本發(fā)明涉及藥物化學和藥物治療領(lǐng)域，更具體涉7-epi-巴卡亭iii衍生物、其的制備方法、藥物組合物和用途。該類化合物可用于治療癌癥，特別是前列腺癌(prostatecarcinoma)、非小細胞肺癌、乳腺癌、結(jié)腸癌、肝癌、卵巢癌等。
背景技術(shù)：
微管蛋白(tubulin)作為胞質(zhì)蛋白，幾乎存在于所有的真核細胞生物中，其分為α，β，γ三種類型，主要功能是聚合形成圓柱形微管纖維從而構(gòu)成微管形成紡錘體參與到細胞的有絲分裂當中1,2。抑制或促進微管的形成從而阻滯細胞的有絲分裂，是目前治療癌癥3和老年黃斑變性4的重要手段。此外，一水合谷氨酸鈉尿酸鹽(痛風的主要致病因子)會通過與微管蛋白相關(guān)的通路機制導致中性粒細胞對促炎蛋白的釋放。所以，抑制微管蛋白的聚合對于痛風以及痛風性關(guān)節(jié)炎的治療可以起到很好的效果5。
因此，針對該靶點開發(fā)的藥物有多方面的應(yīng)用。除了抑制細胞有絲分裂起到抗腫瘤(藥物名稱：taxol)的作用3，對微管蛋白目前還開發(fā)有針對預防和治療感染(藥物名稱：griseofulvin)6、心血管系統(tǒng)疾病(藥物名稱：7-hexanoyltaxol)7-9、眼部疾病(藥物名稱：fosbretabulindisodium)4以及自身免疫性疾病(藥物名稱：brentuximabvedotin)5的藥物。
巴卡亭iii屬于二萜類紫杉烷家族的一個成員10,11，具有以下結(jié)構(gòu)：
其目前主要作為紫杉醇的母體，用于半合成紫杉醇。紫杉醇結(jié)構(gòu)如下：
紫杉醇目前是臨床上非常重要的抗腫瘤制劑，具有很好的抗卵巢癌、乳腺癌、肺癌等活性，其作用于細胞內(nèi)的微管蛋白，促進微管蛋白的聚合，起到穩(wěn)定微管的作用，從而影響細胞的有絲分裂并最終導致細胞死亡12。全世界的很多研究機構(gòu)對其化學性質(zhì)以及構(gòu)效關(guān)系做過很深入的研究。
盡管紫杉醇的抗腫瘤活性非常好，但是卻有一些臨床應(yīng)用問題亟待解決，其中包括水溶性差、多藥耐藥性、嚴重的劑量限制性毒性，后者導致諸如骨髓抑制、外周感覺神經(jīng)病變、過敏反應(yīng)等。這些副作用的產(chǎn)生主要是由于紫杉醇的水溶性較差而采用聚氧乙烯蓖麻油(cremophorel)這種常用的抗腫瘤制劑的溶媒造成的。
因此對于紫杉烷的改造成為了解決上述問題的重要途徑，這也吸引了世界上大批的藥物研究者投入到這項具有前景的研究工作中。其中對于紫杉烷13位側(cè)鏈的構(gòu)效關(guān)系更是進行過系統(tǒng)的研究，o.n.zefirova13、w.-s.fang14等對此做過詳細的綜述。但是，這些研究大多數(shù)是在紫杉醇原有的13位的側(cè)鏈α-羥基-β-氨基酸這類結(jié)構(gòu)上進行的。天然的α-氨基酸作為生物體中最重要的一類分子，一方面構(gòu)建了蛋白質(zhì)的骨架，另一方面廣泛的參與到生物體代謝當中。除此之外，天然的α-氨基酸的各種化學特性，通過蛋白質(zhì)的特定構(gòu)象可以形成特有的活性位點，從而決定了蛋白質(zhì)的諸多功能和生物體的新陳代謝規(guī)律，因此基于氨基酸結(jié)構(gòu)的藥物研究以及具有氨基酸結(jié)構(gòu)的藥物分子也有諸多的報道15。
紫杉醇在生理條件下會自發(fā)的轉(zhuǎn)化成7-epi-紫杉醇16。細胞色素p450(cyp450)是紫杉醇在體內(nèi)的主要代謝酶17，與此同時7-β-羥基又是cyp450識別的主要基團。而7-epi-紫杉醇在體內(nèi)對于cyp450具有很好的穩(wěn)定性以及抑制了紫杉醇的主要代謝產(chǎn)物6-α-紫杉醇的生成18,19。所以這一點對于改善紫杉醇的代謝具有一定的指導作用。同時，制備7-epi-紫杉烷的衍生物對于發(fā)現(xiàn)代謝更好，毒性更低的紫杉烷抗腫瘤制劑具有十分重要的意義。
綜上所述，通過將天然氨基酸這類生物體中常見的活性分子與改造后的紫杉烷母核進行整合，設(shè)計并合成新的紫杉烷衍生物，對開發(fā)新型的治療和預防癌癥、感染、抗心血管系統(tǒng)疾病、眼部疾病、自身免疫性疾病的藥物具有十分重要的意義。
參考文獻
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技術(shù)實現(xiàn)要素：
發(fā)明人在前期對紫杉烷的研究中發(fā)現(xiàn)了一種對紫杉烷母核7位羥基進行構(gòu)型翻轉(zhuǎn)的新方法(申請?zhí)枺篶n201510418981.6)。翻轉(zhuǎn)后的母核的化學性質(zhì)不同于巴卡亭iii，可以不對該母核的其他活性位點進行保護而直接與羧酸在13位羥基進行酯化反應(yīng)。在此基礎(chǔ)上，發(fā)明人運用合理的藥物設(shè)計方法，針對7位羥基翻轉(zhuǎn)后的母核，與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，獲得了一類全新的7-epi-巴卡亭iii衍生物，并測試了此類化合物在體外細胞水平的抗腫瘤活性，結(jié)果證明本專利化合物具有較強的抗腫瘤活性，其中部分化合物對前列腺腫瘤的抑制具有很強選擇性，由此完成了本發(fā)明。
本發(fā)明的一個目的是提供一種通式1所示的7-epi-巴卡亭iii衍生物或其藥學上可接受的鹽。
本發(fā)明的另一個目的是提供本發(fā)明所述7-epi-巴卡亭iii衍生物的制備方法。
本發(fā)明的又一目的涉及一種藥物組合物，其包含本發(fā)明所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽。
本發(fā)明的又一目的涉及本發(fā)明所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽，或包含所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽的藥物組合物在制備治療癌癥的藥物中的應(yīng)用。
本發(fā)明的再一目的涉及本發(fā)明所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽，或包含所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽的藥物組合物在治療癌癥中的應(yīng)用。
根據(jù)本發(fā)明的一個方面，提供如下通式1的7-epi-巴卡亭iii衍生物，或其藥學上可接受的鹽：
其中：
r1、r2和r4各自獨立地選自羥基、巰基、氨基、鹵素、氰基、異氰基、硝基、羧基、c1-c10烷基酰氧基或c6-c12芳基酰氧基；優(yōu)選選自羥基、巰基、氨基、鹵素、氰基、異氰基、硝基、羧基、c1-c6烷基酰氧基和c6-c10芳基酰氧基；最優(yōu)選選自羥基、乙酰氧基和苯甲酰氧基；
r3為α氨基酸、吖丁啶羧酸、氨基己酸、吡咯烷-3-甲酸、3-氨基-3-(2,3-二氫-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-?；姿?、2-(4-(4-氯苯甲?；?苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、環(huán)丙甲酸或6-苯硫基己酸中的一個羧酸基團參與酯化后的殘基，并且該殘基經(jīng)由所述羧酸基團的羰基與氧相連；
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-(2,3-二氫-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?；?苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、環(huán)丙甲酸或6-基苯硫基己酸中的一個或多個氫原子任選地被選自叔丁氧羰基、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、鹵素原子、苯基、c3-c8環(huán)烷基、叔丁基、環(huán)己基氧、芐氧羰基和硝基中的一個或多個取代基取代；
所述α氨基酸選自丙氨酸、纈氨酸、亮氨酸、異亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、絲氨酸、蘇氨酸、半胱氨酸、酪氨酸、天冬氨酸、谷氨酸、賴氨酸、精氨酸、組氨酸、谷氨酰胺和天冬酰胺。
進一步優(yōu)選地，r3選自2-叔丁氧基酰胺基-4-甲硫基丁?；?、2-叔丁氧基酰胺基-3-(1h-吲哚-3-基)-丙?；?-乙酰胺基硫基-2-叔丁氧基酰胺基丙?；?-叔丁氧基酰胺基-3-[1-(甲苯-4-磺?；?-1h-咪唑-4-基]-丙?；?、n-叔丁氧基?；苟∴?3-基?；?-叔丁氧基酰胺基-3-苯基-丙?；?、叔丁氧基?；?乙?；?-叔丁氧基?；?3-甲基-戊?；?、2,6-二叔丁氧基酰基-己?；-叔丁氧基?；?吡咯烷-3-基-甲酰基、3-芐氧基-2-叔丁氧基酰胺基-丙?；?、3-芐基硫基-2-叔丁氧基酰胺基-丙酰基、5-環(huán)己基氧酰基2-叔丁氧基酰胺基-4-環(huán)己基氧?；□；?、2-叔丁氧基酰胺基-3-(4-叔丁氧酰基-苯基)-丙?；?、2-叔丁氧基酰胺基-3-(3,4-二氯-苯基)-丙?；?-叔丁氧基酰胺基-3-環(huán)己基氧?；；?、叔丁氧基酰胺基-苯基-乙?；?-芐基氧-2-叔丁氧酰胺基-丁酰基、2-叔丁氧基酰胺基-丙酰基、6-芐基氧酰胺基-2-叔丁氧酰胺基-己酰基、叔丁氧基酰胺基-環(huán)己基-乙?；?、3-叔丁氧基酰胺基-3-(5,6-二氟-2,3-二氫-1h-茚-1-基)-丙?；?、[4-(2-甲基氨基?；?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?；?-芐基氧酰胺基-丙?；?4-氯-苯氧基)-乙?；?、(4-甲氧基-苯基)-乙?；?-氯-2-吡啶?；h(huán)丙烷基?；?、6-(2,4-二硝基-苯硫基)-己?；?、2-氨基-4-甲硫基丁?；?-氨基-3-環(huán)己基氧?；；?-芐基硫基-2-氨基-丙?；?/p>
更具體而言，r3選自如下取代基：
優(yōu)選地，所述通式1所示的7-epi-巴卡亭iii衍生物具有如下通式2所示的結(jié)構(gòu)：
其中，r3的定義如上所述。
進一步優(yōu)選地，所述通式1所示的7-epi-巴卡亭iii衍生物選自下列化合物：
本發(fā)明中，所述酸中的一個羧基參與酯化后的殘基指的是所述酸中的一個羧基脫去羥基后得到的殘基，并且所述殘基經(jīng)由該羧基的羰基與7-epi-巴卡亭iii母核上的氧連接。
根據(jù)本發(fā)明的7-epi-巴卡亭iii衍生物或其藥學可接受的鹽可以存在為其溶劑合物的形式，例如水合物或溶劑合物，并可能存在多種晶型。
根據(jù)本發(fā)明的另一個方面，提供了一種制備本發(fā)明所述的7-epi-巴卡亭iii衍生物的方法，其包括如下步驟：
其中，r1，r2，r3和r4的定義與前述相同，
使中間體m與化合物b經(jīng)酯化反應(yīng)得到通式1所示的化合物。
所述化合物b選自α氨基酸、吖丁啶羧酸、氨基己酸、吡咯烷-3-甲酸、3-氨基-3-(2,3-二氫-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-?；姿?、2-(4-(4-氯苯甲?；?苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、環(huán)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-(2,3-二氫-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-?；姿?、2-(4-(4-氯苯甲?；?苯氧基)-2-甲基丙酸、苯氧乙酸、吡啶甲酸、環(huán)丙甲酸或6-基苯硫基己酸中的一個或多個氫原子可以任選地被選自叔丁氧羰基、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、鹵素原子、苯基、c3-c8環(huán)烷基、叔丁基、環(huán)己基氧、芐氧羰基和硝基中的一個或多個取代基取代。
進一步優(yōu)選地，所述化合物b可以選自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?；?-l-組氨酸、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-異亮氨酸、(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-芐基-l-絲氨酸、n-叔丁氧羰基-s-芐基-l-半胱氨酸、n-叔丁氧羰基-5-環(huán)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-環(huán)己氧甲?；?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-芐基-l-蘇氨酸、n-叔丁氧羰基-l-丙氨酸、n-叔丁氧羰基-n’-芐氧羰基-l-賴氨酸、n-叔丁氧羰基-l-環(huán)己基甘氨酸、(s)-n3-叔丁氧羰基-3-((s)-5,6-二氟-2,3-二氫-1h-茚-1-基)-丙酸、2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-?；姿?、2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基丙酸、n-芐氧羰基-l-丙氨酸、對氯苯氧乙酸、對甲氧基苯乙酸、4-氯-2-吡啶甲酸、環(huán)丙甲酸、6-(2,4-二硝基苯硫基)己酸、l-蛋氨酸、3-環(huán)己氧甲?；?l-天冬氨酸和s-芐基-l-半胱氨酸。
特別地，所述反應(yīng)如下進行：將中間體m與化合物b投入到溶劑(如無水甲苯)中，氮氣置換并保護反應(yīng)體系，再在氮氣保護下依次投入3倍當量的碳酸二(2-吡啶)酯(dpc)和1倍當量的4-二甲氨基吡啶(dmap)，于78℃～100℃下加熱反應(yīng)得到通式1所示的化合物。
優(yōu)選地，所述方法進一步包括如下步驟：
其中，r1，r2和r4的定義與前述相同。
使化合物a的7位羥基進行構(gòu)型翻轉(zhuǎn)反應(yīng)得到中間體m。
特別地，反應(yīng)如下進行：
將化合物a投入到溶劑dmf中攪拌至溶清，再加入1倍當量氧化銀，100℃下加熱攪拌反應(yīng)。
根據(jù)本發(fā)明的又一方面，提供了一種藥物組合物，其包含本發(fā)明所述的7-epi-巴卡亭iii衍生物或其藥學上可接受的鹽。優(yōu)選地，所述組合物進一步包含藥學上可接受的輔料。
優(yōu)選地，基于所述藥物組合物的總重量，所述通式1所示的7-epi-巴卡亭iii衍生物或其藥學上可接受的鹽的重量比為0.001-99.9％，更優(yōu)選0.1-90％。
本發(fā)明的又一方面提供了本發(fā)明所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽，或包含所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽的藥物組合物在制備治療癌癥的藥物中的應(yīng)用。
本發(fā)明的再一方面涉及一種治療癌癥的方法，所述方法包括給需要該治療的對象服用治療有效量的根據(jù)本發(fā)明所述的7-epi-巴卡亭iii衍生物或其藥學可接受的鹽，或包含所述7-epi-巴卡亭iii衍生物或其藥學可接受的鹽的藥物組合物。
所述癌癥可以選自肺癌(尤其是非小細胞肺癌)、乳腺癌、結(jié)腸癌、肝癌、卵巢癌和前列腺癌。
具體實施方式
在以下的實施例中將進一步舉例說明本發(fā)明。這些實施例僅用于說明本發(fā)明，但不以任何方式限制本發(fā)明。實施例中的所有參數(shù)以及其余的說明，除另有說明外，都是以質(zhì)量(克)為單位。
試劑與儀器
制備本發(fā)明化合物的試劑均來源于商業(yè)購買。重要中間體來源于實驗室制備，制備方法見實施例1。eyelan1001型旋轉(zhuǎn)蒸發(fā)儀(東京理化器械株式會社)；agilent1260型高效液相色譜儀(美國agilent公司)；brukeravance-400或500型核磁共振儀(美國bruker公司)；lcq-deca型質(zhì)譜儀(德國finnigan公司，esi-ms)；watersq-tofultima型質(zhì)譜儀(美國waters公司，hr-esi-ms)。
實施例17-epi-巴卡亭iii的制備
將2.00克巴卡亭iii投入到250毫升圓底燒瓶中，加入150毫升dmf中攪拌至溶清，再加入2.37克氧化銀，氮氣保護，100℃加熱攪拌3小時。待反應(yīng)液冷卻至室溫后，反應(yīng)液加300毫升水稀釋，用乙酸乙酯萃取三次，共600毫升，有機相合并，水洗，飽和食鹽水洗，無水硫酸鈉干燥。減壓蒸餾除去乙酸乙酯，殘余物柱層析分離，洗脫劑為二氯甲烷/甲醇＝60/1，得到7-epi-巴卡亭iii，2.34克，為白色粉末，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)+計算值：609.2306,實測值:609/2309。
實施例27-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)的制備
將40毫克7-epi-巴卡亭iii投入到25毫升圓底燒瓶中，加入3毫升無水甲苯，氮氣保護，攪拌，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攝氏度攪拌反應(yīng)6小時。反應(yīng)加40毫升水淬滅，用乙酸乙酯萃取三次，共80毫升，有機相合并，水洗，飽和食鹽水洗，無水硫酸鈉干燥。減壓蒸餾除去乙酸乙酯，殘余物柱層析分離，洗脫劑為二氯甲烷/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，為白色粉末，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)+計算值：840.3235,實測值:840.3225。
實施例37-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-色氨酸)-酯(i-2)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成51.9毫克n-叔丁氧羰基-l-色氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：895.3629,實測值:895.3655。
實施例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)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成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、試劑及制備方法同實施例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)+計算值：883.3294,實測值:883.3279。
實施例57-epi-巴卡亭iii-13-(n-叔丁氧羰基-n(咪唑)-(4-甲基苯磺酰基)-l-組氨酸)-酯(i-4)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成69.76毫克n-叔丁氧羰基-n(咪唑)-(4-甲基苯磺?；?-l-組氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：978.3689,實測值:978.3682。
實施例67-epi-巴卡亭iii-13-(1-n-叔丁氧羰基-3-吖丁啶羧酸)-酯(i-5)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成34.3毫克1-n-叔丁氧羰基-3-吖丁啶羧酸，其余所需原料、試劑及制備方法同實施例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計算值：92.3202,實測值:792.3192。
實施例77-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-苯丙氨酸)-酯(i-6)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成45.2毫克n-叔丁氧羰基-l-苯丙氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：856.3515,實測值:856.3503。
實施例87-epi-巴卡亭iii-13-(n-叔丁氧羰基-甘氨酸)-酯(i-7)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成29.8毫克n-叔丁氧羰基-甘氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：766.3045,實測值:766.3027。
實施例97-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-異亮氨酸)-酯(i-8)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成39.4毫克n-叔丁氧羰基-l-異亮氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：822.3671,實測值:822.3654。
實施例107-epi-巴卡亭iii-13-((s)-2,6-二叔丁氧羰基氨基己酸)-酯(i-9)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成59.1毫克(s)-2,6-二叔丁氧羰基氨基己酸，其余所需原料、試劑及制備方法同實施例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)+計算值：937.4305,實測值:937.4293。
實施例117-epi-巴卡亭iii-13-((s)-1-叔丁氧羰基-吡咯烷-3-甲酸)-酯(i-10)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成36.64毫克(s)-1-叔丁氧羰基-吡咯烷-3-甲酸，其余所需原料、試劑及制備方法同實施例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)+計算值：806.3358,實測值:806.3350。
實施例127-epi-巴卡亭iii-13-(n-叔丁氧羰基-o-芐基-l-絲氨酸)-酯(i-11)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成50.3毫克n-叔丁氧羰基-o-芐基-l-絲氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：886.3620,實測值:886.3608。
實施例137-epi-巴卡亭iii-13-(n-叔丁氧羰基-s-芐基-l-半胱氨酸)-酯(i-12)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成53.0毫克n-叔丁氧羰基-s-芐基-l-半胱氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：902.3392,實測值:902.3379。
實施例147-epi-巴卡亭iii-13-(n-叔丁氧羰基-5-環(huán)己基-l-谷氨酸)-酯(i-13)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成56.16毫克n-叔丁氧羰基-5-環(huán)己基-l-谷氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：920.4039,實測值:920.4015。
實施例157-epi-巴卡亭iii-13-(n-叔丁氧羰基-o-叔丁基-l-酪氨酸)-酯(i-14)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成57.5毫克n-叔丁氧羰基-o-叔丁基-l-酪氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：928.4090,實測值:928.4082。
實施例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)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成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、試劑及制備方法同實施例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)+計算值：924.2735,實測值:924.2709。
實施例177-epi-巴卡亭iii-13-(n-叔丁氧羰基-3-環(huán)己氧甲酰基-l-天冬氨酸)-酯(i-16)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成57.0毫克n-叔丁氧羰基-3-環(huán)己氧甲?；?l-天冬氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：884.4063,實測值:884.4082。
實施例187-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-2-苯基甘氨酸)-酯(i-17)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成42.8毫克n-叔丁氧羰基-l-2-苯基甘氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：842.3358,實測值:842.3353。
實施例197-epi-巴卡亭iii-13-(n-叔丁氧羰基-o-芐基-l-蘇氨酸)-酯(i-18)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成42.8毫克n-叔丁氧羰基-o-芐基-l-蘇氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：900.3777,實測值:900.3750。
實施例207-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-丙氨酸)-酯(i-19)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成32.2毫克n-叔丁氧羰基-l-丙氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：780.3202,實測值:780.3188。
實施例217-epi-巴卡亭iii-13-(n-叔丁氧羰基-n’-芐氧羰基-l-賴氨酸)-酯(i-20)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成64.8毫克n-叔丁氧羰基-n’-芐氧羰基-l-賴氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：971.4148,實測值:971.4125。
實施例227-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-環(huán)己基甘氨酸)-酯(i-21)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成43.8毫克n-叔丁氧羰基-l-環(huán)己基甘氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：848.3828,實測值:848.3803。
實施例237-epi-巴卡亭iii-13-((s)-n3-叔丁氧羰基-3-((s)-5,6-二氟-2,3-二氫-1h-茚-1-基)-丙酸)-酯(i-22)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成17.02毫克(s)-n3-叔丁氧羰基-3-((s)-5,6-二氟-2,3-二氫-1h-茚-1-基)-丙酸，其余所需原料、試劑及制備方法同實施例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)+計算值：932.3639,實測值:932.3622。
實施例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-?；姿?-酯(i-23)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成30毫克2-(4-(2-(n-甲基-甲酰胺基)-4-吡啶氧基)苯基)-2-?；姿幔溆嗨柙?、試劑及制備方法同實施例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)+計算值：891.2947,實測值:891.2925。
實施例257-epi-巴卡亭iii-13-(2-(4-(4-氯苯甲?；?苯氧基)-2-甲基丙酸)-酯(i-24)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成54.3毫克2-(4-(4-氯苯甲?；?苯氧基)-2-甲基丙酸，其余所需原料、試劑及制備方法同實施例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)+計算值：909.2860,實測值:909.2846。
實施例267-epi-巴卡亭iii-13-(n-芐氧羰基-l-丙氨酸)-酯(i-25)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成47.5毫克n-芐氧羰基-l-丙氨酸，其余所需原料、試劑及制備方法同實施例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)+計算值：814.3045,實測值:814.3038。
實施例277-epi-巴卡亭iii-13-(對氯苯氧乙酸)-酯(i-26)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成31.76毫克對氯苯氧乙酸，其余所需原料、試劑及制備方法同實施例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)+計算值：777.2284,實測值:777.2268。
實施例287-epi-巴卡亭iii-13-(對甲氧基苯乙酸)-酯(i-27)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成35.4毫克對甲氧基苯乙酸，其余所需原料、試劑及制備方法同實施例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)+計算值：757.2831,實測值:757.2821。
實施例297-epi-巴卡亭iii-13-(4-氯-2-吡啶甲酸)-酯(i-28)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成33.6毫克4-氯-2-吡啶甲酸，其余所需原料、試劑及制備方法同實施例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)+計算值：748.2131,實測值:748.2125。
實施例307-epi-巴卡亭iii-13-(環(huán)丙甲酸)-酯(i-29)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成16.96微升環(huán)丙甲酸，其余所需原料、試劑及制備方法同實施例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)+計算值：677.2568,實測值:677.2550。
實施例317-epi-巴卡亭iii-13-(6-(2,4-二硝基苯硫基)己酸)-酯(i-30)的制備
將42.5毫克n-叔丁氧羰基-l-蛋氨酸替換成32毫克6-(2,4-二硝基苯硫基)己酸，其余所需原料、試劑及制備方法同實施例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)+計算值：905.2773,實測值:905.2785。
實施例327-epi-巴卡亭iii-13-(l-蛋氨酸)-酯(i-31)的制備
將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毫升圓底燒瓶中，加入1毫升乙腈，冰水浴，攪拌下再滴加1毫升甲酸，逐漸恢復室溫。反應(yīng)液加過量飽和碳酸氫鈉水溶液至ph為中性，用二氯甲烷萃取三次，共80毫升，有機相合并，水洗，飽和食鹽水洗，無水硫酸鈉干燥。減壓蒸餾除去二氯甲烷，殘余物厚硅膠制備板分離，展開劑為二氯甲烷/甲醇＝40/1，得到7-epi-巴卡亭iii-13-(l-蛋氨酸)-酯(i-31)，33毫克，為白色粉末，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)+計算值：740.2711,實測值:740.2722。
實施例337-epi-巴卡亭iii-13-(3-環(huán)己氧甲酰基-l-天冬氨酸)-酯(i-32)的制備
將55.5毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)替換成150毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-3-環(huán)己氧甲?；?l-天冬氨酸)-酯(i-16)，其余所需原料、試劑及制備方法同實施例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)+計算值：806.3358,實測值:806.3375。
實施例347-epi-巴卡亭iii-13-(s-芐基-l-半胱氨酸)-酯(i-33)的制備
將55.5毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-l-蛋氨酸)-酯(i-1)替換成180毫克7-epi-巴卡亭iii-13-(n-叔丁氧羰基-s-芐基-l-半胱氨酸)-酯(i-12)，其余所需原料、試劑及制備方法同實施例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)+計算值：802.2868,實測值:802.2849。
實施例35
本發(fā)明化合物利用發(fā)光法細胞活力檢測試劑盒(ctg)對人類非小細胞肺癌細胞(a549)、人類乳腺癌細胞(mcf7)、人類結(jié)腸癌細胞(hct116)、人類肝癌細胞(hepg2)、人類卵巢癌細胞(skov3)、人類前列腺癌細胞(du145)百分抑制率的測定
表1.7-epi-巴卡亭iii衍生物對腫瘤細胞抑制率
注：上表中“nt”表示未檢測。