提供了式(I)和式(II)所示的BE‑43547衍生物及其盐及其在制备抗癌药物中的用途,以及式(I)所示化合物的制备方法和前药设计。
Description
技术领域
本本发明提供了一种BE-43547衍生物及其盐,并涉及BE-43547衍生物及其盐的制备方法,及其在制备治疗癌症药物中的用途,本发明属于药物技术领域。
背景技术
BE-43547是由链丝菌Espy A43547(链丝菌属)产生的,具有抗癌活性的一系列化合物的总称。BE-43547系列化合物是一种包含17元环的环状脂肽类化合物。
根据R基团的差别将化合物命名为BE-43547A1、BE-43547A2、BE-43547B1、BE-43547B2、BE-43547B3、BE-43547C1和BE-43547C2七个天然产物,其结构见图1。报道称,BE-43547系列化合物对P388、colon26、DLD-1、PC-13和MKN-45等癌细胞有抑制活性。2016年,Poulsen等人探究了BE-43547A1、BE-43547A2和ent-BE-43547A1对胰腺癌细胞Panc-1的细胞活性,其中,在正常氧含量条件下IC50为1.6~3.2μM,而在缺氧条件下的IC50提高到41~53nM。以BE-43547A2为例,BE-43547A2对胰腺癌细胞Panc-1在缺氧下的细胞毒性是正常氧条件下的60倍。而缺氧是许多实体瘤的基本特征,并且与肿瘤的转移和化疗耐受相关。因此,研究像BE-43547这样的,具有低氧选择细胞毒性的化合物,对于癌症的治疗研究是非常重要的。BE-43547系列化合物与抗菌素Vinylamycin和具有抗癌活性化合物Rakicidins在结构上有类似性。这些化合物都是大环酯肽类天然产物,都含有一种非天然氨基酸4-氨基-2,4-戊二烯酰胺结构片段。此类化合物在抗肿瘤方面均表现出了较好的生物活性,有进一步研究开发的潜力。但是,此类化合物的水溶性较差,不利于药物被机体吸收。对于此类化合物的修饰及其成盐处理,可能有利于增强其成药性。目前,含N类亲核试剂直接对2,4-戊二烯酰基的1,6-加成反应未见报道。本发明通过N类亲核试对2,4-戊二烯酰基的1,6-加成反应,合成了BE-43547衍生物并成盐,该衍生物具有治疗癌症的作用。
发明内容
本发明提供了式(I)和式(II)所示的BE-43547衍生物及其盐,并涉及如式(I)和式(II)所示的BE-43547衍生物及其盐在治疗癌症药物中的应用。为了实现本发明的上述目的,本发明提供如下的技术方案:
一种如式(I)和式(II)所示所示的BE-43547衍生物及其盐,
式(I)中R1和R2可以相同或不同,分别为为氢原子、烷基、取代烷基、芳基、取代芳基、羟基、取代羟基、氨基、取代氨基、烯基、取代烯基、炔基、取代炔基、环状烷基或杂环基;R3为二甲氨基、四氢吡咯基、哌啶基、N-甲基哌嗪基、N-((聚乙二醇基)乙酰基)哌嗪基、N-取代哌嗪基、取代氨基、巯基、取代巯基、烷基、取代烷基、羟基、取代羟基、烯基、取代烯基、芳基、取代芳基、炔基、取代炔基、杂环基、取代杂环基、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;
其与无机酸或有机酸形成的在药学上可接受的盐,包括与R4Z形成的季铵盐,包括氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸、甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、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、取代苯甲酸;R4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;Z为取代磺酸基、取代羧酸基、取代磷酸基。
一种制备式(I)所示BE-43547衍生物及其盐的方法,其特征在于以式(II)所示的化合物为原料,与(III)和(IV)所示的化合物反应得式(I)所示的化合物,提高了化合物的溶解度和成药性。
一种如式(I)所示的BE-43547衍生物及其盐的前药设计方案,其特征在于(I)所示的BE-43547衍生物及其盐可以在体外或体内缓慢释放出(II)所示的活性成分,
一种如式(I)和式(II)所示的BE-43547衍生物及其盐,在制备治疗癌症或治疗癌症的辅助药物中的用途,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。
发明还提供了一种用于治疗癌症的药物组合物,其中含有有效量的式(I)和式(II)所示BE-43547衍生物及其盐在药学上可接受的载体或与其他抗癌药物的组合物。
附图说明
图1.天然产物BE-43547的结构通式
图2.化合物10a-10c的合成
图3.化合物16a-16e的合成
图4.化合物19a-P1、19a-P2和19c的合成
图5.不同化合物对Panc-1细胞系的抗癌活性
图6.前药化合物20a-20i的合成
图7.前药化合物24a和24b的合成
图8.前药化合物20b,20g和20i体外降解速率
图9.前药化合物20i,24a和24b体外释放化合物1a的速率
图10.前药化合物20i,24a和24b在大鼠体内释放化合物1a的速率
图11.前药化合物24a和24b及其前体化合物25a和25b的质量分布图(MALDI-TOF-MS)
具体实施方式
为了理解本发明,下面以实施例进一步说明本发明,但不意于限制本发明的保护范围。
实施例1:BE-43547衍生物及其盐的合成
具体合成路线见图2、图3、图4、图6和图7,具体步骤如下:
化合物4b的合成
将化合物3b(235μL,1.92mmol)溶解于DCM(5mL)置于-78℃低温浴下,然后将现制的烯醇硅醚2a(1.60mmol)和三氟化硼乙醚络合物(240μL,1.92mmol)滴加至反应液进行反应。低温下反应6h后,向反应液中加入饱和碳酸氢钠水溶液(3mL)淬灭反应。淬灭反应后将反应体系温度升至室温,加入DCM(5mL)稀释反应液,然后萃取分液。有机相干燥浓缩后,粗品硅胶柱纯化(石油醚:乙酸乙酯=20:1~8:1)得到粗品化合物。
氩气保护下,将上一步得到的醇化合物溶解于二氯甲烷(5mL)置于室温下搅拌。向反应液中依次加入2,6-lutidine(1.92mmol)和TBSOTf(1.92mmol),室温下搅拌反应1h。向反应液中加入甲醇(0.1mL)淬灭反应,将反应液用5%NaHSO4水溶液洗涤,得到的有机相用无水硫酸钠干燥,过滤后浓缩,得到的粗品用硅胶柱纯化,得到化合物4b(580mg,2步反应产率75%)。
[α]D 23=–27.4(CHCl3,c=1.0).νmax(KBr):2954,1684,1337,1213,1133,1058,837,777,535cm-1;1H NMR(400MHz,CDCl3)δ5.76(ddt,J=16.9,10.2,6.6Hz,1H),5.01–4.94(m,1H),4.94–4.89(m,1H),4.15–4.09(m,1H),3.88(dd,J=7.6,4.9Hz,1H),3.48(d,J=13.8Hz,1H),3.42(d,J=13.8Hz,1H),3.34–3.26(m,1H),2.09–1.93(m,4H),1.93–1.82(m,3H),1.55–1.42(m,2H),1.41–1.29(m,3H),1.29–1.18(m,1H),1.14(s,3H),1.11(d,J=6.7Hz,3H),0.96(s,3H),0.87(s,9H),0.08(d,J=11.1Hz,6H);13C NMR(100MHz,CDCl3)δ174.2,138.9,114.7,72.7,65.6,53.3,48.3,47.9,46.5,44.9,38.7,33.9,33.0,31.8,26.7,26.1,24.4,21.0,20.0,18.2,10.5-4.2,-4.9;HRMS(ESI)calculated forC25H46NO4SSi+[M+H]+:484.2914,found 484.2916.
化合物6b的合成
将化合物4b(2.0g,4.13mmol)溶解于二氯甲烷(30mL)中,用氩气保护反应体系,并将反应体系置于–78℃的低温反应仪中搅拌。向反应液中加入DIBAL-H(1.0M in toluene,5.00mL,5.00mmol),继续反应30分钟。向反应液中加入甲醇(0.2mL)淬灭反应,随后将反应体系的温度升至室温。向反应液中加入2N酒石酸钾钠水溶液(10mL),继续搅拌30分钟,直至反应液明显分层。得到的水相用二氯甲烷萃取(15mL×2),然后将合并的有机相用无水硫酸钠干燥,过滤后浓缩,粗品用硅胶柱纯化得到无色油状化合物(0.91g)。
氩气保护下,将化合物5(1.0g,3.70mmol)溶解于二氯甲烷(20mL),并将其降温至–10℃。向反应液中逐滴加入三氟甲磺酸基二丁硼(1.0M in DCM,3.70mL,3.70mmol)和DIPEA(0.610mL,3.70mmol)。继续搅拌20分钟后,将上一步得到的醛(0.91g,3.36mmol)溶解于二氯甲烷(1mL)后,再滴加至反应液。继续搅拌反应3h后,向反应液中饱和氯化铵水溶液(8mL)萃灭反应。将反应体系升至室温,萃取分液,得到的有机相用无水硫酸钠干燥,过滤后浓缩,粗品用硅胶柱纯化,得到的化合物6b为白色固体(1.10g,2步反应产率48%)。核磁共振氢谱结果显示,此反应的立体选择性d.r.>20:1。
[α]D 24=–69.5(CHCl3,c=1.0);νmax(KBr):2961,2926,2857,1658,1334,1259,1135,1065,833,802,772,537cm-1;1H NMR(400MHz,CDCl3)δ5.81(ddt,J=16.9,10.2,6.6Hz,1H),5.02–4.95(m,1H),4.94–4.89(m,1H),4.12–4.03(m,1H),3.88(t,J=6.3Hz,1H),3.71(d,J=10.3Hz,1H),3.51(d,J=13.8Hz,1H),3.43(d,J=13.8Hz,1H),3.41(d,J=1.2Hz,1H),3.24–3.17(m,1H),2.10–1.98(m,4H),1.91(dd,J=16.9,9.0Hz,3H),1.83–1.74(m,1H),1.60–1.52(m,1H),1.44–1.26(m,6H),1.20(d,J=7.1Hz,3H),1.15(s,3H),0.98(s,3H),0.89(s,9H),0.80(d,J=7.0Hz,3H),0.05(s,6H);13C NMR(100MHz,CDCl3)δ177.96,139.33,114.25,72.04,71.90,65.07,53.20,48.55,47.92,44.77,41.21,40.91,38.48,34.02,33.03,30.05,26.59,26.09,26.01,20.96,20.00,18.24,10.29,9.50,-4.18,-4.38;HRMS(ESI)calculated for C28H52NO5SSi+[M+H]+:542.3332,found 542.3332.
化合物8b的合成
50mL圆底烧瓶中,依次加入化合物6b(0.90g,1.66mmol)和THF:H2O=3:1的混合溶液(8mL),置于室温下搅拌。将一水合氢氧化锂(0.418g,9.97mmol)加至反应体系,继续搅拌反应直至TLC监测到反应物6b被消耗完全。反应约7h后,在控制水浴温度不高于40℃的条件下,将反应液旋蒸除去THF。冰浴下向得到的溶液中滴加浓度为1N盐酸水溶液,直至溶液pH=1,然后用EtOAc(80mL×4)萃取水溶液,将合并的乙酸乙酯相用无水硫酸钠干燥,过滤后浓缩有机相,得到的粗品直接用于下一步缩合反应。
50mL圆底烧瓶中,依次加入上一步得到的羧酸化合物、甘氨酸叔丁酯7(0.327g,2.49mmol)和二氯甲烷(8mL),置于磁力搅拌器上搅拌。将HOBt(0.269g,1.99mmol),EDCI(0.381g,1.99mmol)和DIPEA(0.33mL,1.99mmol)依次加至反应体系,继续搅拌反应3h。向反应液中加入水(1mL)淬灭反应,然后用二氯甲烷(20mL)稀释反应液。分别用1%盐酸水溶液(10mL)、饱和碳酸氢钠(10mL)和饱和食盐水(10mL)洗涤,有机相干燥后过滤,浓缩。得到的粗品用硅胶柱层析纯化,得到的产物8b为无色油状物(330mg,2步反应产率43%)。
[α]D 27=–6.92(CHCl3,c=0.62);νmax(KBr):2934,1745,1643,1543,1253,1159,836,775cm-1;1H NMR(400MHz,CDCl3)δ6.67(t,J=5.3Hz,1H),5.79(ddt,J=16.9,10.1,6.6Hz,1H),5.03–4.95(m,1H),4.95–4.90(m,1H),4.02(s,1H),4.01–3.81(m,3H),3.73(d,J=9.9Hz,1H),2.45(qd,J=7.2,1.7Hz,1H),2.03(h,J=7.4,6.8Hz,2H),1.83–1.73(m,1H),1.46(s,9H),1.46–1.33(m,4H),1.17(d,J=7.1Hz,3H),0.89(s,9H),0.76(d,J=6.9Hz,3H),0.07(d,J=2.6Hz,6H);13C NMR(100MHz,CDCl3)δ177.24,169.22,139.05,114.52,82.42,74.23,73.53,42.35,42.09,40.61,34.02,31.80,28.18,26.05,24.97,18.20,11.26,9.96,-4.29,-4.33;HRMS(ESI)calculated for C24H48NO5Si+[M+H]+:458.3299,found 458.3302.
化合物10b的合成
100mL圆底烧瓶中,加入化合物8b(2.0g,4.36mmol)并用二氯甲烷(30mL),溶解,置于室温下搅拌。然后将戴斯马丁试剂(2.18g,5.13mmol)分批添加至反应体系。反应体系于室温搅拌反应1h。向反应液中加入饱和Na2S2O3水溶液(10mL)和饱和NaHCO3水溶液(10mL)淬灭过量的氧化剂。继续搅拌,直至反应液变澄清后,萃取分液。水相用二氯甲烷萃取(30mL×4),并将合并的有机相用无水硫酸钠干燥,浓缩。粗品用硅胶柱纯化,得到无色油状化合物9b(1.85g,93%)。由于非对映异构体比例约为2:1,因此核磁共振数据表征主要异构体。
氩气保护下,将化合物9b(1.85g,4.05mmol)用THF(30mL)溶解,于-78℃低温下搅拌。将KHMDS(1.0M in THF,0.81mL,0.81mmol)滴加至反应液中,继续搅拌20min,形成烯醇盐。将氧化剂D-CSO(976mg,4.25mmol)溶解于THF(8mL)中,滴加至反应体系。滴加完毕后,继续反应6h。向反应液加入饱和氯化铵水溶液(5mL)淬灭反应,并将反应体系缓慢升至室温。将反应液使用旋转蒸发仪将溶液浓缩,得到的残渣用水(20mL)和乙酸乙酯(50mL)稀释。静置分液后,水相用乙酸乙酯萃取(30mL×3),合并的有机相用无水硫酸钠干燥,过滤后浓缩,硅胶柱层析纯化,得无色油状化合物(1.68g,88%)。
250mL圆底烧瓶中,将化合物(1.68g,3.59mmol)溶解于THF(30mL)中,然后加入TBAF(1.0M in THF,4.28mL,4.28mmol),继续搅拌反应2h。加入饱和氯化铵水溶液(30mL)淬灭反应,然后用乙酸乙酯(40mL)和水(20mL)稀释反应液,分液后得到的水相用乙酸乙酯(20mL×3)萃取。有机相合并后用无水硫酸钠干燥,过滤后浓缩。粗品用短的硅胶柱分离纯化,得到化合物10b为白色固体(1.27g,99%)。
[α]D 27=–40.7(CHCl3,c=0.52);νmax(KBr):3343,3984,2935,1746,1651,1534,1367,1169,1005,917,857,734cm-1;1H NMR(400MHz,CDCl3)δ7.39(s,1H),5.87–5.70(m,1H),5.05–4.90(m,3H),3.95–3.77(m,2H),3.59(brs,2H),2.63–2.54(m,1H),2.14–1.98(m,2H),1.63–1.55(m,2H),1.59(s,3H),1.46(s,9H),1.48–1.27(m,2H),1.09(s,3H);13C NMR(100MHz,CDCl3)δ213.10,171.11,168.61,138.70,114.88,82.77,82.36,74.85,45.84,42.32,34.32,33.67,28.15,24.33,24.05,15.42;HRMS(ESI)calculated for C18H32NO6 +[M+H]+:358.2226,found 358.2222.
化合物12a的合成
将化合物10b(500mg,1.40mmol)加入到含量为10%的丁烯11a的己烷溶液中,再加入grubbs二代催化剂grubbs II(62mg,0.07mmol),在室温下搅拌反应12h。由于化合物11a的沸点较低,反应时应将反应装置密封。将反应液减压浓缩后,使用硅胶柱纯化,得到的化合物存在双键的顺反异构体,无须将异构体分离直接用于下一步加氢还原反应。
将得到的顺反异构体化合物溶解于甲醇(10mL)中,加入10%Pd/C催化剂(10mg,含水量为50%)。然后将反应装置里的空气置换为惰性气体氩气,再将氩气置换为反应需要的氢气进行反应。避免直接用氢气置换空气,造成氢气和空气的混合,产生爆炸危险。反应结束后,将反应液用硅藻土过滤除掉Pd/C催化剂,得到化合物12a(180mg,两步反应产率33%)。
[α]D 23=–59.5(CHCl3,c=0.13);νmax(KBr):2922,1749,1731,1644,1531,1368,1236,1162cm-1;1H NMR(400MHz,CDCl3)δ7.41(t,J=5.5Hz,1H),4.99(s,1H),3.96–3.75(m,2H),3.63–3.52(m,2H),2.69–2.53(m,1H),1.61–1.54(m,1H),1.58(s,3H),1.50–1.43(m,1H),1.46(s,9H),1.37–1.20(m,10H),1.08(d,J=6.1Hz,3H),0.87(t,J=6.5Hz,3H);13CNMR(100MHz,CDCl3)δ213.0,171.2,168.7,82.7,82.3,75.0,45.9,42.3,34.9,32.0,29.6,29.4,28.1,25.0,24.0,22.8,15.4,14.2;HRMS(ESI)calculated for C20H38NO6 +[M+H]+:388.2696,found 388.2696.
化合物15a的合成
将化合物12a(0.150g,0.387mmol)和化合物13(0.314g,0.581mmol)用二氯甲烷(4mL)溶解。控制在0℃下,将催化剂DMAP(9.5mg,0.0774mmol)和缩合剂DIC(0.12mL,0.774mmol)加至反应体系。反应体系温度升至室温后,继续搅拌30min。然后向反应液加入水(10mL)和二氯甲烷(10mL)稀释反应液后,静置分层。有机相干燥浓缩后使用硅胶柱层析纯化(石油醚:乙酸乙酯=9:1~2:1),得无色油状化合物14a(292mg)中仍含有少量杂质。
将化合物14a溶解于DCM(3mL)中,加入TFA(1.0mL)后搅拌反应6h,直至TLC检测到反应物消耗完全。向反应液中加入甲苯(5mL)再旋蒸浓缩,防止直接浓缩导致TFA浓度升高从而引起的副反应。油泵下减压旋蒸,确保除掉过量的TFA,得到黄色油状化合物,直接用于下一步反应。
将HATU(1.84g,4.82mmol)加入到THF(320mL)中,然后将DIPEA(1.60mL,9.64mmol)滴加至反应体系。将上一步得到的粗品化合物溶解于THF(10mL)中,使用注射泵将THF溶液滴加至反应液中,滴加时间为10h。继续搅拌反应12h。随后将反应液旋蒸浓缩,残渣用乙酸乙酯(200mL)稀释后,用硅藻土过滤。滤液分别用2.5%的硫酸氢钠水溶液(50mL)、饱和碳酸氢钠水溶液(50mL)和饱和食盐水(50mL)洗涤。有机相用无水硫酸钠干燥,过滤后浓缩,粗品用硅胶柱层析(二氯甲烷:甲醇=100:3~100:5)纯化,得到白色固体化合物。
将上一步得到的化合物溶解于THF(3mL)中,置于塑料反应瓶中,加入3HF·Et3N(0.2mL,1.25mmol),室温下搅拌反应30h,直至TLC监测到反应完全。反应结束后立即向反应液中加入水(15mL)和乙酸乙酯(35mL)稀释,分离的有机相用无水硫酸钠干燥,硅胶柱纯化,得到白色固体化合物15a(114mg,4步反应产率为47%)。
[α]D 22=+33.3(MeOH:CHCl3=1:1,c=0.20);νmax(KBr):3348,2928,1757,1661,1192cm-1;1H NMR(400MHz,DMSO)δ8.69(t,J=5.9Hz,1H),7.41(d,J=9.3Hz,1H),6.78(s,1H),6.73(dd,J=15.0,3.4Hz,1H),6.16(dd,J=15.1,2.0Hz,1H),5.03(t,J=5.6Hz,1H),4.93(td,J=9.3,2.7Hz,1H),4.63–4.54(m,1H),4.58(d,J=19.2Hz,1H),4.03(d,J=19.3Hz,1H),3.75(dd,J=16.8,5.6Hz,1H),3.63(dd,J=16.8,6.3Hz,1H),3.52–3.40(m,2H),3.36–3.30(m,2H),2.82(s,3H),1.73–1.64(m,1H),1.62(s,3H),1.58–1.45(m,1H),1.35–1.16(m,10H),1.10(d,J=6.7Hz,3H),0.85(t,J=6.7Hz,3H);13C NMR(100MHz,DMSO)δ212.5,173.5,168.9,167.8,166.9,142.9,119.3,80.0,76.8,63.0,51.8,50.1,43.3,43.1,35.0,31.3,28.8,28.6,28.5,24.5,22.1,21.1,15.8,14.0;HRMS(MALDI)calculated forC24H39N3O8Na+[M+Na]+:520.2629,found 520.2633.
化合物16a的合成
将化合物15a(49mg,0.0985mmol)溶解于THF(2mL)中,依次滴加Et3N(0.027mL,0.197mmol)和EtSO2Cl(0.014mL,0.148mmol)至反应液。室温下搅拌反应,并每隔30min用TLC监测反应进程。若TLC监测反应未转化完全,补加Et3N(0.75eq)和EtSO2Cl(0.5eq),直至TLC监测反应完全。随后向反应液中加入少量水(0.010mL)淬灭反应,加入乙酸乙酯稀释溶液后,再加入无水硫酸钠除水。将过滤的溶液浓缩,残渣直接用于下一步反应。
将上一步得到产物用THF(4mL)溶解稀释,向反应液中加入有机中强碱DBU(0.120mL,0.788mmol),搅拌反应50min后,向反应液中加入乙酸乙酯(30mL)稀释反应液,用5%的硫酸氢钠水溶液(10mL)洗涤有机溶液,再用饱和碳酸氢钠水溶液(10mL)洗涤除掉酸性杂质。静置至两相完全分层,有机相干燥浓缩后用硅胶柱纯化得到白色固体化合物16a(38mg,2步反应产率为80%)。
[α]D 23=+30.4(MeOH:CHCl3=1:1,c=0.16);νmax(KBr):2927,1748,1660,1641,1192cm-1;1H NMR(400MHz,DMSO)δ8.78(t,J=6.1Hz,1H),8.69(s,1H),6.99(d,J=15.2Hz,1H),6.73(s,1H),6.33(d,J=15.2Hz,1H),5.77(s,1H),5.41(s,1H),4.97(td,J=9.4,2.5Hz,1H),4.41(d,J=19.2Hz,1H),4.16(d,J=19.3Hz,1H),3.97(dd,J=16.2,5.6Hz,1H),3.69(dd,J=16.3,6.5Hz,1H),3.45–3.35(m,1H),2.87(s,3H),1.75–1.64(m,1H),1.60(s,3H),1.57–1.46(m,1H),1.36–1.14(m,10H),1.08(d,J=6.8Hz,3H),0.85(t,J=6.6Hz,3H);13C NMR(100MHz,DMSO)δ212.1,173.8,168.9,167.8,166.5,139.5,137.3,116.9,114.3,80.7,76.6,50.2,44.3,43.6,35.1,31.3,31.2,28.7,28.6,28.4,24.6,22.1,20.9,15.8,14.0;HRMS(MALDI)calculated for C24H37N3O7Na+[M+Na]+:502.2524,found502.2528.
化合物12b的合成
参照化合物12a的合成方法,得到化合物12b(408mg,2步反应产率为70%)。
[α]D 25=–42.2(CHCl3,c=0.65);νmax(KBr):2927,1748,1729,1651,1367,1227,1165cm-1;1H NMR(400MHz,CDCl3)δ7.39(t,J=4.3Hz,1H),4.96(s,1H),3.86(qd,J=18.0,5.4Hz,2H),3.65–3.51(m,2H),2.56–2.46(m,1H),1.62–1.54(m,1H),1.59(s,3H),1.52–1.40(m,1H),1.46(s,9H),1.27(brs,J=14.7Hz,14H),1.09(d,J=6.0Hz,3H),0.87(t,J=6.7Hz,3H);13C NMR(100MHz,CDCl3)δ212.8,171.2,168.8,82.6,82.3,75.0,45.8,42.3,34.9,39.0,32.0,29.7,29.7,29.4,28.1,25.0,23.8,22.8,15.3,14.2;HRMS(ESI)calculated for C22H42NO6 +[M+H]+:416.3009,found 416.3010.
化合物15b的合成
参照优化后化合物15a的合成方法,得到化合物15b(150mg,4步反应产率为56%)。
[α]D 23=+27.6(MeOH:CHCl3=1:1,c=0.48);νmax(KBr):3347,2928,1758,1655,1192cm-1;1H NMR(400MHz,DMSO)δ8.68(t,J=5.8Hz,1H),7.41(d,J=9.3Hz,1H),6.77(s,1H),6.74(dd,J=15.2,3.4Hz,1H),6.17(d,J=15.0Hz,1H),5.01(t,J=5.4Hz,1H),4.94(td,J=9.5,1.7Hz,1H),4.62–4.55(m,1H),4.59(d,J=19.1Hz,1H),4.02(d,J=19.3Hz,1H),3.76(dd,J=16.7,5.5Hz,1H),3.64(dd,J=16.8,6.2Hz,1H),3.52–3.40(m,2H),3.39–3.31(m,1H),2.83(s,3H),1.73–1.64(m,1H),1.63(s,3H),1.59–1.47(m,1H),1.24(brs,14H),1.10(d,J=6.7Hz,3H),0.85(t,J=6.6Hz,3H);13C NMR(100MHz,DMSO)δ212.4,173.5,168.8,167.8,166.9,142.9,119.4,80.0,76.8,63.0,51.8,50.1,43.3,43.1,35.0,31.3,29.0,28.9,28.8,28.7,28.7,24.4,22.1,21.1,15.8,14.0;HRMS(ESI)calculated forC26H44N3O8 +[M+H]+:526.3125,found 526.3122.
化合物16b的合成
参照化合物16a的合成方法,得到化合物16b(76mg,2步反应产率为98%)。
[α]D 25=+15.0(MeOH:CHCl3=1:1,c=0.12);νmax(KBr):2925,2854,1748,1661,1644,1193cm-1;1H NMR(400MHz,DMSO-d6)δ8.77(t,J=6.0Hz,1H),8.69(s,1H),6.99(d,J=15.1Hz,1H),6.71(s,1H),6.34(d,J=15.2Hz,1H),5.77(s,1H),5.40(s,1H),4.97(t,J=9.4Hz,1H),4.41(d,J=19.3Hz,1H),4.15(d,J=19.3Hz,1H),3.97(dd,J=16.3,5.5Hz,1H),3.69(dd,J=16.2,6.4Hz,1H),3.45–3.36(m,1H),2.87(s,3H),1.73–1.65(m,1H),1.60(s,3H),1.57–1.45(m,1H),1.24(brs,14H),1.08(d,J=6.9Hz,3H),0.85(t,J=6.5Hz,3H);13C NMR(100MHz,DMSO)δ212.0,173.8,168.8,167.7,166.4,139.4,137.3,116.8,114.3,80.7,76.5,50.2,44.3,43.5,35.1,31.3,31.2,29.0,28.7,28.7,24.5,22.1,20.9,15.7,14.0;HRMS(MALDI)calculated for C26H41N3O7Na+[M+Na]+:530.2837,found 530.2840.
化合物12c的合成
参照化合物12a的合成方法,得到化合物12c(290mg,2步反应产率为64%)。
[α]D 24=–39.1(CHCl3,c=0.42);νmax(KBr):3340,2929,2855,1749,1729,1651,1530,1366,1226,1166cm-1;1H NMR(400MHz,CDCl3)δ7.42(t,J=5.5Hz,1H),5.01(s,1H),3.95–3.76(m,2H),3.61–3.50(m,2H),2.67(s,1H),1.62–1.54(m,1H),1.57(s,3H),1.50–1.41(m,1H),1.45(s,9H),1.35–1.18(m,18H),1.07(d,J=5.8Hz,3H),0.87(t,J=6.7Hz,3H);13C NMR(100MHz,CDCl3)δ213.0,171.2,168.6,82.7,82.3,75.0,45.9,42.3,34.9,32.0,29.8,29.9,29.8,29.7,29.7,29.5,29.5,28.1,25.1,24.0,22.8,15.4,14.2;HRMS(ESI)calculated for C24H46NO6 +[M+H]+:466.3139,found 466.3142.
化合物15c的合成
参照优化后化合物15a的合成方法,得到化合物15c(109mg,4步反应产率为44%)。
[α]D 26=+28.4(MeOH:CHCl3=1:1,c=0.83);νmax(KBr):3340,2926,2855,1752,1658,1190,1026,1004cm-1;1H NMR(400MHz,DMSO)δ8.69(t,J=5.8Hz,1H),7.41(d,J=9.3Hz,1H),6.77(s,1H),6.73(dd,J=15.1,3.3Hz,1H),6.16(d,J=14.1Hz,1H),5.02(t,J=5.5Hz,1H),4.93(t,J=8.2Hz,1H),4.64–4.53(m,2H),4.02(d,J=19.3Hz,1H),3.76(dd,J=16.8,5.5Hz,1H),3.63(dd,J=16.8,6.2Hz,1H),3.54–3.40(m,2H),3.37–3.30(m,1H),2.82(s,3H),1.74–1.63(m,1H),1.62(s,3H),1.58–1.46(m,1H),1.23(brs,18H),1.10(d,J=6.7Hz,3H),0.85(t,J=6.7Hz,3H);13C NMR(100MHz,DMSO)δ212.4,173.5,168.8,167.8,166.8,142.9,119.3,80.0,76.8,63.0,51.8,50.1,43.3,43.1,34.9,31.3,29.1,29.0,29.0,28.8,28.7,24.4,22.1,21.1,15.8,14.0;HRMS(ESI)calculated for C28H47N3O8 +[M+H]+:554.3438,found 554.3447.
化合物16c的合成
参照化合物16a的合成方法,得到化合物16c(54mg,2步反应产率为92%)。
[α]D 25=+15.8(MeOH:CHCl3=1:1,c=0.13);νmax(KBr):2924,2853,1749,1660,1529,1193cm-1;1H NMR(400MHz,DMSO)δ8.80(t,J=6.0Hz,1H),8.70(s,1H),6.99(d,J=15.2Hz,1H),6.74(s,1H),6.34(d,J=15.2Hz,1H),5.77(s,1H),5.41(s,1H),4.96(td,J=9.3,1.9Hz,1H),4.41(d,J=19.2Hz,1H),4.16(d,J=19.2Hz,1H),3.97(dd,J=16.2,5.5Hz,1H),3.69(dd,J=16.2,6.6Hz,1H),3.44–3.37(m,1H),2.87(s,3H),1.73–1.63(m,1H),1.60(s,3H),1.56–1.47(m,1H),1.25(brs,J=14.2Hz,18H),1.08(d,J=6.8Hz,3H),0.85(t,J=6.7Hz,3H);13C NMR(100MHz,DMSO)δ212.1,173.8,168.9,167.8,166.5,139.5,137.3,116.9,114.4 80.7,76.6,50.2,44.4,43.6,35.1,31.4,31.2,29.0,29.0,28.8,28.8,24.6,22.2,20.9,15.8,14.0;HRMS(MALDI)calculated for C28H45N3O7Na+[M+Na]+:558.3150,found 558.3155.
化合物12d的合成
参照化合物12a的合成方法,得到化合物12d(400mg,2步反应产率为57%)。
[α]D 27=–36.9(CHCl3,c=0.26);νmax(KBr):2961,2923,1738,1660,1261,1098,1020,801cm-1;1H NMR(400MHz,CDCl3)δ7.39(t,J=5.5Hz,1H),4.95(s,1H),3.90(dd,J=18.0,5.3Hz,1H),3.83(dd,J=18.1,5.5Hz,1H),3.66–3.51(m,2H),2.49(d,J=7.7Hz,1H),1.60–1.56(m,1H),1.59(s,3H),1.51–1.43(m,1H),1.47(s,9H),1.25(brs,26H),1.09(d,J=5.5Hz,3H),0.88(t,J=6.7Hz,3H);13C NMR(100MHz,CDCl3)δ213.2,171.1,168.6,82.7,82.3,75.1,45.9,42.3,35.0,32.1,29.8,29.8,29.8,29.8,29.7,29.5,28.2,25.1,24.1,22.8,15.4,14.3;HRMS(ESI)calculated for C28H54NO6 +[M+H]+:500.3948,found500.3947.
化合物15d的合成
参照优化后化合物15a的合成方法,得到化合物15d(220mg,4步反应产率为59%)。
[α]D 27=+28.6(MeOH:CHCl3=1:1,c=0.28);νmax(KBr):2924,2853,1757,1663,1190cm-1;1H NMR(400MHz,DMSO)δ8.69(t,J=5.9Hz,1H),7.40(d,J=9.3Hz,1H),6.77(s,1H),6.73(dd,J=15.0,3.4Hz,1H),6.16(dd,J=15.1,2.0Hz,1H),5.02(t,J=5.5Hz,1H),4.92(td,J=9.3,2.7Hz,1H),4.65–4.53(m,1H),4.58(d,J=19.2Hz,1H),4.02(d,J=19.3Hz,1H),3.75(dd,J=16.8,5.6Hz,1H),3.63(dd,J=16.8,6.3Hz,1H),3.52–3.39(m,2H),3.38–3.30(m,1H),2.82(s,3H),1.72–1.61(m,1H),1.62(s,3H),1.59–1.44(m,1H),1.23(brs,26H),1.10(d,J=6.7Hz,3H),0.85(t,J=6.9,3H);13C NMR(100MHz,DMSO)δ212.5,173.5,168.9,167.8,166.9,142.9,119.3,80.0,76.8,63.0,51.83 50.1,43.3,43.1,34.9,31.4,29.1,29.1,29.0,29.0,28.9,28.8,24.5,22.2,21.1,15.8,14.0;HRMS(ESI)calculated for C32H55N3O8 +[M+H]+:610.4064,found 610.4072.
化合物16d的合成
参照化合物16a的合成方法,得到化合物16d(71mg,2步反应产率为72%)。
[α]D 27=+12.1(MeOH:CHCl3=1:1,c=0.37);νmax(KBr):2920,1746,1659,1530,1195cm-1;1H NMR(400MHz,DMSO)δ8.83–8.74(m,1H),8.69(s,1H),6.99(d,J=15.2Hz,1H),6.73(s,1H),6.33(d,J=15.2Hz,1H),5.77(s,1H),5.41(s,1H),4.96(t,J=9.5Hz,1H),4.41(d,J=19.2Hz,1H),4.15(d,J=19.3Hz,1H),4.14–4.08(m,1H),3.97(dd,J=15.8,5.5Hz,1H),3.68(dd,J=16.3,6.5Hz,1H),3.45–3.36(m,1H),3.16(d,J=5.3Hz,3H),2.87(s,3H),1.72–1.64(m,1H),1.60(s,3H),1.56–1.44(m,2H),1.23(brs,26H),1.08(d,J=6.8Hz,3H),0.85(t,J=6.6Hz,3H);13C NMR(100MHz,DMSO:CDCl3=1:1)δ211.6,173.8,168.2,167.5,166.3,139.4,137.1,116.5,113.9,80.4,76.3,50.2,44.2,43.5,35.0,31.3,31.2,29.0,28.9,28.9,28.8,28.7,28.6,24.3,22.0,20.8,15.7,13.7;HRMS(MALDI)calculated for C32H53N3O7Na+[M+Na]+:614.3776,found 614.3780.
化合物12e的合成
参照化合物12a的合成方法,得到化合物12e(306mg,2步反应产率为41%)。
[α]D 23=–38.8(CHCl3,c=0.24);νmax(KBr):2921,2851,1737,1661,1524,1369,1246,1163cm-1;1H NMR(400MHz,CDCl3)δ7.39(t,J=5.5Hz,1H),4.96(s,1H),3.90(dd,J=18.1,5.4Hz,1H),3.83(dd,J=18.3,5.5Hz,1H),3.63–3.53(m,2H),2.52(d,J=8.1Hz,1H),1.61–1.55(m,1H),1.59(s,3H),1.50–1.44(m,1H),1.46(s,9H),1.25(s,30H),1.08(d,J=5.6Hz,3H),0.88(t,J=6.6Hz,3H);13C NMR(100MHz,CDCl3)δ213.1,171.1,168.6,82.7,82.3,75.1,45.9,42.3,35.0,32.1,29.8,29.8,29.8,29.8,29.7,29.5,28.2,25.1,24.1,22.8,15.4,14.3;HRMS(MALDI)calculated for C30H57NO6Na+[M+Na]+:550.4078,found550.4081.
化合物15e的合成
参照优化后化合物15a的合成方法,得到化合物15e(165mg,4步反应产率为56%)。
[α]D 23=+29.5(MeOH:CHCl3=1:1,c=0.31);νmax(KBr):2924,2853,1756,1659,1192cm-1;1H NMR(400MHz,DMSO)δ8.68(t,J=5.9Hz,1H),7.40(d,J=9.3Hz,1H),6.77(s,1H),6.73(dd,J=15.1,3.4Hz,1H),6.16(dd,J=15.1,2.0Hz,1H),5.01(t,J=5.6Hz,1H),4.93(td,J=9.3,2.7Hz,1H),4.64–4.54(m,1H),4.59(d,J=19.2Hz,1H),4.00(d,J=19.4Hz,1H),3.76(dd,J=16.8,5.6Hz,1H),3.63(dd,J=16.8,6.3Hz,1H),3.52–3.40(m,2H),3.39–3.31(m,1H),2.82(s,3H),1.71–1.62(m,1H),1.62(s,3H),1.57–1.46(m,1H),1.23(brs,30H),1.10(d,J=6.7Hz,3H),0.85(t,J=6.8Hz,3H);13C NMR(100MHz,DMSO)δ212.4,173.5,168.8,167.8,166.8,142.9,119.3,80.0,76.8,63.0,51.8,50.1,43.2,43.1,34.9,31.3,29.1,29.0,29.0,29.0,28.8,28.7,24.4,22.1,21.0,15.8,13.9;13C NMR(100MHz,DMSO)δ212.47,173.53,168.87,167.76,166.86,142.91,119.34,79.97,76.84,63.00,51.82,50.13,43.25,43.08,34.97,31.27,28.78,28.64,28.50,24.46,22.10,21.06,15.83,14.0;HRMS(MALDI)calculated for C34H59N3O8Na+[M+Na]+:660.4194,found660.4198.
化合物16e的合成
参照化合物16a的合成方法,得到化合物16e(85mg,2步反应产率为87%)。
[α]D 27=+6.67(MeOH:CHCl3=1:1,c=0.23);νmax(KBr):2920,2849,1746,1657,1194cm-1;1H NMR(400MHz,DMSO:CDCl3=1:1)δ8.76(t,J=6.1Hz,1H),8.69(s,1H),6.98(d,J=15.2Hz,1H),6.68(s,1H),6.33(d,J=15.2Hz,1H),5.78(s,1H),5.35(s,1H),4.97(td,J=9.4,2.6Hz,1H),4.43(d,J=19.2Hz,1H),3.96(dd,J=16.2,5.5Hz,1H),3.69(dd,J=16.2,6.5Hz,1H),3.45–3.34(m,1H),2.88(s,3H),1.69–1.61(m,1H),1.60(s,3H),1.56–1.45(m,1H),1.22(brs,30H),1.09(d,J=6.8Hz,3H),0.85(t,J=6.7Hz,3H);13C NMR(100MHz,DMSO:CDCl3=1:1)δ211.9,173.8,168.6,167.6,166.4,139.4,137.2,116.7,114.0,80.6,76.5,50.2,44.3,43.5,35.0,31.3,31.2,29.0,29.0,28.9,28.8,28.7,24.5,22.1,20.9,15.7,13.9;HRMS(MALDI)calculated for C34H57N3O7Na+[M+Na]+:642.4089,found 642.4093.
化合物4a的合成
参照化合物4b的合成方法,得到化合物4a(8.0g,三步产率65%)。
[α]22 D=–26.1(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ4.22–4.10(m,1H),3.87(s,1H),3.43(q,J=13.8Hz,2H),3.18–3.06(m,1H),2.02(dd,J=13.6,7.8Hz,1H),1.93(d,J=14.5Hz,1H),1.88–1.78(m,3H),1.71(s,1H),1.58(d,J=4.5Hz,1H),1.41–1.30(m,2H),1.20(s,22H),1.11(s,3H),1.00(d,J=6.2Hz,3H),0.93(s,3H),0.83(s,12H),0.02(d,J=11.6Hz,6H);13C NMR(100MHz,CDCl3)δ173.2,68.6,65.2,53.6,53.2,48.1,47.7,44.7,38.7,32.8,32.0,29.8,29.8,29.7,29.5,29.4,27.6,26.5,25.8,24.2,22.7,20.8,19.9,19.4,18.0,14.2,1.1,-4.7,-4.9;HRMS(MALDI)calcd for C36H63NO4SSiNa+[M+Na]+678.4558,found 678.4562.
化合物6a的合成
合成步骤同合成化合物6b,残留物通过硅胶柱色谱分离纯化(石油醚/乙酸乙酯=100:1至35:1)得到无色油状化合物6a(5.3g,两步产率72%)。
[α]22 D=-45.7(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ4.29(d,J=9.2Hz,1H),4.15(d,J=6.3Hz,1H),3.93–3.81(m,1H),3.62(s,1H),3.46(q,J=13.8Hz,2H),3.34–3.23(m,1H),2.12–2.03(m,1H),1.97–1.79(m,4H),1.65–1.48(m,2H),1.43–1.31(m,6H),1.24(d,J=11.4Hz,24H),1.15(s,1H),1.13(s,3H),0.96(s,3H),0.87(d,J=6.3Hz,12H),0.07(t,J=6.5Hz,6H);13C NMR(100MHz,CDCl3)δ174.9,73.0,69.9,65.4,53.3,53.1,48.3,47.8,47.2,44.9,44.8,43.7,39.0,38.7,33.1,33.0,32.1,30.3,30.0,29.9,29.8,29.5,29.0,28.1,26.6,25.9,24.3,22.8,22.3,21.3,21.0,12.0,18.0,14.9,14.3,8.5,-4.0,-5.1;HRMS(MALDI)calcd for C36H69NO5SSiNa+[M+Na]+678.4558,found 678.4562.
化合物8a的合成
合成步骤同合成化合物8b,残留物通过硅胶柱色谱法(石油醚/乙酸乙酯=30:1至10:1)进行纯化,得到淡黄色油状化合物8a(4.3g,两步产率90%)。
[α]22 D=+10.7(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.09(t,J=4.9Hz,1H),4.27(s,1H),4.10–4.00(m,1H),3.89(t,J=5.0Hz,2H),3.82(d,J=8.3Hz,1H),2.48(d,J=7.1Hz,1H),1.48(d,J=5.2Hz,1H),1.43(s,9H),1.31–1.14(m,30H),0.89–0.82(m,12H),0.07(s,6H);13C NMR(100MHz,CDCl3)δ177.0,169.1,82.0,77.5,77.4,77.2,76.8,73.7,71.3,46.7,43.3,42.0,32.0,30.4,30.3,29.8,29.7,29.6,29.4,29.0,28.1,27.8,25.9,22.8,22.6,18.0,14.2,11.4,-4.2,-4.8;HRMS(MALDI)calcd for C32H65NO5SiNa+[M+Na]+594.4524,found 594.4528.
化合物9a的合成
合成步骤同合成化合物9b,残留物通过硅胶柱色谱法(石油醚/乙酸乙酯=35:1至15:1)进行纯化,得到淡黄色油状化合物9a(2.0g,85%)。
[α]22 D=–4.3(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.45–6.67(m,1H),4.12–3.76(m,3H),3.58(q,J=7.1Hz,1H),2.89–2.65(m,1H),1.47(d,J=7.2Hz,9H),1.43–1.37(m,2H),1.38–1.32(m,3H),1.26(d,J=17.4Hz,22H),1.14(t,J=6.0Hz,3H),0.94–0.78(m,12H),-0.02(dd,J=23.4,18.4Hz,6H);13C NMR(101MHz,CDCl3)δ213.8,211.4,170.2,169.7,168.7,82.4,82.2,70.5,70.4,59.7,59.5,56.1,54.1,42.2,42.1,32.1,30.4,30.1,23.0,29.8,29.8,29.7,29.5,28.7,28.1,27.8,27.2,25.9,25.9,25.9,22.8,22.1,22.0,18.1,16.0,14.7,14.3,-4.5,-4.6,-4.7;HRMS(MALDI)calcd for C32H63NO5SiNa+[M+Na]+592.4368,found 592.4371.
化合物10a的合成
合成步骤同合成化合物10b,残留物通过硅胶柱色谱法(石油醚/乙酸乙酯=20:1至6:1)纯化,得到白色固体化合物10a(700mg,76%)。
[α]22 D=+15.1(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.40(t,J=4.8Hz,1H),4.97(s,1H),3.83(tdd,J=21.3,15.9,6.2Hz,3H),3.50(dt,J=13.0,6.7Hz,1H),2.71(d,J=8.9Hz,1H),1.63(s,1H),1.57(s,3H),1.46(s,9H),1.29–1.16(m,26H),0.87(t,J=6.6Hz,3H);13C NMR(100MHz,CDCl3)δ213.2,171.0,131.1,82.8,82.4,70.5,65.7,52.9,42.3,32.1,30.7,30.1,30.0,29.8,29.8,29.8,29.8,29.7,29.5,28.1,27.7,24.3,22.8,22.2,19.3,14.3,13.9;HRMS(MALDI)calcd for C26H49NO6Na+[M+Na]+494.3452,found494.3458.
化合物17a的合成
合成步骤同合成化合物14a,残留物通过硅胶柱色谱法(石油醚/乙酸乙酯=10:1至3:1)纯化,得到黄色粘稠状化合物17a(990mg,94%)。[α]22 D=-3.3(c=1.0,CHCl3);1HNMR(400MHz,CDCl3)δ7.61(d,J=7.1Hz,4H),7.50–7.31(m,7H),6.88–6.72(m,1H),6.35(dt,J=85.3,12.0Hz,1H),5.22–4.79(m,2H),4.47(d,J=7.6Hz,1H),4.39(s,1H),4.32–4.04(m,1H),3.98–3.56(m,5H),3.46(q,J=13.8Hz,1H),3.07(s,2H),3.01(d,J=13.9Hz,1H),2.24–1.80(m,2H),1.57(d,J=16.2Hz,3H),1.43(s,16H),1.35–1.11(m,21H),1.10(d,J=6.5Hz,4H),1.04(s,9H),0.94(t,J=7.4Hz,1H),0.86(dd,J=11.5,5.0Hz,3H).HRMS(MALDI)calcd for C55H87N3O11SiNa+[M+Na]+1016.6002,found 1016.6008.
化合物18a的合成
合成步骤同合成化合物15a,得到白色固体化合物18a-P1(71mg,50%)和18a-P2(66mg,78%)
18a-P1:[α]22 D=-13.3(c=1.0,CHCl3);1H NMR(400MHz,DMSO-d6)δ8.74(t,J=5.8Hz,1H),7.45(d,J=9.1Hz,1H),6.77–6.65(m,2H),6.16(d,J=15.1Hz,1H),5.01(t,J=5.6Hz,1H),4.98–4.91(m,1H),4.66(d,J=19.2Hz,1H),4.56(s,1H),4.00(d,J=19.3Hz,1H),3.77(dd,J=16.7,5.7Hz,1H),3.58(dd,J=16.5,5.7Hz,1H),3.53–3.44(m,1H),3.31(dd,J=8.8,3.4Hz,1H),3.16(d,J=5.2Hz,1H),2.84(s,3H),1.63(s,3H),1.54–1.42(m,2H),1.33–1.15(m,25H),0.85(t,J=6.7Hz,3H);13C NMR(100MHz,DMSO-d6)δ211.5,173.8,168.7,167.8,166.8,143.1,119.4,79.3,73.0,62.9,52.0,50.2,50.0,43.3,35.2,31.4,29.6,29.3,29.1,29.1,29.0,28.8,26.3,22.2,21.0,18.2,14.0;HRMS(MALDI)calcd forC30H51N3O8Na+[M+Na]+604.3568,found 604.3570.
18a-P2:[α]22 D=+9.2(c=1.0,CHCl3);1H NMR(400MHz,DMSO-d6)δ8.61–8.49(m,1H),7.56(d,J=8.2Hz,1H),6.54(dd,J=15.2,4.2Hz,1H),6.12(s,1H),6.06(dd,J=15.2,1.5Hz,1H),5.02(t,J=5.4Hz,1H),4.79(p,J=6.1Hz,1H),4.39(d,J=18.9Hz,2H),4.00(d,J=18.9Hz,1H),3.93(dd,J=16.7,7.4Hz,1H),3.62(dd,J=16.7,4.7Hz,1H),3.49(dt,J=12.3,4.8Hz,2H),3.39(dd,J=12.1,5.6Hz,1H),2.85(s,3H),1.59–1.46(m,2H),1.41(s,3H),1.25(d,J=13.4Hz,22H),1.16(d,J=6.2Hz,3H),0.85(t,J=6.8Hz,3H);13C NMR(101MHz,DMSO-d6)δ211.1,171.8,168.5,168.2,166.9,142.1,120.7,79.9,72.1,62.5,52.3,50.9,48.8,42.3,35.0,31.4,29.4,29.1,28.9,28.8,28.1,26.6,22.2,20.9,16.8,14.0;HRMS(MALDI)calcd for C30H51N3O8Na+[M+Na]+604.3568,found 604.3572.
化合物19a的合成
合成步骤同合成化合物16a,得到化合物19a-P1(9mg,2步产率62%)和19a-P2(6mg,2步产率41%)。
19a-P1:[α]22 D=-20.8(c=0.1,CHCl3:MeOH=1:1);1H NMR(400MHz,DMSO-d6)δ8.79(t,J=5.8Hz,1H),8.72(s,1H),6.97(d,J=15.2Hz,1H),6.69(s,1H),6.35(d,J=15.2Hz,1H),5.78(s,1H),5.38(s,1H),5.17–5.06(m,1H),4.45(d,J=19.0Hz,1H),4.16(d,J=19.1Hz,1H),3.98(dd,J=16.0,5.9Hz,1H),3.66(dd,J=16.0,6.2Hz,1H),3.25(dd,J=8.1,4.2Hz,1H),2.89(s,3H),1.58(s,3H),1.54–1.38(m,2H),1.17(d,J=47.9Hz,25H),0.85(t,J=6.6Hz,3H);13C NMR(100MHz,DMSO-d6)δ210.1,173.9,168.5,167.8,166.3,139.5,137.5,117.0,114.2,80.2,72.3,50.4,44.4,35.2,31.3,29.3,29.1,28.9,28.8,26.2,22.1,21.0,17.8,14.0;HRMS(MALDI)calcd for C30H49N3O7Na+[M+Na]+586.3463,found586.3468.
19a-P2:[α]22 D=+10.9(c=0.1,CHCl3:MeOH=1:1);1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.67–8.55(m,1H),6.81(d,J=15.5Hz,1H),6.36(s,1H),6.16(d,J=15.5Hz,1H),5.32(d,J=24.8Hz,2H),4.96–4.85(m,1H),4.45(d,J=18.8Hz,1H),4.06–3.92(m,2H),3.66(dd,J=16.3,4.9Hz,1H),3.44(dd,J=12.8,6.5Hz,1H),2.87(s,3H),1.59–1.46(m,2H),1.42(s,3H),1.30–1.15(m,25H),0.85(t,J=6.6Hz,3H);13C NMR(100MHz,DMSO-d6)δ209.2,172.3,168.6,167.7,166.9,138.5,137.4,119.0,112.4,99.5,79.8,71.5,51.1,49.0,42.8,34.6,31.3,29.3,29.1,28.8,28.8,27.9,26.1,22.1,21.3,16.8,14.0;HRMS(MALDI)calcd for C30H49N3O7Na+[M+Na]+586.3463,found586.3467.
合物4c的合成
参照化合物4b的合成方法,通过硅胶柱色谱法纯化(石油醚/乙酸乙酯=80:1至50:1)得到无色油状化合物4c(7.5g,3步产率54%)。
[α]22 D=-55.2(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ4.07(dd,J=8.8,4.1Hz,1H),3.92(dd,J=7.4,4.6Hz,1H),3.45(q,J=13.8Hz,2H),3.21(dd,J=7.3,3.4Hz,1H),2.05(dd,J=13.7,7.8Hz,1H),1.97–1.82(m,5H),1.81–1.70(m,2H),1.44–1.36(m,4H),1.26(d,J=17.4Hz,44H),1.14(s,3H),0.96(s,3H),0.87(d,J=11.8Hz,15H),0.10(d,J=28.1Hz,6H);13C NMR(101MHz,CDCl3)δ173.2,72.2,65.4,53.7,53.4,48.2,47.9,44.8,38.7,32.9,32.3,32.1,31.6,30.3,29.9,29.8,29.8,29.8,29.7,29.6,29.5,29.5,28.1,26.6,26.1,26.1,23.5,22.8,20.8,20.0,18.3,14.3,-4.2,-5.2;HRMS(MALDI)calcd forC45H87NO4SSiNa+[M+Na]+788.6017,found 788.6020.
化合物8c的合成
参照化合物8b的合成方法,得到无色油状化合物8c(2.1g,4步产率54%)。
[α]22 D=+16.6(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ6.11(t,J=4.9Hz,1H),4.12(d,J=9.0Hz,1H),3.97–3.81(m,4H),2.46(dd,J=8.9,6.9Hz,1H),1.79–1.66(m,1H),1.58–1.47(m,3H),1.45(s,9H),1.38(d,J=11.2Hz,3H),1.35–1.16(m,45H),0.95–0.80(m,15H),0.13–0.02(m,6H);13C NMR(100MHz,CDCl3)δ174.8,169.1,82.2,75.2,72.3,44.9,41.9,41.3,35.0,32.0,30.0,29.9,29.8,29.8,29.7,29.7,29.6,29.6,29.6,29.5,29.5,28.1,27.8,26.0,25.9,25.6,24.5,22.8,22.8,18.0,15.2,14.2,-4.0,-4.8;HRMS(MALDI)calcd for C44H89NO5SiNa+[M+Na]+762.6402,found 762.6406.
化合物9c的合成
参照化合物9b的合成方法,得到无色油状化合物9c(1.5g,72%)。
[α]22 D=–8.9(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ6.68(t,J=4.1Hz,1H),4.00–3.79(m,3H),3.60(t,J=6.9Hz,1H),3.00–2.79(m,1H),1.47(s,11H),1.42(d,J=7.4Hz,3H),1.25(s,42H),1.11(s,2H),0.95–0.82(m,15H),0.02(dd,J=13.9,8.5Hz,6H);13C NMR(100MHz,CDCl3)δ213.4,211.1,170.1,169.7,168.7,168.7,82.3,82.2,73.4,73.3,57.5,56.7,55.7,53.9,42.2,42.1,34.4,34.1,32.16,30.1,30.0,29.9,29.8,29.8,29.7,29.5,29.5,28.2,28.0,27.6,27.5,27.1,26.0,26.0,24.7,23.9,22.8,18.2,16.4,14.9,14.2,-4.4,-4.5;HRMS(MALDI)calcd for C44H87NO5SiNa+[M+Na]+762.6246,found762.6250.
化合物10c的合成
参照化合物10b的合成方法,得到无色油状化合物10c(890mg,82%)。
[α]22 D=-9.8(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.41(s,1H),5.01(s,1H),3.96–3.71(m,2H),3.52(s,2H),2.86(s,1H),1.54(s,3H),1.46(s,9H),1.24(s,48H),0.86(d,J=6.7Hz,6H);13C NMR(100MHz,CDCl3)δ213.3,171.1,168.7,82.7,82.4,77.5,77.4,77.2,76.8,74.3,51.4,42.3,35.7,32.1,29.9,29.8,29.8,29.7,29.7,29.5,28.1,27.7,25.4,24.3,22.8,14.3;HRMS(MALDI)calcd for C38H73NO6SiNa+[M+Na]+662.5330,found662.5335.
化合物17c的合成
参照化合物14a的合成方法,得到黄色粘稠状化合物17c(350mg,97%)。
[α]22 D=-9.8(c=1.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.61(d,J=6.5Hz,4H),7.52–7.32(m,7H),6.80(dd,J=14.9,4.7Hz,1H),6.41(d,J=15.2Hz,1H),5.17(t,J=6.8Hz,1H),5.07(s,1H),4.90(dd,J=24.6,17.1Hz,1H),4.31(dd,J=27.0,20.4Hz,1H),4.14–4.00(m,2H),3.96–3.86(m,2H),3.82–3.62(m,3H),3.03(d,J=35.8Hz,3H),2.02(s,2H),1.63–1.56(m,1H),1.54(s,3H),1.48–1.37(m,18H),1.22(s,42H),1.04(s,9H),0.90(ddd,J=21.7,12.0,7.2Hz,9H);差向异构体在测试的碳谱图中明显,没有解析;HRMS(MALDI)calcd for C67H111N3O11Na+[M+Na]+1184.7880,found 1184.7884.
化合物18c的合成
参照化合物15a的合成方法,得到淡黄色固体化合物18c(29mg,68%)。
[α]22 D=-8.3(c=1.0,CHCl3);1H NMR(400MHz,DMSO-d6)δ8.76(t,J=5.7Hz,1H),7.43(d,J=9.2Hz,1H),6.72(dd,J=15.0,3.1Hz,1H),6.18(d,J=14.8Hz,1H),5.05(s,1H),4.93(t,J=7.8Hz,1H),4.71(d,J=19.2Hz,1H),4.58(d,J=5.9Hz,1H),4.01(d,J=19.4Hz,1H),3.76(dd,J=16.7,5.5Hz,1H),3.58(dd,J=16.5,5.7Hz,1H),3.47(d,J=4.9Hz,1H),3.35(d,J=17.2Hz,3H),2.82(s,3H),1.62(s,3H),1.55(d,J=8.5Hz,1H),1.47–1.39(m,1H),1.27(d,J=35.3Hz,46H),0.84(t,J=6.6Hz,6H);13C NMR(100MHz,DMSO-d6)δ211.2,173.9,168.9,167.8,166.8,143.0,119.4,79.5,75.8,63.0,52.0,50.1,48.3,43.4,35.0,32.2,31.4,30.2,29.7,29.2,29.1,29.1,29.0,28.8,28.7,26.2,24.4,22.2,21.0,14.0;HRMS(MALDI)calcd for C42H75N3O8Na+[M+Na]+772.5446,found 772.5450.
化合物19c的合成
参照化合物16a的合成方法,得到化合物19c(10mg,两步产率69%),为冻干白色粉末。
[α]22 D=-40.4(c=0.1,CHCl3:MeOH=1:1);1H NMR(400MHz,DMSO-d6)δ8.81(t,J=5.9Hz,1H),8.72(s,1H),6.98(d,J=15.2Hz,1H),6.73(d,J=18.9Hz,1H),5.79(s,1H),5.37(s,1H),5.04(t,J=7.4Hz,1H),4.48(d,J=19.2Hz,1H),4.16(d,J=19.2Hz,1H),3.99(dd,J=16.2,5.8Hz,1H),3.65(dd,J=15.9,6.1Hz,1H),2.87(s,2H),2.84(s,1H),1.61(d,J=19.9Hz,6H),1.44(d,J=4.9Hz,1H),1.35–1.05(m,46H),0.85(t,J=6.6Hz,6H);13C NMR(100MHz,MeOH-d4)δ202.94,167.05,160.52,160.42,160.24,131.81,128.92,109.87,108.91,71.71,69.65,69.32,69.00,68.17,42.41,41.16,35.36,26.73,24.49,23.33,22.79,21.04,20.97,20.92,20.75,20.55,18.14,16.48,14.02,11.65,4.94;HRMS(MALDI)calcd for C42H73N3O7Na+[M+Na]+754.5341,found 754.5345.
化合物20a的合成
5mL圆底烧瓶中,加入化合物1a(70mg,0.124mmol),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,白色固体化合物(68mg)。
5mL圆底烧瓶中,加入化合物(30mg)并用4.0M的氯化氢1,6-二氧六环溶液稀释溶解,旋蒸浓缩,得到白色固体化合物20a(30mg,95%)。1H NMR(400MHz,DMSO)δ9.89(s,1H),9.01(s,1H),8.60(t,J=5.9Hz,1H),6.62(s,1H),5.89(t,J=5.7Hz,1H),5.19–5.11(m,1H),4.29(d,J=18.8Hz,1H),4.08(d,J=19.1Hz,1H),3.99–3.81(m,3H),3.74(dd,J=15.5,5.2Hz,1H),3.41–3.32(m,1H),3.14(dd,J=19.5,6.3Hz,1H),2.82(s,3H),2.85–2.74(m,1H),2.69(s,6H),1.62–1.44(m,2H),1.49(s,3H),1.22(br s,22H),1.02(d,J=6.8Hz,3H),0.84(t,J=6.6Hz,3H).
HRMS(MALDI)C32H57N4O7+[M+H]+:理论值609.4222,测量值609.4221。
化合物20b的合成
5mL圆底烧瓶中,加入化合物(38mg)并用2.0mg/mL的富马酸四氢呋喃溶液(3.4mL)溶解,旋蒸浓缩,得到白色固体化合物20b(44mg)。1H NMR(400MHz,DMSO)δ8.96(s,1H),8.56(t,J=5.7Hz,1H),6.58(s,3H),5.80(t,J=5.7Hz,1H),5.19–5.11(m,1H),4.28(d,J=19.0Hz,1H),4.06(d,J=19.0Hz,1H),3.89(dd,J=15.8,6.4Hz,1H),3.76(d,J=13.2Hz,1H),3.70–3.58(m,2H),3.41–3.32(m,1H),3.07(dd,J=19.1,6.6Hz,1H),2.82(s,3H),2.84–2.73(m,1H),2.56(s,6H),1.62–1.41(m,2H),1.48(s,3H),1.22(br s,22H),1.02(d,J=6.7Hz,3H),0.84(t,J=6.4Hz,3H).
HRMS(MALDI)C32H57N4O7+[M+H]+:理论值609.4222,测量值609.4227。
化合物20c的合成
5mL圆底烧瓶中,加入化合物1a(30mg,0.0532mmol),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,白色固体化合物(24mg)。
5mL圆底烧瓶中,加入化合物(24mg)并用2.36mg/mL的二氯乙酸的四氢呋喃溶液(2.1mL)稀释溶解,旋蒸浓缩,得到白色固体化合物20c(29mg,74%)。
1H NMR(400MHz,DMSO)δ8.95(s,1H),8.60–8.51(m,1H),6.74(s,1H),6.00(s,1H),5.89–5.78(m,1H),5.22–5.12(m,1H),4.28(d,J=18.9Hz,1H),4.07(d,J=18.8Hz,1H),3.97–3.57(m,4H),3.44–3.31(m,1H),3.13–3.02(m,1H),2.82(s,3H),2.88–2.74(m,1H),2.62(s,6H),1.64–1.48(m,2H),1.49(s,3H),1.23(s,22H),1.02(d,J=5.5Hz,3H),0.89–0.80(m,3H).HRMS(MALDI)C32H57N4O7+[M+H]+:理论值609.4222,测量值609.4225。
化合物20d的合成
5mL圆底烧瓶中,加入化合物1a(30mg,0.0532mmol),然后加入2.0M四氢吡咯的四氢呋喃溶液(1mL),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,得白色固体化合物置于5mL圆底烧瓶中,加入2.0mg/mL的L-苹果酸四氢呋喃溶液(1.48mL)溶解,旋蒸浓缩,得到白色固体化合物20d(17mg)。
1H NMR(400MHz,DMSO)δ8.75(s,1H),8.54(t,J=5.4Hz,1H),5.82(t,J=5.7Hz,1H),5.18–5.11(m,1H),4.26(d,J=19.0Hz,1H),4.06(d,J=19.0Hz,1H),4.00(dd,J=8.0,5.4Hz,1H),3.88(dd,J=15.6,6.1Hz,1H),3.78(d,J=13.1Hz,1H),3.69–3.60(m,2H),3.43–3.34(m,1H),3.02(dd,J=19.7,6.6Hz,1H),2.98–2.91(m,4H),2.82(s,3H),2.75(dd,J=19.3,4.8Hz,1H),2.55(dd,J=15.6,8.1Hz,1H),2.34(dd,J=15.6,5.4Hz,1H),1.89–1.80(m,4H),1.64–1.45(m,2H),1.50(s,3H),1.23(br s,22H),1.03(d,J=6.8Hz,3H),0.85(t,J=6.7Hz,3H).HRMS(MALDI)C34H59N4O7+[M+H]+:理论值635.4378,测量值635.4380。
化合物20e的合成
5mL圆底烧瓶中,加入化合物1a(30mg,0.0532mmol),然后加入2.0M哌啶的四氢呋喃溶液(1mL),置于50℃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,得白色固体化合物置于5mL圆底烧瓶中,加入4.7mg/mL的二氯乙酸四氢呋喃溶液(0.83mL)溶解,旋蒸浓缩,得到白色固体化合物20e(25mg,61%)。
1H NMR(400MHz,DMSO)δ9.01(s,1H),8.54(t,J=5.7Hz,1H),6.80–6.52(m,1H),6.03(s,1H),5.96–5.86(m,1H),5.22–5.11(m,1H),4.30(d,J=18.9Hz,1H),4.04(d,J=18.9Hz,1H),3.88(dd,J=15.7,6.4Hz,1H),3.93–3.72(m,4H),3.66(dd,J=15.6,5.3Hz,1H),3.41–3.31(m,1H),3.05(dd,J=18.5,7.3Hz,1H),2.81(s,3H),2.83–2.73(m,1H),1.72(s,4H),1.49(s,2H),1.49(s,3H),1.23(br s,22H),1.03(d,J=6.8Hz,3H),0.85(t,J=6.7Hz,3H).HRMS(MALDI)C35H61N4O7+[M+H]+:理论值649.4535,测量值649.4540。
化合物20f的合成
5mL圆底烧瓶中,加入化合物1a(30mg,0.0532mmol),然后加入2.0M吗啡啉的四氢呋喃溶液(1mL),置于50℃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,得白色固体化合物置于5mL圆底烧瓶中,加入2.0mg/mL的甲磺酸四氢呋喃溶液(1.75mL)溶解,旋蒸浓缩,得到白色固体化合物20f(25mg,72%)。
1H NMR(400MHz,DMSO)δ8.63(s,1H),8.52(t,J=5.6Hz,1H),6.62(s,1H),5.94–5.78(m,1H),5.13(t,J=7.4Hz,1H),4.27(d,J=18.9Hz,1H),4.05(d,J=19.0Hz,1H),3.88(dd,J=15.8,6.1Hz,1H),3.85–3.57(m,5H),3.42–3.27(m,3H),3.01(dd,J=19.6,5.6Hz,1H),2.97–2.79(m,4H),2.85–2.73(m,4H),2.37(s,3H),1.65–1.45(m,2H),1.51(s,3H),1.23(s,22H),1.03(d,J=6.8Hz,3H),0.85(t,J=6.5Hz,3H).HRMS(MALDI)C34H59N4O8+[M+H]+:理论值651.4327,测量值651.4330。
化合物20g的合成
5mL圆底烧瓶中,加入化合物1a(30mg,0.0532mmol),然后加入2.0M吗啡啉的四氢呋喃溶液(1mL),置于50℃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,得白色固体化合物置于5mL圆底烧瓶中,加入2.0mg/mL的富马酸四氢呋喃溶液(1.4mL)溶解,旋蒸浓缩,得到白色固体化合物20g(20mg,49%)。
1H NMR(400MHz,DMSO)δ8.53(t,J=5.7Hz,1H),8.41(s,1H),6.58(s,2H),5.51(t,J=5.8Hz,1H),5.19–5.12(m,1H),4.28(d,J=18.9Hz,1H),4.03(d,J=18.9Hz,1H),3.88(dd,J=15.9,6.7Hz,1H),3.62–3.51(m,5H),3.42–3.34(m,1H),3.16–3.08(m,1H),2.96–2.86(m,2H),2.80(s,3H),2.83–2.71(m,1H),2.40–2.26(m,4H),1.61–1.45(m,2H),1.49(s,3H),1.23(s,22H),1.02(d,J=6.9Hz,3H),0.85(t,J=6.7Hz,3H).HRMS(MALDI)C34H59N4O8+[M+H]+:理论值651.4327,测量值651.4329。
化合物20h的合成
5mL圆底烧瓶中,加入化合物1a(30mg,0.0532mmol),然后加入2.0M吗啡啉的四氢呋喃溶液(1mL),置于50℃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,得白色固体化合物置于5mL圆底烧瓶中,加入2.0mg/mL的二氯乙酸四氢呋喃溶液(2.72mL)溶解,旋蒸浓缩,得到浅黄色固体化合物20h(34mg,83%)。
1H NMR(400MHz,DMSO)δ8.58(s,1H),8.53(t,J=5.9Hz,1H),6.20(s,1H),5.70(s,1H),5.14(t,J=7.2Hz,1H),4.28(d,J=18.9Hz,1H),4.05(d,J=18.8Hz,1H),3.88(dd,J=15.9,6.5Hz,1H),3.69–3.57(m,5H),3.50–3.42(m,1H),3.42–3.33(m,1H),3.32–3.23(m,1H),2.97(dd,J=19.3,5.9Hz,1H),2.81(s,3H),2.75(dd,J=18.9,5.2Hz,2H),2.69–2.56(m,5H),1.61–1.46(m,2H),1.49(s,3H),1.23(s,22H),1.02(d,J=6.9Hz,3H),0.85(t,J=6.7Hz,3H).HRMS(MALDI)C34H59N4O8+[M+H]+:理论值651.4327,测量值651.4332。
化合物20i的合成
5mL圆底烧瓶中,加入化合物1a(100mg,0.177mmol),然后加入N-甲基哌嗪(217μL,1.77mmol)和四氢呋喃(2mL),置于40℃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,得白色固体化合物置于5mL圆底烧瓶中,加入的柠檬酸(23mg,0.12mmol)四氢呋喃溶液溶解,旋蒸浓缩,得到浅黄色固体化合物20i(103mg,68%)。
1H NMR(400MHz,DMSO-d6)δ8.48(t,J=6.0Hz,1H),8.37(s,1H),6.57(s,1H),5.50(t,J=6.0Hz,1H),5.21–5.10(m,1H),4.27(d,J=18.9Hz,1H),4.03(d,J=18.9Hz,1H),3.88(dd,J=15.9,6.8Hz,1H),3.58(dd,J=15.9,5.2Hz,1H),3.39(p,J=7.0Hz,1H),3.11(d,J=13.7Hz,1H),2.97–2.87(m,2H),2.74(dd,J=18.7,5.4Hz,1H),2.44–2.25(m,8H),2.18(s,3H),1.61–1.44(m,2H),1.49(s,3H),1.23(brs,22H),1.02(d,J=6.9Hz,3H),0.85(t,J=6.7Hz,3H).HRMS(MALDI)C35H62N5O7+[M+H]+:理论值664.4644,测量值664.4647。
化合物21的合成
参照化合物20i的合成方法,得到白色固体化合物21(600mg,90%)。
1H NMR(400MHz,DMSO-d6)δ8.51(t,J=6.1Hz,1H),8.39(s,1H),6.58(s,1H),5.50(t,J=6.0Hz,1H),5.19–5.12(m,1H),4.29(d,J=18.9Hz,1H),4.01(d,J=18.8Hz,1H),3.88(dd,J=16.0,6.7Hz,1H),3.59(dd,J=16.0,5.2Hz,1H),3.42–3.35(m,1H),3.34–3.25(m,4H),3.15(d,J=13.2Hz,1H),2.98–2.87(m,2H),2.82–2.71(m,1H),2.80(s,3H),2.39–2.22(m,4H),1.64–1.44(m,2H),1.50(s,3H),1.38(s,9H),1.23(brs,23H),1.03(d,J=6.8Hz,3H),0.85(t,J=6.5Hz,3H).
化合物23a的合成
将化合物21(230mg,0.307mmol)溶解于二氯甲烷(5mL)中,加入三氟乙酸(0.56mL),室温下搅拌反应4h。随后向反应液中加入甲苯(8mL)稀释反应液,油泵下旋蒸除掉挥发性试剂,得到氨基化合物浅黄色固体残渣,直接用于下一步反应。
将化合物25a(200mg,0.20mmol)溶解于二氯甲烷(2mL)中,置于0℃下搅拌,向反应液中滴加草酰氯(170μL,2.00mmol)。滴加完毕后,将反应装置移至室温反应2h。使用旋蒸将溶剂和过量的草酰氯除去,得到酰氯22a为白色固体化合物,直接用于下一步反应。
称量上一步得到的氨基化合物(190mg,0.167mmol),并将酰氯22a加入反应烧瓶中,加入二氯甲烷(2mL)溶解。然后,加入三乙胺(93μL,0.668mmol),搅拌反应1.5h。将反应液旋干后,用硅胶柱层析纯化,得到化合物23a为白色膏状物(160mg,80%)。
1H NMR(400MHz,DMSO-d6)δ8.48(d,J=6.2Hz,1H),8.40(s,1H),6.58(s,1H),5.51(d,J=6.2Hz,1H),5.17(t,J=8.5Hz,1H),4.28(d,J=18.9Hz,1H),4.03(d,J=17.0Hz,1H),3.89(dd,J=16.0,6.6Hz,1H),3.73–3.28(m,ca.80H),3.24(s,3H),3.18–2.87(m,2H),2.82–2.72(m,1H),2.81(s,3H),2.41–2.21(m,4H),1.62–1.46(m,2H),1.49(s,3H),1.23(s,22H),1.03(d,J=6.8Hz,3H),0.90–0.79(m,3H).
mPEG600-COOH(25a):MALDI-TOF-MS:质量分布中位值为596.99;23a:MALDI-TOF-MS:质量分布中位值为1184.68,如图11。
化合物23b的合成
参照化合物23a的合成方法,得到化合物23b为白色固体(44mg,43%)。
1H NMR(400MHz,DMSO-d6)δ8.51(t,J=6.0Hz,1H),8.43(s,1H),6.60(s,1H),5.59–5.48(m,1H),5.16(t,J=8.8Hz,1H),4.29(d,J=18.9Hz,1H),4.03(d,J=15.2Hz,1H),3.89(dd,J=15.9,6.5Hz,1H),3.74–3.29(m,ca.570H),3.24(s,3H),3.12–2.88(m,3H),2.80(s,3H),2.42–2.29(m,4H),1.64–1.43(m,2H),1.49(s,3H),1.23(s,22H),1.03(d,J=6.8Hz,3H),0.85(t,J=6.6Hz,3H).
mPEG5000-COOH(25b):MALDI-TOF-MS:质量分布中位值为5359.21;23b:MALDI-TOF-MS:质量分布中位值为6035.04,如图11。
化合物24a和24b的制备
参照化合物20i的制备方法,分别将化合物23a和23b溶解于四氢呋喃中,加入等摩尔量柠檬酸,制备得到化合物24a和24b。
实施例2:BE-43547衍生物及其盐对人非小细胞肺癌细胞系A549,人急性骨髓白血病细胞系KG1a,人胰腺癌细胞系Panc-1和人胶质母细胞瘤细胞系U87细胞系的抑制作用
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. BE-43547衍生物及其盐对各种癌细胞的抑制活性(IC50,μM)
实施例3:前药化合物20b,20g和20i体外降解速率
分别将20b,20g和20i溶解于pH值为7.4的磷酸缓冲液(0.02M)中,置于37℃下,分别在不同时间点抽取缓冲液,用高效液相色谱检测,计算剩余前药化合物的百分含量。高效液相色谱条件:戴安U3000型高效液相色谱系统;流动相为90%乙腈(0.1%三氟乙酸)和10%水(0.1%三氟乙酸);流速1mL/min;检测器为紫外检测器;检测波长210nm;色谱柱为C18色谱柱。结果如图8所示,表示前药化合物的百分含量随时间的变化曲线。结果显示,前药化合物20g和20i的体外稳定性优于前药化合物20b。
实施例4:前药化合物20i,24a和24b体外释放化合物1a的速率
为了检测前药化合物在体外释放得到活性成分1a的速率,分别将20i,24a和24b溶解于pH值为7.4的磷酸缓冲液(0.02M)中,置于37℃下,分别在不同时间点抽取缓冲液,用高效液相色谱检测活性成分1a的峰面积,计算剩活性成分1a含量。高效液相色谱条件与实施例3相同。结果如图9所示,表示活性成分1a的含量随时间的变化曲线。结果显示,前药化合物24b的体外稳定性优于前药化合物24a和20i。
实施例5:前药化合物20i,24a和24b在大鼠体内释放化合物1a的速率
为了检测前药化合物在体外释放得到活性成分1a的速率,分别将20i,24a和24b溶解于生理盐水中,采用尾静脉注射的给药方式给大鼠给药。给药剂量如图10所示,分别在不同时间点抽取大鼠血液,用液质联用仪器检测活性成分1a含量。结果如图10所示,表示大鼠血浆中活性成分1a的含量随时间的变化曲线。结果显示,前药化合物24b在大鼠体内的暴露量明显优于前药化合物24a和20i。
Claims (5)
1.一种如式(I)所示的BE-43547衍生物及其盐,
式(I)中R1为-(CH2)12CH3,R2为-CH3;R3为二甲氨基、四氢吡咯基、哌啶基、N-甲基哌嗪基或N-((聚乙二醇基)乙酰基)哌嗪基;
其盐为与R4Z形成的季铵盐,其中R4Z为氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸、甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、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、取代苯甲酸。
2.一种制备如权利要求1所述式(I)所示BE-43547衍生物及其盐的方法,其特征在于以式(II)所示的化合物为原料,与(III)和(IV)所示的化合物反应得式(I)所示的化合物,
3.一种如权利要求1所述式(I)所示的BE-43547衍生物及其盐在制备用于治疗癌症或治疗癌症的辅助药物中的用途,其特征在于(I)所示的BE-43547衍生物及其盐在体外或体内缓慢释放出(II)所示的活性成分,
其中癌症为白血病、肺癌、胰腺癌或神经胶质瘤。
4.一种如权利要求1所述式(I)所示的BE-43547衍生物及其盐在制备治疗癌症或治疗癌症的辅助药物中的用途,其中癌症为白血病、肺癌、胰腺癌或神经胶质瘤。
5.一种药物组合物,其中含有有效量的如权利要求1所述式(I)所示BE-43547衍生物及其盐和药学上可接受的载体。
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JPH10147594A (ja) * | 1996-11-19 | 1998-06-02 | Banyu Pharmaceut Co Ltd | 抗腫瘍性物質be−43547類 |
CN108530515A (zh) * | 2017-03-02 | 2018-09-14 | 天津尚德药缘科技股份有限公司 | 天然产物be-43547环状母核的制备方法 |
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JPH10147594A (ja) * | 1996-11-19 | 1998-06-02 | Banyu Pharmaceut Co Ltd | 抗腫瘍性物質be−43547類 |
CN108530515A (zh) * | 2017-03-02 | 2018-09-14 | 天津尚德药缘科技股份有限公司 | 天然产物be-43547环状母核的制备方法 |
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Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products;Nikolaj L. Villadsen, et al.;《NATURE CHEMISTRY》;第9卷;第264-272页 * |
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