CN1086512A - 紫杉酚中间体的制备方法 - Google Patents

紫杉酚中间体的制备方法 Download PDF

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CN1086512A
CN1086512A CN93103662A CN93103662A CN1086512A CN 1086512 A CN1086512 A CN 1086512A CN 93103662 A CN93103662 A CN 93103662A CN 93103662 A CN93103662 A CN 93103662A CN 1086512 A CN1086512 A CN 1086512A
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罗·A·赫顿
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Abstract

本发明公开了通式如下的β-内酰胺以及制备紫 杉酚中间体的方法，该方法包括使β-内酰胺与醇在 活化剂存在下反应生成紫杉酚中间体。
式中R1是芳基，取代芳基，烷基，烯基或炔基； R2是氢，烷基，酰基，乙缩醛，乙氧乙基或其他羟基保 护基团，以及R3是芳基，取代芳基，烷基，烯基或炔 基。

Description

本发明涉及新的β-内酰胺，它们的制备方法以及使用这种β-内酰胺制备紫杉酚的方法。
萜烃中的紫杉烷（taxane）族（紫杉酚是其中的一员），在生物和化学领域已引起了人们的极大关注。紫杉酚是一种有前途的癌症化疗药物，其具有广谱抗白血病和抗肿瘤活性并具有以下结构：
Figure 931036623_IMG5
由于紫杉酚具有上述活性，目前在法国和美国正进行临床试验。
目前用于临床试验的紫杉酚来源于几种紫杉的树皮。但是，在上述的生长缓慢的常绿树中，只有少量的树皮发现有紫杉酚，因此，有限的紫杉酚来源不能满足需要。近年来，化学工作者们已花费精力试图开发一种可行的制备紫杉酚的合成路线。迄今为止，结果还不能令人完全满意。
已提出的一种合成路线涉及从商品化学品出发合成四环紫杉烷核。Holton等人在JACS110，6558（1988）中报道了紫杉酚同族的紫杉精的合成方法。尽管该方法取得了进展，但是紫杉酚最终的总的合成方法似乎步骤多，费时而且费用高。
Greene等人在JACS  110，5917（1988）中叙述了另一种紫杉酚的制备方法，该方法包括使用紫杉酚同族，即具有如下结构式的10-脱乙酰基-浆果赤霉素Ⅲ：
Figure 931036623_IMG6
由于可以从欧紫杉叶中获取，10-脱乙酰基-浆果赤霉素Ⅲ比紫杉酚更易得到。根据Greene等人的方法，通过联结上C10乙酰基和通过用β-酰氨基羧酸单元对C13醇进行酯化，联结上C13β-酰氨基酯侧链，将10-脱乙酰基浆果赤霉素Ⅲ转化成紫杉酚。尽管该方法步骤相对少，但是，β-酰氨基羧酸单元的合成却是一个产率低的多步骤反应，并且偶合反应时间长，产率也低。该偶合反应是一个关键步骤，在紫杉酚或其生物活性衍生物的每个可行的合成方法中均需要该反应，因为正如Wani等人指出的，C13位上联有β-酰氨基酯侧链是抗肿瘤活性所必需的。
合成紫杉酚和其他抗肿瘤药剂的主要困难是缺乏易于连结在C13位氧原子上，以提供β-酰氨酯侧链的单元。研究这种单元并以高产率连接的方法将有利于紫杉酚的合成和具有改性核取代基或改性C13侧链的相关抗肿瘤药剂的合成。一种新的易获得的侧链前体化学单元和将其连接在C13氧原子上的有效方法的发现满足了这一需要。
本发明的目的是提供一种用于合成紫杉酚的侧链前体并提供一种高产率地连接侧链前体的方法，进而提供紫杉酚中间体。
具体地讲，本发明涉及下式β-内酰胺（1）的侧链前体：
Figure 931036623_IMG7
式中R1是芳基，取代芳基，烷基，链烯基或链炔基;R2是氢，乙氧基乙基，乙缩醛或其他羟基保护基团;以及R3是芳基，取代芳基，链烯基或链炔基。
本发明还涉及制备紫杉酚中间体的方法，该方法包括在有效条件下，在足量的活化剂存在下，使醇与β-内酰胺（1）反应，生成可用作合成紫杉酚中间体的β-酰氨基酯。
本发明还涉及制备紫杉酚的方法，该方法包括在有效条件下，在足量的活化剂存在下，使醇与β-内酰胺（1）反应，生成β-酰胺基酯紫杉酚中间体。然后，用该中间体合成紫杉酚。
本发明的其他目的和特征在以下的叙述中是显见的。
本发明涉及β-内酰胺（1）及其衍生物，其结构由下式代表：
Figure 931036623_IMG8
如上所述，R1是芳基，取代芳基，烷基，链烯基或链炔基;R2是氢，乙氧基乙基，乙缩醛或其他羟基保护基团;R3是芳基，取代芳基，烷基，链烯基或链炔基。推荐的是：R1是苯基，取代苯基或芳基;R2是乙氧乙基，2，2，2-三氯乙氧甲基或其他乙缩醛羟基保护基团;和R3是苯基，取代苯基或芳基。两个优选的β-内酰胺（其中R1和R3是苯基）的结构如下：
Figure 931036623_IMG9
按照IUPAC原则，β-内酰胺（2）和（3）的命名分别是1-苯甲酰基-4-苯基-3-（1-乙氧乙氧基）氮杂环丁烷-2-酮（2）和1-苯甲酰基-4-苯基-3-（2，2，2-三氯乙氧甲氧基）氮杂环丁烷-2-酮（3）。最优选的β-内酰胺是β-内酰胺（2）。
根据本发明，提供了一种制备紫杉酚中间体的方法，天然紫杉酚和非天然紫杉酚具有以下结构式：
Figure 931036623_IMG10
式中，
A和B分别是氢或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，或者
A和B一起形成氧代基;
L和D分别是氢或羟基或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，
E和F分别是氢或低级烷酰氧基，烯酰氧基，炔酰氧基或芳酰氧基，或者
E和F一起形成氧代基;
G是氢或羟基或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，或者
G和M一起形成氧代基或亚甲基，或者
G和M一起形成氧代环丙基环，或者
M和F一起形成氧代环丁基环;
J是氢，羟基，或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基
I是氢，羟基或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，或者
I和J一起形成氧代基;以及
K是氢，羟基，或低级烷氧基、烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基;和
P和Q分别昌氢或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，或者
P和Q一起形成氧代基;
S和T分别是氢或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，或者
S和T一起形成氧代基;
U和V分别是氢或低级烷基、烯基、炔基、芳基或取代芳基;以及
W是芳基，取代芳基，低级烷基、烯基或炔基。
紫杉酚中的烷基，无论是上述定义的单独基团还是与各种取代基组合的基团，最好是主链含1至6个碳原子并且含至多10个碳原子的低级烷基。它们可以是直链的或者支链的，包括甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，芳基，己基等等。
紫杉酚中的烯基，无论是上述定义的单独基团还是与各种取代基组合的基团，最好是主链含1至6个碳原子并且含至多10个碳原子的低级烯基。它们可以是直链的或者是支链的，包括乙烯基，丙烯基，异丙烯基，丁烯基，异丁烯基，芳基，己烯基等。
紫杉酚中的炔基，无论是上述定义的单独基团还是与各种取代基组合的基团，最好是主链含1至6个碳原子并且含至多10个碳原子的低级烷基。它们可以是直链的或者支链的，包括乙炔基，丙炔基，丁炔基，异丁炔基，芳炔基，己炔基等。
烷酰氧基的例子有乙酸根，丙酸根，丁酸根，戊酸根，异丁酸根等。优选的烷酰氧基是乙酸根。
紫杉酚中的芳基部分，无论是单独或与各种取代基组合的基团，含有6至10个碳原子，包括苯基，α-萘基或β-萘基等。取代基包括烷氧基，羟基，卤素，烷基，芳基，烯基，酰基，酰氧基，硝基，氨基，酰氨基等。苯基是优选的芳基。
下表Ⅰ列举了优选的取代基A，B，D，L，E，F，G，M，I，J，K，P，Q，S，T，U，V，和W。
Figure 931036623_IMG11
以下给出具有通式结构的化合物的例子
Figure 931036623_IMG12
Figure 931036623_IMG13
Figure 931036623_IMG14
Figure 931036623_IMG15
依据本发明的方法，在醇和活化剂存在下，最好在叔胺如三乙胺，二异丙基乙基胺，吡啶，N-甲基咪唑和4-二甲基氨基吡啶（DMAP）存在下，β-内酰胺（1）转化成β-酰氨基酯。例如，在4-二甲基氨基吡啶（DMAP）存在下，β-内酰胺（1）与具有紫杉烷四环核和C13羟基的化合物反应，得到在C13位上具有β-酰氨基酯基的物质。
优选的醇是7-O-三乙基甲硅烷基浆果赤霉素Ⅲ，它可以通过Greene等人在JACS  110，5917（1988）中所述方法或其他方法来制备。正如Greene等人指出，按照如下反应式，10-脱乙酰基浆果赤霉素Ⅲ转化成7-O-三乙基甲硅烷基浆果赤霉素Ⅲ：
Figure 931036623_IMG16
在据称是最佳的条件下，10-脱乙酰基浆果赤霉素Ⅲ与20当量（C2H5）3SiCl在23℃、氩气氛下，在50ml吡啶/mmol 10-脱乙酰基浆果赤霉素Ⅲ存在下，反应20小时，生成产物7-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ（32a），提纯后产率为84-86%。然后，在0℃、氩气氛下，反应产物用5当量的CH3COCl和25ml吡啶/mmol（32a）乙酰化48小时，得到7-O-三乙基甲硅烷基浆果赤霉素Ⅲ（32b），产率86%。见Greene等人：JACS110，5917-5918（1988）。
如以下反应式所示，7-O-三乙基甲硅烷基浆果赤霉素Ⅲ（32b）可以与本发明的β-内酰胺在室温下反应得到紫杉酚中间体，其中C7和C2′位上的羟基分别被三乙基甲硅烷基和乙氧基乙基保护。然后这些基团在温和条件下水解以不影响酯键或紫杉酚取代基。
Figure 931036623_IMG17
尽管上述反应式涉及的是天然紫杉酚产品的合成，但是，经改进后可用于β-内酰胺或四环醇（可从天然或非天然来源获得），制备包括在本发明内的其他合成紫杉酚。
另一个方案是，β-内酰胺（1）可以在活化剂和7-O-三乙基甲硅烷基浆果赤霉素Ⅲ以外的醇存在下转化成β-酰氨基酯，得到紫杉酚中间体。然后用紫杉酚中间体，按照合适的反应合成紫杉酚。
β-内酰胺中的烷基，无论是上述定义的单独基团还是与其他取代基的组合基团，最好是主链含有1至6个碳原子并且最多含15个碳原子的低级烷基。它们可以是直链的或者是支链的，包括甲基，乙基，丙基，异丙基，丁基，叔丁基，芳基，己基等。
β-内酰胺中的烯基，无论是上述定义的单独基团还是与其他取代基的组合基团，最好是主链含2至6个碳原子的并且含至多15个碳原子的低级烯基。它们可以是直链的或者是支链的，包括乙烯基，丙烯基，异丙烯基，丁烯基，异丁烯基，芳基，己烯基等。
β-内酰胺中的炔基，无论是上述定义的单独基团还是与其取代基的组合基团，阳好是主链含2至6个碳原子的并且含至多15个碳原子的低级炔基。它们可以是直链的或者是支链的，包括乙炔基，丙炔基，丁炔基，异丁炔基，芳基，己炔基等。
β-内酰胺中的烷酰氧基的例子包括乙酸根，丙酸根，丁酸根，戊酸根，异丁酸根等。优选的烷酰氧基是乙酸根。
所述的β-内酰胺的芳基部分，无论是单独基团或与其他取代基的组合基团，含有6至15个碳原子，并且包括苯基，α-萘基或β-萘基等。取代基包括烷氧基，羟基，卤素，烷基，芳基，烯基，酰基，酰氧基，硝基，氨基，酰氨基等。苯基是优选的芳基。
如上所述，β-内酰胺（1）中的R2可以是烷基，酰基，乙氧乙基，2，2，2-三氯乙氧甲基或其他的羟基保护基团如乙缩醛和醚，例如甲氧甲基，苯甲酰氧甲基;酯如乙酸酯，碳酸酯。例如碳酸甲酯等。各种羟基保护基及其合成方法见诸“Protective Groups in Organic Synthesis”，T.W.Greene著，John Wiley and Son出版（1981）。选择的羟基保护基应该在温和条件下易于除去以不破坏紫杉酚中间体中的酯键或其他取代基。优选的R2是乙氧乙基或2，2，2-三氯乙氧甲基，最好是乙氧乙基。
以下列举了优选的β-内酰胺取代基R1，R2和R3。
Figure 931036623_IMG18
以下给出具有通式结构的化合物例子：
Figure 931036623_IMG19
由于β-内酰胺1具有几个不对称碳，所以本领域技术人员知道，具有不对称碳原子的本发明化合物可以以非对映异构体、外消旋体或光学活性形式存在。所有这些形式均被认为在本发明范围之内。更具体地说，本发明包括对映异构体，非对映异构体，外消旋混合物和上述异构体的混合物。
β-内酰胺（1）可以从易获取的原料出发来制备，如以下制备β-内酰胺（2）反应式所示：
Figure 931036623_IMG20
试剂：（a）三乙胺，CH2cl2，25℃，18小时
（b）4当量硝酸高铈铵，CH3CN，-10℃，10分钟;
（c）KOH，THF，H2O，0℃，30分钟
（d）乙基乙烯基醚，THF，甲苯磺酸（催化），0℃，1.5小时;
（e）CH3Li，***，-78℃，10分钟，苯甲酰氯，-78℃，1小时。
起始原料易于获得。α-酰氧基乙酰氯从乙醇酸出发制备，并且在叔胺存在下，与由醛和对-甲氧苯胺制得的亚胺环缩合作用，得到1-对-甲氧苯基-3-酰氧基-4-芳基氮杂环丁烷-2-酮。
对-甲氧苯基通过用硝酸高铈铵氧化可以容易地除去，酰氧基可以在类似于本技术领域已知的标准条件下水解，得到3-羟基-4-芳基氮杂环丁烷-2-酮。
3-羟基基团可以用各种标准的保护基如1-乙氧乙基进行保护。最好是，在保护之前，通过相应的2-甲氧基-2-（三氟甲基）苯基乙酸酯的重结晶，外消旋的3-羟基-4-芳基氮杂环丁烷-2-酮解析成纯的对映异构体，而且只用右旋的对映异构体制备紫杉酚。在任何情况下，通过用碱处理，最好用正丁基锂和芳酰基氯在-78℃或低于-78℃下处理，将3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮转化成β-内酰胺（2）。
以下实施例用以描述本发明。
实施例1
顺-1-苯甲酰基-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷酮（2）的制备
顺-1-对甲氧苯基-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮：
于-20℃下向由962mg（4.56mmol）亚胺（由苯甲醛和对甲氧苯胺制得）和在15mlCH2Cl2中的0.85ml（6.07mmol）三乙胺组成的溶液中，滴加413mg（3.04mmol）α-乙酰氧基乙酰氯在15mlCHcl中的溶液。反应混合物于25℃下加热18小时。然后用100mlCH2cl2稀释反应混合物并且用30ml10%HCl水溶液萃取该溶液。依次用30ml水和30ml饱和碳酸氢钠水溶液洗涤有机层，硫酸钠干燥，浓缩得到固体。用50ml己烷研制该固体并过滤混合物。剩余固体在乙酸乙酯/己烷中重结晶，得到645mg（68%）顺-1-对甲氧苯基-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮，白色晶体，熔点163℃。
顺-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮：
于-10℃下，向20.2g顺-1-对甲氧苯基-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮和700ml乙腈组成的溶液中缓慢地滴加硝酸高铈铵和450ml水组成的溶液，历时1小时。混合物在-10℃下搅拌30分钟，并且用500ml***稀释。水层用2份各100ml***萃取，合并的有机层依次用2份各100ml水，2份各100ml饱和亚硫酸氢钠水滴液和2份各100ml饱和碳酸氢钠水溶液洗涤，并且浓缩得到18.5g固体。固体在丙酮/己烷中重结晶得到12.3g（92%）顺-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮，白色晶体，熔点152-154℃。
顺-3-羟基-4-苯基氮杂环丁烷-2-酮：
于0℃，通过滴液漏斗，向由200ml  THF和280ml  1M氢氧化钾水溶液组成的混合物中滴加4.59g（22.4mmol）顺-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮和265mlTHF的溶液，历时40分钟。溶液在0℃下搅拌1小时并且加入100ml水和100ml饱和碳酸氢钠溶液。混合物用4份各200ml乙酸乙酯萃取，合并的有机层在硫酸钠中干燥并且浓缩得到3.54g（97%）外消旋的顺-3-羟基-4-苯基氮杂环丁烷-2-酮，白色晶体，熔点147-149℃。通过它的2-甲氧基-2-（三氟甲基）苯基乙酸酯在己烷/丙酮中重结晶并且随后水解，该原料解析成它的对映体，〔α〕25 Hg177°。
顺-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮：
于0℃向3.41g（20.9mmol）顺-3-羟基-4-苯基氮杂环丁烷-2-酮与15mlTHF的溶液中加入5ml乙基乙烯基醚和20mg（0.2mmol）甲磺酸。混合物在0℃下搅拌20分钟，用20ml饱和碳酸氢钠水溶液稀释并用三份各40ml乙酸乙酯萃取。合并的乙酸乙酯层在硫酸钠中干燥并且浓缩，得到4.87g（99%）顺-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮，无色油状物。
顺-1-苯甲酰基-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮：
于-78℃，向2.35g（10mmol）顺-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮与40mlTHF的溶液中加入6.1ml（10.07mmol）1.65M的正丁基锂-己烷溶液。混合物在-78℃下搅拌10分钟并加1.42g（10.1mmol）苯甲酰氯与10mlTHF组成的溶液。该混合物于-78℃下搅拌1小时并用70ml饱和碳酸氢钠水溶液稀释，用3份各50ml乙酸乙酯萃取。合并的乙酸乙酯萃取液在硫酸钠中干燥并且浓缩得到3.45g油状物。油状物在硅胶柱上层析，用乙酸乙酯/己烷洗脱，得到3.22g（95%）顺-1-苯甲酰基-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮（2），为无色油状物。
实施例2
由顺-1-苯甲酰基-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮（2）制备β-酰氨基酯
苄基-3-苯甲酰氨基-3-苯基-2-羟基丙酸酯：
向88mg（0.26mmol）顺-1-苯甲酰基-3-（1-乙氧乙氧基）-4-苯基氮杂环丁烷-2-酮与0.3mlTHF的溶液中加入28mg（0.26mmol）苄醇和32mg（0.26mmol）4-二甲基氨基吡啶（DMAP）。在25℃下反应5小时后，混合物用10ml饱和碳酸氢钠水溶液稀释并且用3份各20ml乙酸乙酯萃取。合并的乙酸乙酯层依次用10ml15%Hcl水溶液和10ml饱和碳酸氢钠溶液萃取，在硫酸钠中干燥并且浓缩得到112mg（100%）苄基酯，油状物，纯度＞95%经NMR分析。向该油状物与4mlTHF的溶液中加入1ml10%Hcl水溶液。混合物在25℃下搅拌30分钟，用20ml饱和碳酸氢钠水溶液稀释并且用4份各30ml乙酸乙酯萃取。合并的乙酸乙酯萃取液在硫酸钠中干燥并且浓缩得到固体。该固体在氯仿中重结晶得到92mg（95%）苄基-3-苯甲酰氨基-3-苯基-2-羟基丙酸酯，白色晶体，熔点129-131℃。
紫杉酚：
向小型反应容器中加入109mg（0.320mmol）（+）-顺-1-苯甲酰基-3-（1-乙氧乙氧基-4-苯基-氮杂环丁烷-2-酮，45mg（0.064mmol）7-O-三乙基甲硅烷基浆果赤霉素Ⅲ，7.8mg（0.064mmol）4-二甲基氨基吡啶（DMAP）和0.032ml吡啶。混合物在25℃下搅拌12小时并用100ml乙酸乙酯稀释。乙酸乙酯溶液用20ml10%硫酸铜水溶液萃取，在硫酸钠中干燥并且浓缩。残余物通过硅胶柱过滤并用乙酸乙酯洗脱。在快速硅胶柱色谱中用乙酸乙酯/己烷洗脱随后在乙酸乙酯/己烷中重结晶得到61mg（92%）2′-（1-乙氧乙氧基）-7-O-三乙基甲硅烷基紫杉酚，2∶1非对映体混合物。
将5mg2′-（1-乙氧乙氧基）-7-O-三乙基甲硅烷基紫杉酚溶解于2ml乙醇中并且加入0.5ml0.5%HCl水溶液。混合物在0℃下搅拌30小时并且用50ml乙酸乙酯稀释。溶液用20ml饱和碳酸氢钠水溶液萃取，在硫酸钠中干燥并且浓缩。残余物以硅胶柱色谱提纯，用乙酸乙酯/己烷洗脱，得到4.5mg（约90%）紫杉酚，各项技术指数都与标准样品相同。
如上所述，可以认为已经达到了本发明的几个目的。
由于在不违背本发明范围下可以对上述组合物和方法作各种变更，因此上述所有叙述内容均被认为是说明性的，而不是用来限制它。

Claims (4)

1、一种制备紫杉酚中间体的方法，包括使具有下式的醇：
Figure 931036623_IMG2
式中：
A和B分别是氢或代级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，或者
A和B一起形成氧代基；
L和D分别是氢或羟基或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，
E和F分别是氢或低级烷酰氧基，烯酰氧基，炔酰氧基或芳酰氧基，或者
E和F一起形成氧代基；
G是氢或羟基或低级烷酰氧基、烯酰氧基、炔酰氧基权芳酰氧基，或者
G和M一起形成氧代基或亚甲基，或者
G和M一起形成环氧乙烷，或者
M和F一起形成环氧丙烷(oxetane)
J是氢，羟基，或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氨基
I是氢，羟基或低级烷酰氧基、烯酰氧基，炔酰氧基或芳酰氧基，或者
I和J一起形成氧代基；以及
K是氢，羟基，或低级烷氧基、烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基；和
P和Q分别是氢或低级烷酰氧基、烯酰氧基、炔酰氧基或芳酰氧基，或者
P和Q一起形成氧代基；
与具有下式的β-内酰胺反应：
Figure 931036623_IMG3
(式中，R1是苯基，α-萘基，β-萘基，C1-10烷基，C2-10烯基或C2-10炔基，R2是羟基保护基；和R3是苯基，α-萘基，β-萘基，C1-10烷基，C2-10烯基或C2-10炔基)，
所述的醇和β-内酰胺的反应是在活性剂存在下进行的，生成适合作为合成紫杉粉中间体的β-酰氨基酯。
2、权利要求1的方法，其中所述的醇具有如下结构：
Figure 931036623_IMG4
其中R4为氢或低级烷酰基，烯酰基，炔酰基或芳酰基。
3、权利要求1的方法，其中所述的活化剂是叔胺。
4、权利要求1的方法，其中所述的活化剂是三乙胺，二异丙基乙基胺，吡啶，N-甲基-咪唑，或4-二甲基吡啶。
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CN100375744C (zh) * 1997-11-18 2008-03-19 阿文蒂斯药物股份有限公司 紫杉化合物类衍生物的制备方法

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