CN104693156A - 9,10-二羟基-1-去氧紫杉醇类似物及其制备方法 - Google Patents

9,10-二羟基-1-去氧紫杉醇类似物及其制备方法 Download PDF

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CN104693156A
CN104693156A CN201410564263.5A CN201410564263A CN104693156A CN 104693156 A CN104693156 A CN 104693156A CN 201410564263 A CN201410564263 A CN 201410564263A CN 104693156 A CN104693156 A CN 104693156A
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李青峰
林海霞
崔永梅
徐培佩
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University of Shanghai for Science and Technology
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    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

本发明涉及一种9,10-二羟基-1-去氧紫杉醇类似物及其制备方法。该类似物的结构式为：

Description

9,10-二羟基-1-去氧紫杉醇类似物及其制备方法
技术领域
本发明涉及一种去氧紫杉醇类似物及其合成方法。特别涉及一种侧链C-N-3,改造的9,10-二羟基-1-去氧紫杉醇类似物及其制备方法。
技术背景
紫杉醇(Paclitaxol，商品名Taxol)是从红豆杉属(Taxus)植物中分离提取的一种具有独特抗癌活性的新型抗癌药。其结构如下：
它的结构新颖、作用机制独特、活性强、作用广谱，经临床证明紫杉醇是治疗乳腺癌、子宫癌、胰腺癌和结肠癌等多种癌症的特效药。已于1992年年底被美国FDA正式批准为治疗卵巢癌和子宫癌的新药上市，是近年来国际上公认的最好的抗肿瘤药物之一。但是，它的天然含量甚微、限制采集、水溶性极低，还存在耐药性、毒副作用等问题，因此紫杉醇及其类似物的新资源研究倍受关注，以含量较高的紫杉烷二萜成分(Taxoids)为前体半合成紫杉醇及其衍生物是解决资源短缺和改进综合性能的主要途径之一。
发明内容
本发明的目的之一在于提供一系列一种侧链C-N-3,改造的9,10-二羟基-1-去氧紫杉醇类似物去氧紫杉醇类似物。
本发明的目的之二在于提供该类似物的制备方法。
为达到上述目的，本发明采用如下反应机理：
其中：a-j中的R分别为：为：甲基苯基、甲氧基苯基、丙基苯基、乙基苯基、氟苯基、甲基氯苯、溴苯基、呋喃基、噻吩基或苯并呋喃基。
根据上述反应机理，本发明采用如下技术方案：
一种9,10-二羟基-1-去氧紫杉醇类似物，其特征是：具有下列化学分子结构通式：
一种制备上述的9,10-二羟基-1-去氧紫杉醇类似物的方法，其特征在于该方法的具体步骤为：
a.将原料1-去羟基巴卡亭VI(1)与水合肼按1:300～400的摩尔比溶于质量百分比浓度为95％的酒精中，室温下搅拌15～18小时；调节体系的pH值为6～7，乙酸乙酯萃取，有机相经干燥，去除溶剂得粗产物；该粗产物经分离纯化，得无 色透明晶体4,7,9,10,13-五去乙酰基-1-去氧巴卡亭VI，即化合物2，其结构式为：
b.将步骤a所得化合物2和2,2-二甲氧基丙烷按1:2～5的摩尔比溶于二氯甲烷溶剂中，再加入催化剂用量的蒙脱土K10，在30～50℃温度下搅拌至反应完全；除去催化剂和溶剂后，该粗产物经分离纯化，得白色固体7,13-三去乙酰基-9,10-O-异亚丙基-1-去氧巴卡亭VI，即化合物3，其结构式为：
c.将苯异丝氨酸(1equiv)4溶于无水甲醇中，惰性气氛保护下，冰水浴下加入二氯亚砜(1.5equiv)，过夜反应。蒸出溶剂，乙酸乙酯和水萃取，取有机相干燥后旋干，经分离提纯，得甲酯化中间体；
d.将该甲酯化中间体化合物溶于四氢呋喃和饱和碳酸氢钠溶液混合溶液中，冰水浴下按摩尔比1：3加入酰氯，室温下搅拌反应至反应结束，蒸除四氢呋喃，经乙酸乙酯萃取、干燥后，蒸除溶剂，得粗产物；该粗产物经分离提纯得产物5a-j；
e.将化合物5a-j溶于重蒸的甲苯中，加入催化量的对甲苯磺酸吡啶盐，和1.5个当量的，N2保护，110℃下搅拌两个小时。乙酸乙酯萃取，无水硫酸钠干燥，减压蒸除溶剂；粗产物经柱层析纯化(石油醚：乙酸乙酯＝5：1)的黄色油状液体6a-j；
f.将化合物6a-j加入无水甲醇中，加入NaOH溶液(1.2equiv)，室温下搅拌2h。反应结束后，减压蒸除溶剂，用无水乙醚萃取，取下层水相，加入3N盐酸调节PH＝2(出现大量白色固体)，用乙酸乙酯萃取，无水硫酸钠干燥。将压蒸除得产物。
g.将上述所得粗产物，化合物3，DCC(2equiv)，DMAP(1equiv)溶于5mL的甲苯中，50℃下搅拌两个小时。TLC跟踪反应结束，过滤除去不溶固体，有机相用乙酸乙酯稀释，干燥，减压蒸除溶剂；粗产物经柱层析纯化(石油醚：乙酸乙酯＝1：1)的白色固体7a-j；
h.将化合物7a-j溶于无水甲醇中，加入0.7个当量的对苯甲磺酸，室温下反应6h，TLC跟踪反应结束，混合液用乙酸乙酯稀释，无水硫酸钠干燥，减压蒸除溶剂，粗产物经薄层层析分离(石油醚：乙酸乙酯＝2：1)的最终产物8a-j。
本发明的9,10-二羟基-1-去氧紫杉醇类似物在7、9、10位上是裸露的羟基，能够大大提高该类化合物的水溶性，13位侧链由各种取代基，丰富了该类化合物，为研究这类化合物活性构效关系鉴定了非常有意义的基础。
具体实施方式
实施例1：制备化合物3’-N-对甲苯酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
A.1-去羟基巴卡亭VI1(419mg,0.6mmol)溶于20mL95％酒精中，加入10mL水合肼，室温下搅拌15小时。用0.2N稀盐酸中和，乙酸乙酯萃取，有机相用饱和食盐水洗三次，无水硫酸钠干燥，减压蒸除溶剂。粗产物用甲醇和正己烷重结晶，得无色透明晶体7,9,10,13-四去乙酰基-1-去氧巴卡亭VI2为227mg，产率为87％；
B.B.化合物2(239mg,0.5mmol)溶于18mL二氯甲烷和1.5mL甲醇，完全溶解后再加入2,2-二甲氧基丙烷(0.4mL,2.0mmol)，搅拌均匀，再加入Mont K10为24mg，室温下搅拌0.5小时；减压蒸馏除去低沸点的溶剂，较多的乙酸乙酯溶解后，抽滤除去Mont K10固体粉末，滤液水洗数次，无水硫酸钠干燥，减压蒸馏除去溶剂。粗产物用乙酸乙酯重结晶，得7,13-二去乙酰基-9,10-O-异亚丙基-1-去氧巴卡亭VI3为236mg，产率为92％；
C.将原料苯异丝氨酸(4)(100mg,0.5mmol)溶于3ml的无水甲醇中，N2保护，0℃下加入SOCl2(92mg,0.76mmol)0.05ml，过夜反应。用饱和碳酸氢钠淬灭反应，去除溶剂，水相用乙酸乙酯萃取三次，合并有机相，有机相用饱和食盐水洗3次，无水Na2SO4干燥，减压蒸除溶剂得甲酯化中间体117mg；将甲酯化中间体化合物溶于THF(10mL)和饱和碳酸氢钠溶液(10mL)混合溶液中，0℃下加入对甲基苯酰氯(192mg，0.15mmol)1.5equiv，室温下搅拌3h。TLC跟踪至反应结束，减压蒸除THF，水相用乙酸乙酯萃取3次，合并有机相，有机相用饱和食盐水洗3次用无水NaSO4干燥，减压蒸除溶剂；粗产物经柱层析纯化(石油醚：乙酸乙酯＝3：1)的白色固体产物160mg(5a)，产率为85％；
1HNMR(500MHz,CDCl3)δ(ppm):2.42(s,3H),3.86(s,3H),4.66(d,J＝5.2Hz,1H),5.76(dd,J＝2.4Hz,1H),6.96(br,1H),7.25(d,J＝7.5Hz,2H),7.32(t,J＝15.4Hz,1H),7.39(d,J＝15.5Hz,2H),7.47(d,J＝7.7Hz,2H),7.69(d,J＝8.5Hz,2H)；13C-NMR(125MHz,DMSO-d6)δ(ppm):21.47,53.24,54.91,73.33,126.95,127.15,127.93,128.72,129.16,129.29,130.19,131.15,138.78,142.32,167.01,173.45；
D.将化合物5a溶于20mL重蒸的甲苯中，加入催化量的对甲苯磺酸吡啶盐(12.5mg，0.05mmol)0.1equiv，和4-甲氧基苯甲醛二甲缩醛(114mg，0.63mmol)1.5equiv，N2保护，110℃下搅拌两个小时。用饱和饱和碳酸氢钠淬灭反应，乙酸乙酯萃取3次，合并有机相，有机相用饱和食盐水洗3次，无水Na2SO4干燥，减压蒸除溶剂；粗产物经柱层析纯化(石油醚：乙酸乙酯＝5：1)的黄色油状液体110mg(6a)，产率为80％；
1HNMR(CDCl3,500MHz)δ(ppm):2.31(s,3H),3.81(s,3H),3.82(s,3H),4.88(s,1H),5.45(br,1H),6.87(d,J＝8.5Hz),6.94(br,1H),7.04(d,J＝8Hz,2H),7.24(d,J＝7Hz,2H),7.30-7.35(m,3H),7.46(br,1H)；
13C-NMR(125MHz,CDCl3)δ(ppm):21.41,52.70,55.27,113.51,127.06,127.21,128.01,128.64,128.76,128.90,129.14,130.02,130.17,132.72,141.03,159.50,170.55；
F.将化合物7用于8mL的无水甲醇中，加入4mLNaOH溶液，室温下搅拌2h。反应结束后，减压蒸除溶剂，用2mL无水乙醚萃取，取下层水相，加入3N盐酸调节PH＝2(出现大量白色固体)，用乙酸乙酯萃取3次，合并有机相，有机相 用饱和食盐水洗3次，无水NaSO4干燥。将压蒸除得产物。将所得产物，化合物3(75.19mg，0.13mmol)，DCC(54.37mg，0.26mmol)，DMAP(16.1mg，0.13mmol)溶于5mL的甲苯中，50℃下搅拌两个小时。TLC跟踪反应结束，过滤除去不溶固体，有机相用乙酸乙酯稀释，饱和食盐水洗3次，用无水NaSO4干燥，减压蒸除溶剂；粗产物经柱层析纯化(石油醚：乙酸乙酯＝1：1)的白色固体115mg(7a).产率为85％。
1HNMR(CDCl3,500MHz)δ(ppm):1.28(s,3H),1.54(s,3H),1.56(s,3H),1.65-1.69(m,1H),1.71(s,3H),1.83(s,3H),1.85-1.88(m,1H),1.99(s,3H),2.03(s,3H),2.30(s,3H),2.45-2.53(m,1H),2.59-2.66(m,1H),2.76(d,J＝6.6Hz,1H),3.83(s,3H),4.09-4.15(m,3H),4.32-4.37(q,J＝26.5Hz,2H),4.60(d,J＝10.0Hz,1H),4.90(d,J＝9.6Hz,1H),4.94(br,1H),5.07(d,J＝12.3Hz,2H),5.58(br,1H),5.82(dd,J＝3.3Hz,J＝2.2Hz,1H),6.17(t,J＝18.8Hz,1H),6.88(d,J＝8.7Hz,2H),7.02(d,J＝8.5Hz,3H),7.19(d,J＝10.0Hz,2H),7.29-7.36(m,5H),7.46(t,J＝15.5Hz,3H),7.60(t,J＝9.7Hz,1H),8.05(d,J＝6.6Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):13.06,15.56,21.41,22.06,26.54,26.78,26.94,27.13,31.96,36.74,38.71,41.94,42.41,47.81,55.31,71.72,72.14,74.42,76.39,81.19,83.80,84.59,107.50,113.57,127.22,128.17,128.22,128.63,128.77,128.84,128.89,129.04,129.55,129.82,129.95,132.63,133.60,133.68,138.80,159.93,165.07,169.32,170.85；G.将化合物7a溶于4mL的无水甲醇中，加入对苯甲磺酸(16.2mg，0.7mmol)，室温下反应6h，TLC跟踪反应结束，混合液用乙酸乙酯稀释，饱和碳酸氢钠和饱和食盐水分别洗3次，无水NaSO4干燥，减压蒸除溶剂，粗产物经薄层层析分离得白色固体30mg(8a)，产率为40％。
1HNMR(500MHz,CDCl3)δ(ppm):1.15(s,3H,CH3),1.57(s,3H,CH3),1.41-1.71(m,1H),1.71(s,3H,CH3),1.79(s,3H,CH3),1.84-1.95(m,2H),2.27(s,3H,CH3),2.42(s,3H,CH3),2.4-2.6(m,2H),3.36(br,s,1H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.6(br,s,1H),4.76(d,J＝2.5Hz,1H),4.83(d,J＝10.0Hz),4.92-4.97(d,J＝2Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5,1.5Hz,1H),5.88(dd,J＝9.5,2.5Hz,1H),5.9-5.94(m,1H),7.22(d,2H),7.30-7.37(d,J＝3Hz,2H),7.46-7.51(m,4H),7.54-7.46(m,2H),7.64(t,J＝9Hz,1H),7.70(d,J＝7.5Hz,2H),8.07(d,J＝7.0Hz,2H).13C NMR(125MHz,CDCl3)δ(ppm):
12.62,15.12,21.43,22.66,25.65,29.61,31.90,37.82,38.15,43.91,44.58,47.20,55.25,71.27,73.95,74.01,76.88,77.21,79.08,82.60,83.95,127.01,127.24,128.01,129.38,129.51,129.75,130.88,133.64,133.94,138.32,138.41,142.45,165.05,166.66,171.14,171.31.HR-MS:calcd for C46H53NO12([M+H]+),812.3746；found,812.3654。
实施例二：制备化合物3’-N-对甲氧苯酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
8b
方法同实施示例一：
5b:1HNMR(CDCl3,500MHz)δ(ppm):3.85(s,3H),3.87(s,3H),4.65(s,1H),5.74(d,J＝9.5Hz,1H),6.94(d,J＝8.4Hz,3H),7.32(t,J＝15.5Hz,1H),7.38(t,J＝15.4Hz,2H),7.47(d,J＝8.3Hz,2H),7.76(d,J＝8.5Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):29.70,53.29,54.81,55.44,73.31,113.84,126.27,126.89,127.91,128.54,128.75,128.93,138.86,162.71,166.38,173.43；
6b:1HNMR(CDCl3,500MHz)δ(ppm):3.77(s,3H),3.82(s,6H),4.86(d,J＝3.3Hz),5.47(br,1H),6.72(d,J＝9.4Hz,2H),6.87(d,J＝9.3Hz,2H),6.94(br,1H),7.29-7.35(m,6H),7.48(br,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):14.43,52.27,55.29,113.50,127.03,127.69,128.01,128.69,128.73,129.30,130.08,159.88,161.61,170.53；
7b:1HNMR(CDCl3,500MHz)δ(ppm):1.27(s,3H),1.54(s,3H),1.55(s,3H),1.65-1.69(m,1H),1.71(s,3H),1.83(s,3H),1.85-1.88(m,1H),1.98(s,3H),2.03(s,3H),2.30(s,3H),2.45-2.53(m,1H),2.59-2.66(m,1H),2.76(d,J＝6.6Hz,1H),3.76(s,3H),3.84(s,3H),4.09-4.15(m,2H),4.32-4.37(m,2H),4.60(d,J＝11.1Hz,1H),4.91(d,J＝9.9Hz,2H),4.94(br,1H),5.07(d,J＝12.2Hz,2H),5.61(br,1H),5.8(dd,J＝1.1Hz,J＝2.4Hz,1H),6.17(t,J＝18.8Hz,1H),6.72(d,J＝9.3Hz,2H),6.89(d,J＝8.6Hz,2H),7.01(br,H),7.29-7.35(m,6H),7.44-7.49(m,3H),7.59(t,J＝15.5 Hz,1H),8.05(d,J＝6.6Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):13.02,14.19,15.60,21.45,22.03,24.95,26.52,26.78,26.90,27.11,31.96,36.71,38.64,41.88,42.36,47.82,55.30,60.38,71.70,72.09,74.38,76.36,81.13,83.77,84.553,107.42,113.48,113.54,127.17,127.61,128.17,128.63,128.79,128.87,129.32,129.54,129.79,130.02,133.61,133.65,138.81,159.91,161.53,161.58,165.05,169.33,170.87；
8b:1HNMR(CDCl3,500MHz)δ(ppm):1.15(s,3H,CH3),1.57(s,3H,CH3),1.41-1.71(m,1H),1.71(s,3H,CH3),1.79(s,3H,CH3),1.84-1.95(m,2H),2.27(s,3H,CH3),2.4(s,3H,CH3),2.4-2.6(m,2H),3.36(br,s,1H),3.8(s,3H),4.20(d,J＝8.0Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.6(br,s,1H),4.76(d,J＝2.5Hz,1H),4.83(d,J＝10.0Hz),4.92-4.97(d,J＝2.2Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5,1.5Hz,1H),5.88(dd,J＝9.5,2.5Hz,1H),5.9-5.94(m,1H),6.92(d,J＝3Hz,2H),7.30-7.43(m,4H),7.30-7.40(m,3H),7.64(t,J＝7.0Hz,1H),7.70(d,J＝7.5Hz,2H),8.07(d,J＝7.0Hz,2H).13C-NMR(125MHz,CDCl3)δ(ppm):12.62,14.11,16.12,21.10,22.67,26.45,26.72,29.32,37.84,37.91,43.92,44.52,47.11,54.40,55.41,60.44,71.35.71.31,73.94,74.07,76.85,77.24,79.07,82.65,83.87,113.88,125.93,127.28,127.94,128.67,128.94,129.51,129.75,133.64,133.91,138.38,138.54,162.41,165.04,166.17,171.17,171.37；HR-MS:calcd for C46H53NO13([M+H]+),828.3595；found,812.3574。
实施例三：制备化合物3’-N-对已基苯酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同实施示例一：
5c:1HNMR(CDCl3,500MHz)δ(ppm):1.26(t,J＝15Hz,3H),2.70(q,J＝39.3Hz,2H),3.76(s,3H),4.10(d,J＝4.4Hz,1H),4.63(s,1H),5.77(d,J＝9.6Hz,1H),7.20(d,J＝6.5Hz,2H),7.26-7.36(m,4H),7.45(d,J＝7.7Hz,2H),7.71(d,J＝7.3Hz,2H),8.02(d,J＝7.3Hz,1H)；13C-NMR(125MHz,CDCl3)δ(ppm):15.33,28.78,53.04,55.11,73.46,126.98,127.34,127.79,127.94,128.05,128.63,130.30,131.32,148.45, 167.27,173.42；
6c:1HNMR(CDCl3,500MHz)δ(ppm):1.20(t,J＝15.5Hz,3H),2.62(q,J＝24.4Hz,2H),3.82(s,3H),3.83(s,3H),4.10(d,J＝4.4Hz,1H),4.88(s,1H),5.47(br,1H),6.87(d,J＝8.8Hz,2H),6.92(br,1H),7.07(d,J＝9.4Hz,2H),7.26(d,J＝8.4Hz,3H),7.31-7.34(m,3H),7.45(m,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):14.20,15.24,21.40,28.40,28.71,52.73,55.27,60.48,113.32,127.06,127.25,127.71,128.00,128.64,128.75,130.03,132.93,147.21,159.88170.55；
7c:1HNMR(CDCl3,500MHz)δ(ppm):0.90(t,J＝15.5Hz,3H),1.29(s,3H),1.55(s,3H),1.57(s,3H),1.60(t,J＝15.5Hz),1.66-1.70(m,1H),1.72(s,3H),1.84(s,3H),1.85-1.89(m,1H),2.00(s,3H),2.04(s,3H),2.55-2.65(m,4H),2.76(d,J＝5.3Hz,1H),3.84(s,3H),4.32-4.38(m,2H),4.61(d,J＝10.3Hz,1H),4.91(d,J＝10.4Hz,1H),4.96(br,1H),5.07(t,J＝10.3Hz,2H),5.82(dd,J＝1.2Hz,J＝1.2Hz,1H),6.18(t,J＝19.3Hz,1H),6.78(d,J＝10.4Hz,2H),7.03(d,J＝7.2Hz,2H),7.21(d,J＝7.7Hz,4H),7.34(br,4H),7.46(t,J＝15.4Hz,3H),7.59(t,J＝15.3Hz,1H),8.05(d,J＝7.7Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):13.02,15.24,15.60,22.05,26.52,26.79,26.91,27.13,28.69,31.97,36.73,38.66,41.90,42.38,47.83,55.25,55.29,71.71,72.11,74.39,76.38,81.16,83.78,84.55,107.32,107.49,113.36,113.53,127.29,127.68,128.17,128.21,128.52,128.63,128.76,128.91,129.81,129.81,129.96,130.13,132.82,133.62,133.69,138.81,159.92,165.07,169.33,170.85；
8c:1HNMR(CDCl3,500MHz)δ(ppm):0.82-1.12(m,2H),1.17(s,3H,CH3),1.57(s,3H,CH3),1.54-1.70(m,1H),1.76(s,3H,CH3),1.83(s,3H,CH3),1.86-1.97(m,2H),2.29(s,3H,CH3),2.71(q,2H),2.4-2.6(m,2H),2.85(d,J＝2.5Hz,1H),3.36(br,s,1H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.66-4.77(m,3H),4.83(d,J＝10.0Hz,2H),4.97(d,J＝2Hz,2H),5.76(dd,J＝5.5,1.5Hz,1H),5.83(dd,J＝9.5,2.5Hz,1H),5.9-5.94(m,1H),7.31-7.60(m,9H),7.66(d,J＝5Hz,2H),8.07-8.1(m,3H).13C-NMR(125MHz,CDCl3)δ(ppm):12.61,13.95,14.15,15.14,15.31,17.74,21.57,22.61,26.45,28.74,29.61,31.64,38.05,43.60,45.14,47.44,53.40,55.35,71.84,73.84,76.80,77.17,79.07,82.50,83.84,127.05,127.38,127.94,128.07,128.54,128.74,129.54,129.70,129.85,131.18, 133.47,133.64,134.08,138.34,148.68,165.04,171.18,171.34；HR-MS:calcd for C47H55NO12([M+H]+),826.3800；found,826.3766。
实施例四：制备化合物3’-N-对丙基苯酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同示例一：
5d:1HNMR(CDCl3,500MHz)δ(ppm):0.95(t,J＝15.5Hz,3H),1.61-1.68(m,2H),2.61(t,J＝15.3Hz,2H),3.76(s,3H),4.10(d,J＝4.3Hz,1H),4.60(s,1H),5.74(dd,J＝2.3Hz,J＝2.2Hz,1H),7.17(d,J＝8.4Hz,2H),7.26-7.34(m,4H),7.43(d,J＝7.2Hz,2H),7.69(d,J＝8.3Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):13.75,24.32,37.87,52.98,55.10,73.43,126.97,127.23,127.75,128.61,128.64,131.38,138.86,146.89,167.21,173.32；
6d:1HNMR(CDCl3,500MHz)δ(ppm):0.91(t,J＝15.5Hz,3H),1.57-1.65(m,2H),2.56(t,J＝15.3Hz,2H),3.82(s,3H),3.83(s,3H),4.89(br,1H),6.86(br,1H),7.05(d,J＝8.8Hz,2H),7.25(d,J＝9.7Hz,3H),7.32(br,4H)；13C-NMR(125MHz,CDCl3)δ(ppm):13.68,24.21,37.80,52.72,55.25,113.48,127.08,127.15,128.00,128.31,128.64,128.75,132.97,159.89,170.54；
7d:1HNMR(CDCl3,500MHz)δ(ppm):0.90(t,J＝15Hz,3H),1.28(s,3H),1.55(s,3H),1.56(s,3H),1.60(t,J＝15.4Hz),1.66-1.70(m,1H),1.72(s,3H),1.84(s,3H),1.85-1.89(m,1H),2.00(s,3H),2.01-2.07(m,1H),2.56(t,J＝15.3Hz,2H),2.45-2.53(m,1H),2.59-2.66(m,1H),2.76(d,J＝5.3Hz,1H),3.83(s,3H),4.35(q,J＝25.2Hz,2H),4.61(d,J＝10.4Hz,1H),4.91(d,J＝10.5Hz,1H),4.96(br,1H),5.07(t,J＝10.2Hz,2H),5.82(dd,J＝1.3Hz,J＝1.2Hz,1H),6.18(t,J＝19.8Hz,1H),6.87(br,2H),7.03(d,J＝7.2Hz,2H),7.21(d,J＝7.2 Hz,3H),7.34(br,4H),7.46(t,J＝15.2Hz,2H),7.59(t,J＝15.2Hz,1H),8.05(d,J＝7.5Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):13.02,13.08,14.20,15.59,21.03,22.06,24.21,26.52,26.78,26.1,27.12,31.97,36.73,37.78,38.66,41.89,42.37,47.82,55.30,60.37,71.69,72.11,74.39,76.36,81.16,83.78,84.52,107.48,113.53,127.17,128.18,128.28,128.63,128.76,128.90,129.80,129.94,132.85,133.61,133.69,138.80,159.93,165.05,169.35,170.83；
8d:1HNMR(CDCl3,500MHz)δ(ppm):0.8-0.9(m,2H),0.94-0.97(t,3H),1.16(s,3H,CH3),1.57(s,3H,CH3),1.41-1.71(m,1H),1.76(s,3H,CH3),1.81(s,3H,CH3),1.86-1.98(m,2H),2.29(s,3H,CH3),2.4(s,3H,CH3),2.4-2.6(m,2H),2.63-2.66(t,3H),2.84(d,1H),3.36(br,s,1H),3.8(s,3H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.52(br,s,1H),4.77(br,1H),4.83(d,J＝10.0Hz),4.92-4.97(d,J＝2Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5,1.5Hz,1H),5.88(dd,J＝9.5,2.5Hz,1H),5.9-5.94(m,1H),7.26(d,J＝3Hz,2H),7.30-7.43(m,4H),7.30-7.40(m,3H),7.64(t,J＝9.6,7.5,2.0Hz,1H),7.70(d,J＝7.5Hz,2H),8.07(d,J＝7.0Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):12.11,13.45,14.04,15.14,21.47,22.65,24.25,26.45,27.15,31.67,37.84,38.04,43.85,44.67,47.24,54.47,60.44,71.25,71.34,76.94,77.24,79.02,82.60,83.80,127.00,127.34,127.94,128.64,128.85,129.54,129.72,131.41,133.34,133.97,138.31,138.54,147.24,165.00,166.74,171.27,171.44；HR-MS:calcd for C48H57NO12([M+H]+),840.3959；found,840.3969。
实施例五：制备化合物3’-N-对氟苯酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同示例一：
5e:1H NMR(500MHz,CDCl3)δ(ppm):3.83(s,3H),4.64(d,J＝2.2Hz,1H),4.60(s,1H),5.74(dd,J＝2.3 and 2.5Hz,1H),7.08(t,J＝18.5Hz,2H),7.31(t,J＝15.0Hz,1H),7.37(t,J＝15.5Hz,2H),7.45(d,J＝8.0Hz,2H),7.76-7.80(m,2H)；13C NMR(125MHz,CDCl3)δ(ppm):53.23,55.02,73.25,115.57,126.91,128.00,128.76,129.47,129.54,130.13,130.15,138.59,163.88,165.89,166.01,173.39；
6e:1H NMR(500MHz,CDCl3)δ(ppm):3.82(s,3H),3.84(s,3H),4.89(br,1H),5.45(br,1H),6.87(d,J＝8.5Hz,2H),6.92(t,J＝17.5Hz,2H),7.25-7.36(m,7H),7.43(br,2H)；13C NMR(125MHz,CDCl3)δ(ppm):52.78,55.27,113.58,115,46,127.04,128.76,128.78,129.43,129.50,129.65,131.77,160.01,170.41；
7e:1HNMR(500MHz,CDCl3)δ(ppm):1.28(s,3H),1.55(s,3H),1.56(s,3H),1.66-1.70(m,1H),1.71(s,3H),1.84(s,3H),1.85-1.88(m,1H),1.99(s,3H),2.01(s,3H),2.45-2.53(m,1H),2.59-2.66(m,1H),2.76(d,J＝6.5Hz,1H),3.83(s,3H),4.09-4.15(m,3H),4.32-4.37(m,2H),4.61(d,J＝11.5Hz,1H),4.90(d,J＝10.3Hz,1H),4.94(br,1H),5.07(d,J＝12.5Hz,2H),5.58(br,1H),5.04(dd,J＝3.5 and 2.4Hz,1H),6.87-6.93(m,4H),7.28-7.38(m,6H),7.47(t,J＝16.5Hz,3H),7.60(t,J＝14.5Hz,1H),8.05(d,J＝8.0Hz,2H)；13C NMR(125MHz,CDCl3)δ(ppm):13.01,14.20,15.55,21.04,22.07,26.50,26.77,26.90,27.11,31.95,36.73,38.66,41.90,42.37,47.79,60.38,71.66,71.75,72.12,74.37,81.19,83.76,88.51,107.52,113.64,115.26,115.44,128.39,128.63,128.88,128.90,129.44,129.52,129.56,129.80,133.63,133.83,160.06,165.04,169.33,170.68；
8e:1H NMR(500MHz,CDCl3)δ(ppm):1.08(s,3H,CH3),1.25(s,3H,CH3),1.71(s,3H,CH3),1.85(s,3H,CH3),1.95(s,3H,CH3),1.86-1.98(m,2H),2.29(s,3H,CH3),2.10-2.16(m,1H),2.56-2.70(m,2H),3.86(s,1H),3.96(s,1H),4.05(d,J＝8.5Hz,1H),4.19-4.27(m,2H),4.42(dd,J＝8.3Hz,1H),4.71(d,J＝2.2Hz,1H),4.96(d,J＝2.5Hz 1H),4.77(br,1H),4.83(d,J＝10.0Hz,2H),4.92-4.97(d,J＝2.6Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5 and 1.5Hz,1H),5.88(dd,J＝9.5 and 2.5Hz,1H),5.9-5.94(m,1H),7.13-7.16(t,2H),7.30-7.43(m,4H),7.30-7.40(m,4H),7.88(m,2H),8.07(d,J＝7.0Hz,2H).13C NMR(125MHz,CDCl3)δ(ppm):11.91,13.64,15.05,21.81,22.65,24.84,25.55,26.44,26.72,29.32,29.74,31.67,31.94,33.84,37.44,37.94,38.07,43.95,44.61,47.14,54.57,71.24,73.85,74.14,76.85,77.27,78.95,82.67,115.61,115.81,127.37,128.67,128.85,129.35,129.47,129.50,129.70,129.84,133.44,133.85,138.27,138.44,163.90,165.90,165.04,165.47, 171.15,171.34.HR-MS:calcd for C45H50FNO12([M+Na]+),838.3215；found,838.3183；
实施例六：制备化合物3’-N-对甲基氯苯酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同示例一：
5f:1H NMR(500MHz,CDCl3)(ppm):3.84(s,3H),4.60(s,1H),4.65(d,J＝1.0Hz,1H),5.75(d,J＝9.5Hz,1H),7.13(d,J＝9.0Hz,1H),7.3(t,J＝14.4Hz,1H),7.38(t,J＝15.6Hz,2H),7.45(t,J＝16.0Hz,4H),7.77(d,J＝8.0Hz,2H)；13C NMR(125MHz,CDCl3)δ(ppm):45.33,53.27,54.98,73.25,126.91,127.60,128.00,128.77,133.93,138.57,141.16,166.44,173.38；
6f:1H NMR(500MHz,CDCl3)δ(ppm):3.79(s,3H),3.82(s,3H),4.50(s,2H),4.89(br,1H),5.42(br,1H),6.85(s,2H),7.18-7.36(m,9H),7.43(br,2H)；13C NMR(125MHz,CDCl3)δ(ppm):14.20,21.02,45.39,52.75,55.26,60.36,113.55,127.41,128.14,128.42,128.79,135.64,159.98,170.39；
7f:1H NMR(500MHz,CDCl3)δ(ppm):1.28(s,3H),1.33-1.45(m,1H),1.56(s,3H),1.67(br,1H),1.71(s,3H),1.99(s,3H),2.05(s,3H),2.46-2.85(m,2H),3.49(br,1H),3.83(s,3H),4.11(s,1H),4.34(s,2H),4.52(br,2H),4.61(d,J＝1.0Hz,1H),4.90(d,J＝1.2Hz,1H),4.97(br,1H),5.07(s,1H),5.82(s,1H),6.17(s,1H),6.89(br,2H),7.17-7.65(m,14H),8.05(s,2H)；13C NMR(125MHz,CDCl3)δ(ppm):13.02,15.56,22.09,24.95,26.50,26.91,27.12,31.96,33.92,36.74,38.66,41.89,42.37,45.39,47.79,55.30,71,66,72.12,74.38,76.37,81.18,83.76,84.51,107.50,113.53,113.63,127.45,128.39,128.64,128.86,128.93,129.52,129.80,133.81,135.54,138.64,165.05,169.33,170.67；
8f:1H NMR(500MHz,CDCl3)δ(ppm):1.16(s,3H,CH3),1.56(s,3H,CH3),1.71(s, 2H),1.41-1.71(m,1H),1.76(s,3H,CH3),1.80(s,3H,CH3),1.84-1.95(m,2H),2.28(s,3H,CH3),2.4(s,3H,CH3),2.4-2.6(m,2H),2.83(t,1H),3.36(br,1H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.6(br,1H),4.76(d,J＝2.5Hz,1H),4.83(d,J＝10.3Hz,1H),4.92-4.97(d,J＝2.7Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5,1.5Hz,1H),5.88(dd,J＝9.5 and 2.5Hz,1H),5.9-5.94(m,1H),7.31-7.41(m,3H),7.46-7.65(m,6H),7.82(d,J＝2.5Hz,2H),8.07(m,3H).13CNMR(125MHz,CDCl3)δ(ppm):16.00,18.22,22.30,28.55,37.50,40.25,45.31,45.40,49.72,55.50,70.55,71.45,72.25,72.90,73.25,76.42,81.23,84.56,127.56,127.95,128.25,128.52,129.45,131.33,133.82,135.32,136.02,137.56,165.56,167.15,171.16,171.33；HR-MS:calcd for C46H52ClNO12([M+Na]+),868.3076,found 868.3017；
实施例七：制备化合物3’-N-对溴苯酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同示例一：
5g:1HNMR(CDCl3,500MHz)δ(ppm):3.86(s,3H),4.65(d,J＝2.2Hz,1H),5.72(dd,J＝2.1Hz,J＝2.1Hz,1H),7.04(d,J＝9.5Hz,1H),7.30-7.34(m,1H),7.39(t,J＝15.5Hz,1H),7.46(d,J＝7.7Hz,2H),7.57(d,J＝8.8Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):53.33,54.96,73.16,121.55,126.90,128.07,128.71,128.81,131.62,131.83,131.89,132.80,138.48,166.03,173.38；
6g:1HNMR(CDCl3,500MHz)δ(ppm):3.82(s,3H),3.83(s,3H),4.88(s,1H),5.37(br,1H),6.87(d,J＝7.7Hz,2H),7.17(d,J＝8.3Hz,2H),7.26(br,1H),7.31-7.35(m,3H),7.37(d,J＝9.2Hz,2H),7.43(br,1H)；13C-NMR(125MHz,CDCl3)δ(ppm):14.21,21.04,52.79,55.28,60.38,113.58,127.02,128.23,128.70,128.79,129.53,131.49,134.47,160.03,170.35；
7g:1HNMR(CDCl3,500MHz)δ(ppm):1.28(s,3H),1.53(s,6H),1.56(s,3H),1.65-1.69(m,1H),1.71(s,3H),1.84(s,3H),1.85-1.94(m,1H),1.98(s,3H),2.01(s,3H),2.46-2.53(m,1H),2.58-2.66(m,1H),2.75(d,J＝5.5Hz,2H),3.83(s,3H),4.32-4.36(m,2H),4.60(d,J＝10.0Hz,1H),4.96(br,1H),5.07(s,1H),5.82(d,J＝6.6Hz,1H),6.17(t,J＝18.2Hz,1H),6.89(br,2H),7.14(d,J＝7.7Hz,2H),7.28-7.39(m,8H),7.46(t,J＝15.5Hz,3H),7.59(t,J＝15.2Hz,1H),8.05(d,J＝8.4Hz,2H)；13C-NMR(125MHz,CDCl3)δ(ppm):13.01,14.21,15.55,21.04,22.08,26.50,26.76,26.91,27.12,31.95,36.73,38.66,41.87,42.37,47.78,55.31,60.38,71.64,72.12,74.37,81.19,83.76,84.50,107.51,113.66,128.42,128.64,128.91,129.52,129.80,131.47,133.64,133.86,134.38,138.57,160.09,165.07,169.33,170.63；
8g:1HNMR(CDCl3,500MHz)δ(ppm):1.16(s,3H,CH3),1.55(s,3H,CH3),1.41-1.71(m,1H),1.76(s,3H,CH3),1.80(s,3H,CH3),1.84-1.95(m,2H),2.28(s,3H,CH3),2.4(s,3H,CH3),2.4-2.6(m,2H),2.83(d,1H),3.36(br,s,1H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.6(br,s,1H),4.76(d,J＝2.5Hz,1H),4.83(d,J＝10.0Hz),4.92-4.97(d,J＝2Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5,1.5Hz,1H),5.88(dd,J＝9.5,2.5Hz,1H),5.9-5.94(m,1H),7.31-7.40(m,3H),7.46-7.51(m,5H),7.56-7.65(m,2H),7.70(d,J＝7.5Hz,2H),8.07(d,J＝7.0Hz,2H).13C-NMR(125MHz,CDCl3)δ(ppm):12.65,14.12,15.15,19.27,22.75,26.49,29.67,31.65,38.76,43.92,44.63,47.10,54.42,60.41,71.21,71.26,71.32,73.82,74.14,76.85,77.26,78.94,82.67,83.88,126.66,127.20,128.18,128.66,128.70,129.50,129.77,131.88,132.66,133.64,133.88,138.10,138.42,165.50,165.57,171.10,171.22；HR-MS:calcd for C45H50ClNO12([M+Na]+),898.2414,found898.2400；
实施例八：制备化合物3’-N-2-呋喃酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同示例一：
5h:1H NMR(500MHz,CDCl3)δ(ppm):3.37(d,J＝3.3Hz,2H),3.86(s,3H),4.63(br,1H),5.72(dd,J＝2.0 and 2.2Hz,1H),6.51(dd,J＝2.0 and 1.0Hz,1H),7.12(d,J＝4.5Hz,2H),7.19(br,1H),7.32(t,J＝15.5Hz,1H),7.38(t,J＝15.0Hz,2H),7.46-7.49(m,2H)；13C NMR(125MHz,CDCl3)δ(ppm):53.31,55.08,112.23,114.89,126.95,128.00,128.76,138.62,144.19,147.43,157.64,173.26；
6h:1H NMR(500MHz,CDCl3)δ(ppm):3.80(s,3H),3.84(s,3H),4.95(br,1H),5.84(br,1H),6.37(dd,J＝and 1.0Hz,1H),6.88(d,J＝10.5Hz,2H),6.94(d,J＝2.4Hz,2H),7.02(s,1H),7.29-7.37(m,6H),7.50(d,J＝8.5Hz,2H)；13C NMR(125MHz,CDCl3)δ(ppm):14.20,21.03,52.82,55.26,60.38,63.90,64.02,111.67,113.48,117.57,127.95,128.57,128.79,128.97,129.72,144.98,147.01,158.91,159.97,170.42；
7h:1H NMR(500MHz,CDCl3)δ(ppm):1.26(s,3H),1.53(s,6H),1.65-1.69(m,1H),1.71(s,3H),1.83(s,3H),1.84-1.89(m,1H),1.95(s,3H),2.01(s,3H),2.48-2.55(m,1H),2.61-2.67(m,1H),2.77(d,J＝5.5Hz,2H),3.82(s,3H),4.32-4.37(q,J＝22.5Hz,2H),4.60(d,J＝10.6Hz,1H),4.91(d,J＝9.7Hz,1H),5.03-5.09(m,2H),5.08(s,3H),5.82(d,J＝6.5Hz,1H),5.98(s,1H),6.17(t,J＝17.6Hz,1H),6.36(dd,J＝1.0 and 1.2Hz,1H),6.87(d,J＝9.5Hz,2H),6.95(d,J＝3.4Hz,1H),7.18(s,1H),7.30-7.35(m,4H),7.40-7.51(m,6H),7.59(t,J＝15.5Hz,1H),8.05(d,J＝8.2Hz,2H)；13C NMR(125MHz,CDCl3)δ(ppm):13.01,14.02,15.48,21.04,22.03,26.54,26.85,26.88,27.10,31.92,36.74,38.65,41.89,42.35,47.85,55.26,60..37,71,68,71.92,72.13,74.35,76.36,81.14,83.75,84.52,91.84,107.44,111.74,128.63,128.98,129.53,133.63,133.70,138.59,145.02,146.86,159.98,165.04,169.46；
8h:1H NMR(500MHz,CDCl3)δ(ppm):1.15(s,3H,CH3),1.61(s,3H,CH3), 1.46-1.73(m,1H),1.75(s,3H,CH3),1.80(s,3H,CH3),1.85-1.98(m,2H),2.27(s,3H,CH3),2.4(s,3H,CH3),2.4-2.6(m,2H),3.36(br,1H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.6(br,1H),4.76(d,J＝2.5Hz,1H),4.83(d,J＝10.5Hz,1H),4.92-4.97(d,J＝2.7Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5 and 1.5Hz,1H),5.88(dd,J＝9.5 and 2.5Hz,1H),5.90-5.94(m,1H),6.51(m,1H),7.13(d,2H),7.30-7.39(m,3H),7.46-7.52(m,4H),7.64(t,J＝10.6Hz,1H),8.07(d,J＝7.0Hz,2H).13CNMR(125MHz,CDCl3)δ(ppm):12.64,14.12,15.11,21.02,22.65,26.41,26.75,31.68,37.98,43.98,44.65,47.15,53.81,60.46,71.14,71.27,71.33,74.07,76.88,77.24,79.05,82.78,83.88,112.38,115.08,127.34,128.0,128.65,129.35,129.76,133.68,133.98,138.38,138.42,144.38,147.47,157.68,165.04,170.97,171.25；HR-MS:calcd for C43H49NO13([M+Na]+),810.3102,found810.3070；
实施例九：制备化合物3’-N-2-噻吩酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同示例一：
5i:1H NMR(500MHz,CDCl3)δ(ppm):3.35(d,J＝3.0Hz,2H),3.74(s,3H),4.63(br,1H),5.35(dd,J＝2.0 and 2.2Hz,1H),6.21(dd,J＝2.5 and 1.0Hz,1H),7.20(d,J＝4.0Hz,2H),7.30(br,1H),7.35(t,J＝15.5Hz,1H),7.51(t,J＝15.3Hz,2H),7.52-7.56(m,2H)；13CNMR(125MHz,CDCl3)δ(ppm):29.71,53.35,54.83,73.18,126.92,127.71,128.00,128.54,128.77,130.46,138.24,138.61,161.28,173.29；
6i:1H NMR(500 MHz,CDCl3)δ(ppm):3.8(s,3H),3.84(s,3H),4.96(d,J＝2.5Hz,1H),5.76(d,J＝2.3Hz,1H),6.85(t,J＝9.8Hz,1H),6.90(d,J＝16.0Hz,2H),6.99(s,1H),7.05(d,J＝4.0Hz,1H),7.34-7.39(m,5H),7.43(d,J＝5.5Hz,1H),7.55(d,J＝8.5Hz,2H)；13CNMR(125MHz,CDCl3)δ(ppm):52.88,55.29,64.91,91.81, 113.52,126.92,127.49,128.26,128.88,129.15,129.52,129.93,131.22,138.37,139.02,160.07,163.90,170.39；
7i:1H NMR(500MHz,CDCl3)δ(ppm):1.26(s,3H),1.53(s,3H),1.55(s,3H),1.65-1.69(m,1H),1.71(s,3H),1.83(s,3H),1.84-1.89(m,1H),1.95(s,3H),2.05(s,3H),2,48-2,55(m,1H),2.61-2.67(m,1H),2.77(d,J＝5.5Hz,2H),3.84(s,3H),4.09-4.15(m,3H),4.32-4.37(q,J＝26.6Hz,2H),4.60(d,J＝10.5Hz,1H),4.91(d,J＝9.5Hz,1H),5.03-5.09(m,3H),5.82(d,J＝6.2Hz,1H),5.91(s,1H),6.18(t,J＝20.5Hz,1H),6.86(t,J＝9.7Hz,1H),6.91(d,J＝8.8Hz,2H),7.04(d,J＝3.5Hz,1H),7.14(s,1H),7.37-7.49(m,8H),7.54-7.61(m,3H),8.05(d,J＝7.5Hz,2H)； 13CNMR(125MHz,CDCl3)δ(ppm):13.04,14.20,15.63,21.04,22.03,26.55,26.84,26.90,27.11,31.96,36.72,38.65,41.87,42.37,47.85,55.29,60.38,65.35,71.72,71.95,72.08,74.36,76.37,81.14,83.77,84.56,92.08,107.44,113.58,127.07,127.49,128.37,128.62,128.93,129.23,129.55,129.81,130.00,131.24,133.61,133.70,138.15,138.64,160.09,163.46,15.06,169.41,171.00；
8i:1H NMR(500MHz,500MHz)δ(ppm):1.16(s,3H,CH3),1.62(s,3H,CH3),1.54-1.70(m,1H),1.76(s,3H,CH3),1.81(s,3H,CH3),1.86-1.97(m,2H),2.27(s,3H,CH3),2.4-2.6(m,2H),2.85(d,J＝2.5Hz,1H),3.36(br,1H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.6Hz,1H),4.66-4.77(m,3H),4.83(d,J＝10.5Hz,1H),4.97(d,J＝2.2Hz,2H),5.76(dd,J＝5.5 and 1.5Hz,1H),5.83(dd,J＝9.5and 2.5Hz,1H),5.9-5.94(m,1H),7.08(t,J＝10.7Hz,1H),7.31-7.40(d,J＝3Hz,4H),7.46-7.53(m,4H),7.56-7.64(m,2H),8.07(d,J＝7.9Hz,2H).13C NMR(125MHz,CDCl3)δ(ppm):12.64,15.33,22.62,26.45,29.7,31.74,31.85,38.16,43.98,44.63,47.27,54.57,71.29,71.32,73.90,74.14,76.81,77.27,79.07,82.77,83.97,127.31,127.70,128.17,128.63,128.74,129.54,129.75,130.58,133.64,133.97,138.21,138.48,138.57,161.14,165.08,171.08,171.60；HR-MS:calcd for C43H49SO12([M+H]+),804.3053,found 804.3060；
实施例十：制备化合物3’-N-2-苯丙呋喃酰-(7,9,10)-三去乙酰基-1-去羟基紫杉醇类似物的制备方法，该化合物的结构式为：
方法同示例一：
5j:1H NMR(500MHz,CDCl3)δ(ppm):3.87(s,3H),4.67(d,J＝2.0Hz,1H),5.79(d,J＝9.5Hz,1H),7.29-7.35(m,2H),7.38-7.46(m,3H),7.49-7.54(m,4H),7.67(d,J＝8.0Hz,2H)；13CNMR(125MHz,CDCl3)δ(ppm):30.33,53.33,54.36,73.19,111.15,111.94,122.74,123.77,127.01,128.08,128.80,138.49,148.09,158.28,173.19；
6j:1H NMR(500MHz,CDCl3)δ(ppm):3.80(s,3H),3.85(s,3H),5.01(s,1H),5.95(br,1H),6.90(d,J＝8.5Hz,2H),7.13(br,1H),7.20-7.24(m,2H),7.30-7.39(m,4H),7.45(d,J＝7.4Hz,2H),7.55(d,J＝8.0Hz,2H)；13CNMR(125MHz,CDCl3)δ(ppm):14.22,21.03,52.84,55.25,60.37,64.35,91.78,111.88,113.34,113.56,122.62,123.72,126.69,127.12,128.06,128.64,129.03,147.85,154.87,160.06,170.36；
7j:1H NMR(500MHz,CDCl3)δ(ppm):1.26(s,3H),1.49(s,6H),1.56(s,3H),1.65-1.69(m,1H),1.69(s,3H),1.84(s,3H),1.87-1.94(m,1H),1.98(s,3H),2.01(s,3H),2.46-2.53(m,1H),2.58-2.66(m,1H),2.75(d,J＝5.5Hz,2H),3.83(s,3H),4.32-4.36(m,2H),4.60(d,J＝10.2Hz,1H),4.96(br,1H),5.07(s,1H),5.82(d,J＝6.5Hz,1H),6.17(t,J＝18.6Hz,1H),7.23(d,J＝4.5Hz,2H),7.42(d,J＝7.5Hz,2H),7.28-7.39(m,8H),7.46(t,J＝15.4Hz,3H),7.59(t,J＝15.5Hz,1H),8.05(d,J＝8.4Hz,2H)；13CNMR(125MHz,CDCl3)δ(ppm):12.01,15.21,15.55,25.04,26.08,26.50,26.76,26.91,28.12,31.95,36.73,39.66,41.87,42.37,47.78,55.31,58.38,71.68,72.12,74.37,80.19,83.76,85.50,111.51,113.66,126.42,129.64,131.91,132..52,133.80,134.47,136.64,133.78,139.38,140.57,150.65,160.09,165.07,169.33,170.63；
8j:1H NMR(500MHz,CDCl3)δ(ppm):1.16(s,3H,CH3),1.65(s,3H,CH3),1.71(s,2H),1.41-1.71(m,1H),1.76(s,3H,CH3),1.81(s,3H,CH3),1.84-1.95(m,2H),2.28(s,3H,CH3),2.4(s,3H,CH3),2.4-2.6(m,2H),2.83(d,J＝2.4Hz 1H),3.36(br, 1H),4.20(d,J＝8.5Hz,1H),4.26-4.30(m,2H),4.36(d,J＝8.0Hz,1H),4.6(br,1H),4.76(d,J＝2.5Hz,1H),4.83(d,J＝10.0Hz,1H),4.92-4.97(d,J＝2.7Hz,2H),5.3(s,3H,CH3),5.74(dd,J＝5.5 and 1.5Hz,1H),5.88(dd,J＝9.5 and 2.5Hz,1H),5.90-5.94(m,1H),7.31-7.52(m,7H),7.53-7.57(t,2H),7.60-7.69(m,3H),7.85(d,J＝2.5Hz,1H),8.20(d,J＝5.6Hz,2H)；13C NMR(125MHz,CDCl3)δ(ppm):12.54,14.11,23.10,25.55,31.65,37.8,838.04,43.97,44.65,47.14,54.15,71.15,71.20,76.85,77.14,79.06,82.65,83.88,111.10,111.80,122.74,123.87,126.97,127.37,127.57,128.14,128.67,129.57,129.78,133.68,133.91,138.14,138.47,148.17,154.72,158.12,165.08,170.87,171.14.HR-MS:calcd for C47H51NO13([M+Na]+),860.3258,found 860.3244；
实施例十一：抗肿瘤生物活性体外筛选试验
MTT法。96孔板每孔加入浓度为4-5×104个/ml的细胞悬液100μl，置37℃，5％CO2培养箱内。24h后，加入样品液，10μl/孔，设双复孔，37℃，5％CO2作用72h。每孔加入5mg/ml的MTT溶液20μl，作用4h后加入溶解液，100μl/孔，置培养箱内，溶解后用全波长多功能酶标仪测570nm OD值。
表1化合物8b，8c，8e，8d，8h对人体肿瘤的体外增殖抑制作用
A549(人肺腺癌细胞)；MDA-MB-231(人乳腺癌细胞)；PC-3(人前列腺癌细胞

Claims (2)

1.一种9,10-二羟基-1-去氧紫杉醇类似物，其特征在于该类似物的结构式为：
其中：R为：甲基苯基、甲氧基苯基、丙基苯基、乙基苯基、氟苯基、甲基氯苯、溴苯基、呋喃基、噻吩基或苯并呋喃基。
2.一种制备根据权利要求1所述的9,10-二羟基-1-去氧紫杉醇类似物的方法，其特征在于该方法的具体步骤为：
a．将原料1-去羟基巴卡亭VI（1）与水合肼按1:300~400的摩尔比溶于质量百分比浓度为95%的酒精中，室温下搅拌15～18小时；调节体系的pH值为6~7，乙酸乙酯萃取，有机相经干燥，去除溶剂得粗产物；该粗产物经分离纯化，得无色透明晶体4,7,9,10,13-五去乙酰基-1-去氧巴卡亭VI，即化合物2，其结构式为：；
b．将步骤a所得化合物2和 2,2-二甲氧基丙烷按1:2~5的摩尔比溶于二氯甲烷溶剂中，再加入催化剂用量的蒙脱土K10，在30~50oC温度下搅拌至反应完全；除去催化剂和溶剂后，该粗产物经分离纯化，得白色固体7,13-三去乙酰基-9,10-O-异亚丙基-1-去氧巴卡亭VI，即化合物3，其结构式为：；
c．将苯异丝氨酸4(1equiv）溶于无水甲醇中，惰性气氛保护下，冰水浴下加入二氯亚砜（1.5equiv），过夜反应；蒸出溶剂，乙酸乙酯和水萃取，取有机相干燥后旋干，经分离提纯，得甲酯化中间体；将该甲酯化中间体化合物溶于四氢呋喃和饱和碳酸氢钠溶液混合溶液中，冰水浴下按摩尔比1：3加入酰氯，室温下搅拌反应至反应结束，蒸除四氢呋喃，经乙酸乙酯萃取、干燥后，蒸除溶剂，得粗产物；该粗产物经分离提纯得产物5a-j；
d. 将化合物5a-j溶于重蒸的甲苯中，加入催化量的对甲苯磺酸吡啶盐，和1.5个当量的，N2保护，110oC下搅拌两个小时；乙酸乙酯萃取，无水硫酸钠干燥，减压蒸除溶剂；粗产物经柱层析纯化（石油醚：乙酸乙酯=5：1）的黄色油状液体6a-j.
e. 将化合物6a-j加入无水甲醇中，加入NaOH溶液（1.2个当量），室温下搅拌2h；反应结束后，减压蒸除溶剂，用无水乙醚萃取，取下层水相，加入3N盐酸调节PH=2（出现大量白色固体），用乙酸乙酯萃取，无水硫酸钠干燥；将压蒸除得产物，将所得产物，化合物3，DCC(2eq)，DMAP（1eq）溶于5mL的甲苯中，50 oC下搅拌两个小时，TLC跟踪反应结束，过滤除去不溶固体，有机相用乙酸乙酯稀释，干燥，减压蒸除溶剂；粗产物经柱层析纯化（石油醚：乙酸乙酯=1：1）的白色固体7a-j.
f. 将化合物7a-j溶于无水甲醇中，加入0.7个当量的对苯甲磺酸，室温下反应6h，TLC跟踪反应结束，混合液用乙酸乙酯稀释，无水硫酸钠干燥，减压蒸除溶剂，粗产物经薄层层析分离（石油醚：乙酸乙酯=2：1）的最终产物8a-j。
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