本发明涉及药物化学和药物治疗领域，更具体涉7-epi-巴卡亭iii衍生物、其的制备方法、药物组合物和用途。该类化合物可用于治疗癌症，特别是前列腺癌(prostatecarcinoma)、非小细胞肺癌、乳腺癌、结肠癌、肝癌、卵巢癌等。
背景技术：
微管蛋白(tubulin)作为胞质蛋白，几乎存在于所有的真核细胞生物中，其分为α，β，γ三种类型，主要功能是聚合形成圆柱形微管纤维从而构成微管形成纺锤体参与到细胞的有丝分裂当中1,2。抑制或促进微管的形成从而阻滞细胞的有丝分裂，是目前治疗癌症3和老年黄斑变性4的重要手段。此外，一水合谷氨酸钠尿酸盐(痛风的主要致病因子)会通过与微管蛋白相关的通路机制导致中性粒细胞对促炎蛋白的释放。所以，抑制微管蛋白的聚合对于痛风以及痛风性关节炎的治疗可以起到很好的效果5。
因此，针对该靶点开发的药物有多方面的应用。除了抑制细胞有丝分裂起到抗肿瘤(药物名称：taxol)的作用3，对微管蛋白目前还开发有针对预防和治疗感染(药物名称：griseofulvin)6、心血管系统疾病(药物名称：7-hexanoyltaxol)7-9、眼部疾病(药物名称：fosbretabulindisodium)4以及自身免疫性疾病(药物名称：brentuximabvedotin)5的药物。
巴卡亭iii属于二萜类紫杉烷家族的一个成员10,11，具有以下结构：
其目前主要作为紫杉醇的母体，用于半合成紫杉醇。紫杉醇结构如下：
紫杉醇目前是临床上非常重要的抗肿瘤制剂，具有很好的抗卵巢癌、乳腺癌、肺癌等活性，其作用于细胞内的微管蛋白，促进微管蛋白的聚合，起到稳定微管的作用，从而影响细胞的有丝分裂并最终导致细胞死亡12。全世界的很多研究机构对其化学性质以及构效关系做过很深入的研究。
尽管紫杉醇的抗肿瘤活性非常好，但是却有一些临床应用问题亟待解决，其中包括水溶性差、多药耐药性、严重的剂量限制性毒性，后者导致诸如骨髓抑制、外周感觉神经病变、过敏反应等。这些副作用的产生主要是由于紫杉醇的水溶性较差而采用聚氧乙烯蓖麻油(cremophorel)这种常用的抗肿瘤制剂的溶媒造成的。
因此对于紫杉烷的改造成为了解决上述问题的重要途径，这也吸引了世界上大批的药物研究者投入到这项具有前景的研究工作中。其中对于紫杉烷13位侧链的构效关系更是进行过系统的研究，o.n.zefirova13、w.-s.fang14等对此做过详细的综述。但是，这些研究大多数是在紫杉醇原有的13位的侧链α-羟基-β-氨基酸这类结构上进行的。天然的α-氨基酸作为生物体中最重要的一类分子，一方面构建了蛋白质的骨架，另一方面广泛的参与到生物体代谢当中。除此之外，天然的α-氨基酸的各种化学特性，通过蛋白质的特定构象可以形成特有的活性位点，从而决定了蛋白质的诸多功能和生物体的新陈代谢规律，因此基于氨基酸结构的药物研究以及具有氨基酸结构的药物分子也有诸多的报道15。
紫杉醇在生理条件下会自发的转化成7-epi-紫杉醇16。细胞色素p450(cyp450)是紫杉醇在体内的主要代谢酶17，与此同时7-β-羟基又是cyp450识别的主要基团。而7-epi-紫杉醇在体内对于cyp450具有很好的稳定性以及抑制了紫杉醇的主要代谢产物6-α-紫杉醇的生成18,19。所以这一点对于改善紫杉醇的代谢具有一定的指导作用。同时，制备7-epi-紫杉烷的衍生物对于发现代谢更好，毒性更低的紫杉烷抗肿瘤制剂具有十分重要的意义。
综上所述，通过将天然氨基酸这类生物体中常见的活性分子与改造后的紫杉烷母核进行整合，设计并合成新的紫杉烷衍生物，对开发新型的治疗和预防癌症、感染、抗心血管系统疾病、眼部疾病、自身免疫性疾病的药物具有十分重要的意义。
参考文献
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技术实现要素：
发明人在前期对紫杉烷的研究中发现了一种对紫杉烷母核7位羟基进行构型翻转的新方法(申请号：cn201510418981.6)。翻转后的母核的化学性质不同于巴卡亭iii，可以不对该母核的其他活性位点进行保护而直接与羧酸在13位羟基进行酯化反应。在此基础上，发明人运用合理的药物设计方法，针对7位羟基翻转后的母核，与天然氨基酸或者天然氨基酸衍生物以及其他一些羧酸整合，获得了一类全新的7-epi-巴卡亭iii衍生物，并测试了此类化合物在体外细胞水平的抗肿瘤活性，结果证明本专利化合物具有较强的抗肿瘤活性，其中部分化合物对前列腺肿瘤的抑制具有很强选择性，由此完成了本发明。
本发明的一个目的是提供一种通式1所示的7-epi-巴卡亭iii衍生物或其药学上可接受的盐。
本发明的另一个目的是提供本发明所述7-epi-巴卡亭iii衍生物的制备方法。
本发明的又一目的涉及一种药物组合物，其包含本发明所述7-epi-巴卡亭iii衍生物或其药学可接受的盐。
本发明的又一目的涉及本发明所述7-epi-巴卡亭iii衍生物或其药学可接受的盐，或包含所述7-epi-巴卡亭iii衍生物或其药学可接受的盐的药物组合物在制备治疗癌症的药物中的应用。
本发明的再一目的涉及本发明所述7-epi-巴卡亭iii衍生物或其药学可接受的盐，或包含所述7-epi-巴卡亭iii衍生物或其药学可接受的盐的药物组合物在治疗癌症中的应用。
根据本发明的一个方面，提供如下通式1的7-epi-巴卡亭iii衍生物，或其药学上可接受的盐：
其中：
r1、r2和r4各自独立地选自羟基、巯基、氨基、卤素、氰基、异氰基、硝基、羧基、c1-c10烷基酰氧基或c6-c12芳基酰氧基；优选选自羟基、巯基、氨基、卤素、氰基、异氰基、硝基、羧基、c1-c6烷基酰氧基和c6-c10芳基酰氧基；最优选选自羟基、乙酰氧基和苯甲酰氧基；
r3为α氨基酸、吖丁啶羧酸、氨基己酸、吡咯烷-3-甲酸、3-氨基-3-(2,3-二氢-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-酰基甲酸、2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、环丙甲酸或6-苯硫基己酸中的一个羧酸基团参与酯化后的残基，并且该残基经由所述羧酸基团的羰基与氧相连；
所述α氨基酸、吖丁啶羧酸、氨基己酸、吡咯烷-3-甲酸、3-氨基-3-(2,3-二氢-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-酰基甲酸、2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、环丙甲酸或6-基苯硫基己酸中的一个或多个氢原子任选地被选自叔丁氧羰基、c1-c6烷基、c1-c6烷氧基、c1-c6烷基酰胺基、苯基c1-c6烷基、c1-c6烷基磺酰基、卤素原子、苯基、c3-c8环烷基、叔丁基、环己基氧、苄氧羰基和硝基中的一个或多个取代基取代；
所述α氨基酸选自丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸、谷氨酰胺和天冬酰胺。
进一步优选地，r3选自2-叔丁氧基酰胺基-4-甲硫基丁酰基、2-叔丁氧基酰胺基-3-(1h-吲哚-3-基)-丙酰基、3-乙酰胺基硫基-2-叔丁氧基酰胺基丙酰基、2-叔丁氧基酰胺基-3-[1-(甲苯-4-磺酰基)-1h-咪唑-4-基]-丙酰基、n-叔丁氧基酰基吖丁啶-3-基酰基、2-叔丁氧基酰胺基-3-苯基-丙酰基、叔丁氧基酰基-乙酰基、2-叔丁氧基酰基-3-甲基-戊酰基、2,6-二叔丁氧基酰基-己酰基、n-叔丁氧基酰基-吡咯烷-3-基-甲酰基、3-苄氧基-2-叔丁氧基酰胺基-丙酰基、3-苄基硫基-2-叔丁氧基酰胺基-丙酰基、5-环己基氧酰基2-叔丁氧基酰胺基-4-环己基氧酰基丁酰基、2-叔丁氧基酰胺基-3-(4-叔丁氧酰基-苯基)-丙酰基、2-叔丁氧基酰胺基-3-(3,4-二氯-苯基)-丙酰基、2-叔丁氧基酰胺基-3-环己基氧酰基丙酰基、叔丁氧基酰胺基-苯基-乙酰基、3-苄基氧-2-叔丁氧酰胺基-丁酰基、2-叔丁氧基酰胺基-丙酰基、6-苄基氧酰胺基-2-叔丁氧酰胺基-己酰基、叔丁氧基酰胺基-环己基-乙酰基、3-叔丁氧基酰胺基-3-(5,6-二氟-2,3-二氢-1h-茚-1-基)-丙酰基、[4-(2-甲基氨基酰基-吡啶-4-基氧)-苯基]-氧代-乙酰基、2-[4-(4-氯-苯甲酰基)-苯氧基]-2-甲基-丙酰基、2-苄基氧酰胺基-丙酰基、(4-氯-苯氧基)-乙酰基、(4-甲氧基-苯基)-乙酰基、4-氯-2-吡啶酰基、环丙烷基酰基、6-(2,4-二硝基-苯硫基)-己酰基、2-氨基-4-甲硫基丁酰基、2-氨基-3-环己基氧酰基丙酰基和3-苄基硫基-2-氨基-丙酰基；
更具体而言，r3选自如下取代基：
优选地，所述通式1所示的7-epi-巴卡亭iii衍生物具有如下通式2所示的结构：
其中，r3的定义如上所述。
进一步优选地，所述通式1所示的7-epi-巴卡亭iii衍生物选自下列化合物：
本发明中，所述酸中的一个羧基参与酯化后的残基指的是所述酸中的一个羧基脱去羟基后得到的残基，并且所述残基经由该羧基的羰基与7-epi-巴卡亭iii母核上的氧连接。
根据本发明的7-epi-巴卡亭iii衍生物或其药学可接受的盐可以存在为其溶剂合物的形式，例如水合物或溶剂合物，并可能存在多种晶型。
根据本发明的另一个方面，提供了一种制备本发明所述的7-epi-巴卡亭iii衍生物的方法，其包括如下步骤：
其中，r1，r2，r3和r4的定义与前述相同，
使中间体m与化合物b经酯化反应得到通式1所示的化合物。
所述化合物b选自α氨基酸、吖丁啶羧酸、氨基己酸、吡咯烷-3-甲酸、3-氨基-3-(2,3-二氢-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-酰基甲酸、2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、环丙甲酸和6-苯硫基己酸，
所述α氨基酸、吖丁啶羧酸、氨基己酸、吡咯烷-3-甲酸、3-氨基-3-(2,3-二氢-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-酰基甲酸、2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、环丙甲酸或6-基苯硫基己酸中的一个或多个氢原子可以任选地被选自叔丁氧羰基、c1-c6烷基、c1-c6烷氧基、c1-c6烷基酰胺基、苯基c1-c6的烷基、c1-c6的烷基磺酰基、卤素原子、苯基、c3-c8环烷基、叔丁基、环己基氧、苄氧羰基和硝基中的一个或多个取代基取代。
进一步优选地，所述化合物b可以选自n-叔丁氧羰基-l-蛋氨酸、n-叔丁氧羰基-l-色氨酸、s-乙酰胺基甲基-n-叔丁氧羰基-l-半胱氨酸、n-叔丁氧羰基-n(咪唑)-(4-甲基苯磺酰基)-l-组氨酸、1-n-叔丁氧羰基-3-吖丁啶羧酸、n-叔丁氧羰基-l-苯丙氨酸、n-叔丁氧羰基-甘氨酸、n-叔丁氧羰基-l-异亮氨酸、(s)-2,6-二叔丁氧羰基氨基己酸、(s)-1-叔丁氧羰基-吡咯烷-3-甲酸、n-叔丁氧羰基-o-苄基-l-丝氨酸、n-叔丁氧羰基-s-苄基-l-半胱氨酸、n-叔丁氧羰基-5-环己基-l-谷氨酸、n-叔丁氧羰基-o-叔丁基-l-酪氨酸、n-叔丁氧羰基-l-3,4-二氯苯丙氨酸、n-叔丁氧羰基-3-环己氧甲酰基-l-天冬氨酸、n-叔丁氧羰基-l-2-苯基甘氨酸、n-叔丁氧羰基-o-苄基-l-苏氨酸、n-叔丁氧羰基-l-丙氨酸、n-叔丁氧羰基-n’-苄氧羰基-l-赖氨酸、n-叔丁氧羰基-l-环己基甘氨酸、(s)-n3-叔丁氧羰基-3-((s)-5,6-二氟-2,3-二氢-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-酰基甲酸、2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸、n-苄氧羰基-l-丙氨酸、对氯苯氧乙酸、对甲氧基苯乙酸、4-氯-2-吡啶甲酸、环丙甲酸、6-(2,4-二硝基苯硫基)己酸、l-蛋氨酸、3-环己氧甲酰基-l-天冬氨酸和s-苄基-l-半胱氨酸。
特别地，所述反应如下进行：将中间体m与化合物b投入到溶剂(如无水甲苯)中，氮气置换并保护反应体系，再在氮气保护下依次投入3倍当量的碳酸二(2-吡啶)酯(dpc)和1倍当量的4-二甲氨基吡啶(dmap)，于78℃～100℃下加热反应得到通式1所示的化合物。
优选地，所述方法进一步包括如下步骤：
其中，r1，r2和r4的定义与前述相同。
使化合物a的7位羟基进行构型翻转反应得到中间体m。
特别地，反应如下进行：
将化合物a投入到溶剂dmf中搅拌至溶清，再加入1倍当量氧化银，100℃下加热搅拌反应。
根据本发明的又一方面，提供了一种药物组合物，其包含本发明所述的7-epi-巴卡亭iii衍生物或其药学上可接受的盐。优选地，所述组合物进一步包含药学上可接受的辅料。
优选地，基于所述药物组合物的总重量，所述通式1所示的7-epi-巴卡亭iii衍生物或其药学上可接受的盐的重量比为0.001-99.9％，更优选0.1-90％。
本发明的又一方面提供了本发明所述7-epi-巴卡亭iii衍生物或其药学可接受的盐，或包含所述7-epi-巴卡亭iii衍生物或其药学可接受的盐的药物组合物在制备治疗癌症的药物中的应用。
本发明的再一方面涉及一种治疗癌症的方法，所述方法包括给需要该治疗的对象服用治疗有效量的根据本发明所述的7-epi-巴卡亭iii衍生物或其药学可接受的盐，或包含所述7-epi-巴卡亭iii衍生物或其药学可接受的盐的药物组合物。
所述癌症可以选自肺癌(尤其是非小细胞肺癌)、乳腺癌、结肠癌、肝癌、卵巢癌和前列腺癌。
具体实施方式
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。实施例中的所有参数以及其余的说明，除另有说明外，都是以质量(克)为单位。
试剂与仪器
制备本发明化合物的试剂均来源于商业购买。重要中间体来源于实验室制备，制备方法见实施例1。eyelan1001型旋转蒸发仪(东京理化器械株式会社)；agilent1260型高效液相色谱仪(美国agilent公司)；brukeravance-400或500型核磁共振仪(美国bruker公司)；lcq-deca型质谱仪(德国finnigan公司，esi-ms)；watersq-tofultima型质谱仪(美国waters公司，hr-esi-ms)。
实施例17-epi-巴卡亭iii的制备
将2.00克巴卡亭iii投入到250毫升圆底烧瓶中，加入150毫升dmf中搅拌至溶清，再加入2.37克氧化银，氮气保护，100℃加热搅拌3小时。待反应液冷却至室温后，反应液加300毫升水稀释，用乙酸乙酯萃取三次，共600毫升，有机相合并，水洗，饱和食盐水洗，无水硫酸钠干燥。减压蒸馏除去乙酸乙酯，残余物柱层析分离，洗脱剂为二氯甲烷/甲醇＝60/1，得到7-epi-巴卡亭iii，2.34克，为白色粉末，收率78％。1hnmr(400mhz,cdcl3)δ8.13(d,j＝7.17hz,2h),7.64(t,j＝7.42hz,1h),7.51(t,j＝7.65hz,2h),6.83(s,1h),5.72(d,j＝7.36hz,1h),4.96(dd,j＝3.04,9.09hz,1h),4.87(d,j＝11.67hz,1h),4.85–4.78(m,1h),4.45–4.33(m,2h),4.03(d,j＝7.47hz,1h),3.69(dd,1h),2.37(s,4h),2.36–2.24(m,4h),2.21(s,3h),2.00(s,3h),1.80(s,1h),1.65(s,3h),1.13(s,3h),1.07(s,3h)；13cnmr(126mhz,cdcl3)δ207.16,171.96,169.00,166.72,143.21,133.28,131.78,129.64,129.00,128.23,82.21,81.36,78.66,78.35,77.20,75.13,74.74,67.37,57.24,41.70,40.27,38.08,34.95,26.03,22.10,20.52,19.86,15.77,15.23；hrms(esi):c31h38o11na(m+na)+计算值：609.2306,实测值:609/2309。
实施例27-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)的制备
将40毫克7-epi-巴卡亭iii投入到25毫升圆底烧瓶中，加入3毫升无水甲苯，氮气保护，搅拌，再依次加入42.5毫克n-叔丁氧羰基-l-蛋氨酸，53.4毫克碳酸二吡啶酯(dpc)，8.3毫克4-二甲氨基吡啶(dmap)。80摄氏度搅拌反应6小时。反应加40毫升水淬灭，用乙酸乙酯萃取三次，共80毫升，有机相合并，水洗，饱和食盐水洗，无水硫酸钠干燥。减压蒸馏除去乙酸乙酯，残余物柱层析分离，洗脱剂为二氯甲烷/甲醇＝80/1，得到7-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)，24毫克，为白色粉末，收率43％。1hnmr(400mhz,cdcl3)δ8.09(d,j＝7.77hz,2h),7.64(t,j＝7.25hz,1h),7.52(t,j＝7.54hz,2h),6.82(s,1h),6.21(t,1h),5.76(d,1h),5.19(d,1h),4.92(dd,1h),4.72(s,1h),4.53(td,j＝3.62,8.60hz,1h),4.44–4.31(m,2h),3.97(d,j＝7.35hz,1h),3.71(dd,j＝3.80,11.42hz,1h),2.70–2.55(m,2h),2.51(s,3h),2.42–2.23(m,5h),2.21(s,3h),2.16(s,3h),2.01–1.88(m,4h),1.87(s,1h),1.67(s,3h),1.47(s,9h),1.19(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ207.12,172.36,172.15,169.31,167.07,155.49,139.67,133.81,133.60,130.05,129.23,128.76,82.71,82.05,80.39,79.11,78.10,77.64,75.59,75.16,70.93,57.67,52.75,42.54,40.39,36.25,35.38,32.10,30.05,29.69,28.31,26.00,22.74,20.88,16.11,15.62,15.55；hrms(esi):c41h55o14nnas(m+na)+计算值：840.3235,实测值:840.3225。
实施例37-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-色氨酸)-酯(i-2)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成51.9毫克n-叔丁氧羰基-l-色氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末42.5毫克，收率71％。1hnmr(400mhz,cdcl3)δ8.24(s,1h),8.10(d,j＝7.92hz,2h),7.65(d,j＝7.66hz,2h),7.53(t,j＝7.66hz,2h),7.38(d,j＝8.14hz,1h),7.21(dt,j＝7.24,21.21hz,2h),7.09(d,j＝2.00hz,1h),6.78(s,1h),6.11(t,j＝8.70hz,1h),5.74(d,j＝7.53hz,1h),5.11(d,j＝8.01hz,1h),4.91(dd,j＝3.42,8.96hz,1h),4.77–4.64(m,2h),4.42–4.31(m,2h),3.90(d,j＝7.65hz,1h),3.69(dd,j＝3.97,11.45hz,1h),3.46–3.36(m,1h),3.29–3.18(m,1h),2.40–2.26(m,5h),2.26–2.19(m,5h),1.79(s,1h),1.66(s,6h),1.44(s,9h),1.19(s,3h),1.15(s,3h)；13cnmr(101mhz,cdcl3)δ206.88,172.05,171.70,168.97,166.57,154.75,139.70,135.78,133.33,132.55,129.65,128.86,128.29,126.96,122.15,122.10,119.49,118.11,110.94,109.36,82.26,81.43,79.76,78.77,77.70,77.15,75.19,74.74,70.33,57.12,54.00,42.07,39.89,35.83,34.86,27.92,27.84,25.49,21.82,20.60,20.47,15.73,14.50；hrms(esi):c47h56n2o14nafor(m+na)+计算值：895.3629,实测值:895.3655。
实施例47-epi-巴卡亭iii-13-(s-乙酰胺基甲基-n-叔丁氧羰基-l-半胱氨酸)-酯(i-3)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成49.8毫克s-乙酰胺基甲基-n-叔丁氧羰基-l-半胱氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末32.6毫克，收率56％。1hnmr(400mhz,cdcl3)δ8.12(d,j＝7.62hz,2h),7.65(t,j＝7.40hz,1h),7.53(t,j＝7.68hz,2h),6.84(s,1h),6.49(s,1h),6.20(t,j＝9.60hz,1h),5.77(d,j＝7.35hz,1h),5.54(d,j＝8.20hz,1h),4.96(dd,j＝3.33,9.01hz,1h),4.76(d,j＝11.70hz,1h),4.62–4.53(m,1h),4.49(dd,j＝6.48,13.97hz,1h),4.42(d,j＝8.69hz,1h),4.38–4.29(m,2h),3.94(d,j＝7.37hz,1h),3.72(dd,j＝3.63,11.39hz,1h),3.16–3.08(m,1h),3.07–2.96(m,1h),2.49(s,3h),2.43–2.24(m,4h),2.22(s,3h),2.02(s,3h),1.94(s,1h),1.90(s,3h),1.67(s,3h),1.50(s,9h),1.23(s,3h),1.17(s,3h)；13cnmr(126mhz,cdcl3)δ206.79,171.48,170.71,169.83,168.85,166.58,139.62,133.31,132.71,129.59,128.76,128.26,82.18,81.49,80.45,78.77,77.63,77.05,75.23,74.85,71.14,57.06,53.70,42.18,41.75,39.90,35.55,34.78,33.60,27.83,25.47,22.69,21.87,20.79,20.38,15.73,14.32；hrms(esi):c42h56o15n2nas(m+na)+计算值：883.3294,实测值:883.3279。
实施例57-epi-巴卡亭iii-13-(n-叔丁氧羰基-n(咪唑)-(4-甲基苯磺酰基)-l-组氨酸)-酯(i-4)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成69.76毫克n-叔丁氧羰基-n(咪唑)-(4-甲基苯磺酰基)-l-组氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末12.1毫克，收率18％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.79hz,2h),7.94(s,1h),7.81(d,j＝8.08hz,2h),7.65(t,j＝7.25hz,1h),7.53(t,j＝7.69hz,2h),7.38(d,j＝8.09hz,2h),7.12(s,1h),6.79(s,1h),6.15(t,j＝8.65hz,1h),5.76(d,j＝7.41hz,1h),5.67(d,j＝8.37hz,1h),4.93(dd,j＝3.38,8.46hz,1h),4.70–4.58(m,2h),4.38(q,j＝8.84hz,2h),3.95(d,j＝7.41hz,1h),3.70(dd,j＝3.30,11.74hz,1h),3.17(dd,j＝4.62,14.75hz,1h),3.03(dd,j＝6.62,15.03hz,1h),2.50(s,3h),2.46(s,3h),2.37–2.24(m,4h),2.22(s,3h),1.79(s,1h),1.78(s,3h),1.67(s,3h),1.44(s,9h),1.18(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ207.20,172.19,171.38,169.33,167.05,155.32,146.52,140.07,139.48,136.55,134.67,133.82,133.18,130.53,130.04,129.23,128.78,127.35,115.07,82.71,82.07,80.23,79.06,78.14,77.66,75.56,75.12,70.87,57.64,52.86,42.48,40.37,36.30,35.40,30.21,28.28,25.98,22.63,21.74,20.91,16.12,15.37；hrms(esi):c49h60o16n3s(m+h)+计算值：978.3689,实测值:978.3682。
实施例67-epi-巴卡亭iii-13-(1-n-叔丁氧羰基-3-吖丁啶羧酸)-酯(i-5)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成34.3毫克1-n-叔丁氧羰基-3-吖丁啶羧酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末29.5毫克，收率56.2％。1hnmr(400mhz,cdcl3)δ8.08(d,j＝7.56hz,2h),7.65(t,j＝7.42hz,1h),7.52(t,j＝7.61hz,2h),6.82(s,1h),6.23(t,j＝8.61hz,1h),5.76(d,j＝7.28hz,1h),4.94(dd,j＝3.24,9.09hz,1h),4.62(d,j＝11.64hz,1h),4.44–4.32(m,2h),4.25–4.11(m,4h),3.94(d,j＝7.23hz,1h),3.71(dd,j＝4.09,11.44hz,1h),3.49–3.37(m,1h),2.36(s,4h),2.31–2.23(m,3h),2.22(s,3h),1.86(s,4h),1.66(s,3h),1.47(s,9h),1.22(s,3h),1.17(s,3h)；13cnmr(126mhz,cdcl3)δ207.11,171.90,171.46,169.35,167.04,155.97,139.95,133.86,133.44,129.99,129.22,128.76,82.63,82.27,80.29,79.08,78.12,77.57,75.55,75.18,70.55,57.59,42.58,40.38,36.00,35.34,32.10,28.35,25.98,22.31,20.98,20.90,16.16,15.06；hrms(esi):c40h51o14nna(m+na)+7计算值：92.3202,实测值:792.3192。
实施例77-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-苯丙氨酸)-酯(i-6)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成45.2毫克n-叔丁氧羰基-l-苯丙氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末39.6毫克，收率69.6％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.74hz,2h),7.65(t,j＝7.30hz,1h),7.52(t,j＝7.58hz,2h),7.34(dt,j＝6.79,12.94hz,3h),7.22(d,j＝7.42hz,2h),6.79(s,1h),6.14(t,j＝8.44hz,1h),5.75(d,j＝7.51hz,1h),5.00(d,j＝8.38hz,1h),4.93(dd,j＝2.82,8.61hz,1h),4.70(d,j＝11.65hz,1h),4.61(q,j＝7.47hz,1h),4.37(q,j＝8.65hz,2h),3.92(d,j＝7.16hz,1h),3.70(dd,j＝4.28,11.03hz,1h),3.21(dd,j＝6.26,13.79hz,1h),3.13–3.00(m,1h),2.39(s,3h),2.37–2.23(m,4h),2.21(s,3h),1.86(s,1h),1.69(s,3h),1.66(s,3h),1.43(s,9h),1.20(s,3h),1.15(s,3h)；13cnmr(126mhz,cdcl3)δ207.25,172.08,169.37,167.03,155.05,140.00,135.42,133.78,133.12,130.07,129.36,129.28,129.16,128.90,128.73,127.40,82.73,81.97,80.30,79.21,78.12,77.60,75.61,75.20,70.93,57.57,54.65,42.53,40.37,38.39,36.29,35.33,28.31,28.26,25.97,22.48,21.02,20.92,16.16,15.10；hrms(esi):c45h55o14nna(m+na)+计算值：856.3515,实测值:856.3503。
实施例87-epi-巴卡亭iii-13-(n-叔丁氧羰基-甘氨酸)-酯(i-7)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成29.8毫克n-叔丁氧羰基-甘氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末42.8毫克，收率84.4％。1hnmr(400mhz,cdcl3)δ8.07(d,j＝7.66hz,2h),7.63(t,j＝7.35hz,1h),7.51(t,j＝7.62hz,2h),6.81(s,1h),6.20(t,j＝8.56hz,1h),5.74(d,j＝7.36hz,1h),5.22(t,j＝3.87hz,1h),4.91(dd,1h),4.70(d,1h),4.43–4.29(m,2h),4.06(dd,1h),3.93(s,2h),3.74–3.61(m,1h),2.42(s,3h),2.40–2.23(m,4h),2.20(s,3h),1.97(s,1h),1.85(s,3h),1.65(s,3h),1.47(s,9h),1.17(s,3h),1.14(s,3h)；13cnmr(126mhz,cdcl3)δ207.18,171.77,169.94,169.38,167.00,155.74,139.97,133.83,133.45,130.00,129.24,128.76,82.63,82.11,80.42,79.01,78.18,77.56,75.59,75.20,70.67,57.59,42.50,40.43,36.05,35.30,28.31,25.98,22.58,20.89,20.84,16.18,15.12；hrms(esi):c38h49o14nna(m+na)+计算值：766.3045,实测值:766.3027。
实施例97-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-异亮氨酸)-酯(i-8)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成39.4毫克n-叔丁氧羰基-l-异亮氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末38.2毫克，收率70.0％。1hnmr(400mhz,cdcl3)δ8.11(d,j＝7.43hz,2h),7.65(t,j＝7.47hz,1h),7.53(t,j＝7.58hz,2h),6.85(s,1h),6.21(t,j＝8.62hz,1h),5.77(d,j＝7.15hz,1h),5.06(d,j＝9.29hz,1h),4.94(dd,j＝3.21,8.65hz,1h),4.72(d,j＝11.49hz,1h),4.45–4.31(m,3h),3.99(d,j＝7.31hz,1h),3.72(dd,j＝4.49,11.14hz,1h),2.47(s,3h),2.44–2.24(m,5h),2.21(s,3h),2.07–2.00(m,1h),1.90(s,3h),1.68(s,3h),1.48(s,9h),1.27(s,2h),1.21(s,3h),1.17(s,3h),1.08(d,j＝6.70hz,3h),0.94(t,j＝7.27hz,3h)；13cnmr(126mhz,cdcl3)δ206.76,171.68,171.66,168.92,166.64,155.44,139.47,133.36,132.96,129.60,128.78,128.32,82.28,81.67,79.68,78.71,77.71,77.18,75.20,74.72,70.16,58.21,57.22,42.10,39.95,36.98,35.94,34.95,27.87,25.48,23.41,22.16,20.50,20.44,15.72,15.65,15.00,11.00；hrms(esi):c42h57o14nna(m+na)+计算值：822.3671,实测值:822.3654。
实施例107-epi-巴卡亭iii-13-((s)-2,6-二叔丁氧羰基氨基己酸)-酯(i-9)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成59.1毫克(s)-2,6-二叔丁氧羰基氨基己酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末19.8毫克，收率31.4％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.48hz,2h),7.65(t,j＝7.49hz,1h),7.52(t,j＝7.56hz,2h),6.82(s,1h),6.20(d,j＝9.25hz,1h),5.76(d,j＝7.51hz,1h),5.24(d,j＝7.93hz,1h),4.93(dd,j＝3.32hz,1h),4.77–4.62(m,2h),4.46–4.26(m,3h),3.97(d,j＝7.41hz,1h),3.71(dd,1h),3.24–3.05(m,2h),2.45(s,3h),2.42–2.25(m,4h),2.21(s,3h),2.05–1.93(m,1h),1.87(s,3h),1.86–1.71(m,4h),1.67(s,3h),1.56(dd,j＝7.24,14.70hz,2h),1.47(s,9h),1.46(s,9h),1.19(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ206.64,171.97,171.56,168.84,166.54,155.64,155.09,139.33,133.30,133.01,129.54,128.74,128.25,82.20,81.62,79.68,78.54,77.62,77.14,75.06,74.65,70.18,57.14,42.01,39.87,39.40,35.76,34.90,31.45,29.20,27.94,27.84,27.51,25.49,22.16,22.05,20.37,15.62,14.93；hrms(esi):c47h66o16n2na(m+na)+计算值：937.4305,实测值:937.4293。
实施例117-epi-巴卡亭iii-13-((s)-1-叔丁氧羰基-吡咯烷-3-甲酸)-酯(i-10)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成36.64毫克(s)-1-叔丁氧羰基-吡咯烷-3-甲酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末18.0毫克，收率33.7％。1hnmr(400mhz,cdcl3)δ8.09(d,j＝7.81hz,2h),7.64(t,j＝7.43hz,1h),7.51(t,j＝7.77hz,2h),6.82(s,1h),6.19(t,j＝8.86hz,1h),5.76(d,j＝7.45hz,1h),4.95(dd,j＝3.23,8.85hz,1h),4.64(d,j＝10.42hz,1h),4.46–4.32(m,2h),3.96(d,j＝7.31hz,1h),3.85–3.61(m,3h),3.61–3.50(m,1h),3.48–3.36(m,1h),3.17–3.04(m,1h),2.41(s,3h),2.39–2.23(m,5h),2.21(s,3h),1.91–1.80(m,5h),1.66(s,3h),1.48(s,9h),1.21(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ207.15,172.49,171.44,169.35,167.02,154.11,140.26,140.16,133.82,133.36,130.01,129.27,128.73,82.68,82.27,79.94,79.12,78.14,77.60,75.54,75.22,70.21,57.59,48.50,48.30,45.16,44.78,43.44,42.58,40.37,36.06,35.34,29.71,28.47,25.98,22.43,21.02,20.90,16.14,15.06；hrms(esi):c41h53o14nna(m+na)+计算值：806.3358,实测值:806.3350。
实施例127-epi-巴卡亭iii-13-(n-叔丁氧羰基-o-苄基-l-丝氨酸)-酯(i-11)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成50.3毫克n-叔丁氧羰基-o-苄基-l-丝氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末35.7毫克，收率60.6％。1hnmr(400mhz,cdcl3)δ8.09(d,j＝7.71hz,2h),7.65(t,j＝7.35hz,1h),7.53(t,j＝7.56hz,2h),7.40–7.30(m,4h),7.29(s,1h),6.82(s,1h),6.24(t,j＝8.51hz,1h),5.77(d,j＝7.35hz,1h),5.52(d,j＝9.06hz,1h),4.94(dd,j＝3.54,8.82hz,1h),4.66(d,j＝11.54hz,1h),4.58(d,j＝11.89hz,1h),4.56–4.46(m,2h),4.45–4.35(m,2h),4.01(dd,j＝3.00,9.31hz,1h),3.97(d,j＝7.33hz,1h),3.80(dd,j＝3.25,9.27hz,1h),3.72(dd,j＝3.89,11.38hz,1h),2.40(s,3h),2.39–2.24(m,4h),2.22(s,3h),1.76(s,1h),1.68(s,6h),1.48(s,9h),1.20(s,3h),1.16(s,3h)；13cnmr(101mhz,cdcl3)δ207.15,171.87,170.00,169.38,167.06,155.53,140.16,136.91,133.83,133.33,130.03,129.22,128.78,128.54,128.06,127.74,82.70,82.20,80.42,79.02,78.15,77.68,75.52,75.13,73.44,70.76,69.74,57.62,54.16,42.46,40.37,36.33,35.42,28.33,26.04,22.65,20.90,16.13,15.05；hrms(esi):c46h57o15nna(m+na)+计算值：886.3620,实测值:886.3608。
实施例137-epi-巴卡亭iii-13-(n-叔丁氧羰基-s-苄基-l-半胱氨酸)-酯(i-12)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成53.0毫克n-叔丁氧羰基-s-苄基-l-半胱氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末39.5毫克，收率65.8％。1hnmr(400mhz,cdcl3)δ8.09(d,j＝7.05hz,2h),7.64(tt,j＝1.29,6.99hz,1h),7.51(t,j＝7.71hz,2h),7.41–7.30(m,5h),6.82(s,1h),6.20–6.11(m,1h),5.75(d,j＝7.36hz,1h),5.31(d,j＝6.56hz,1h),4.94(dd,j＝3.42,9.01hz,1h),4.68(d,j＝11.64hz,1h),4.59–4.51(m,1h),4.41–4.35(m,2h),3.96(d,j＝7.42hz,1h),3.79(s,2h),3.72(ddd,j＝1.65,4.58,11.63hz,1h),2.97(dd,j＝4.76,13.33hz,1h),2.85(dd,j＝6.53,13.33hz,1h),2.42(s,3h),2.37–2.27(m,4h),2.22(s,3h),1.85(s,3h),1.72(s,1h),1.67(s,3h),1.49(s,9h),1.19(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ207.18,171.97,170.68,169.38,167.04,155.15,139.83,137.21,133.82,133.38,130.04,129.21,128.89,128.79,128.76,127.51,82.73,82.10,80.53,79.11,78.11,77.64,75.57,75.14,71.20,57.63,53.34,42.49,40.37,36.99,36.28,35.39,33.43,28.33,26.00,22.61,20.91,16.15,15.45；hrms(esi):c46h57o14nnas(m+na)+计算值：902.3392,实测值:902.3379。
实施例147-epi-巴卡亭iii-13-(n-叔丁氧羰基-5-环己基-l-谷氨酸)-酯(i-13)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成56.16毫克n-叔丁氧羰基-5-环己基-l-谷氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末46.8毫克，收率76.4％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.46hz,2h),7.64(t,j＝7.39hz,1h),7.52(t,j＝7.69hz,2h),6.83(s,1h),6.18(t,j＝8.61hz,1h),5.75(d,j＝7.41hz,1h),5.21(d,j＝8.72hz,1h),4.94(dd,j＝3.02,8.62hz,1h),4.86–4.76(m,1h),4.70(d,j＝11.65hz,1h),4.46–4.33(m,3h),3.97(d,j＝7.35hz,1h),3.71(dd,j＝3.86,11.40hz,1h),2.49(s,3h),2.47–2.23(m,8h),2.21(s,3h),2.01–1.94(m,1h),1.90(s,3h),1.82–1.69(m,4h),1.67(s,3h),1.61–1.51(m,1h),1.46(s,9h),1.43–1.25(m,5h),1.20(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ207.20,172.19,171.86,169.38,167.03,155.48,139.80,133.80,133.43,130.05,129.23,128.76,82.73,81.98,80.30,79.09,78.13,77.63,75.59,75.19,73.26,70.97,57.63,53.17,42.54,40.35,36.24,35.36,31.60,31.57,30.52,28.30,27.40,25.96,25.32,23.75,22.56,20.96,20.90,16.14,15.39；hrms(esi):c47h63o16nna(m+na)+计算值：920.4039,实测值:920.4015。
实施例157-epi-巴卡亭iii-13-(n-叔丁氧羰基-o-叔丁基-l-酪氨酸)-酯(i-14)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成57.5毫克n-叔丁氧羰基-o-叔丁基-l-酪氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末22.2毫克，收率35.9％。1hnmr(400mhz,cdcl3)δ8.11(d,j＝7.76hz,2h),7.65(t,j＝7.45hz,1h),7.54(t,j＝7.59hz,2h),7.11(d,j＝8.20hz,2h),6.98(d,j＝8.07hz,2h),6.81(s,1h),6.13(t,j＝8.25hz,1h),5.76(d,j＝7.45hz,1h),5.01–4.89(m,2h),4.69(d,j＝11.29hz,1h),4.59(q,j＝7.61hz,1h),4.38(q,j＝8.67hz,2h),3.95(d,j＝7.16hz,1h),3.71(dd,j＝3.89,11.45hz,1h),3.20(dd,j＝6.30,14.25hz,1h),2.99(dd,j＝7.69,13.76hz,1h),2.41(s,3h),2.39–2.26(m,4h),2.22(s,3h),1.67(s,7h),1.43(s,9h),1.36(s,9h),1.21(s,3h),1.16(s,3h)；13cnmr(101mhz,cdcl3)δ207.22,172.15,172.08,169.30,167.06,155.05,154.70,139.92,133.75,133.23,130.06,129.61,129.25,128.78,124.41,82.72,82.01,80.24,79.23,78.64,78.10,77.62,75.60,75.17,70.98,57.59,54.60,42.53,40.38,37.75,36.31,35.36,28.80,28.27,25.98,22.51,20.99,20.89,16.15,15.33；hrms(esi):c49h63o15nna(m+na)+计算值：928.4090,实测值:928.4082。
实施例167-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-3,4-二氯苯丙氨酸)-酯(i-15)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成57.0毫克n-叔丁氧羰基-l-3,4-二氯苯丙氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末17.3毫克，收率28.1％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.68hz,2h),7.66(t,j＝7.45hz,1h),7.53(t,j＝7.71hz,2h),7.43(d,j＝8.23hz,1h),7.34(d,j＝1.70hz,1h),7.08(dd,j＝1.72,8.18hz,1h),6.82(s,1h),6.18(t,j＝8.86hz,1h),5.77(d,j＝7.43hz,1h),5.04(d,j＝8.40hz,1h),4.95(dd,j＝3.26,8.97hz,1h),4.66(d,j＝11.61hz,1h),4.63–4.56(m,1h),4.45–4.33(m,2h),3.97(d,j＝7.33hz,1h),3.72(dd,j＝3.61,11.34hz,1h),3.27(dd,j＝5.35,13.97hz,1h),2.94(dd,j＝8.06,14.30hz,1h),2.43(s,3h),2.40–2.25(m,4h),2.23(s,3h),1.84(s,3h),1.79(s,1h),1.68(s,3h),1.43(s,9h),1.22(s,3h),1.18(s,3h)；13cnmr(101mhz,cdcl3)δ207.03,171.95,171.53,169.36,167.09,154.98,139.43,135.78,133.85,133.67,132.76,131.58,131.19,130.68,130.05,129.18,128.77,128.44,82.70,82.16,80.64,79.11,78.06,77.63,77.23,75.54,75.10,71.31,57.66,54.10,42.57,40.37,37.57,36.23,35.39,28.21,26.04,22.63,20.90,16.10,15.39；hrms(esi):c45h53o14ncl2na(m+na)+计算值：924.2735,实测值:924.2709。
实施例177-epi-巴卡亭iii-13-(n-叔丁氧羰基-3-环己氧甲酰基-l-天冬氨酸)-酯(i-16)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成57.0毫克n-叔丁氧羰基-3-环己氧甲酰基-l-天冬氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末33.0毫克，收率54.7％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.48hz,2h),7.65(t,j＝7.37hz,1h),7.53(t,j＝7.56hz,2h),6.82(s,1h),6.17(t,j＝8.63hz,1h),5.76(d,j＝7.27hz,1h),5.56(d,j＝8.85hz,1h),4.94(dd,j＝3.43,8.76hz,1h),4.79(td,j＝4.06,9.06hz,1h),4.70–4.58(m,2h),4.44–4.34(m,2h),3.97(d,j＝7.36hz,1h),3.71(dd,j＝3.54,11.45hz,1h),3.06–2.90(m,2h),2.45(s,3h),2.41–2.24(m,4h),2.22(s,4h),1.90–1.81(m,5h),1.69(s,3h),1.48(s,9h),1.45–1.24(m,8h),1.20(s,3h),1.16(s,3h)；13cnmr(101mhz,cdcl3)δ207.11,171.92,170.50,169.99,169.38,167.04,155.39,139.81,133.82,133.37,130.05,129.21,128.77,82.73,82.19,80.54,79.12,78.09,77.65,77.23,75.54,75.11,74.22,71.23,57.63,50.20,42.52,40.35,37.11,36.43,35.39,31.52,28.31,25.97,25.19,23.72,23.69,22.53,20.93,20.90,16.12,15.17；hrms(esi):c46h62o16n(m+h)+计算值：884.4063,实测值:884.4082。
实施例187-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-2-苯基甘氨酸)-酯(i-17)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成42.8毫克n-叔丁氧羰基-l-2-苯基甘氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末11.7毫克，收率20.9％。1hnmr(400mhz,cdcl3)δ8.12(d,j＝7.76hz,2h),7.66(t,j＝7.52hz,1h),7.54(t,j＝7.56hz,2h),7.41(s,5h),6.70(s,1h),6.10(t,j＝8.71hz,1h),5.74(d,j＝7.50hz,1h),5.59(d,j＝7.62hz,1h),5.30(d,j＝7.20hz,1h),4.94(dd,j＝3.32,8.86hz,1h),4.62(d,j＝11.59hz,1h),4.45–4.31(m,2h),3.88(d,j＝7.37hz,1h),3.67(dd,j＝4.00,10.91hz,1h),2.53(s,3h),2.41–2.24(m,4h),2.16(s,3h),1.78(s,1h),1.68(s,3h),1.65(s,3h),1.47(s,9h),1.17(s,3h),1.13(s,3h)；13cnmr(126mhz,cdcl3)δ206.71,171.36,170.46,168.79,166.57,154.33,139.91,135.33,133.31,132.50,129.57,128.75,128.26,126.84,82.18,81.52,79.95,78.69,77.51,77.10,75.07,74.69,70.65,57.64,57.08,41.94,39.87,35.95,34.85,27.82,25.49,22.28,20.47,20.31,15.61,14.24；hrms(esi):c44h53o14nna(m+na)+计算值：842.3358,实测值:842.3353。
实施例197-epi-巴卡亭iii-13-(n-叔丁氧羰基-o-苄基-l-苏氨酸)-酯(i-18)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成42.8毫克n-叔丁氧羰基-o-苄基-l-苏氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末52.7毫克，收率38.4％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.99hz,2h),7.65(t,j＝7.37hz,1h),7.52(t,j＝7.70hz,2h),7.36–7.29(m,3h),7.27(s,2h),6.79(s,1h),6.22–6.14(m,1h),5.77(d,j＝7.33hz,1h),5.43(d,j＝9.49hz,1h),4.95(dd,j＝3.30,9.00hz,1h),4.65(t,j＝11.92hz,2h),4.43–4.33(m,4h),4.32–4.23(m,1h),3.96(d,j＝7.41hz,1h),3.71(dd,j＝3.34,11.31hz,1h),2.43(s,3h),2.40–2.25(m,4h),2.22(s,3h),1.78(s,3h),1.74(s,1h),1.68(s,3h),1.49(s,9h),1.39(d,j＝6.20hz,3h),1.21(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ206.63,171.41,169.85,168.84,166.56,155.66,139.57,137.09,133.30,132.73,129.54,128.74,128.27,127.95,127.75,127.27,126.78,82.21,81.74,79.80,78.59,77.63,77.18,75.04,74.66,73.74,70.29,69.66,58.21,57.10,41.99,39.85,35.97,34.92,27.82,25.50,22.12,20.42,20.38,15.64,14.72；hrms(esi):c47h59o15nna(m+na)+计算值：900.3777,实测值:900.3750。
实施例207-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-丙氨酸)-酯(i-19)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成32.2毫克n-叔丁氧羰基-l-丙氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末41.6毫克，收率80.5％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.89hz,2h),7.65(t,j＝7.43hz,1h),7.52(t,j＝7.68hz,2h),6.82(s,1h),6.20(t,j＝8.83hz,1h),5.76(d,j＝7.47hz,1h),5.16(d,j＝7.79hz,1h),4.94(dd,j＝3.37,8.74hz,1h),4.68(d,j＝11.56hz,1h),4.45–4.31(m,3h),3.98(d,j＝7.44hz,1h),3.75–3.65(m,1h),2.47(s,3h),2.41–2.24(m,4h),2.21(s,3h),1.87(s,3h),1.82(s,1h),1.67(s,3h),1.53(d,j＝7.26hz,3h),1.48(s,9h),1.19(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ206.63,172.52,171.52,168.83,166.55,154.66,139.41,133.31,133.02,129.53,128.74,128.26,82.19,81.62,79.71,78.50,77.63,77.14,75.05,74.65,70.07,57.16,48.88,41.99,39.90,35.65,34.89,27.83,25.53,22.05,20.38,20.32,18.27,15.61,14.86；hrms(esi):c39h51o14nna(m+na)+计算值：780.3202,实测值:780.3188。
实施例217-epi-巴卡亭iii-13-(n-叔丁氧羰基-n’-苄氧羰基-l-赖氨酸)-酯(i-20)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成64.8毫克n-叔丁氧羰基-n’-苄氧羰基-l-赖氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末28.6毫克，收率44.2％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.59hz,2h),7.65(t,j＝7.65hz,1h),7.53(t,j＝7.65hz,2h),7.41–7.30(m,5h),6.83(s,1h),6.19(t,j＝8.36hz,1h),5.76(d,j＝7.07hz,1h),5.23(d,j＝8.65hz,1h),5.17–5.05(m,2h),4.99–4.84(m,2h),4.66(d,j＝11.47hz,1h),4.47–4.26(m,3h),3.97(d,j＝7.55hz,1h),3.71(dd,j＝2.98,11.01hz,1h),3.24(dp,j＝6.58,13.46hz,2h),2.44(s,3h),2.39–2.24(m,4h),2.21(s,3h),2.09–1.93(m,1h),1.87(s,3h),1.81(s,1h),1.74–1.70(m,1h),1.67(s,3h),1.65–1.53(m,2h),1.47(s,11h),1.20(s,3h),1.17(s,3h)；13cnmr(126mhz,cdcl3)δ206.62,171.95,171.56,168.85,166.54,156.04,136.03,133.31,133.05,129.54,128.74,128.26,128.03,127.64,82.18,81.64,79.75,78.53,77.62,77.14,75.05,74.64,70.22,66.22,57.15,42.01,39.98,39.88,35.73,34.90,31.54,29.06,27.83,25.50,22.16,22.04,20.38,15.60,14.95；hrms(esi):c50h64016n2na(m+na)+计算值：971.4148,实测值:971.4125。
实施例227-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-环己基甘氨酸)-酯(i-21)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成43.8毫克n-叔丁氧羰基-l-环己基甘氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末36.8毫克，收率65.3％。1hnmr(400mhz,cdcl3)δ8.10(d,j＝7.77hz,2h),7.65(t,j＝7.31hz,1h),7.53(t,j＝7.71hz,2h),6.85(s,1h),6.19(t,j＝8.91hz,1h),5.77(d,j＝7.30hz,1h),5.10(d,j＝9.18hz,1h),4.95(dd,j＝3.42,8.81hz,1h),4.75(d,j＝11.59hz,1h),4.39(q,j＝8.66hz,2h),4.31(dd,j＝3.83,9.06hz,1h),3.99(d,j＝7.35hz,1h),3.72(dd,j＝3.77,11.99hz,1h),2.46(s,3h),2.42–2.25(m,4h),2.21(s,3h),2.01–1.89(m,4h),1.88–1.72(m,4h),1.68(s,3h),1.54(d,j＝12.71hz,1h),1.48(s,9h),1.41–1.22(m,4h),1.20(s,3h),1.19–1.07(m,5h)；13cnmr(126mhz,cdcl3)δ206.70,171.58,168.87,166.58,155.33,139.47,133.30,132.93,129.55,128.73,128.27,82.23,81.60,79.59,78.63,77.66,77.13,75.15,74.68,70.05,57.96,57.16,42.03,40.23,39.92,35.88,34.88,29.78,27.83,26.81,25.61,25.42,25.28,25.19,22.12,20.42,20.37,15.66,14.90；hrms(esi):c44h59o14nna(m+na)+计算值：848.3828,实测值:848.3803。
实施例237-epi-巴卡亭iii-13-((s)-n3-叔丁氧羰基-3-((s)-5,6-二氟-2,3-二氢-1h-茚-1-基)-丙酸)-酯(i-22)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成17.02毫克(s)-n3-叔丁氧羰基-3-((s)-5,6-二氟-2,3-二氢-1h-茚-1-基)-丙酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末8.9毫克，收率14.3％。1hnmr(400mhz,cdcl3)δ8.13(dd,j＝1.23,8.30hz,2h),7.70–7.63(m,1h),7.55(t,j＝7.69hz,2h),7.03(ddd,j＝7.47,10.25,22.25hz,2h),6.84(s,1h),6.26(td,j＝1.18,8.92hz,1h),5.79(d,j＝7.36hz,1h),5.02–4.92(m,2h),4.70(d,j＝11.53hz,1h),4.48–4.34(m,2h),4.24–4.13(m,1h),3.98(d,j＝7.24hz,1h),3.72(ddd,j＝1.68,4.70,11.29hz,1h),3.49(s,1h),3.08–2.95(m,1h),2.90–2.77(m,1h),2.69(d,j＝5.09hz,2h),2.42–2.32(m,6h),2.32–2.20(m,5h),2.08–1.95(m,1h),1.89(d,j＝1.24hz,3h),1.79(s,1h),1.68(s,3h),1.44(s,9h),1.23(s,3h),1.18(s,3h)；13cnmr(101mhz,cdcl3)δ207.20,171.71,169.35,167.18,140.16,133.91,133.36,130.05,129.16,128.81,82.62,82.19,79.18,78.21,77.60,75.61,75.20,69.87,57.62,42.58,40.46,36.02,35.34,30.62,28.30,25.96,22.40,20.96,20.90,16.20,15.17；hrms(esi):c48h57o14nf2na(m+na)+计算值：932.3639,实测值:932.3622。
实施例247-epi-巴卡亭iii-13-(2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-酰基甲酸)-酯(i-23)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成30毫克2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-酰基甲酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末22毫克，收率38％。1hnmr(400mhz,cdcl3)δ8.53(d,j＝5.87hz,1h),8.17(d,j＝8.89hz,2h),8.12(dd,j＝1.10,8.21hz,2h),8.04(d,j＝5.38hz,1h),7.83(d,j＝2.27hz,1h),7.68–7.62(m,1h),7.53(t,j＝7.71hz,2h),7.26(d,j＝8.89hz,2h),7.13(dd,j＝2.53,5.51hz,1h),6.88(s,1h),6.43(t,j＝8.61hz,1h),5.79(d,j＝7.32hz,1h),4.95(dd,j＝3.18,8.98hz,1h),4.78(d,j＝11.55hz,1h),4.46–4.31(m,2h),4.01(d,j＝7.43hz,1h),3.72(dd,j＝3.09,11.62hz,1h),3.50(d,j＝6.91hz,1h),3.05(d,j＝5.13hz,3h),2.45(t,j＝9.14hz,2h),2.34–2.30(m,4h),2.24(s,3h),2.00(d,j＝1.27hz,3h),1.83(s,1h),1.68(s,3h),1.21(s,6h)；13cnmr(126mhz,cdcl3)δ206.68,183.33,171.88,168.84,166.72,163.82,163.64,162.33,159.74,152.34,149.80,138.71,133.63,133.44,132.39,129.62,128.71,128.55,128.34,119.88,115.26,111.09,82.23,81.40,78.74,77.71,77.10,75.19,74.75,71.37,57.27,42.23,40.11,35.43,34.87,25.77,25.64,22.26,21.72,20.45,15.69,14.90,13.69；hrms(esi):c46h48o15n2na(m+na)+计算值：891.2947,实测值:891.2925。
实施例257-epi-巴卡亭iii-13-(2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸)-酯(i-24)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成54.3毫克2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末11毫克，收率18.2％。1hnmr(400mhz,cdcl3)δ7.82(d,j＝7.96hz,2h),7.76(d,j＝7.89hz,2h),7.53–7.42(m,3h),7.33–7.28(m,4h),6.86(d,j＝7.62hz,2h),6.82(s,1h),6.30(t,j＝8.84hz,1h),5.68(d,j＝7.70hz,1h),4.91(d,j＝7.36hz,1h),4.75(d,j＝11.12hz,1h),4.30(q,j＝8.72hz,2h),3.87(d,j＝7.56hz,1h),3.70(d,j＝7.03hz,1h),2.45(s,3h),2.41–2.24(m,3h),2.22(s,3h),2.09–2.03(m,1h),1.85(d,j＝4.78hz,6h),1.79–1.72(m,4h),1.65(s,3h),1.25(s,3h),1.16(s,3h)；13cnmr(126mhz,cdcl3)δ206.73,193.44,173.37,171.81,168.83,166.53,158.36,139.72,137.94,135.38,133.42,132.73,131.64,130.53,130.31,129.21,128.50,128.14,127.99,115.93,82.25,81.41,79.12,79.00,77.52,76.98,75.29,74.88,70.59,57.03,42.20,39.91,35.14,34.79,27.15,25.48,22.46,21.61,20.83,20.43,15.72,14.28；hrms(esi):c48h51o14clna(m+na)+计算值：909.2860,实测值:909.2846。
实施例267-epi-巴卡亭iii-13-(n-苄氧羰基-l-丙氨酸)-酯(i-25)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成47.5毫克n-苄氧羰基-l-丙氨酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末64.9毫克，收率96.2％。1hnmr(400mhz,cdcl3)δ8.09(d,j＝7.72hz,2h),7.64(t,j＝7.30hz,1h),7.52(t,j＝7.62hz,2h),7.37(d,j＝3.97hz,6h),6.82(s,1h),6.19(t,j＝8.34hz,1h),5.76(d,j＝7.33hz,1h),5.52(d,j＝8.59hz,1h),5.22–5.06(m,3h),4.93(dd,j＝3.10,8.75hz,1h),4.67(d,j＝11.41hz,1h),4.51–4.31(m,3h),3.97(d,j＝7.90hz,1h),3.70(dd,j＝4.24,11.46hz,1h),2.45(s,2h),2.39–2.24(m,4h),2.21(s,3h),1.97(s,1h),1.87(s,3h),1.66(s,3h),1.55(d,j＝7.22hz,2h),1.18(s,3h),1.15(s,3h)；13cnmr(126mhz,cdcl3)δ207.10,172.72,171.96,169.35,167.05,155.70,139.73,136.05,133.84,133.65,130.06,129.22,128.78,128.60,128.53,128.32,128.09,82.70,82.17,78.99,78.12,77.65,75.55,75.13,70.85,67.13,57.68,49.86,42.51,40.40,36.20,35.40,26.04,22.57,20.89,20.83,18.77,16.11,15.37；hrms(esi):c42h49o14nna(m+na)+计算值：814.3045,实测值:814.3038。
实施例277-epi-巴卡亭iii-13-(对氯苯氧乙酸)-酯(i-26)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成31.76毫克对氯苯氧乙酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末53.1毫克，收率82.5％。1hnmr(400mhz,cdcl3)δ8.08(d,j＝7.60hz,2h),7.65(t,j＝7.37hz,1h),7.51(t,j＝7.72hz,2h),7.30(d,j＝9.10hz,2h),6.89(d,j＝8.90hz,2h),6.81(s,1h),6.21(t,j＝8.62hz,1h),5.75(d,j＝7.42hz,1h),4.95(dd,j＝3.29,9.04hz,1h),4.73(s,2h),4.69(d,j＝11.55hz,1h),4.44–4.31(m,2h),3.94(d,j＝7.34hz,1h),3.72(dd,j＝1.40,4.62hz,1h),2.43(s,3h),2.40–2.21(m,5h),2.20(s,3h),1.76(s,3h),1.66(s,3h),1.18(s,3h),1.15(s,3h)；13cnmr(126mhz,cdcl3)δ207.09,171.73,169.34,168.15,167.01,156.05,139.71,133.85,133.58,130.00,129.72,129.25,128.74,127.26,115.85,82.63,82.14,79.16,78.10,77.55,75.59,75.21,71.07,65.69,57.59,42.55,40.47,36.15,35.32,25.98,22.21,20.90,20.87,16.15,15.05；hrms(esi):c39h43o13clna(m+na)+计算值：777.2284,实测值:777.2268。
实施例287-epi-巴卡亭iii-13-(对甲氧基苯乙酸)-酯(i-27)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成35.4毫克对甲氧基苯乙酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末59.6毫克，收率95.2％。1hnmr(400mhz,cdcl3)δ8.09(d,j＝7.77hz,2h),7.65(t,j＝7.43hz,1h),7.52(t,j＝7.68hz,2h),7.24(d,j＝8.50hz,2h),6.91(d,j＝8.50hz,2h),6.81(s,1h),6.15(t,j＝8.64hz,1h),5.76(d,j＝7.38hz,1h),4.96(dd,j＝3.03,8.99hz,1h),4.69(d,j＝11.57hz,1h),4.39(q,j＝8.68hz,2h),3.96(d,j＝7.33hz,1h),3.83(s,3h),3.75–3.65(m,3h),2.41(s,3h),2.39–2.25(m,4h),2.20(s,3h),1.83(s,1h),1.79(s,3h),1.66(s,3h),1.18(s,3h),1.15(s,3h)；13cnmr(126mhz,cdcl3)δ207.26,171.65,171.28,169.35,167.00,159.00,140.69,133.79,133.00,130.17,130.02,129.34,128.72,125.10,114.21,82.66,82.20,79.21,78.20,77.60,75.61,75.28,70.06,57.57,55.31,42.50,40.54,40.43,36.23,35.36,25.93,22.48,20.95,20.87,16.19,15.18；hrms(esi):c40h46o13na(m+na)+计算值：757.2831,实测值:757.2821。
实施例297-epi-巴卡亭iii-13-(4-氯-2-吡啶甲酸)-酯(i-28)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成33.6毫克4-氯-2-吡啶甲酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末43.6毫克，收率70.5％。1hnmr(400mhz,cdcl3)δ8.68(d,j＝5.19hz,1h),8.19(d,j＝1.45hz,1h),8.08(d,j＝7.80hz,2h),7.61(t,j＝7.31hz,1h),7.57(dd,j＝1.74,5.17hz,1h),7.48(t,j＝7.68hz,2h),6.88(s,1h),6.39(t,j＝8.77hz,1h),5.79(d,j＝7.43hz,1h),4.96(dd,j＝3.24,8.97hz,1h),4.78(d,j＝11.57hz,1h),4.43–4.33(m,2h),4.02(d,j＝7.41hz,1h),3.73(dd,j＝3.66,11.47hz,1h),2.52–2.41(m,2h),2.41(s,3h),2.39–2.25(m,2h),2.22(s,3h),2.01(s,3h),1.97(s,1h),1.68(s,3h),1.27(s,3h),1.19(s,3h)；13cnmr(126mhz,cdcl3)δ206.83,171.94,168.91,166.58,163.66,150.16,148.66,145.01,139.83,133.30,132.92,129.57,128.84,128.25,127.03,125.60,82.29,81.51,78.88,77.71,77.17,75.21,74.88,71.29,57.18,42.20,39.98,35.96,34.92,25.67,21.72,20.68,20.46,15.72,14.84；hrms(esi):c37h40o12nclna(m+na)+计算值：748.2131,实测值:748.2125。
实施例307-epi-巴卡亭iii-13-(环丙甲酸)-酯(i-29)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成16.96微升环丙甲酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末46.7毫克，收率83.7％。1hnmr(400mhz,cdcl3)δ8.10(s,2h),7.65(t,j＝7.51hz,1h),7.52(t,j＝7.72hz,2h),6.85(s,1h),6.09(t,j＝8.67hz,1h),5.77(d,j＝7.37hz,1h),4.97(dd,j＝3.34,9.10hz,1h),4.70(d,j＝11.60hz,1h),4.46–4.34(m,2h),3.99(d,j＝7.35hz,1h),3.72(dd,j＝4.38,11.15hz,1h),2.46(s,3h),2.43–2.24(m,5h),2.22(s,3h),1.93(s,3h),1.67(s,4h),1.19(s,3h),1.16(s,3h),1.14–0.95(m,4h)；13cnmr(101mhz,cdcl3)δ206.87,173.95,171.27,168.96,166.57,140.43,133.32,132.49,129.59,128.88,128.27,82.21,81.71,78.68,77.85,77.19,76.80,75.10,74.76,69.40,57.15,42.01,39.99,35.89,34.93,25.55,22.05,20.47,20.40,15.73,14.81,12.38,8.77,8.61；hrms(esi):c35h42o12na(m+na)+计算值：677.2568,实测值:677.2550。
实施例317-epi-巴卡亭iii-13-(6-(2,4-二硝基苯硫基)己酸)-酯(i-30)的制备
将42.5毫克n-叔丁氧羰基-l-蛋氨酸替换成32毫克6-(2,4-二硝基苯硫基)己酸，其余所需原料、试剂及制备方法同实施例2，得白色粉末24毫克，收率31.9％。1hnmr(400mhz,cdcl3)δ9.11(d,j＝2.35hz,1h),8.40(dd,j＝2.53,8.92hz,1h),8.10(d,j＝7.82hz,2h),7.64(t,j＝7.10hz,1h),7.60–7.47(m,3h),6.83(s,1h),6.19(t,j＝8.96hz,1h),5.76(d,j＝7.30hz,1h),4.96(dd,j＝3.40,8.87hz,1h),4.64(d,j＝11.29hz,1h),4.47–4.31(m,2h),3.97(d,j＝7.43hz,1h),3.71(dd,j＝3.49,11.56hz,1h),3.10(t,j＝7.19hz,2h),2.51(dq,j＝7.23,13.67hz,2h),2.43(s,3h),2.39–2.25(m,4h),2.22(s,3h),1.94–1.85(m,5h),1.85–1.77(m,2h),1.75(s,1h),1.69–1.67(m,2h),1.64(s,3h),1.21(s,3h),1.17(s,3h)；13cnmr(126mhz,cdcl3)δ206.70,172.03,171.17,168.91,166.59,146.54,144.43,143.36,139.99,133.36,132.78,129.57,128.83,128.27,126.67,126.32,121.37,82.17,81.82,78.71,77.76,77.15,75.13,74.76,69.12,57.16,42.07,40.01,35.61,34.92,33.63,31.95,27.91,26.71,25.52,23.87,22.10,20.45,20.42,15.72,14.79；hrms(esi):c43h50o16n2nas(m+na)+计算值：905.2773,实测值:905.2785。
实施例327-epi-巴卡亭iii-13-(l-蛋氨酸)-酯(i-31)的制备
将55.5毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)投入到25毫升圆底烧瓶中，加入1毫升乙腈，冰水浴，搅拌下再滴加1毫升甲酸，逐渐恢复室温。反应液加过量饱和碳酸氢钠水溶液至ph为中性，用二氯甲烷萃取三次，共80毫升，有机相合并，水洗，饱和食盐水洗，无水硫酸钠干燥。减压蒸馏除去二氯甲烷，残余物厚硅胶制备板分离，展开剂为二氯甲烷/甲醇＝40/1，得到7-epi-巴卡亭iii-13-(l-蛋氨酸)-酯(i-31)，33毫克，为白色粉末，收率67.8％。1hnmr(400mhz,cdcl3)δ8.08(d,j＝7.84hz,2h),7.64(t,j＝7.44hz,1h),7.56–7.46(m,2h),6.82(s,1h),6.18(t,j＝8.88hz,1h),5.75(d,j＝7.39hz,1h),4.94(dd,j＝3.19,8.86hz,1h),4.67(s,1h),4.38(q,j＝8.64hz,2h),3.96(d,j＝7.32hz,1h),3.85–3.61(m,2h),2.73(hept,j＝6.48hz,2h),2.45(s,3h),2.38–2.23(m,4h),2.20(s,3h),2.17(s,3h),2.06–1.92(m,2h),1.91(s,1h),1.88(s,3h),1.87–1.77(m,2h),1.66(s,3h),1.20(s,3h),1.15(s,3h)；13cnmr(126mhz,cdcl3)δ207.15,171.80,169.35,166.97,140.01,133.81,133.40,130.01,129.28,128.74,82.68,82.12,79.09,78.11,77.62,75.55,75.18,70.40,57.62,42.54,40.35,36.31,35.36,30.39,25.98,22.65,20.93,20.88,16.11,15.54,15.49；hrms(esi):c36h47o12nnas(m+na)+计算值：740.2711,实测值:740.2722。
实施例337-epi-巴卡亭iii-13-(3-环己氧甲酰基-l-天冬氨酸)-酯(i-32)的制备
将55.5毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)替换成150毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-3-环己氧甲酰基-l-天冬氨酸)-酯(i-16)，其余所需原料、试剂及制备方法同实施例32，得白色粉末88毫克，收率66.2％。1hnmr(500mhz,cdcl3)δ8.07(d,j＝7.31hz,2h),7.63(t,j＝7.41hz,1h),7.50(t,j＝7.72hz,2h),6.80(s,1h),6.16(t,j＝8.45hz,1h),5.74(d,j＝7.41hz,1h),4.92(dd,j＝3.26,9.01hz,1h),4.81(tt,j＝3.77,9.04hz,1h),4.60(d,j＝11.56hz,1h),4.36(q,j＝8.71hz,2h),3.96(d,j＝7.35hz,1h),3.88(s,1h),3.69(dd,j＝3.49,11.07hz,1h),2.93(d,j＝16.24hz,1h),2.71(dd,j＝7.87,15.86hz,1h),2.40(s,3h),2.37–2.21(m,5h),2.20(s,3h),1.84(s,3h),1.78–1.68(m,3h),1.65(s,3h),1.60–1.51(m,1h),1.50–1.25(m,8h),1.18(s,3h),1.14(s,3h)；13cnmr(126mhz,cdcl3)δ207.09,171.76,170.24,169.33,166.97,139.96,133.80,133.40,130.00,129.27,128.73,82.71,82.23,79.04,78.11,77.64,75.49,75.13,73.90,70.68,57.64,42.50,40.35,36.29,35.40,31.62,31.59,26.01,25.25,23.75,22.47,20.89,20.85,16.08,15.33；hrms(esi):c41h53o14nna(m+na)+计算值：806.3358,实测值:806.3375。
实施例347-epi-巴卡亭iii-13-(s-苄基-l-半胱氨酸)-酯(i-33)的制备
将55.5毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)替换成180毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-s-苄基-l-半胱氨酸)-酯(i-12)，其余所需原料、试剂及制备方法同实施例32，得白色粉末94毫克，收率58.9％。1hnmr(400mhz,cdcl3)δ8.07(d,j＝7.72hz,2h),7.63(t,j＝7.30hz,1h),7.50(t,j＝7.63hz,2h),7.40–7.29(m,5h),6.82(s,1h),6.11(t,j＝8.63hz,1h),5.75(d,j＝7.37hz,1h),4.93(dd,j＝3.23,8.99hz,1h),4.66(d,j＝9.91hz,1h),4.37(q,j＝8.70hz,2h),3.95(d,j＝7.28hz,1h),3.80(s,2h),3.72(d,j＝3.47hz,1h),3.63(s,1h),2.94(d,j＝13.59hz,1h),2.68(dd,j＝8.17,13.08hz,1h),2.43–2.29(m,6h),2.29–2.15(m,5h),1.97(s,2h),1.83(s,3h),1.66(s,3h),1.17(s,3h),1.15(s,3h)；13cnmr(126mhz,cdcl3)δ207.14,171.66,169.35,166.95,139.92,137.53,133.80,133.39,130.00,129.26,128.87,128.78,128.74,127.47,82.69,82.20,79.06,78.12,77.62,75.55,75.14,70.78,57.64,42.50,40.36,36.96,36.33,35.40,26.01,22.50,20.89,16.13,15.47；hrms(esi):c41h49o12nnas(m+na)+计算值：802.2868,实测值:802.2849。
实施例35
本发明化合物利用发光法细胞活力检测试剂盒(ctg)对人类非小细胞肺癌细胞(a549)、人类乳腺癌细胞(mcf7)、人类结肠癌细胞(hct116)、人类肝癌细胞(hepg2)、人类卵巢癌细胞(skov3)、人类前列腺癌细胞(du145)百分抑制率的测定
表1.7-epi-巴卡亭iii衍生物对肿瘤细胞抑制率
注：上表中“nt”表示未检测。