雪胆甲素衍生物及其制备方法和应用

IPC分类号 : C07J3/00I,C07J7/00I,A61P35/00I

申请号

CN201911107026.5

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专利类型: 发明专利
法律状态: 有权
申请日: 2019-11-13
公开号: 110818759B
公开日: 2020-02-21
主分类号: C07J3/00I
专利权人: 山东省医学科学院药物研究所(山东省抗衰老研究中心、山东省新技术制药研究所)

专利摘要

本发明公开了雪胆甲素衍生物其制备方法及其医药用途。具体公开了一类雪胆甲素衍生物(I)，通过雪胆甲素的2，3和16位羟基及其17位支链进行结构修饰，SRB法筛选结果表明：雪胆甲素2，3，16位羟基被乙酰基保护，17位支链被2‑肼基吡啶、2，4，6三氯苯肼或2，4‑二硝基苯肼取代并且羟基被乙酰基保护后的化合物具有较强的抑制肿瘤细胞(SKOV3，LOVO，HT‑29，HepG2，MCF‑7)增殖的作用。同时，这些衍生物对正常细胞HEK293的IC50增大，提示该类衍生物相对于雪胆甲素，其选择性增强。

权利要求

1.通式(I)所示化合物,

其中R1为

R2为R3为R4为

2.如权利要求1所述的化合物,其特征在于，所述

R1为，R2为R3为R4为

3.权利要求1所述的化合物的制备方法，其特征在于，包括如下步骤：

R1为

4.权利要求1-2任一所述的化合物在制备预防和/或治疗癌症药物中的应用。

5.权利要求1-2任一所述的化合物在制备预防和/或治疗卵巢腺癌药物中的应用。

6.权利要求1-2任一所述的化合物在制备抑制SKOV 3细胞增殖药物中的应用。

说明书

技术领域

本发明涉及药物化学领域，具体涉及一类雪胆甲素衍生物其制备方法、并包含其药物制剂及其医药用途。

背景技术

雪胆甲素(cucurbitacin IIa，Cu IIa)是葫芦烷型四环三萜类化合物，主要存在于葫芦科雪胆属植物雪胆(Hemsleya)的块根中，具有抗肿瘤、抑菌、抗胃溃疡、清热、解毒、止痛、抗HIV等作用，广泛用于治疗肝炎、冠心病和气管炎等疾病。雪胆甲素结构式如下：

雪胆甲素(cucurbitacin IIa，Cu IIa)主要存在于葫芦科雪胆属植物雪胆(Hemsleya)的块根中，具有抗肿瘤、抑菌、抗胃溃疡、清热、解毒、止痛、抗体外HIV等作用，广泛用于治疗肝炎、冠心病和气管炎等疾病。研究发现雪胆甲素具有抑制人宫颈癌细胞(Hela细胞)的活性，其IC₅₀为0.389μM。Boykin等发现雪胆甲素可通过诱导肌动蛋白聚集、抑制JAK2/STAT3 下游的生长素而诱导细胞经历PARP介导的细胞凋亡。高申等发现雪胆甲素对人非小细胞肺癌A549细胞有抑制作用。陈育林等研究发现雪胆甲素对肺癌细胞NCI-H460和A549的半抑制浓度(IC₅₀)分别为224.9nM，108.3nM。由于雪胆甲素对人正常细胞HEK293的IC₅₀为 0.5μM，选择性较差，因此，提高雪胆甲素类衍生物对细胞的选择性，增强对肿瘤细胞的抗增殖活性，减小对正常细胞的毒性，对雪胆甲素的结构优化及其衍生物的成药性研究具有重要的意义。

发明内容

本发明解决的技术问题是提供一类雪胆甲素衍生物、其制备方法以及其在制备预防和/或治疗癌症药物中的应用。

R¹为：

R²为： R³为： R⁴为：。

具体到实施例中的某个化合物，对化合物进行了编号，具体哪个编号的化合物中R¹为什么基团，在基团的下方有相应的编号。

其中，化合物编号为

4a-4g时，R²,R³,R⁴为OAc；

6a,6b时,R²,R³,R⁴为OH；

9a-9o时,R²,R³,R⁴为OH。

优选的，上述的化合物中，所述

进一步优选的，上述的化合物中，所述

上述的化合物的制备方法，包括如下步骤：

R¹为：

(a)乙酸酐，4-二甲氨基吡啶，乙酸酐，吡啶，r.t.5min。(b)甲醇，硼氢化钠，0℃，6h；高碘酸钠，水：四氢呋喃1:1,r.t., 10h。(c)冰乙酸，氨类化合物，r.t.16h。

上述的化合物的制备方法，包括如下步骤：

(a)吡啶，盐酸羟胺，50℃,12h。(b)氢氧化钠，甲醇，r.t.，10h。

上述的化合物的制备方法，包括如下步骤：

(a)次氯酸钠，甲醇，r.t.，30min.(b)氢氧化钠，盐酸，甲醇，90℃，5h.(c)DMTMM，N-甲基吗啉，胺，甲醇，r.t.，12h.

上述化合物在制备预防和/或治疗癌症药物中的应用。

上述的化合物在制备预防和/或治疗卵巢腺癌药物中的应用。

上述的化合物在制备抑制SKOV 3细胞增殖药物中的应用。

有益技术效果：

对从金佛山雪胆中提取的雪胆甲素的2，3和16位羟基及其17位支链进行结构修饰，根据化合物的理化性质并结合X-ray、IR、NMR、HRMS等技术对合成的化合物进行结构鉴定。采用SRB法测定合成的化合物对人肺癌(A549)、卵巢癌(SKOV3)、结肠癌(LOVO，SW620，HT-29)、肝癌(HepG2)、乳腺癌(MCF-7)等癌细胞的抗增殖活性，结果显示部分化合物具有较好的抗肿瘤细胞增殖作用。

通过雪胆甲素的2，3和16位羟基及其17位支链进行结构修饰，SRB法筛选结果表明：雪胆甲素2，3，16位羟基被乙酰基保护，17位支链被2-肼基吡啶、2，4，6三氯苯肼或2， 4-二硝基苯肼取代并且羟基被乙酰基保护后的化合物具有较强的抑制肿瘤细胞(SKOV3，LOVO，HT-29，HepG2，MCF-7)增殖的作用。同时，这些衍生物对正常细胞HEK293的IC₅₀增大，提示该类衍生物相对于雪胆甲素，其选择性增强，具有成药性研究的价值。

具体实施方式

下面结合具体实施方式来对本发明作更进一步的说明，以便本领域的技术人员更了解本发明，但并不以此限制本发明。

本发明通式(I)所示的化合物的制备方法：

1.化合物4a～4g的合成

R¹为：

(a)乙酸酐，4-二甲氨基吡啶，乙酸酐，吡啶，r.t.5min。(b)甲醇，硼氢化钠，0℃，6h；高碘酸钠，水：四氢呋喃1:1,r.t.,

10h。(c)冰乙酸，氨类化合物，r.t.16h。化合物4a～4g的合成

实施例1化合物4a的合成

将雪胆甲素(1)(500mg,0.89mmol)溶于吡啶(3.5mL)中，加入乙酸酐(2mL)，DMAP(22mg,0.18mmol)，于室温，氮气保护下搅拌反应5min，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝20:1)。加入乙酸乙酯稀释，反应液依次用1M盐酸，水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝100：1)纯化得白色固体化合物(2)(611mg,95％)。将化合物(2)(150mg,0.22mmol) 溶于甲醇(6mL)中，在冰浴条件下缓慢加入硼氢化钠(28mg,0.87mmol)，室温反应6h， TLC检测原料消失(展开剂：二氯甲烷-甲醇＝15:1)。向反应液中加入乙酸乙酯稀释，依次用1M盐酸，水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品溶于四氢呋喃水溶液(THF:H₂O＝1:1,10mL)中，加入高碘酸钠(355mg,1.65mmol)，反应过夜， TLC检测原料消失(展开剂：二氯甲烷-甲醇＝20:1)。减压蒸除四氢呋喃，有机相用乙酸乙酯萃取，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝200:1)纯化得白色固体化合物(3)(97mg,84％)。

将化合物(3)(40mg,0.075mmol)溶于冰醋酸(4mL)中，加入2,4-二硝基苯肼(30mg,0.15mmol)，于室温，氮气保护下，反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝25:1)。反应液用水稀释，有机相用乙酸乙酯萃取，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝200:1)纯化得黄色固体化合物4a(37.2mg,70％)。HRMS(ESI):m/z calcd for C₃₆H₄₆N₄NaO₁₁(M+Na)⁺:733.3061found:733.3041.¹H NMR(400MHz,Pyridine-d₅)δ11.01(s,1H,NH),9.08(d,J＝2.6Hz,1H,C-3’-H),8.33-8.25(m,1H,C-5’-H),8.02(d,J＝9.6Hz,1H,C-6’-H),6.44(t,J＝8.0Hz,1H,C-16-H),5.80-5.73(m,1H,C-6-H),5.46(ddd,J＝11.5,9.9,4.4Hz,1H,C-2-H),5.05(d,J＝10.0 Hz,1H,C-3-H),3.52(d,J＝7.1Hz,1H,C-17-H),3.20(d,J＝14.6Hz,1H,C-12a-H),2.79(d,J＝ 12.8Hz,1H,C-8-H),2.43-2.28(m,3H,C-12b-H,C-7a-H,C-1a-H),2.19(m,1H,C-15a-H),2.21(s, 3H,CH₃),2.15(s,3H,CH₃),2.05(s,3H,CH₃),2.01(s,3H,CH₃),1.97(d,J＝7.9Hz,1H,C-10-H), 1.90(dd,J＝19.2,5.7Hz,1H,C-7b-H),1.66(d,J＝13.9Hz,1H,C-15b-H),1.51-1.37(m,1H, C-1b-H),1.33(s,3H,CH₃),1.25(s,3H,CH₃),1.19(s,3H,CH₃),1.17(s,3H,CH₃),0.83(s,3H, CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ211.05,170.71,170.42,170.32,155.29,145.23,139.43, 138.05,130.26,129.69,123.42,120.43,116.61,78.33,73.99,71.63,59.63,50.40,48.83,48.10, 47.13,43.41,43.26,42.16,33.47,31.18,24.62,23.95,22.58,21.13,20.85,20.74,20.17,19.83, 18.83,17.40.

实施例2-7中化合物4b-4g的制备方法同实施例1，区别在于使用不同的胺类试剂合成，具体每个实施例中使用的胺类试剂在相应实施例中有记载：

实施例2化合物4b的合成

所用胺类试剂为4-硝基苯肼，产物为黄色固体，产率为83％。HRMS(ESI):m/zcalcd for C₃₆H₄₇N₃NaO₉(M+Na)⁺:688.3210found:688.3190.¹H NMR(400MHz,Pyridine-d₅)δ8.21(d,J ＝8.8Hz,2H,C-3’-H,C-5’-H),7.37(d,J＝8.8Hz,2H,C-2’-H,C-6’-H),6.51(t,J＝8.1Hz,1H, C-16-H),5.77-5.68(m,1H,C-6-H),5.45(td,J＝11.0,4.3Hz,1H,C-2-H),5.06(d,J＝10.0Hz,1H, C-3-H),3.45(d,J＝7.2Hz,1H,C-17-H),3.22(d,J＝14.5Hz,1H,C-12a-H),2.79(d,J＝12.9Hz, 1H,C-8-H),2.36-2.19(m,4H,C-12b-H,C-7a-H,C-1a-H,C-15a-H),2.16(s,3H,CH₃),2.14(s, 3H),1.98(s,6H,CH₃,CH₃),1.95-1.83(m,2H,C-10-H,C-7b-H),1.63(d,J＝13.9Hz,1H, C-15b-H),1.42(d,J＝12.4Hz,1H,C-1b-H),1.32(s,3H,CH₃),1.23(s,3H,CH₃),1.18(s,3H, CH₃),1.14(s,3H,CH₃),0.79(s,3H,CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ211.38,170.73, 170.41,170.28,152.50,147.58,139.56,139.41,126.35,126.35,120.47,112.06,112.06,78.37, 74.40,71.64,59.36,50.05,48.79,47.97,47.43,43.59,43.30,42.14,33.45,31.18,24.61,23.94, 22.56,21.15,20.84,20.73,20.19,19.88,18.82,17.92.

实施例3化合物4c的合成

所用胺类试剂为苯磺酰肼，产物为白色固体，产率为74％。HRMS(ESI):m/z calcdfor C₃₆H₄₉N₂O₉S(M+H)⁺:685.3159found:685.3135.¹H NMR(400MHz,Pyridine-d₅)δ11.55(s,1H, NH),8.27-8.21(m,2H,C-2’-H,C-6’-H),7.51(m,3H,C-3’-H,C-4’-H,C-5’-H),6.20(t,J＝8.0Hz, 1H,C-16-H),5.71(m,1H,C-6-H),5.42(dq,J＝8.2,5.6,5.0Hz,1H,C-2-H),5.02(m,1H,C-3-H), 3.32(dd,J＝7.2,2.1Hz,1H,C-17-H),3.09(d,J＝14.6Hz,1H,C-12a-H),2.73(d,J＝13.0Hz,1H, C-8-H),2.32-2.22(m,3H,C-12b-H,C-7a-H,C-1a-H),2.12(s,3H,CH₃),2.07(s,3H,CH₃),2.03 (m,1H,C-15a-H),1.97(s,3H,CH₃),1.93(s,3H,CH₃),1.83-1.77(m C-10-H,C-7b-H),1.55(d,J＝ 13.9Hz,1H,C-15b-H),1.37(m,1H,,C-1b-H),1.22(s,3H,CH₃),1.19(S,3H,CH₃),1.16(s,3H, CH₃),1.09(s,3H,CH₃),0.56(s,3H,CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ211.22,170.52, 170.41,170.28,154.90,140.17,139.38,132.91,129.12,129.12,128.53,128.53,120.41,78.35, 74.55,71.61,58.74,49.79,48.69,47.86,47.32,43.60,43.12,42.11,33.42,31.14,24.60,23.86, 22.57,21.14,20.84,20.73,20.12,19.46,18.75,18.42.

实施例4化合物4d的合成

所用胺类试剂为2-肼吡啶，产物为白色固体，产率为84％。HRMS(ESI):m/z calcdfor C₃₅H₄₈N₃O₇(M+H)⁺:622.3492found:622.3763.¹H NMR(400MHz,Pyridine-d₅)δ9.76(s,1H, NH),8.28(d,J＝4.8Hz,1H,C-6’-H),7.62-7.51(m,2H,C-4’-H,C-5’-H),6.71(t,J＝6.0Hz,1H, C-3’-H),6.49(t,J＝8.0Hz,1H,C-16-H),5.73(d,J＝5.5Hz,1H,C-6-H),5.46(m,1H,C-2-H), 5.04(d,J＝10.0Hz,1H,C-3-H),3.41(d,J＝7.1Hz,1H,C-17-H),3.19(d,J＝14.5Hz,1H, C-12a-H),2.79(d,J＝13.0Hz,1H,C-8-H),2.37(d,J＝14.7Hz,1H,C-12b-H),2.33–2.15(m,3H, C-7a-H,C-1a-H,C-15a-H),2.13(s,3H,CH₃),2.12(s,3H,CH₃),2.02(s,3H,CH₃),1.98(s,3H, CH₃),1.91(d,J＝7.9Hz,1H,C-10-H),1.86(dd,J＝19.4,5.9Hz,1H,C-7b-H),1.61(d,J＝13.9 Hz,1H,C-15b-H),1.41(m,1H,C-1b-H),1.31(s,3H,CH₃),1.23(s,3H,CH₃),1.17(s,3H,CH₃), 1.12(s,3H,CH₃),0.76(s,3H,CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ211.44,170.73,170.42, 170.29,158.94,148.23,144.29,139.43,138.05,120.46,115.38,107.65,78.38,74.41,71.65,59.13, 49.97,48.79,47.90,47.42,43.66,43.33,42.14,33.45,31.19,24.62,23.95,22.59,21.15,20.86, 20.74,20.18,19.81,18.82,17.40.

实施例5化合物4e的合成

所用胺类试剂为氨基硫脲，产物为白色固体，产率为77％。HRMS(ESI):m/z calcdfor C₃₁H₄₆N₃O₇S(M+H)⁺:604.3056found:604.3035.¹H NMR(400MHz,Pyridine-d₅)δ10.73(s,1H, NH),9.69(s,1H,NH₂),8.47(s,1H,NH₂),6.49(t,J＝8.1Hz,1H,C-16-H),5.71(s,1H,C-6-H), 5.43(td,J＝11.0,4.4Hz,1H,C-2-H),5.05(s,5H,C-3-H),5.01(s,1H),3.33(d,J＝7.1Hz,1H, 1H,C-17-H),3.14(d,J＝14.5Hz,1H,C-12a-H),2.74(d,J＝12.9Hz,1H,C-8-H),2.36–2.22(m, 4H,C-12b-H,C-7a-H,C-1a-H,C-15a-H),2.13(s,3H,CH₃),2.11(s,3H,CH₃),2.02(s,3H,CH₃), 1.98(s,3H,CH₃),1.82(m,2H,C-10-H,C-7b-H),1.52(d,J＝13.8Hz,1H,C-15b-H),1.39(d,J＝ 12.5Hz,1H,C-1b-H),1.26(s,3H,CH₃),1.20(s,3H,CH₃),1.15(s,3H,CH₃),1.09(s,3H,CH₃), 0.70(s,3H,CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ211.17,181.22,170.86,170.43，170.33, 149.29,139.41,120.40,78.33,73.51,71.64,59.69,50.14,48.75,47.97,47.29,43.15,43.10,42.13, 33.42,31.14,24.60,23.93,22.59,21.21,20.87,20.76,20.13,19.69,18.75,17.99.

实施例6化合物4f的合成

所用胺类试剂为2-氯-6-肼基吡啶，产物为白色固体，产率为77％。HRMS(ESI):m/zcalcd for C₃₅H₄₇ClN₃O₇(M+H)⁺:656.3103found:656.3087.¹H NMR(400MHz,Chloroform-d)δ8.24 (dd,J＝4.9,1.5Hz,1H,C-6’-H),7.56(dd,J＝7.7,1.5Hz,1H,C-4’-H),6.74-6.69(m,1H,C-5’-H), 5.90(t,J＝7.9Hz,1H,,C-16-H),5.77(d,J＝5.6Hz,1H,C-6-H),5.02(ddd,J＝11.7,10.0,4.4Hz, 1H,C-2-H),4.69(d,J＝10.0Hz,1H,C-3-H),3.37(d,J＝7.0Hz,1H,C-17-H),3.18(d,J＝14.6 Hz,1H,C-12a-H),2.45(m,1H,C-8-H),2.30(d,J＝14.4Hz,1H,C-12b-H),2.17-22.10(m,3H, C-7a-H,C-1a-H,C-15a-H),2.07(s,3H,CH₃),2.00(s,6H,CH₃,CH₃),1.98(s,4H,CH₃,C-10-H), 1.87(dt,J＝12.8,4.4Hz,1H,C-7b-H),1.57(d,J＝14.1Hz,1H,C-15b-H),1.28(s,3H,CH₃),1.25 (m,1H,C-1b-H),1.09(s,3H,CH₃),1.06(d,J＝4.2Hz,6H,CH₃,CH₃),0.74(s,3H,CH₃).¹³C NMR(100MHz,Chloroform-d)δ211.62,170.78,170.53,170.27,150.43,148.38,146.37,139.14, 137.35,120.12,115.73,115.07,74.90,70.98,59.01,50.68,48.84,47.42,46.60,43.42,43.32,41.81, 33.39,30.62,24.41,23.94,22.52,21.24,21.02,20.89,20.85,20.11,20.04,18.84,16.21.

实施例7化合物4g的合成

所用胺类试剂为2,4,6-三氯苯肼，产物为白色固体，产率为80％。HRMS(ESI):m/zcalcd for C₃₆H₄₆Cl₃N₂O₇(M+H)⁺:723.2370found:723.2359.¹H NMR(400MHz,Chloroform-d)δ7.28(s, 2H,C-3’-H,C-5’-H),7.02(s,1H,NH),5.84-5.74(m,2H,C-16-H,C-6-H),5.07-4.97(m,1H, C-2-H),4.69(d,J＝10.0Hz,1H,C-3-H),3.24-3.14(m,2H,C-17-H,C-12a-H),2.51-2.37(m,2H, C-8-H,C-7a-H),2.34(d,J＝14.3Hz,1H,C-12b-H),2.06(s,3H,CH₃),2.05-2.00(m,2H,C-1a-H, C-15a-H)1.99(s,6H,CH₃,CH₃),1.94(s,3H,CH₃),1.92-1.82(m,2H,C-10-H,C-7b-H),1.46(d,J ＝14.2Hz,1H,C-15b-H),1.30(m,1H,C-1b-H),1.26(s,3H,CH₃),1.09(s,3H,CH₃),1.06(s,3H, CH₃).1.06(s,3H,CH₃),0.67(s,3H,CH₃).¹³C NMR(100MHz,Chloroform-d)δ211.43,170.54, 170.39,170.74,147.27,139.16,138.51128.82,128.82,127.48,126.37,120.30,78.01,77.16,74.45, 71.04,58.77,49.80,48.90,47.60,47.20,43.55,43.37,41.92,33.47,30.71,24.50,23.91,22.68, 21.28,21.13,20.98,20.12,19.95,18.94,16.61.

2.化合物6a与6b的合成

实施例8化合物6a与6b的合成

(a)吡啶，盐酸羟胺，50℃,12h。(b)氢氧化钠，甲醇，r.t.，10h。

化合物6a、6b的合成

将化合物(3)(100mg,0.189mmol)溶于吡啶(8mL)中，于氮气保护下，加入盐酸羟胺(26.2 mg,0.377mmol)，于50℃下反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝20:1)。乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝100:1)纯化得白色固体化合物5a(86.2 mg,55％)，5b(65.1mg,42％)。5a:White solid,HRMS(ESI):m/z calcd forC₃₀H₄₄NO₈(M+H)⁺: 546.3067found:546.3052.¹H NMR(400MHz,Pyridine-d₅)δ12.88(s,1H,N-OH),6.33(t,J＝8.1 Hz,1H,C-16-H),5.71(d,J＝5.6Hz,1H,C-6-H),5.46(td,J＝10.7,10.1,4.3Hz,1H,C-2-H),5.04 (d,J＝10.1Hz,1H,C-3-H),3.36(d,J＝7.3Hz,1H,C-17-H),3.10(d,J＝14.6Hz,1H,C-12a-H), 2.76(d,J＝13.1Hz,1H,C-8-H),2.39(d,J＝14.6Hz,1H,C-12b-H),2.35-2.27(m,2H, C-1a-H,C-7a-H),2.13(s,3H,CH₃),2.10(s,1H,C-15a-H),2.07(s,3H,CH₃),2.05(s,3H,CH₃), 1.98(s,3H,CH₃),1.86-1.79(m,2H,C-10-H,C-7b-H),1.57(d,J＝13.9Hz,1H,C-15b-H),1.41(d, J＝12.4Hz,1H,C-1b-H),1.26(s,3H,CH₃),1.23(s,3H,CH₃),1.16(s,3H,CH₃),1.11(s,3H, CH₃),0.79(s,3H,CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ211.42,170.39,170.25,152.78,139.41, 120.43,78.38,74.23,71.62,57.03,49.75,48.74,47.63,47.33,43.70,43.28,42.12,33.45,31.17, 29.95,24.60,23.92,22.56,21.08,20.83,20.72,20.15,19.83,18.77,15.55.5b:White solid,HRMS(ESI):m/z calcd for C₃₀H₄₄NO₈(M+H)⁺:546.3067found:546.3047.¹H NMR(400MHz,Pyridine-d₅)δ12.70(s,1H,N-OH),5.87(t,J＝8.1Hz,1H,C-16-H),5.72(d,J＝5.6Hz,1H,C-6-H),5.48(td,J＝10.8,4.4Hz,1H,C-2-H),5.02(m,1H,C-3-H),4.61(d,J＝7.4Hz,1H,C-17-H),3.60(d,J＝15.4Hz,1H,C-12a-H),2.83(d,J＝13.0Hz,1H,C-8-H),2.70(d,J＝15.4Hz, 1H,C-12b-H),2.39-2.18(m,3H,C-1a-H,C-7a-H,C-15a-H),2.13(s,3H,CH₃),2.12(s,3H,CH₃), 2.06(s,3H,CH₃),1.97(s,3H,CH₃),1.91(d,J＝8.5Hz,1H,C-10-H),1.84(d,J＝5.9Hz,1H, C-7b-H),1.65(d,J＝14.0Hz,1H,C-15b-H),1.38(s,3H,CH₃),1.25(m,1H,C-1b-H),1.19(s,3H, CH₃),1.16(s,6H,CH₃,CH₃),0.87(s,3H,CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ212.35, 170.58,170.44,170.20,154.33,139.46,120.39,78.58,75.57,71.63,52.21,49.41,48.75,48.46, 47.69,44.00,43.28,42.11,33.51,31.30,24.64,24.09,22.44,21.22,21.00,20.85,20.74,20.58, 20.36,19.08.

将化合物5a(50mg,0.09mmol)溶于甲醇(3mL)中，加入氢氧化钠(18.3mg，0.46mmol)，于室温反应10小时，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。旋蒸蒸除溶剂，乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝25:1)纯化得白色固体化合物6a(34.3 mg,91％)。White solid,HRMS(ESI):m/z calcd for C₂₄H₃₈NO₅(M+H)⁺:420.2750found:420.2740. ¹H NMR(400MHz,Pyridine-d₅)δ5.73(d,J＝5.6Hz,1H,C-6-H),5.52(t,J＝7.8Hz,1H,C-2-H), 4.10(ddd,J＝11.0,9.1,4.1Hz,1H,C-16-H),3.39(dd,J＝17.6,7.9Hz,2H,C-12a-H,C-17-H), 3.29(d,J＝14.3Hz,1H,C-3-H),2.77(d,J＝13.0Hz,1H,C-8-H),2.48(d,J＝14.3Hz, 1H,C-12b-H),2.45-2.29(m,2H,C-7a-H,C-1a-H),2.07(s,3H,CH₃),2.04-1.84(m,3H,C-15a-H, C-10-H,C-7b-H),1.59(s,3H),1.53(d,J＝12.0Hz,1H,C-15b-H),1.49(s,3H,CH₃),1.30(s, 4H,C-1b-H,CH₃),1.23(s,3H,CH₃),0.89(s,3H,CH₃).¹³C NMR(100MHz,Pyridine-d₅)δ212.35, 154.44,142.39,118.54,81.28,70.88,70.78,61.23,50.72,49.26,48.05,47.57,45.98,43.91,42.72, 34.57,34.27,25.37,24.19,22.27,20.28,20.08,19.18,15.92.

将化合物5b(55mg,0.1mmol)溶于甲醇(3mL)中，加入氢氧化钠(18.3mg，0.46mmol)，于室温反应10小时，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。旋蒸蒸除溶剂，乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物6b(39mg, 93％)。White solid,HRMS(ESI):m/z calcd for C₂₄H₃₈NO₅(M+H)⁺:420.2750found:420.2736.¹H NMR(400MHz,Chloroform-d)δ5.75(d,J＝5.4Hz,1H,C-6-H),3.95(d,J＝7.3Hz,1H,C-2-H), 3.55(ddd,J＝11.3,9.2,4.4Hz,1H,C-16-H),3.40-3.33(m,2H,C-12a-H,C-17-H),3.26(d,J＝15.3 Hz,1H,C-3-H),2.89(d,J＝9.3Hz,1H,C-8-H),2.48-2.37(m,2H,C-12b-H,C-7a-H),2.26(dd,J＝ 15.3,4.6Hz,1H,C-1a-H),2.03-1.96(m,4H,C-15a-H,CH₃),1.91(t,J＝6.0Hz,1H,C-10-H), 1.84-1.78(m,1H,C-7b-H),1.59(d,J＝4.6Hz,1H,C-15b-H),1.37(d,J＝4.4Hz,3H,CH₃),1.28 (d,J＝4.0Hz,1H,C-1b-H),1.20(d,J＝4.3Hz,3H,CH₃),1.09(d,J＝4.7Hz,3H,CH₃),0.97(d,J ＝4.3Hz,3H,CH₃),0.75(d,J＝4.3Hz,3H,CH₃).¹³C NMR(100MHz,Chloroform-d)δ213.72, 157.94,141.80,119.42,81.26,72.62,71.06,52.89,52.46,49.75,49.00,48.32,46.20,44.18,42.74, 34.45,33.89,25.02,24.48,22.00,21.33,20.37,20.27,19.89。

3.化合物9a～9q的合成

R¹为：

(a)次氯酸钠，甲醇，r.t.，30min.(b)氢氧化钠，盐酸，甲醇，90℃，5h.(c)DMTMM，N-甲基吗啉，胺，甲醇，r.t.，12h. 化合物9a～9q的合成

实施例9化合物9a的合成

将化合物(3)(940mg,1.5mmol)溶于甲醇(30mL)中，向反应液中加入次氯酸钠溶液(6mL)，室温反应30min，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝50:1)纯化得白色固体化合物7(510g,81％)。将化合物(7)(630mg,1.5mmol)溶于甲醇(30mL)中，加入氢氧化钠(160mg，4mmol)，于90℃回流反应5h，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。反应液冷却至室温，加入3M盐酸，调节pH为1～2，乙酸乙酯萃取，有机相依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离 (流动相：二氯甲烷-甲醇＝6:1)纯化得白色固体化合物8(475mg,78％)。将化合物8(50 mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入正丙胺(11.1μL，0.135mmol)， DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失 (展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9a(51.1mg,93％)。White solid,HRMS(ESI):m/z calcd for C₂₆H₄₂NO₅(M+H)⁺:448.3063found:448.3015.¹H NMR(600MHz,Chloroform-d)δ5.72(d,J ＝4.1Hz,1H,C-6-H),4.82(m,1H,C-2-H),3.58-3.49(m,1H,C-16-H),3.25-3.05(m,3H,C-1’-H, C-12a-H),2.91(dd,J＝9.3,3.1Hz,1H,C-17-H),2.83(dd,J＝6.8,1.9Hz,1H,C-3-H),2.44-2.37 (m,1H,C-8-H),2.35-2.31(m,1H,C-12b-H),2.28(dd,J＝14.5,3.6Hz,1H,C-7a-H),1.99-1.89(m, 2H,C-1a-H,C-15a-H),1.84-1.77(m,1H,C-10-H),1.57-1.45(m,3H,C-7b-H,C-2’-H),1.27-1.21 (m,4H,C-15b-H,CH₃),1.18(s,3H,CH₃),1.07(d,J＝2.8Hz,3H,CH₃),1.06-1.00(m,1H, C-1b-H)0.93(dd,J＝8.3,5.2Hz,6H,CH₃,CH₃),0.72(d,J＝3.0Hz,3H,CH₃).¹³C NMR(150 MHz,Chloroform-d)δ213.14,172.18,140.87,118.86,80.50,72.24,70.55,59.61,49.81,49.02, 48.12,46.43,45.13,43.27,42.01,41.49,33.81,33.20,24.65,23.89,22.87,21.59,20.09,19.66, 18.99,11.50.

实施例10化合物9b的合成

将化合物(8)(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入正戊胺(12mg，0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9b(47mg,80％)。White solid,HRMS(ESI):m/z calcd for C₂₈H₄₆NO₅(M+H)⁺:476.3376 found:476.3367.¹H NMR(600 MHz,Chloroform-d)δ5.72(dt,J＝6.3,2.1Hz,1H,C-6-H),4.80(ddd,J＝9.0,6.8,1.7Hz,1H, C-2-H),3.53(m,1H,C-16-H)3.27(dt,J＝13.1,7.3Hz,1H,C-1’-H),3.15(dt,J＝13.1,7.2Hz,1H, C-1’-H),3.07(d,J＝14.2Hz,1H,C-12a-H),2.91(d,J＝9.2Hz,1H,C-17-H),2.81(d,J＝6.8Hz, 1H,C-3-H),2.45-2.36(m,1H,C-7a-H),2.36-2.29(m,1H,C-8-H),2.27(d,J＝14.4Hz,1H, C-12b-H),1.94(ddd,J＝21.7,10.0,5.0Hz,3H,C-15a-H,C-10-H,C-7b-H),1.81(dt,J＝12.4,4.1 Hz,1H,C-1a-H),1.53-1.28(m,7H,C-2’-H,C-3’-H,C-4’-H,C-15b-H),1.23(s,3H,CH₃),1.18(s, 3H,CH₃),1.08(s,3H,CH₃),1.04(m,1H,C-1b-H),0.93(d,J＝5.2Hz,3H,CH₃),0.90(t,J＝7.0 Hz,3H,CH₃),0.72(s,3H,CH₃).¹³C NMR(150MHz,Chloroform-d)δ213.15,172.09,140.79, 118.79,80.47,72.09,70.43,59.41,49.71,48.95,48.01,46.28,45.04,43.23,41.89,39.52,33.71, 32.99,29.16,29.05,24.51,23.79,22.24,21.37,19.98,19.53,18.82,13.85.

实施例11化合物9c的合成

将化合物8(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入正己胺(14mg，0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9c(47mg,78％)。White solid, HRMS(ESI):m/z calcd for C₂₉H₄₈NO₅(M+H)⁺:490.3532found:490.3914.¹H NMR(600MHz, Chloroform-d)δ5.72(d,J＝5.8Hz,1H,C-6-H),4.82(t,J＝7.9Hz,1H,C-2-H),3.56-3.50(m,1H, C-16-H),3.28(dt,J＝14.4,7.2Hz,1H,C-1’-H),3.18-3.12(m,1H,C-1’-H),3.07(d,J＝14.4Hz,1H,C-12a-H),2.91(d,J＝9.3Hz,1H,C-17-H),2.81(d,J＝6.8Hz,1H,C-3-H),2.44-2.37(m,1H, C-7a-H),2.30(t,J＝15.2Hz,2H,C-8-H,C-12b-H),1.97-1.92(m,2H,C-15a-H,C-10-H),1.91(d, J＝8.0Hz,1H,C-7b-H),1.81(dt,J＝12.5,4.1Hz,1H,C-1a-H),1.51-1.25(m,9H,C-15b-H, C-2’-H,C-3’-H,C-4’-H,C-5’-H),1.26(d,J＝5.1Hz,2H),1.23(s,3H,CH₃),1.18(s,3H,CH₃), 1.07(s,3H,CH₃),1.06-1.01(m,1H,C-1b-H),0.92(s,3H,CH₃),0.89(t,J＝6.7Hz,3H,CH₃),0.72 (s,3H,CH₃).¹³C NMR(150MHz,Chloroform-d)δ212.94,172.04,140.89,118.88,80.54,72.28, 70.59,59.61,49.79,49.02,48.12,46.44,45.13,43.28,42.00,39.69,33.84,33.16,31.49,29.61, 26.71,24.66,23.90,22.59,21.58,20.12,19.64,19.01,14.05.

实施例12化合物9d的合成

将化合物8(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入四氢吡咯 (10mg，0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9d(44mg,78％)。White solid, HRMS(ESI):m/z calcd for C₂₇H₄₂NO₅(M+H)⁺:460.3063found:460.3060.¹H NMR(600MHz,Pyridine-d₅)δ6.92(d,J＝3.7Hz,1H,OH),6.48(s,1H,OH),6.25(s,1H,OH),5.75(d,J＝5.6Hz, 1H,C-6-H),5.63t,J＝7.8Hz,1H,C-2-H),5.06(s,H₂O),4.13(td,J＝11.5,10.5,4.0Hz,1H, C-16-H),3.64-3.56(m,MeOH,C-12a-H),3.52(d,J＝13.9Hz,1H,C-17-H),3.48-3.42(m,2H, C-3-H,C-2’-H),3.42-3.37(m,1H,C-5’-H),3.28(dd,J＝9.8,6.9Hz,1H,C-2’-H),3.21-3.16(m, 1H,C-5’-H),2.89(d,J＝13.0Hz,1H,C-8-H),2.48-2.42(m,1H,C-7a-H),2.35(m,1H,C-1a-H), 2.32(d,J＝14.0Hz,1H,C-12b-H),2.11(dd,J＝12.9,9.2Hz,1H,C-15a-H),1.97(q,J＝8.4,6.4 Hz,2H,C-7b-H,C-10-H),1.88(d,J＝12.9Hz,1H,C-15b-H),1.68(s,3H),1.61-1.55(m,1H, C-1b-H),1.54-1.36(m,7H,CH₃,C-3’-H,C-4’-H),1.33(s,3H),1.25(s,3H),1.07(s,3H).¹³C NMR(150MHz,Pyridine-d₅)δ212.09,170.71,142.46,118.61,81.42,73.71,70.88,58.97,51.40, 49.42,49.28,47.70,46.87,46.23,46.17,43.83,42.87,34.72,34.29,26.23,25.47,24.35,24.19, 22.35,21.12,20.30,19.35.

实施例13化合物9e的合成

将化合物8(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入吗啉(12mg， 0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9e(44mg,75％)。White solid,HRMS(ESI): m/z calcd for C₂₇H₄₂NO₆(M+H)⁺:476.3012found:476.3005.¹H NMR(600MHz,Chloroform-d)δ 5.73(d,J＝5.5Hz,1H,C-6-H),5.01-4.96(m,1H,C-2-H),3.74-3.24(m,10H,morpholine,C-16-H, C-12a-H),3.12(d,J＝13.7Hz,1H,C-17-H),2.91(d,J＝9.2Hz,1H,C-3-H),2.45-2.37(m,1H, C-7a-H),2.33(d,J＝12.2Hz,1H,C-8-H),2.12(d,J＝13.7Hz,1H,C-12b-H),2.01-1.94(m,2H, C-7b-H,C-15a-H),1.92(d,J＝7.9Hz,1H,C-10-H),1.82-1.76(m,1H,C-1a-H),1.53(d,J＝1.7 Hz,1H,C-15b-H),1.31(s,3H,CH₃),1.19(s,3H,CH₃),1.08(s,3H,CH₃),1.04(m,1H,C-1b-H), 0.94(s,3H,CH₃),0.71(s,3H,CH₃).¹³C NMR(150MHz,Chloroform-d)δ212.17,171.03,140.79, 118.90,77.16,73.39,70.46,66.94,66.83,55.20,50.80,49.09,48.76,46.81,46.60,44.94,43.39, 42.78,41.99,33.79,33.01,24.59,23.82,21.54,20.25,20.00,19.07.

实施例14化合物9f的合成

将化合物8(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入环己胺(13.5mg，0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9f(48mg,80％)。White solid, HRMS(ESI):m/z calcd for C₂₉H₄₆NO₅(M+H)⁺:488.3376found:488.3367.¹H NMR(400MHz,Chloroform-d)δ5.76(d,J＝5.7Hz,1H,C-6-H),4.85(m,1H,C-2-H),3.77-3.68(m,1H,C-1’-H), 3.57-3.50(m,1H,C-16-H),3.35(s,1H,CD₃OD),3.18(d,J＝14.5Hz,1H,C-12a-H),2.89(t,J＝ 7.8Hz,2H,C-17-H,C-3-H),2.51-2.39(m,2H,C-8-H,C-7a-H),2.19(d,J＝14.4Hz,1H, C-12b-H),2.05-1.63(m,6H,C-1a-H,C-15a-H,C-2’-H,C-6’-H,C-10-H,C-7b-H),1.50(d,J＝13.3 Hz,1H,C-15b-H),1.45-1.32(m,4H,CH₃,C-1b-H),1.32–1.15(m,5H,C-3’-H,C-5’-H,CH₃), 1.10(s,3H,CH₃),0.97(s,3H,CH₃),0.72(s,3H,CH₃).¹³C NMR(100MHz,Chloroform-d)δ214.55,172.18,141.94,119.54,81.35,72.81,71.19,60.05,54.25,50.76,49.89,49.33,47.15,45.96, 44.33,42.89,34.58,34.08,34.04,33.36,26.23,25.78,25.78,25.11,24.59,22.00,20.47,20.34, 19.45.

实施例15化合物9g的合成

将化合物8(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入间甲氧基苯胺(16.6mg，0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9g(59mg,93％)。White solid,HRMS(ESI):m/z calcd for C₃₀H₄₂NO₆(M+H)⁺:512.3012found:512.3000.¹H NMR(600 MHz,Acetone-d₆)δ7.44(s,1H,C-2’-H),7.19(s,2H,C-5’-H,C-6’-H),6.64(d,J＝1.2Hz,1H, C-4’-H),5.74(d,J＝6.2Hz,1H,C-6-H),4.94(ddt,J＝9.3,7.2,2.1Hz,1H,C-2-H),4.41(d,J＝ 4.2Hz,1H,C-3-H),3.88(s,1H,OH),3.77(s,3H,OCH₃),3.71(s,1H,OH),3.56-3.49(m,1H, C-16-H),3.36-3.30(m,1H,C-12a-H),3.15(d,J＝6.6Hz,1H,C-17-H),2.86(d,J＝9.2Hz,1H, C-8-H),2.50-2.39(m,2H,C-1a-H,C-7a-H),2.24(d,J＝14.5Hz,1H,C-12b-H),2.04-1.96(m,2H, C-10-H,C-15a-H),1.75(dt,J＝12.4,4.0Hz,1H,C-7b-H),1.53(dd,J＝13.1,1.5Hz,1H, C-15b-H),1.35(s,3H,CH₃),1.19(s,3H,CH₃),1.05(s,3H,CH₃),1.01-0.95(m,4H,C-1b-H,CH₃), 0.78(s,3H,CH₃).¹³C NMR(150MHz,Acetone-d₆)δ210.90,170.24,160.14,141.72,140.56, 129.42,118.35,111.34,108.70,104.98,80.63,72.12,70.22,60.79,54.57,50.20,48.70,48.37, 46.27,45.47,43.44,41.86,33.73,33.48,24.44,23.79,21.21,19.63,19.54,18.68.

实施例16化合物9h的合成

将化合物8(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入苯胺(12.6 mg，0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9h(53mg,90％)。White solid,HRMS(ESI):m/z calcd for C₂₉H₄₀NO₅(M+H)⁺:482.2906found:488.2888.¹H NMR(400MHz,Acetone-d₆)δ7.69-7.64(m,2H,C-2’-H,C-6’-H),7.29(t,J＝7.8Hz,2H,C-3’-H,C-5’-H),7.05(t, J＝7.4Hz,1H,C-4’-H),5.75(d,J＝6.2Hz,1H,C-6-H),4.93(d,J＝8.6Hz,1H,C-2-H),4.35(d,J ＝4.0Hz,1H,OH),3.80(s,1H,OH),3.62(d,J＝20.9Hz,1H,OH),3.51(t,J＝5.5Hz,1H, C-16-H),3.32(d,J＝14.4Hz,1H,C-12a-H),3.15(d,J＝6.6Hz,1H,C-17-H),2.86(m,2H,C-8-H, C-3-H),2.50-2.40(m,2H,C-7a-H,C-1a-H),2.26(d,J＝14.4Hz,1H,C-12b-H),2.05-2.0(m,2H, C-15a-H,C-10-H),1.78-1.71(m,1H,C-7b-H),1.57-1.51(m,1H,C-15b-H),1.36(s,3H,CH₃), 1.19(s,3H,CH₃),1.05(s,3H,CH₃),1.01-0.94(m,4H,,C-1b-H,CH₃),0.79(s,3H).¹³C NMR(100 MHz,Acetone-d₆)δ211.83,171.15,142.75,140.41,129.62,129.62,124.18,120.20,120.20,119.35, 81.66,73.16,71.22,61.68,51.15,49.71,49.33,47.28,46.50,44.46,42,83,34.77,34.46,25.40, 24.78,22.18,20.59,20.44,19.65.

实施例17化合物9i的合成

将化合物8(50mg,0.123mmol)溶于甲醇(3mL)中，在氮气保护下，依次加入2-氯苄胺(20mg，0.135mmol)，DMTMM(37.4mg,0.135mmol)，N-甲基吗啉(30μL)，室温反应过夜，TLC检测原料消失(展开剂：二氯甲烷-甲醇＝10:1)。减压蒸除溶剂，乙酸乙酯稀释，依次用水，饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(流动相：二氯甲烷-甲醇＝20:1)纯化得白色固体化合物9i(51mg,78％)。White solid, HRMS(ESI):m/z calcd for C₃₀H₄₁ClNO₅(M+H)⁺:530.2673found:530.2673.¹H NMR(600MHz,Acetone-d₆)δ7.44-7.26(m,4H,benzene ring),5.72(dt,J＝6.2,2.0Hz,1H,C-6-H),4.89(t,J＝ 7.9Hz,1H,C-2-H),4.58(dd,J＝15.3,5.9Hz,1H,C-7’-H),4.45(dd,J＝15.4,5.7Hz,1H, C-7’-H),3.51(ddd,J＝11.4,9.2,4.1Hz,1H,C-16-H),3.22(dd,J＝14.5,1.5Hz,1H,C-12a-H), 3.04(d,J＝6.8Hz,1H,C-17-H),2.85(d,J＝9.2Hz,1H,C-3-H),2.46-2.37(m,2H,C-7a-H, C-1a-H),2.29(d,J＝14.5Hz,1H,C-12b-H),2.00-1.92(m,3H,C-8-H,C-15a-H,C-10-H),1.75(dt, J＝12.3,4.0Hz,1H,C-7b-H),1.49(dd,J＝13.2,1.6Hz,1H,C-15b-H),1.31(S,3H),1.17(s,3H), 1.04(s,3H),1.02-0.97(m,1H,C-1b-H),0.96(s,3H).¹³CNMR(150MHz,Acetone-d₆)δ211.94, 172.33,142.43,137.36,133.55,130.33,129.93,129.34,127.73,119.00,81.30,72.98,70.92,60.23, 50.53,49.35,48.84,46.99,46.31,44.12,42.56,41.47,34.38,34.15,25.16,24.50,21.97,20.38, 20.09,19.36.

实施例18化合物9j的合成

雪胆甲素衍生物及其制备方法和应用专利购买费用说明