海洋微生物来源的二倍半萜AsperterpinolB衍生物及合成方法与抗炎应用与流程

本发明涉及药物化学领域，具体地说，涉及海洋微生物来源的二倍半萜asperterpinolb衍生物的制备和其衍生物在抗炎药物方面的应用。

背景技术：

炎症，是免疫的基本防御机制，是对有害刺激、感染或者组织损伤引起的适应性反应。然而，炎症本身可能会导致组织损伤并导致许多疾病或者是癌症(r.medzhitovetal.,2008；r.medzhitovetal.,2010)。因此，一般认为控制炎症反应是有益的(例如，在预防感染方面)，但是如果失调(例如，引起脓毒性的)会成为有害休克。

炎症与一氧化氮有着密切关系。一氧化氮(nitricoxide，no)是一种重要的细胞内和细胞间的高度活性信号分子，在心血管、神经和神经生理及病理生理机制的调节免疫系统中扮演重要角色。它可以调节血管系统中的血管张力，是免疫系统中重要的宿主防御效应物；另一方面，它是一个自由基(no^.)，在病理过程中是细胞毒素，特别是在炎症过程中(aldertonetal.,2001；bogdan,2001；dawnandbolli,2002；moncadaandhiggs,1991)。胞内l-精氨酸(l-arginine)经一氧化氮合成酶(nos)催化分解为l-瓜氨酸和no自由基。机体中nos可分为结构型nos(cnos)和诱导型nos(inos)两大类，而cnos又可分为神经元型一氧化氮合成酶(nnos)，存在于神经元细胞；和内皮型一氧化氮合成酶(enos)，存在于内皮细胞。cnos催化产生固定量的no，主要维持机体的正常生理活动，包括血管扩张、平滑肌松弛及抑制血小板凝集等作用；当致炎因子如lps刺激巨噬细胞会产生inos，inos诱导产生大量的n0(lanasetal.,2008；mackenzieetal.,2008)，造成血管过度舒张和细胞损伤，导致炎症反应及相关病变，如败血性休克、中风、dna损伤、基因突变或细胞癌变等(kanwaretal.,2009)，因此对inos酶的抑制可能有利于炎症性疾病的治疗(bogdanetal.,2001；kronckeetal.,1998)。

目前，临床上使用的抗炎药物主要是非甾体类抗炎药。非甾体类抗炎药，在世界范围内普遍使用处方药和非处方制剂。这些药物在用于治疗短期常见的疼痛疾病，如头痛、月经疼痛，还有用于长期治疗慢性炎性疾病，如风湿性关节炎(y.c.leeetal,.2012；c.pereira-leiteetal.,2017)。这种非甾类药物治疗方法很普遍，但是存在的缺点就是出现广泛的不良反应。非甾体类抗炎药(nsaids)长期治疗会诱导gi毒性包括胃食管反流、出血、穿孔和阻塞，严重增加了血管和胃肠道的风险，同时心脏衰竭的风险也会翻一倍(y.c.leeetal.,2012；c.pereira-leiteetal.,2017)。因此，在发明阿司匹林100多年后，仍然需要一个安全、无毒副作用的抗炎药物非常重要。

海洋特殊生态环境中的生物，其代谢产物丰富新颖，是具有新药开发潜力的新领域，拓展新药的重要资源。人们从海洋生物中提取出的海洋天然产物代谢物如萜类、甾醇类、多糖、生物碱、脂肪酸和蛋白质，这些海洋天产物具有良好的生物活性包括抗菌、抗真菌、抗原生生物、抗结核、抗病毒、抗炎、酶抑制剂等药理活性(alejandroetal.,2013)，对开发高效安全抗炎药物提供重要资源。人们发现萜类具有良好的抗炎活性，如来自无脊椎海鸡冠(俗称珊瑚虫)的elisabethinh(shi,y.petal.,2009)、durumhemiketalolidec(cheng,s.yetal.,2009)、l.crassumditerpenes(wanzolaetel.,2010)，来自海绵的tedanol(costantinoetal.,2009)和coscinolactams(demarinoetal.,2009)，来自海鞘的rossinonesa&b(appletonetal.,2009)，这些萜类化合物具有很强的抗炎活性ic50值达10um以内。

本专利的asperterpinolb是一种结构稀有的的5/8/6/6的四环骨架，从红树林内生真菌曲霉菌085242中分离出来的二倍半萜(ze’enetal.,2013)。因此本发明对其进行结构修饰，得到一系列具有很好的抗炎活性化合物，为临床治疗选择提供了新的可能选择。

技术实现要素：

本发明的目的之一是提供一类对炎症具有良好治疗效果的二倍半萜asperterpinolb衍生物或其药学上可接受的盐或立体异构体及其前药分子。

实现上述目的的技术方案如下：

通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜asperterpinolb的衍生物或者其药学上可接受的盐或立体异构体或其前药分子，具有式i，ⅱ，ⅲ或ⅳ的结构。

通过与酸酐类化合物构成酯键的二倍半萜asperterpinolb的衍生物中，酸酐化合物优选地，酸酐化学结构可不同，包括，但不局限于，乙酸酐、丙酸酐、丁酸酐、异丁酸酐、正己酸酐、丁二酸酐、戊二酸酐、一氯二氟乙酸酐；通过与胺类化合物构成酰胺键的二倍半萜asperterpinolb的衍生物中，胺类化学结构可不同，包括，但不局限于，正丙胺，环己胺，呋喃甲胺，苯乙胺，噻吩甲按，环己烯乙胺，噻吩乙胺，对溴苯胺，庚胺，呋喃乙胺，4-(2-氨乙基)吗啉，二烯丙氨，四氢吡咯烷，o-苄基羟胺，四氢异喹啉，n-(3-氨丙基)-吗啡啉，吗啡，1-三氟甲基环戊氨，对甲氧基苯胺，环丙氨，环戊胺，萘胺，3-溴-吡啶-2-氨，3-溴-1-氢吡唑-4-氨。

本发明的另一目的是提供二倍半萜asperterpinolb衍生物的合成方法。

实现上述目的技术方案如下：

通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜asperterpinolb的衍生物。

1)二倍半萜asperterpinolb与酰卤、羧酸、酸酐反应成具有式i结构的酯类衍生物。

2)结构式为的二倍半萜asperterpinolb衍生物与胺类化合物反应生成具有结构式ⅱ的酰胺类衍生物。

3)二倍半萜asperterpinolb在三氟化硼乙醚作用下五元环脱水生成具有式ⅲ的衍生物。

4)结构为的二倍半萜asperterpinolb先与无水二氯亚砜反应生成中间体酰氯再与胺类化合物反应生成具有式ⅳ的衍生物。

所述胺类化合物为伯胺或仲胺。

本发明的另一目的是提供一种治疗炎症的药用化合物。

实现上述目的技术方案如下：

一种治疗炎症的药用衍生物，其药学活性成份通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜asperterpinolb的衍生物或者其药学上可接受的盐或立体异构体或其前药分子。

本发明的另一目的是提供上述二倍半萜asperterpinolb的衍生物或者其药学上可接受的盐或立体异构体或其前药分子的应用。

实现上述目的技术方案如下：

上述通过通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜asperterpinolb的衍生物或者其药学上可接受的盐或立体异构体或其前药分子在制备抗炎药物中的应用。

本发明通过将二倍半萜asperterpinolb进行衍生化，得到新的化学实体，得到的新化合物具有很好的治疗炎症的效果，为临床治疗选择提供了新的药物。

具体实施方式

通过以下实施例对本发明具体实施方法进行描述，但该实施例并非用于限制本发明的保护范围。

实施例1

asb-1:(2as,6as,6bs,12s,12as,13r,13as,z)-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,12,12a,13,13a-tetradecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-13-ol的合成

实验步骤：

称取asb(38.7mg，0.103mmol，1eq)于50ml的圆底烧瓶，加入2ml二氯甲烷溶解，1ml注射器滴加三氟化硼乙醚(质量分数为46.5％-49.5％)(50ul，0.135mmol，1.3eq)于溶液中，室温搅拌反应半小时，半小时反应完加三乙胺停止反应，调节ph至中性，加饱和食盐水15ml及二氯甲烷(3×20ml)萃取，分离得有机相，加无水硫酸镁干燥，减压蒸馏得粗产品，石油醚乙酸乙酯体系(v:v＝1：10)柱层析得白色固体38.5mg，产率为95％。

白色固体,产率为95％,m.p.122.5-124.7℃.¹hnmr(500mhz,cdcl3)δ5.60(d,j＝11.3hz,1h),5.15–4.68(m,1h),3.94(d,j＝5.8hz,1h),3.16(s,1h),2.66(dd,j＝18.5,5.5hz,1h),2.41(dd,j＝11.1,9.8hz,1h),2.26–2.17(m,1h),1.90(dd,j＝13.9,10.4hz,1h),1.85–1.76(m,2h),1.64(s,3h),1.42(ddd,j＝11.4,9.6,3.7hz,3h),1.34–1.21(m,4h),1.19–1.10(m,2h),1.08–1.02(m,2h),0.97(t,j＝10.3hz,1h),0.91(s,3h),0.89(s,3h),0.87(d,j＝5.4hz,3h),0.83(s,3h),0.64(d,j＝7.2hz,3h).

eims:calcdforc25h40o:356.found:356.

实施例2

asb-s1:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-ylacetate的合成

实验步骤：

称取asb(42.3mg，0.11mmol，1eq)于50ml两口圆底烧瓶，加2ml无水吡啶溶解，加入酸酐(1.1mmol，10eq)，置于90℃油浴锅冷凝回流反应，tlc跟踪反应直至反应完全。冷却至室温加2mhcl溶液停反应，调节溶液ph至2，搅拌15min，加饱和食盐水15ml和ea(3×15ml)萃取得有机相，无水硫酸镁干燥，减压蒸馏得粗产品，石油醚乙酸乙酯体系(v:v＝1:2)柱层析得纯白色固体。

白色固体,产率为67.6％,m.p.58.2-60.8℃.¹hnmr(500mhz,cdcl3)δ4.73(d,j＝6.5hz,1h),4.57(d,j＝10.7hz,1h),2.99(d,j＝2.1hz,1h),2.79(dd,j＝17.7,6.6hz,1h),2.61(t,j＝14.7hz,1h),2.29–2.17(m,2h),2.03(s,3h),1.68(ddd,j＝10.2,9.7,5.8hz,2h),1.63(s,3h),1.60(dd,j＝13.1,6.0hz,1h),1.53(td,j＝11.4,3.8hz,1h),1.40(td,j＝13.5,3.8hz,2h),1.35–1.25(m,6h),1.21–1.10(m,3h),1.09(s,3h),0.91(s,3h),0.90–0.84(m,6h),0.78(s,3h).

hrms(esi)for[m+na]⁺:calcdforc27h44o3na:439.31827.found:439.31755.

实施例3

asb-s2:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-ylbutyrate的合成

实验步骤：同实施例2

白色固体,产率为72.04％,m.p.51.7-54.7℃.¹hnmr(500mhz,cdcl3)δ4.75(d,j＝6.5hz,1h),4.57(d,j＝10.7hz,1h),3.01(d,j＝1.8hz,1h),2.78(dd,j＝17.8,6.5hz,1h),2.62(t,j＝14.8hz,1h),2.22(ddd,j＝18.3,14.3,7.0hz,4h),1.73–1.65(m,3h),1.64(d,j＝0.5hz,1h),1.63(s,3h),1.62–1.49(m,2h),1.43–1.36(m,2h),1.35–1.24(m,6h),1.19–1.09(m,3h),1.08(s,3h),0.97–0.92(m,3h),0.91(s,3h),0.88(d,j＝6.8hz,6h),0.77(s,3h).

hrms(esi)for[m+na]⁺:calcdforc29h48o3na:467.34957.found:467.3492.

实施例4

asb-s3:4-(((2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-4-oxobutanoicacid的合成

实验步骤：同实施例2

白色固体，产率为81％；m.p.130.1-131.7℃；¹hnmr(400mhz,cdcl3)δ4.77(d,j＝6.5hz,1h),4.55(d,j＝10.8hz,1h),2.99(s,1h),2.77(dd,j＝17.7,6.5hz,1h),2.63(ddd,j＝26.4,11.6,7.3hz,5h),2.21(dd,j＝20.9,13.6hz,2h),1.67(d,j＝8.4hz,2h),1.63(s,3h),1.61–1.46(m,2h),1.46–1.20(m,8h),1.14(dd,j＝17.8,14.0hz,3h),1.07(s,3h),0.90(s,3h),0.88–0.82(m,6h),0.77(s,3h)；¹³cnmr(100mhz,cdcl3)δ:177.17,171.80,132.70,127.20,77.32,77.00,76.68,47.66,43.00,42.00,40.20,38.56,38.47,37.49,36.69,36.25,33.98,33.80,33.41,31.44,29.39,29.04,29.00,25.95,25.62,23.43,17.47,15.91,12.37；

hrms(esi)for[m-h]^-:calcdforc29h45o5：473.32615.found:473.32678.

实施例5

asb-s4:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-ylpropionate的合成

实验步骤：同实施例2

白色固体,产率为78.08％,m.p.108.8-109.4℃.¹hnmr(400mhz,cdcl3)δ4.74(d,j＝6.4hz,1h),4.56(d,j＝10.7hz,1h),2.99(s,1h),2.78(dd,j＝17.8,6.5hz,1h),2.61(t,j＝14.6hz,1h),2.29(q,j＝7.6hz,2h),2.25–2.14(m,2h),1.73–1.64(m,2h),1.62(s,3h),1.61–1.47(m,3h),1.42–1.22(m,8h),1.18–1.15(m,1h),1.15–1.11(m,3h),1.10(s,1h),1.07(s,3h),0.89(s,3h),0.89–0.83(m,6h),0.76(s,3h).

hrms(esi)for[m+na]⁺:calcdforc28h46o3na:453.33392.found:453.33326.

实施例6

asb-s5:5-(((2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-5-oxopentanoicacid的合成

实验步骤：同实施例2

白色固体，产率为86.69％；m.p.66.1-76.9℃；¹hnmr(400mhz,cdcl3)δ4.74(d,j＝6.4hz,1h),4.56(d,j＝10.7hz,1h),2.98(s,1h),2.78(dd,j＝18.0,6.6hz,1h),2.60(t,j＝14.9hz,1h),2.42(t,j＝7.2hz,2h),2.36(td,j＝7.3,2.4hz,2h),2.25–2.15(m,2h),1.99–1.90(m,2h),1.67(d,j＝8.3hz,1h),1.63(s,3h),1.61–1.47(m,2h),1.43–1.24(m,10h),1.18–1.08(m,3h),1.07(s,3h),0.90(s,3h),0.87(d,j＝4.6hz,5h),0.76(s,3h)；

hrms(esi)for[m-h]^-:calcdforc30h47o5:487.3418.found:487.34256

实施例7

asb-s6:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-ylhexanoate的合成

实验步骤：同实施例2

白色固体,产率为86.54％,m.p.74.8-75.9℃.¹hnmr(400mhz,cdcl3)δ4.74(d,j＝6.4hz,1h),4.57(d,j＝10.7hz,1h),3.00(s,1h),2.78(dd,j＝17.8,6.5hz,1h),2.61(t,j＝14.7hz,1h),2.30–2.24(m,2h),2.24–2.14(m,2h),1.74–1.64(m,3h),1.63(s,3h),1.62–1.48(m,4h),1.45–1.21(m,12h),1.20–1.09(m,3h),1.08(s,3h),0.90(s,3h),0.87(t,j＝9.8hz,8h),0.77(s,3h).

hrms(esi)for[m+na]⁺:calcdforc31h52o3na:495.38087.found:495.38027.

实施例8

asb-s9:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-ylisobutyrate的合成

实验步骤:同实施例2

白色固体,产率为84.18％,m.p.104.6-106.1℃.¹hnmr(400mhz,cdcl3)δ4.72(d,j＝6.4hz,1h),4.58(d,j＝10.7hz,1h),3.02(s,1h),2.77(dd,j＝18.0,6.4hz,1h),2.62(t,j＝14.9hz,1h),2.49(dq,j＝14.0,7.0hz,1h),2.25–2.13(m,2h),1.73–1.65(m,2h),1.63(s,3h),1.61–1.45(m,3h),1.44–1.22(m,9h),1.15(d,j＝1.4hz,3h),1.13(t,j＝2.1hz,3h),1.11–1.09(m,1h),1.08(s,3h),0.90(s,3h),0.89–0.83(m,6h),0.75(s,3h)

hrms(esi)for[m+na]⁺:calcdforc29h48o3na:467.34957.found:467.34877.

实施例9

asb-s10:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl2-chloro-2,2-difluoroacetate的合成

实验步骤：同实施例2

白色固体,产率为89％,m.p.124.8-125.4℃.¹hnmr(400mhz,cdcl3)δ6.28(d,j＝11.1hz,1h),4.95(d,j＝6.1hz,1h),3.34(d,j＝10.5hz,1h),2.87(dd,j＝18.4,6.0hz,1h),2.74(t,j＝13.6hz,1h),2.40(d,j＝18.4hz,1h),2.35–2.25(m,1h),1.88–1.71(m,3h),1.69(s,3h),1.66–1.58(m,1h),1.44–1.08(m,11h),1.02(s,3h),0.91(s,3h),0.88(s,3h),0.77(s,3h),0.68(d,j＝6.9hz,3h).

实施例10

asb-n1:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-oxo-4-(propylamino)butanoate的合成

实验步骤：

称取asb-cooh(67.4mg,0.142mmol,1eq)于20ml的螺纹口样品瓶，2ml无水二氯甲烷溶解化合物，再称取edc(57.2mg,0.298mmol,2eq)，hobt(75.2mg,0.5565mmol,4eq)于反应液中，室温反应4h后，再加胺(0.3mmol,2eq)加进去反应4h-12h，tlc跟踪反应。反应完后，室温减压旋蒸除去二氯甲烷，0.5mhcl和ea(v:v＝1:1)萃取得有机相(50ml的分液漏斗萃取)，所得有机相再转移至125ml的分液漏斗依次加饱和食盐水(2×20ml)，5％的碳酸氢钠溶液(2×20ml)，加饱和食盐水(3×20ml)，最后测萃取的那一次的饱和食盐水的ph，ph呈中性即可。加无水硫酸钠干燥有机相，45℃减压蒸馏得粗产品，乙酸乙酯石油醚体系柱层析得纯化合物。

白色固体,产率为60.9％,m.p.66.0-66.5℃.¹hnmr(500mhz,cdcl3)δ5.68(s,1h),4.75(d,j＝6.5hz,1h),4.57(dd,j＝21.7,8.8hz,1h),3.19(td,j＝13.6,6.5hz,2h),2.98(s,1h),2.78(dd,j＝17.8,6.5hz,1h),2.70–2.54(m,3h),2.45(t,j＝6.8hz,2h),2.31–2.14(m,2h),1.72–1.65(m,2h),1.63(s,3h),1.54(ddt,j＝29.1,14.5,7.2hz,5h),1.39(td,j＝13.8,3.6hz,2h),1.29(ddd,j＝14.0,11.9,3.1hz,6h),1.15(ddd,j＝23.4,12.7,7.5hz,3h),1.08(s,3h),0.92(d,j＝7.4hz,2h),0.91(s,3h),0.87(dd,j＝11.8,8.4hz,6h),0.78(s,3h).

hrms(esi)for[m+na]⁺:calcdforc32h53o4nna:538.38668.found:538.38560.

实施例11

asb-n2:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-(cyclohexylamino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率40.5％,m.p.69.1-69.7℃.¹hnmr(500mhz,cdcl3)δ5.53(d,j＝6.9hz,1h),4.75(d,j＝6.5hz,1h),4.54(d,j＝10.7hz,1h),3.82–3.66(m,1h),2.98(s,1h),2.76(dt,j＝25.5,12.8hz,1h),2.67–2.55(m,3h),2.42(t,j＝6.8hz,2h),2.25–2.16(m,2h),1.93–1.84(m,2h),1.73–1.64(m,4h),1.62(s,3h),1.54(ddd,j＝22.7,11.5,7.8hz,3h),1.43–1.23(m,10h),1.21–1.09(m,6h),1.08(s,3h),0.90(s,3h),0.86(dd,j＝10.9,7.1hz,6h),0.77(s,3h)

hrms(esi)for[m+na]⁺:calcdforc35h57o4nna:578.41798；found:578.41690

实施例12

asb-n3:(2as,6as,6bs,9z,11r,12r,12az,13as)-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,13a-tetradecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-oxo-4-(propylamino)butanoate的合成

实验步骤：

称取asb-cooh(45.4mg，0.096mmol，1eq)于50ml圆底烧瓶中，2ml无水二氯甲烷溶解，冰浴下加入二氯亚砜(42ul，0.58mmol，6eq)，冰浴下反应6h。待原料完全转化，35℃减压蒸馏二氯甲烷及socl2。继续加无水二氯甲烷，冰浴下加正丙胺(26ul，0.316mmol，3.3eq)及tea，室温搅拌反应。tlc跟踪反应完后，加2mhcl溶液调至ph至中性，加二氯甲烷及饱和食盐水萃取的得有机相，加无水硫酸钠干燥，35℃减压蒸馏得粗产品，甲醇二氯甲烷体系(v:v＝1:200)柱层析得纯化合物。

白色固体,产率为56.3％；m.p.49.9-52.0℃；¹hnmr(400mhz,cdcl3)δ5.72(s,1h),5.59(d,j＝11.3hz,1h),4.97–4.89(m,1h),4.81(d,j＝6.0hz,1h),3.20(dd,j＝13.5,6.6hz,2h),3.00(s,1h),2.75–2.63(m,3h),2.45(t,j＝6.9hz,2h),2.33(dd,j＝24.3,14.8hz,2h),1.97–1.82(m,2h),1.75(td,j＝13.4,4.1hz,1h),1.59(d,j＝13.9hz,3h),1.52(dt,j＝14.5,7.4hz,2h),1.47–1.36(m,3h),1.34–1.10(m,5h),1.08–1.01(m,2h),0.93(t,j＝8.3hz,2h),0.89(dd,j＝8.7,4.3hz,7h),0.86(s,3h),0.82(s,3h),0.68(d,j＝7.2hz,3h)

hrms(esi)for[m+na]⁺:calcdforc32h51o3nna:520.37612；found:520.37544

实施例13

asb-n4:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-((furan-2-ylmethyl)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率90.2％,m.p.76.1-78.0℃.¹hnmr(400mhz,cdcl3)δ7.33(d,j＝1.3hz,1h),6.35–6.26(m,1h),6.21(d,j＝3.2hz,1h),6.01(s,1h),4.74(d,j＝6.5hz,1h),4.54(d,j＝10.7hz,1h),4.46–4.36(m,2h),2.96(s,1h),2.76(dd,j＝17.8,6.5hz,1h),2.64(t,j＝6.8hz,2h),2.58(d,j＝14.1hz,1h),2.48(t,j＝6.8hz,2h),2.25–2.14(m,2h),1.66(dd,j＝16.7,8.4hz,3h),1.62(s,3h),1.60–1.45(m,3h),1.42–1.33(m,2h),1.31–1.22(m,5h),1.13(dd,j＝21.4,8.7hz,3h),1.07(s,3h),0.91(d,j＝11.7hz,3h),0.86(t,j＝3.4hz,5h),0.76(s,3h).hrms(esi)for[m+na]⁺:calcdforc34h51o5nna:576.36594；found:576.36511.

实施例14

asb-n5:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-(phenethylamino)butanoate的合成

实验步骤：同实施例10

白色固体，产率为77％,m.p.60.1-62.1℃.¹hnmr(400mhz,cdcl3)δ7.31(t,j＝7.3hz,2h),7.25–7.12(m,3h),5.64(s,1h),4.73(d,j＝6.5hz,1h),4.54(d,j＝10.7hz,1h),3.51(d,j＝5.9hz,2h),2.97(s,1h),2.85–2.72(m,3h),2.68–2.53(m,3h),2.41(t,j＝6.7hz,2h),2.21(dd,j＝15.2,8.9hz,2h),1.73–1.63(m,2h),1.62(s,3h),1.60–1.47(m,3h),1.38(dd,j＝18.4,8.0hz,2h),1.33–1.22(m,6h),1.14(dd,j＝21.6,9.1hz,3h),1.07(s,3h),0.90(s,3h),0.87(t,j＝3.4hz,5h),0.76(s,3h)

hrms(esi)for[m+na]⁺:calcdforc37h55o4nna:600.40233；found:600.40134

实施例15

asb-n6:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-oxo-4-((thiophen-2-ylmethyl)amino)butanoate的合成

实验步骤：同实施例10

白色固体，产率85.13％,m.p.58.1-59.0℃.¹hnmr(400mhz,cdcl3)δ7.20(dd,j＝4.9,1.1hz,1h),6.94(dd,j＝8.4,3.5hz,2h),6.05(s,1h),4.74(d,j＝6.4hz,1h),4.59(d,j＝5.6hz,2h),4.54(d,j＝10.7hz,1h),2.96(s,1h),2.76(dd,j＝17.8,6.5hz,1h),2.68–2.53(m,3h),2.48(t,j＝6.8hz,2h),2.25–2.15(m,2h),1.67(dd,j＝15.1,6.8hz,2h),1.62(s,3h),1.57(dd,j＝13.0,6.1hz,1h),1.50(dd,j＝10.8,7.8hz,2h),1.38(dd,j＝20.9,9.2hz,2h),1.26(dd,j＝17.3,10.2hz,6h),1.13(dd,j＝21.1,8.5hz,3h),1.07(s,3h),0.89(s,3h),0.86(t,j＝3.4hz,5h),0.76(s,3h)

hrms(esi)for[m+na]⁺:calcdforc34h51o4nnas:592.3431；found:592.34214

实施例16

asb-n7:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((2-(cyclohex-1-en-1-yl)ethyl)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为83.69％,m.p.100.3-102.8℃.¹hnmr(400mhz,cdcl3)δ5.61(s,1h),5.45(s,1h),4.74(d,j＝6.5hz,1h),4.53(d,j＝10.8hz,1h),3.30(dd,j＝12.5,6.5hz,2h),2.97(s,1h),2.77(dd,j＝17.7,6.5hz,1h),2.64–2.54(m,3h),2.43(t,j＝6.9hz,2h),2.26–2.16(m,2h),2.10(t,j＝6.7hz,2h),1.99(s,2h),1.90(s,2h),1.72–1.63(m,3h),1.61(s,3h),1.60–1.46(m,5h),1.39(dd,j＝22.3,10.2hz,3h),1.26(dd,j＝19.1,10.1hz,6h),1.18–1.08(m,3h),1.07(s,3h),0.89(s,3h),0.86(t,j＝3.4hz,5h),0.76(s,3h).

hrms(esi)for[m+na]⁺:calcdforc37h59o4nna:604.43363；found:604.43275

实施例17

asb-n8:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-((2-(thiophen-2-yl)ethyl)amino)butanoate的合成

实验步骤：同实施例10

淡粉色固体，产率79.3％,m.p.70.3-72.2℃.¹hnmr(400mhz,cdcl3)δ7.15(d,j＝5.1hz,1h),6.94(dd,j＝5.0,3.5hz,1h),6.83(d,j＝3.3hz,1h),5.85(s,1h),4.73(d,j＝6.5hz,1h),4.54(d,j＝10.7hz,1h),3.56–3.47(m,2h),3.02(t,j＝6.7hz,2h),2.97(s,1h),2.77(dd,j＝17.8,6.5hz,1h),2.69–2.53(m,3h),2.43(t,j＝6.8hz,2h),2.27–2.14(m,2h),1.67(dd,j＝16.4,8.1hz,3h),1.62(s,3h),1.61–1.44(m,3h),1.43–1.21(m,7h),1.21–1.08(m,3h),1.05(d,j＝19.9hz,3h),0.96–0.89(m,3h),0.87(t,j＝3.4hz,5h),0.76(s,3h)

hrms(esi)for[m+na]⁺:calcdforc35h53o4nnas:606.35875；found:606.35734

实施例18

asb-n9:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-((4-bromophenyl)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为75.69％,m.p.194.6-195.9℃.¹hnmr(400mhz,cdcl3)δ7.89(s,1h),7.39(s,4h),4.76(d,j＝6.4hz,1h),4.54(d,j＝10.7hz,1h),2.97(s,1h),2.83–2.67(m,3h),2.67–2.53(m,3h),2.27–2.16(m,2h),1.72–1.64(m,2h),1.62(s,3h),1.60–1.44(m,3h),1.43–1.19(m,8h),1.13(dd,j＝20.4,8.2hz,3h),1.07(s,3h),0.89(s,3h),0.87(t,j＝3.4hz,5h),0.76(s,3h).

hrms(esi)for[m+na]⁺:calcdforc35h50o4nbrna:650.28154；found:650.28136.

实施例19

asb-n10:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-(heptylamino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色油状物，产率为70.69％，m.p.¹hnmr(400mhz,cdcl3)δ5.71(s,1h),4.73(d,j＝6.5hz,1h),4.53(d,j＝10.7hz,1h),3.21(dd,j＝13.0,6.6hz,2h),2.96(s,1h),2.76(dd,j＝17.9,6.6hz,1h),2.66–2.53(m,3h),2.43(t,j＝6.7hz,2h),2.27–2.14(m,2h),1.66(dd,j＝17.3,8.6hz,4h),1.61(s,3h),1.59–1.42(m,4h),1.42–1.18(m,15h),1.18–1.08(m,3h),1.06(s,3h),0.89(s,3h),0.85(d,j＝3.4hz,8h),0.73(d,j＝22.3hz,3h)

hrms(esi)for[m+na]⁺:calcdforc36h61o4nna:594.44928；found:594.44892

实施例20

asb-n11:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((2-(furan-2-yl)ethyl)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为79.75％,m.p.56.4-58.4℃.¹hnmr(400mhz,cdcl3)δ7.32(s,1h),6.29(s,1h),6.07(s,1h),5.85(s,1h),4.73(d,j＝6.4hz,1h),4.54(d,j＝10.4hz,1h),3.52(d,j＝5.9hz,2h),2.97(s,1h),2.90–2.70(m,3h),2.70–2.51(m,3h),2.44(t,j＝6.4hz,2h),2.22(d,j＝17.6hz,2h),1.65(s,4h),1.62(s,3h),1.60–1.46(m,2h),1.38(t,j＝13.7hz,2h),1.29(d,j＝13.3hz,5h),1.18–1.10(m,2h),1.07(s,3h),0.90(s,3h),0.89–0.79(m,6h),0.76(s,3h)；

hrms(esi)for[m+na]⁺:calcdforc35h53o5nna:590.38159；found:590.38071

实施例21

asb-n12:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-((2-morpholinoethyl)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体,产率为51.77％,m.p.64.0-66.2℃.¹hnmr(400mhz,cdcl3)δ6.21(s,1h),4.71(d,j＝6.4hz,1h),4.51(d,j＝7.3hz,1h),3.76–3.60(m,4h),3.32(dd,j＝11.1,5.5hz,2h),2.94(s,1h),2.74(dd,j＝17.8,6.6hz,1h),2.63–2.52(m,3h),2.50–2.32(m,8h),2.18(dd,j＝19.5,12.4hz,3h),1.70–1.61(m,2h),1.59(s,3h),1.57–1.53(m,1h),1.52–1.44(m,1h),1.34(d,j＝13.8hz,2h),1.26(d,j＝14.8hz,5h),1.15–1.06(m,3h),1.04(s,3h),0.87(s,3h),0.86–0.79(m,6h),0.74(s,3h)

hrms(esi)for[m+h]⁺:calcdforc35h59o5n2:587.44185；found:587.44143.

实施例22

asb-n13:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-(diallylamino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为71.68％,m.p.66.9-68.9℃.¹hnmr(400mhz,cdcl3)δ5.75(dddd,j＝22.1,16.4,10.9,5.4hz,2h),5.25–5.06(m,4h),4.74(d,j＝6.5hz,1h),4.52(d,j＝10.8hz,1h),3.96(t,j＝7.7hz,2h),3.89(d,j＝4.8hz,2h),2.99(s,1h),2.76(dd,j＝17.7,6.6hz,1h),2.60(d,j＝9.4hz,4h),2.20(dd,j＝19.7,12.7hz,2h),1.73–1.62(m,3h),1.61(s,3h),1.58(d,j＝6.0hz,1h),1.51(td,j＝11.4,3.6hz,1h),1.43–1.21(m,8h),1.13(dd,j＝21.6,8.8hz,3h),1.06(s,3h),0.89(s,3h),0.88–0.82(m,6h),0.76(s,3h)

hrms(esi)for[m+na]⁺:calcdforc35h55o4nna:576.40233；found:576.40181.

实施例23

asb-n14:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-oxo-4-(pyrrolidin-1-yl)butanoate的合成

实验步骤：同实施例10

白色固体，产率为64.65％,m.p.148.2-148.9℃.¹hnmr(400mhz,cdcl3)δ4.73(d,j＝6.6hz,1h),4.51(d,j＝10.8hz,1h),3.51–3.33(m,4h),2.98(s,1h),2.75(dd,j＝17.8,6.6hz,1h),2.64–2.58(m,2h),2.55(d,j＝5.9hz,2h),2.27–2.17(m,2h),1.98–1.90(m,2h),1.87–1.79(m,2h),1.66(dd,j＝14.6,7.8hz,3h),1.60(s,3h),1.59–1.44(m,2h),1.37(t,j＝13.2hz,2h),1.25(t,j＝13.7hz,5h),1.16–1.08(m,2h),1.06(s,3h),0.88(s,3h),0.87–0.81(m,6h),0.72(d,j＝20.8hz,3h)

hrms(esi)for[m+na]⁺:calcdforc33h53o4nna:550.38668；found:550.38594

实施例24

asb-n15:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-((benzyloxy)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为71.2％,m.p.69.8-71.5℃.¹hnmr(400mhz,cdcl3)δ8.59(s,1h),7.45–7.30(m,5h),4.88(s,2h),4.71(d,j＝5.2hz,1h),4.53(d,j＝10.7hz,1h),2.95(s,1h),2.76(dd,j＝17.8,6.4hz,1h),2.58(t,j＝10.3hz,3h),2.36–2.13(m,4h),1.72–1.64(m,2h),1.61(s,3h),1.59–1.54(m,1h),1.50(dd,j＝15.3,7.3hz,1h),1.42–1.32(m,2h),1.31–1.20(m,6h),1.17–1.07(m,3h),1.06(s,3h),0.89(s,3h),0.88–0.82(m,6h),0.75(s,3h)

hrms(esi)for[m+na]⁺:calcdforc36h53o5nna:602.38159；found:602.38068.

实施例25

asb-n16:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-(3,4-dihydroisoquinolin-2(1h)-yl)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为68.9％,m.p.66.5-67.4℃.¹hnmr(500mhz,cdcl3)δ7.24–7.04(m,4h),4.76(d,j＝6.6hz,1h),4.71(s,1h),4.64(s,1h),4.54(d,j＝10.7hz,1h),3.81(t,j＝5.9hz,1h),3.70(t,j＝6.0hz,1h),3.01(s,1h),2.91(t,j＝5.8hz,1h),2.84(t,j＝5.8hz,1h),2.78(dd,j＝17.7,6.6hz,1h),2.75–2.68(m,2h),2.68–2.63(m,2h),2.61(t,j＝12.0hz,1h),2.24(dd,j＝14.8,8.8hz,2h),1.77–1.64(m,4h),1.62(s,3h),1.57(d,j＝7.3hz,1h),1.56–1.48(m,1h),1.42–1.33(m,2h),1.32–1.25(m,4h),1.25–1.22(m,1h),1.13(dd,j＝11.5,4.9hz,2h),1.08(s,3h),0.90(s,3h),0.87(dd,j＝8.7,5.1hz,6h),0.76(d,j＝5.0hz,3h).

hrms(esi)for[m+na]⁺:calcdforc38h55o4nna:612.40233；found:612.40165.

实施例26

asb-n17:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl7-morpholino-4-oxoheptanoate的合成

实验步骤：同实施例10

白色固体，产率为71.95％,m.p.68.6-70.9℃.¹hnmr(500mhz,cdcl3)δ6.90(s,1h),4.72(d,j＝6.5hz,1h),4.52(d,j＝10.4hz,1h),3.81–3.71(m,4h),3.37–3.28(m,2h),2.96(s,1h),2.75(dd,j＝17.7,6.6hz,1h),2.61(t,j＝6.8hz,2h),2.58–2.45(m,6h),2.42(t,j＝6.8hz,2h),2.25–2.17(m,2h),1.75–1.63(m,4h),1.61(s,3h),1.59–1.55(m,1h),1.50(td,j＝11.4,3.6hz,1h),1.42–1.33(m,2h),1.29(d,j＝4.0hz,1h),1.26(d,j＝3.3hz,3h),1.25–1.20(m,2h),1.18–1.08(m,3h),1.06(s,3h),0.88(d,j＝8.0hz,3h),0.85(d,j＝6.6hz,5h),0.76(s,3h)

实施例27

asb-n18:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-morpholino-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为82.9％,m.p.63.8-65.8℃.¹hnmr(500mhz,cdcl3)δ4.75(d,j＝6.5hz,1h),4.53(d,j＝10.7hz,1h),3.69–3.43(m,8h),2.99(s,1h),2.77(dd,j＝17.7,6.6hz,1h),2.64–2.59(m,4h),2.28–2.17(m,2h),1.73–1.63(m,4h),1.62(s,3h),1.59(d,j＝5.1hz,1h),1.51(td,j＝11.4,3.7hz,1h),1.38(dd,j＝21.3,8.7hz,2h),1.32–1.21(m,6h),1.18–1.08(m,3h),1.07(s,3h),0.90(s,3h),0.86(d,j＝4.8hz,6h),0.76(s,3h)

hrms(esi)for[m+na]⁺:calcdforc33h53o5nna:566.38159；found:566.38068.

实施例28

asb-n19:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-(2-(trifluoromethyl)pyrrolidin-1-yl)butanoate的合成

实验步骤：同实施例10

白色固体，产率为62.75％,m.p162.3-163.4℃.¹hnmr(500mhz,cdcl3)δ4.92–4.64(m,2h),4.53(t,j＝11.0hz,1h),3.80–3.43(m,2h),2.99(s,1h),2.86–2.65(m,3h),2.65–2.49(m,3h),2.22(dd,j＝17.8,10.5hz,2h),2.16(s,1h),2.15–2.09(m,1h),2.00(dt,j＝19.6,9.5hz,2h),1.72–1.63(m,3h),1.62(s,3h),1.61–1.56(m,1h),1.55–1.48(m,1h),1.42–1.33(m,2h),1.32–1.28(m,2h),1.26(s,2h),1.23(dd,j＝8.5,5.5hz,1h),1.18–1.08(m,3h),1.07(s,3h),0.90(s,3h),0.86(d,j＝6.9hz,6h),0.76(s,3h).

hrms(esi)for[m+na]⁺:calcdforc34h52o4nf3na:618.37406；found:618.37329.

实施例29

asb-n20:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-((4-methoxyphenyl)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为75.57％,m.p.90.5-92.5℃.¹hnmr(400mhz,cdcl3)δ7.58(s,1h),7.38(d,j＝8.8hz,2h),6.83(d,j＝8.8hz,2h),4.76(d,j＝6.4hz,1h),4.53(d,j＝10.7hz,1h),3.77(s,3h),2.97(s,1h),2.77(dd,j＝17.9,6.5hz,1h),2.70(t,j＝6.4hz,2h),2.60(dd,j＝18.0,11.2hz,3h),2.21(t,j＝12.6hz,2h),1.74–1.62(m,3h),1.61(s,3h),1.60–1.51(m,2h),1.49(d,j＝11.1hz,1h),1.42–1.22(m,7h),1.19–1.08(m,3h),1.06(s,3h),0.88(s,3h),0.87(d,j＝6.4hz,5h),0.76(s,3h)

hrms(esi)for[m+na]⁺:calcdforc36h53o5nna:602.38159；found:602.38147.

实施例30

asb-n21:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-(cyclopropylamino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为78％,m.p.138.4-141.7℃.

hrms(esi)for[m+na]⁺:calcdforc32h51o4nna:536.37103；found:536.37073.

实施例31

asb-n22:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-(cyclopentylamino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为80.5％,m.p.73.7-75.1℃.¹hnmr(600mhz,cdcl3)δ5.65(d,j＝6.6hz,1h),4.74(d,j＝6.5hz,1h),4.53(d,j＝10.7hz,1h),4.21–4.13(m,1h),2.97(s,1h),2.76(dd,j＝17.8,6.6hz,1h),2.67–2.54(m,3h),2.41(t,j＝6.9hz,2h),2.28–2.13(m,2h),1.96(td,j＝12.8,6.9hz,2h),1.79–1.63(m,5h),1.61(s,3h),1.57(ddd,j＝11.3,7.5,3.6hz,2h),1.50(td,j＝11.5,3.5hz,1h),1.41–1.32(m,4h),1.31–1.23(m,6h),1.17–1.09(m,3h),1.07(s,3h),0.92–0.88(m,3h),0.86(dd,j＝13.6,9.4hz,6h),0.77(s,3h)

hrms(esi)for[m+na]⁺:calcdforc34h55o4nna:564.40233；found:564.40198.

实施例32

asb-n23:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-(naphthalen-1-ylamino)-4-oxobutanoate的合成

实验步骤：同实施例10

淡粉色固体，产率为42.12％,m.p.86.1-90.1℃.¹hnmr(600mhz,cdcl3)δ8.09(s,1h),7.94(dd,j＝15.7,7.8hz,2h),7.86(d,j＝7.9hz,1h),7.69(d,j＝8.0hz,1h),7.50(ddd,j＝26.5,15.2,7.3hz,3h),4.82(d,j＝6.2hz,1h),4.54(d,j＝10.6hz,1h),2.98(s,1h),2.81(s,4h),2.60(t,j＝14.7hz,1h),2.24(dd,j＝20.4,12.9hz,2h),1.70–1.63(m,2h),1.61(s,3h),1.59–1.47(m,3h),1.41–1.31(m,2h),1.31–1.19(m,9h),1.15–1.07(m,3h),1.06(s,3h),0.92–0.87(m,6h),0.86(s,3h),0.76(s,3h)

hrms(esi)for[m+na]⁺:calcdforc39h53o4nna:622.38668；found:622.38612.

实施例33

asb-n24:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl4-((3-bromopyridin-2-yl)amino)-4-oxobutanoate的合成

实验步骤：同实施例10

白色固体，产率为55％,m.p.57.2-59.2℃.¹hnmr(600mhz,cdcl3)δ8.34(d,j＝3.9hz,1h),8.03(s,1h),7.86(dd,j＝7.9,1.4hz,1h),6.99–6.88(m,1h),4.77(d,j＝6.4hz,1h),4.54(d,j＝10.7hz,1h),3.11–2.94(m,3h),2.78(dd,j＝17.7,6.6hz,1h),2.75–2.70(m,2h),2.60(t,j＝14.4hz,1h),2.28–2.19(m,2h),1.70–1.64(m,2h),1.62(s,3h),1.57(dd,j＝13.5,4.6hz,1h),1.51(td,j＝11.6,3.9hz,1h),1.40–1.31(m,2h),1.30–1.27(m,2h),1.23(ddd,j＝16.1,7.0,4.4hz,5h),1.16–1.08(m,3h),1.07(s,3h),0.89(s,3h),0.89–0.85(m,6h),0.74(s,3h)

hrms(esi)for[m+h]⁺:calcdforc34h50o4n2br:629.29485；found:629.29474.

实施例34

asb-n25:(2as,6as,6bs,11r,12r,12as,13r,13as,z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1h-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((4-bromo-1h-pyrazol-3-yl)amino)-4-oxobutanoate的合成

实验步骤：

称取asb-cooh(67.4mg,0.142mmol,1eq)于50ml圆底烧瓶，2ml无水1,2-二氯乙烷溶解化合物，再称取edc(57.2mg,0.298mmol,2eq)，hobt(75.2mg,0.5565mmol,4eq)于反应液中，室温反应4h后，再胺(0.3mmol,2eq)80℃冷凝回流反应12h，tlc跟踪反应。反应完后，冷凝室温减压旋蒸除去溶剂，0.5mhcl和ea(v:v＝1:1)萃取得有机相(50ml的分液漏斗萃取)，所得有机相再转移至125ml的分液漏斗依次加饱和食盐水(2×20ml)，5％的碳酸氢钠溶液(2×20ml)，加饱和食盐水(3×20ml)，最后测萃取的那一次的饱和食盐水的ph，ph呈中性即可。加无水硫酸钠干燥有机相，45℃减压蒸馏得粗产品，乙酸乙酯石油醚体系柱层析得纯化合物。

白色固体，产率为60.5％.¹hnmr(600mhz,cdcl3)δ8.06(s,1h),4.76(d,j＝6.5hz,1h),4.55(d,j＝10.7hz,1h),4.16(dd,j＝31.0,26.6hz,1h),3.29–3.19(m,2h),2.97(d,j＝2.2hz,1h),2.83–2.74(m,1h),2.70(t,j＝6.7hz,2h),2.60(t,j＝14.7hz,1h),2.21(dt,j＝17.1,14.3hz,2h),1.71–1.64(m,2h),1.62(s,3h),1.61–1.55(m,1h),1.51(td,j＝11.7,3.7hz,1h),1.41–1.34(m,2h),1.32–1.24(m,6h),1.17–1.08(m,3h),1.07(s,3h),0.89(d,j＝8.3hz,3h),0.87(t,j＝3.5hz,6h),0.74(s,3h)；

hrms(esi)for[m+na]⁺:calcdforc32h48o4n3brna:640.27204；found:640.27167.

下面为本发明化合物抗炎活性测定结果

实验材料：raw264.7细胞，96孔板，lps，酶标仪，mtt溶液，

试验方法：

1.化合物对no生成量的影响

取对数生长期的raw264.7细胞，按1×10⁵个/孔将其接种于96孔板，100μl/孔。放入培养箱中培养24h使细胞贴壁并进入对数生长期，更换新的完全培养基，加入lps(终浓度1μg/ml)和样品溶液或吲哚美辛溶液，每个浓度设3孔重复。阳性对照组只加lps不加药物，阴性对照组只加细胞和完全培养基，空白孔只加完全培养基。培养箱培养24h后，取细胞培养上清液50μl加入新的96孔板，再分别加入一氧化氮检测试剂i与一氧化氮检测试剂ⅱ各50μl。用酶标仪测定540nm处的吸光度(od)。

2.化合物对细胞活力的影响

取对数生长期的raw264.7细胞，按1×10⁵个/孔将其接种于96孔板，100μl/孔。放入培养箱中培养24h使细胞贴壁并进入对数生长期，更换新的完全培养基，加入lps(终浓度1μg/ml)和样品溶液或吲哚美辛溶液，每个浓度设3孔重复。阳性对照组只加lps不加药物，阴性对照组只加细胞和完全培养基，空白孔只加完全培养基。培养箱培养24h后，每孔加入1mg/ml的mtt溶液50μl，培养箱继续培养4h，吸去培养基和mtt，再向各孔中加入150μl的dmso，震荡混匀，用酶标仪测定490nm处的吸光度值(od)。药物对细胞生长的抑制作用以存活率表示，存活率越高表明药物毒性越低。

下表为部分化合物的生物活性数据：

表2化合物的抗炎活性结果(ic50μm)

以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。