CN1064958C - 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

Info

Publication number
CN1064958C
CN1064958C CN931036623A CN93103662A CN1064958C CN 1064958 C CN1064958 C CN 1064958C CN 931036623 A CN931036623 A CN 931036623A CN 93103662 A CN93103662 A CN 93103662A CN 1064958 C CN1064958 C CN 1064958C
Authority
CN
China
Prior art keywords
acyloxy
aryl
hydrogen
phenyl
alkynes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CN931036623A
Other languages
English (en)
Other versions
CN1086512A (zh
Inventor
罗·A·赫顿
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Florida State University
Original Assignee
Florida State University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DD341149A external-priority patent/DD300428A5/de
Application filed by Florida State University filed Critical Florida State University
Publication of CN1086512A publication Critical patent/CN1086512A/zh
Application granted granted Critical
Publication of CN1064958C publication Critical patent/CN1064958C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Cash Registers Or Receiving Machines (AREA)
  • Orthopedics, Nursing, And Contraception (AREA)

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

紫杉酚中间体的制备方法
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 9310366200051
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JACS110，5917(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-脱乙酰基一浆果赤霉素III：
Figure 9310366200061
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：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 9310366200081
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：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：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一起形成氧杂环丙基环，或者
M和F一起形成氧杂环丁基环；
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；
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。
表1
以下给出具有通式结构的化合物的例子
Figure 9310366200141
Figure 9310366200151
本发明涉及一种制备下式紫杉酚中间体的方法，
Figure 9310366200171
式中：
A和B分别是氢或低级烷酰氧基、链烯酰氧基、炔酰氧基或C6-10芳酰氧基，或者
A和B一起形成氧代基；
E和F分别是氢或低级烷酰氧基，链烯酰氧基，炔酰氧基或C6-10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、链烯酰氧基、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一起形成环氧乙烷，或者
M和F一起形成氧杂环丁烷
J是氢，羟基，或低级烷酰氧基、链烯酰氧基、炔酰氧基或C6-10芳酰氨基
I是氢，羟基或低级烷酰氧基、链烯酰氧基，炔酰氧基或C6-10芳酰氧基，或者
I和J一起形成氧代基；
K是氢，羟基，或低级烷氧基、烷酰氧基、链烯酰氧基、炔酰氧基或C6-10芳酰氧基；和
X1为OR2且R2为羟基保护基，
Q和P分别是氢或低级烷酰氧基，烯酰氧基，炔酰氧基或芳酰氧基，
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，
U是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基，或C2-10炔基；
V是氢；以及
W是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基，或C2-10炔基；
该方法包括使下式醇其中A，B，E，F，G，I，J，K，M，Q，P，L和D定义如上，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，与下式β-内酰胺
Figure 9310366200182
其中R1是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基或C2-10炔基；R2是羟基保护基；以及R3是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基，或C2-10炔基；在活化剂存在下进行接触，以使β-内酰胺与醇反应生成适用作合成紫杉酚的中间体的β-酰氨基酯。
上述方法中，其中所述醇具有以下结构式：
Figure 9310366200191
其中R4是低级烷酰基，链烯酰基，烷酰基或C6-10芳酰基；Ph是苯基；以及Ac是乙酰基。
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JACS110，5917(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 9310366200201
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CH3 COCl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m(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。
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 9310366200231
以下给出具有通式结构的化合物例子：
Figure 9310366200232
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 9310366200241
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，乙醚，-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15ml CH2cl2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100ml CH2cl2稀释反应混合物并且用30ml 10％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乙醚稀释。水层用2份各100ml乙醚萃取，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280ml1M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265ml THF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， 177°。
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15ml THF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40ml THF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10ml THF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10ml 5％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4ml THF的溶液中加入1ml 10％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20ml 10％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5mg 2′-(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0．5ml 0．5％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)

1．一种制备下式紫杉酚中间体的方法，
Figure 9310366200021
式中：
A和B分别是氢或低级烷酰氧基、链烯酰氧基、炔酰氧基或C6-10芳酰氧基，或者
A和B一起形成氧代基；
E和F分别是氢或低级烷酰氧基，链烯酰氧基，炔酰氧基或C6-10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、链烯酰氧基、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一起形成环氧乙烷，或者
M和F一起形成氧杂环丁烷
J是氢，羟基，或低级烷酰氧基、链烯酰氧基、炔酰氧基或C6-10芳酰氨基
I是氢，羟基或低级烷酰氧基、链烯酰氧基，炔酰氧基或C6-10芳酰氧基，或者
I和J一起形成氧代基；
K是氢，羟基，或低级烷氧基、烷酰氧基、链烯酰氧基、炔酰氧基或C6-10芳酰氧基；和
X1为OR2且R2为羟基保护基，
Q和P分别是氢或低级烷酰氧基，烯酰氧基，炔酰氧基或芳酰氧基，
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，
U是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基，或C2-10炔基；
V是氢；以及
W是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基，或C2-10炔基；
该方法包括使下式醇
Figure 9310366200031
其中A，B，E，F，G，I，J，K，M，Q，P，L和D定义如上，与下式β-内酰胺
Figure 9310366200041
其中R1是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基或C2-10炔基；R2是羟基保护基；以及R3是苯基，α-萘基，β-萘基，C1-10烷基，C2-10链烯基，或C2-10炔基；在活化剂存在下进行接触，以使β-内酰胺与醇反应生成适用作合成紫杉酚的中间体的β-酰氨基酯。
2．权利要求1的方法，其中所述醇具有以下结构式：
Figure 9310366200042
其中R4是低级烷酰基，链烯酰基，烷酰基或C6-10芳酰基；Ph是苯基；以及Ac是乙酰基。
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。
CN931036623A 1989-05-31 1993-04-05 紫杉酚中间体的制备方法 Expired - Lifetime CN1064958C (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US35963489A 1989-05-31 1989-05-31
US359,634 1989-05-31
US07/415,028 US5175315A (en) 1989-05-31 1989-09-29 Method for preparation of taxol using β-lactam
DD341149A DD300428A5 (de) 1989-05-31 1990-05-30 Verfahren zur herstellung von taxol

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN90103963A Division CN1057082C (zh) 1989-05-31 1990-05-30 紫杉酚的制备方法

Publications (2)

Publication Number Publication Date
CN1086512A CN1086512A (zh) 1994-05-11
CN1064958C true CN1064958C (zh) 2001-04-25

Family

ID=27179947

Family Applications (2)

Application Number Title Priority Date Filing Date
CN90103963A Expired - Lifetime CN1057082C (zh) 1989-05-31 1990-05-30 紫杉酚的制备方法
CN931036623A Expired - Lifetime CN1064958C (zh) 1989-05-31 1993-04-05 紫杉酚中间体的制备方法

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN90103963A Expired - Lifetime CN1057082C (zh) 1989-05-31 1990-05-30 紫杉酚的制备方法

Country Status (28)

Country Link
US (1) US5175315A (zh)
EP (1) EP0400971B1 (zh)
JP (2) JPH0830050B2 (zh)
KR (1) KR0130387B1 (zh)
CN (2) CN1057082C (zh)
AT (1) ATE168997T1 (zh)
AU (1) AU630696B2 (zh)
BG (1) BG61074B2 (zh)
CA (2) CA2214051C (zh)
DE (1) DE69032512T2 (zh)
DK (1) DK0400971T3 (zh)
EG (1) EG19555A (zh)
ES (1) ES2122957T3 (zh)
FI (1) FI102176B1 (zh)
HU (1) HU208003B (zh)
IE (1) IE62678B1 (zh)
IL (1) IL94426A (zh)
MX (1) MX9203429A (zh)
NO (1) NO174099C (zh)
NZ (1) NZ233663A (zh)
OA (1) OA09740A (zh)
PL (2) PL163946B1 (zh)
PT (1) PT94187B (zh)
RO (1) RO111766B1 (zh)
RU (1) RU2097374C1 (zh)
SG (1) SG43234A1 (zh)
YU (1) YU97590A (zh)
ZA (1) ZA903809B (zh)

Families Citing this family (152)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY110249A (en) * 1989-05-31 1998-03-31 Univ Florida State Method for preparation of taxol using beta lactam
FR2658510B1 (fr) * 1990-02-21 1992-04-30 Rhone Poulenc Sante Nouveau derive de la beta-phenylisoserine, sa preparation et son emploi.
US5380916A (en) * 1990-11-02 1995-01-10 University Of Florida Method for the isolation and purification of taxane derivatives
US5475120A (en) * 1990-11-02 1995-12-12 University Of Florida Method for the isolation and purification of taxol and its natural analogues
CA2071160A1 (en) * 1991-07-31 1993-02-01 Vittorio Farina Asymmetric synthesis of taxol side chain
US5714513A (en) * 1991-09-23 1998-02-03 Florida State University C10 taxane derivatives and pharmaceutical compositions
US6011056A (en) * 1991-09-23 2000-01-04 Florida State University C9 taxane derivatives and pharmaceutical compositions containing them
CA2418125C (en) * 1991-09-23 2007-12-04 Florida State University Beta-lactams useful in the preparation of substituted isoserine esters
US7074945B2 (en) * 1991-09-23 2006-07-11 Florida State University Metal alkoxide taxane derivatives
US6335362B1 (en) * 1991-09-23 2002-01-01 Florida State University Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them
US5284864A (en) 1991-09-23 1994-02-08 Florida State University Butenyl substituted taxanes and pharmaceutical compositions containing them
US5998656A (en) * 1991-09-23 1999-12-07 Florida State University C10 tricyclic taxanes
US5399726A (en) * 1993-01-29 1995-03-21 Florida State University Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups
US6794523B2 (en) 1991-09-23 2004-09-21 Florida State University Taxanes having t-butoxycarbonyl substituted side-chains and pharmaceutical compositions containing them
US5654447A (en) * 1991-09-23 1997-08-05 Florida State University Process for the preparation of 10-desacetoxybaccatin III
US6018073A (en) * 1991-09-23 2000-01-25 Florida State University Tricyclic taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them
US5739362A (en) * 1991-09-23 1998-04-14 Florida State University Taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them
US5721268A (en) * 1991-09-23 1998-02-24 Florida State University C7 taxane derivatives and pharmaceutical compositions containing them
US5728725A (en) * 1991-09-23 1998-03-17 Florida State University C2 taxane derivaties and pharmaceutical compositions containing them
US5990325A (en) * 1993-03-05 1999-11-23 Florida State University Process for the preparation of 9-desoxotaxol, 9-desoxobaccatin III and analogs thereof
US6521660B2 (en) 1991-09-23 2003-02-18 Florida State University 3′-alkyl substituted taxanes and pharmaceutical compositions containing them
US5728850A (en) * 1991-09-23 1998-03-17 Florida State University Taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them
US6005138A (en) * 1991-09-23 1999-12-21 Florida State University Tricyclic taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them
US5710287A (en) * 1991-09-23 1998-01-20 Florida State University Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them
US5430160A (en) 1991-09-23 1995-07-04 Florida State University Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides
US5283253A (en) * 1991-09-23 1994-02-01 Florida State University Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them
US6495704B1 (en) 1991-09-23 2002-12-17 Florida State University 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes
US5489601A (en) * 1991-09-23 1996-02-06 Florida State University Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them
US6028205A (en) * 1991-09-23 2000-02-22 Florida State University C2 tricyclic taxanes
DE69333675T2 (de) * 1992-01-15 2006-02-02 E.R. Squibb & Sons, Inc. Enzymatische Verfahren zur Trennung von Enantiomerengemischen von Verbindungen, die als Zwischenprodukte zur Herstellung von Taxanen nützlich sind
FR2687145B1 (fr) * 1992-02-07 1994-03-25 Rhone Poulenc Rorer Sa Nouveaux anhydrides d'acides, leur preparation et leur emplot et
US5272171A (en) * 1992-02-13 1993-12-21 Bristol-Myers Squibb Company Phosphonooxy and carbonate derivatives of taxol
FR2703994B1 (fr) * 1993-04-16 1995-05-24 Rhone Poulenc Rorer Sa Procédé de préparation de beta-lactames.
FR2688499B1 (fr) * 1992-03-10 1994-05-06 Rhone Poulenc Rorer Sa Procede de preparation de la beta-phenylisoserine et de ses analogues.
US5939561A (en) * 1992-03-10 1999-08-17 Rhone-Poulence Rorer S.A. Process for the preparation of β-phenylisoserine and β-lactam and their analogues
WO1993021173A1 (en) * 1992-04-17 1993-10-28 Abbott Laboratories Taxol derivatives
JPH069600A (ja) * 1992-05-06 1994-01-18 Bristol Myers Squibb Co タクソールのベンゾエート誘導体
US5254580A (en) * 1993-01-19 1993-10-19 Bristol-Myers Squibb Company 7,8-cyclopropataxanes
US5294637A (en) * 1992-07-01 1994-03-15 Bristol-Myers Squibb Company Fluoro taxols
EP0582469A2 (en) * 1992-08-06 1994-02-09 Wisconsin Alumni Research Foundation Process for preparing taxol-type compound from beta-lactam precursors
US5319112A (en) * 1992-08-18 1994-06-07 Virgnia Tech Intellectual Properties, Inc. Method for the conversion of cephalomannine to taxol and for the preparation of N-acyl analogs of taxol
US5470866A (en) * 1992-08-18 1995-11-28 Virginia Polytechnic Institute And State University Method for the conversion of cephalomannine to taxol and for the preparation of n-acyl analogs of taxol
FR2696462B1 (fr) * 1992-10-05 1994-11-25 Rhone Poulenc Rorer Sa Procédé d'obtention de la désacétyl-10 baccatine III.
FR2696463B1 (fr) 1992-10-05 1994-11-25 Rhone Poulenc Rorer Sa Procédé d'obtention de la désacétyl-10 baccatine III.
FR2696458B1 (fr) * 1992-10-05 1994-11-10 Rhone Poulenc Rorer Sa Procédé de préparation de dérivés du taxane.
US5411984A (en) * 1992-10-16 1995-05-02 Virginia Tech Intellectual Properties, Inc. Water soluble analogs and prodrugs of taxol
US5420337A (en) * 1992-11-12 1995-05-30 E. R. Squibb & Sons, Inc. Enzymatic reduction method for the preparation of compounds useful for preparing taxanes
ES2252368T3 (es) * 1992-11-13 2006-05-16 Florida State University Composiciones farmaceuticas que contiene taxanos isobutenil sustituidos.
ES2199955T3 (es) * 1992-11-13 2004-03-01 Florida State University Taxanos que tienen una cadena lateral alquilo sustituido y composiciones farmaceuticas que las contienen.
DE69333208T2 (de) * 1992-11-13 2004-04-08 Florida State University, Tallahassee Isobutenyl-substituierte taxane und deren pharmazeutische zusammensetzungen
US5380751A (en) * 1992-12-04 1995-01-10 Bristol-Myers Squibb Company 6,7-modified paclitaxels
CA2109861C (en) * 1992-12-04 1999-03-16 Shu-Hui Chen 6,7-modified paclitaxels
US5279949A (en) * 1992-12-07 1994-01-18 Board Of Trustees Operating Michigan State University Process for the isolation and purification of taxol and taxanes from Taxus spp
FR2698871B1 (fr) * 1992-12-09 1995-02-24 Rhone Poulenc Rorer Sa Nouveau taxoïdes, leur préparation et les compositions pharmaceutiques qui les contiennent.
IL107950A (en) 1992-12-15 2001-04-30 Upjohn Co b 7, b 8 - Matano - Taxols, their preparation and pharmaceutical preparations against malignant tumors containing them
EP0626953A4 (en) * 1992-12-23 1995-05-03 Bristol Myers Squibb Co NEW SIDE CHAINS WEARING TAXANS AND THEIR INTERMEDIATE PRODUCTS.
US5973160A (en) * 1992-12-23 1999-10-26 Poss; Michael A. Methods for the preparation of novel sidechain-bearing taxanes
US5646176A (en) * 1992-12-24 1997-07-08 Bristol-Myers Squibb Company Phosphonooxymethyl ethers of taxane derivatives
IL108316A (en) * 1993-01-15 2006-10-31 Univ Florida State History of C-10 Texan and pharmaceuticals containing them
US6339164B1 (en) 1993-01-29 2002-01-15 Florida State University C2 substituted phenyl taxane derivatives and pharmaceutical compositions containing them
ZA94128B (en) * 1993-02-01 1994-08-19 Univ New York State Res Found Process for the preparation of taxane derivatives and betalactam intermediates therefor
US6187916B1 (en) * 1993-02-01 2001-02-13 Research Foundation Of State University Of New York Process for the preparation of taxane derivatives and β-lactam intermediates therefor
US6593482B2 (en) * 1993-02-01 2003-07-15 Aventis Pharma S.A. Methods for preparing new taxoids and pharmaceutical compositions containing them
US5684175A (en) * 1993-02-05 1997-11-04 Napro Biotherapeutics, Inc. C-2' hydroxyl-benzyl protected, N-carbamate protected (2R, 3S)- 3-phenylisoserine and production process therefor
US5948919A (en) * 1993-02-05 1999-09-07 Napro Biotherapeutics, Inc. Paclitaxel synthesis from precursor compounds and methods of producing the same
EP1260507A1 (en) * 1993-02-05 2002-11-27 Bryn Mawr College Synthesis of taxol, analogs and intermediates with variable A-nng side chains
DK0688212T3 (da) * 1993-03-05 2002-10-07 Univ Florida State C9-taxanderivater og farmaceutiske præparater indeholdende disse
US6710191B2 (en) * 1993-03-05 2004-03-23 Florida State University 9β-hydroxytetracyclic taxanes
WO1994020485A1 (en) * 1993-03-05 1994-09-15 Florida State University Process for the preparation of 9-desoxotaxanes
TW467896B (en) * 1993-03-19 2001-12-11 Bristol Myers Squibb Co Novel β-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes
PT690712E (pt) * 1993-03-22 2002-05-31 Univ Florida State Taxanos possuindo uma cadeia lateral substituida com piridilo
WO1994021251A1 (en) * 1993-03-22 1994-09-29 Florida State University Taxanes having an amino substituted side-chain
ES2242807T3 (es) * 1993-03-22 2005-11-16 Florida State University Taxanos que tienen furilo o tienilo sustituido en la cadena lateral sustituida.
US5475011A (en) * 1993-03-26 1995-12-12 The Research Foundation Of State University Of New York Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment
US5965739A (en) * 1993-06-11 1999-10-12 Pharmacia & Upjohn Company Δ6,7 -taxols antineoplastic use and pharmaceutical compositions containing them
TW397866B (en) 1993-07-14 2000-07-11 Bristol Myers Squibb Co Enzymatic processes for the resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes
US6005120A (en) 1993-07-20 1999-12-21 Florida State University Tricyclic and tetracyclic taxanes
US5405972A (en) * 1993-07-20 1995-04-11 Florida State University Synthetic process for the preparation of taxol and other tricyclic and tetracyclic taxanes
ES2133710T3 (es) * 1993-11-25 1999-09-16 Warwick Int Group Composiciones blanqueantes.
IL127599A (en) * 1994-01-28 2004-06-01 Upjohn Co Process for preparing isotaxol analogs
US5508447A (en) * 1994-05-24 1996-04-16 Board Of Regents, The University Of Texas System Short synthetic route to taxol and taxol derivatives
US5602272A (en) * 1994-06-21 1997-02-11 Bristol-Myers Squibb Company Reduction and resolution methods for the preparation of compounds useful as intemediates for preparing taxanes
CN1073105C (zh) * 1994-07-26 2001-10-17 因迪纳有限公司 具有抗肿瘤活性的半合成紫杉烷
US6201140B1 (en) 1994-07-28 2001-03-13 Bristol-Myers Squibb Company 7-0-ethers of taxane derivatives
CA2170661A1 (en) 1995-03-22 1996-09-23 John K. Thottathil Novel methods for the preparation of taxanes using oaxzolidine intermediates
US5675025A (en) * 1995-06-07 1997-10-07 Napro Biotherapeutics, Inc. Paclitaxel synthesis from precursor compounds and methods of producing the same
US5780653A (en) * 1995-06-07 1998-07-14 Vivorx Pharmaceuticals, Inc. Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers
US5760251A (en) * 1995-08-11 1998-06-02 Sepracor, Inc. Taxol process and compounds
US5840748A (en) * 1995-10-02 1998-11-24 Xechem International, Inc. Dihalocephalomannine and methods of use therefor
US5807888A (en) * 1995-12-13 1998-09-15 Xechem International, Inc. Preparation of brominated paclitaxel analogues and their use as effective antitumor agents
US5654448A (en) * 1995-10-02 1997-08-05 Xechem International, Inc. Isolation and purification of paclitaxel from organic matter containing paclitaxel, cephalomannine and other related taxanes
US5854278A (en) * 1995-12-13 1998-12-29 Xechem International, Inc. Preparation of chlorinated paclitaxel analogues and use thereof as antitumor agents
US6177456B1 (en) 1995-10-02 2001-01-23 Xechem International, Inc. Monohalocephalomannines having anticancer and antileukemic activity and method of preparation therefor
US5688977A (en) * 1996-02-29 1997-11-18 Napro Biotherapeutics, Inc. Method for docetaxel synthesis
US6107497A (en) * 1996-02-29 2000-08-22 Napro Biotherapeutics, Inc. Intermediate for use in docetaxel synthesis and production method therefor
IL126856A0 (en) * 1996-05-06 1999-09-22 Univ Florida State 1-Deoxy baccatin iii 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof
US5635531A (en) * 1996-07-08 1997-06-03 Bristol-Myers Squibb Company 3'-aminocarbonyloxy paclitaxels
US5750737A (en) * 1996-09-25 1998-05-12 Sisti; Nicholas J. Method for paclitaxel synthesis
US5912264A (en) * 1997-03-03 1999-06-15 Bristol-Myers Squibb Company 6-halo-or nitrate-substituted paclitaxels
US6017935A (en) * 1997-04-24 2000-01-25 Bristol-Myers Squibb Company 7-sulfur substituted paclitaxels
ATE252569T1 (de) * 1997-05-02 2003-11-15 Pharmachemie Bv Verfahren zur herstellung von baccatin iii und seiner derivate ausgehend von 10-deacetylbaccatin iii.
US7288665B1 (en) * 1997-08-18 2007-10-30 Florida State University Process for selective derivatization of taxanes
ATE234800T1 (de) 1997-08-21 2003-04-15 Univ Florida State Verfahren zur synthese von taxanen
EP1033372A4 (en) * 1997-11-18 2000-10-04 Chugai Pharmaceutical Co Ltd COMPOSITIONS WITH ANTI-TUMOR ACTIVITY
FR2771092B1 (fr) * 1997-11-18 1999-12-17 Rhone Poulenc Rorer Sa Procede de preparation de derives de la classe des taxoides
US5917062A (en) * 1997-11-21 1999-06-29 Indena S.P.A Intermediates and methods useful in the semisynthesis of paclitaxel and analogs
EP0933360A1 (en) * 1997-12-22 1999-08-04 Pharmachemie B.V. Synthesis of new beta-lactams
HUP0101457A3 (en) * 1997-12-31 2003-01-28 Bristol Myers Squibb Co Antitumor 2-aroyl-4-acyl paclitaxel analogs and medicaments containing them , their intermediates and method for producing them
US6156789A (en) * 1998-03-17 2000-12-05 Rhone-Poulenc Rorer S.A. Method for treating abnormal cell proliferation in the brain
US6025516A (en) * 1998-10-14 2000-02-15 Chiragene, Inc. Resolution of 2-hydroxy-3-amino-3-phenylpropionamide and its conversion to C-13 sidechain of taxanes
ES2273698T3 (es) 1999-05-28 2007-05-16 Bristol-Myers Squibb Company Semisintesis de pactitaxel usando dialquildiclorosilanos.
CA2385528C (en) 1999-10-01 2013-12-10 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
IT1317731B1 (it) * 2000-01-18 2003-07-15 Indena Spa Tassani semisintetici con attivita' antitumorale ed antiangiogenetica.
HUP0200721A3 (en) * 2000-02-02 2005-02-28 Univ Florida State Res Found C10 carbamoyloxy substituted taxanes as antitumor agents and pharmaceutical compositions containing them and their use
JP2003522170A (ja) 2000-02-02 2003-07-22 フロリダ・ステイト・ユニバーシティ・リサーチ・ファウンデイション・インコーポレイテッド 抗腫瘍剤としてのｃ７カーボネート置換タキサン
KR20010112393A (ko) * 2000-02-02 2001-12-20 플로리다 스테이트 유니버시티 리서치 파운데이션, 인크 항종양제로서 ｃ７ 헤테로치환된 아세테이트 탁산
RU2264400C2 (ru) 2000-02-02 2005-11-20 Флорида Стейт Юниверсити Рисерч Фаундейшн, Инк. Таксан, фармацевтическая композиция на его основе и способ ингибирования роста опухоли
US6664275B2 (en) * 2000-02-02 2003-12-16 Fsu Research Foundation, Inc. C10 heterosubstituted acetate taxanes
US6649632B2 (en) * 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US6638973B2 (en) * 2000-02-02 2003-10-28 Fsu Research Foundation, Inc. Taxane formulations
DE60133600T2 (de) * 2000-02-02 2009-06-10 Florida State University Research Foundation, Inc., Tallahassee C7-carbamoyloxysubstituierte taxane als antitumormittel
CO5280224A1 (es) 2000-02-02 2003-05-30 Univ Florida State Res Found Taxanos sustituidos con ester en c7, utiles como agentes antitumorales y composiciones farmaceuticas que los contienen
US6916942B2 (en) * 2000-02-03 2005-07-12 Bristol-Myers Squibb Company Process for the preparation of C-4 carbonate taxanes
US6452024B1 (en) 2000-02-22 2002-09-17 Chaichem Pharmaceuticals International Process for extraction and purification of paclitaxel from natural sources
CZ2003837A3 (cs) 2000-09-22 2004-12-15 Bristol-Myers Squibb Company Způsob pro snížení toxicity při kombinovaných chemoterapiích
US6479679B1 (en) 2001-04-25 2002-11-12 Napro Biotherapeutics, Inc. Two-step conversion of protected taxane ester to paclitaxel
US6452025B1 (en) 2001-04-25 2002-09-17 Napro Biotherapeutics, Inc. Three-step conversion of protected taxane ester to paclitaxel
US7063977B2 (en) * 2001-08-21 2006-06-20 Bristol-Myers Squibb Company Enzymatic resolution of t-butyl taxane derivatives
CN1596250A (zh) * 2001-11-30 2005-03-16 布里斯托尔-迈尔斯斯奎布公司 紫杉醇溶剂化物
AU2003273671A1 (en) * 2002-10-09 2004-05-04 Phytogen Life Sciences, Inc. Novel taxanes and methods related to use and preparation thereof
US6759539B1 (en) 2003-02-27 2004-07-06 Chaichem Pharmaceuticals International Process for isolation and purification of paclitaxel from natural sources
US7030253B2 (en) * 2003-08-07 2006-04-18 Bristol-Myers Squibb Company Process for preparing 4-alkyl- or 4-aryl-oxycarbonyl paclitaxel analogs and novel intermediates
US7064980B2 (en) * 2003-09-17 2006-06-20 Sandisk Corporation Non-volatile memory and method with bit line coupled compensation
US7202370B2 (en) 2003-10-27 2007-04-10 Conor Medsystems, Inc. Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III
SV2006002010A (es) * 2004-02-13 2006-08-23 Univ Florida State Res Found Taxanos sustituidos con esteres de ciclopentilo en c10
US20050192445A1 (en) * 2004-03-01 2005-09-01 Phytogen Life Sciences Inc. Semi-synthesis of taxane intermediates and aziridine analogues and their conversion to paclitaxel and docetaxel
WO2005087222A1 (en) 2004-03-05 2005-09-22 Florida State University Research Foundation, Inc. C7 lactyloxy-substituted taxanes
JP2008530122A (ja) * 2005-02-14 2008-08-07 フロリダ・ステイト・ユニバーシティ・リサーチ・ファウンデイション・インコーポレイテッド Ｃ１０シクロプロピルエステル置換タキサン組成物
WO2006116532A2 (en) * 2005-04-28 2006-11-02 University Of Massachusetts Lowell Synthesis of oligo/poly(catechins) and methods of use
KR20080030013A (ko) * 2005-06-10 2008-04-03 플로리다 스테이트 유니버시티 리서치 파운데이션, 인크 폴리시클릭 융합 고리 화합물의 제조 방법
BRPI0613568A2 (pt) * 2005-06-10 2012-03-20 Florida State University Research Foundation, Inc. Síntese de beta-lactama
EP1893594A2 (en) * 2005-06-10 2008-03-05 Florida State University Research Foundation, Inc. Processes for the preparation of paclitaxel
EP2029563A4 (en) * 2006-06-12 2009-12-02 Canada Inc 6570763 SEMI-SYNTHETIC PATHWAY FOR THE PREPARATION OF PACLITAXEL, DOCETAXEL AND 10-DEACETYLBACCATINE III FROM 9-DIHYDRO-13-ACETYLBACCATINE III
US7847111B2 (en) 2006-06-19 2010-12-07 Canada Inc. Semi-synthetic route for the preparation of paclitaxel, docetaxel, and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III
GB0701523D0 (en) * 2007-01-26 2007-03-07 Chatham Biotec Ltd Semi-synthetic process for the preparation of taxane derivatives
EP2276755A4 (en) * 2008-03-31 2011-05-04 Univ Florida State Res Found C (10) -ETHYESTER- AND C (10) -CYCLOPROPYLESTER-SUBSTITUTED TAXANES
CA2723654A1 (en) 2008-05-07 2009-11-12 Ivax Research, Llc Processes for preparation of taxanes and intermediates thereof
GB0907973D0 (en) 2009-05-08 2009-06-24 Modern Biosciences Plc Combination therapy
JP2013512893A (ja) 2009-12-07 2013-04-18 マピ ファーマ リミテッド デフェラシロクスの調製方法、及びデフェラシロクスの多形体
KR101899248B1 (ko) 2017-05-31 2018-09-14 박웅준 슬라브 단열재 고정구
KR101941847B1 (ko) 2017-05-31 2019-01-25 석영숙 벽체용 단열재 고정구
KR20190019653A (ko) 2017-08-18 2019-02-27 박웅준 벽체용 단열재 고정구

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2601676B1 (fr) * 1986-07-17 1988-09-23 Rhone Poulenc Sante Procede de preparation du taxol et du desacetyl-10 taxol
FR2601675B1 (fr) * 1986-07-17 1988-09-23 Rhone Poulenc Sante Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2629819B1 (fr) * 1988-04-06 1990-11-16 Rhone Poulenc Sante Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii
FR2629818B1 (fr) * 1988-04-06 1990-11-16 Centre Nat Rech Scient Procede de preparation du taxol
US5015744A (en) * 1989-11-14 1991-05-14 Florida State University Method for preparation of taxol using an oxazinone
US5136060A (en) * 1989-11-14 1992-08-04 Florida State University Method for preparation of taxol using an oxazinone

Also Published As

Publication number Publication date
RO111766B1 (ro) 1997-01-30
ATE168997T1 (de) 1998-08-15
ZA903809B (en) 1991-03-27
DK0400971T3 (da) 1999-04-26
JP2500198B2 (ja) 1996-05-29
CA2214051C (en) 2001-09-25
EP0400971B1 (en) 1998-07-29
IL94426A (en) 1998-06-15
EP0400971A2 (en) 1990-12-05
FI902660A0 (fi) 1990-05-29
NO902404L (no) 1990-12-03
CN1057082C (zh) 2000-10-04
CA2214051A1 (en) 1990-11-30
PT94187B (pt) 1996-08-30
US5175315A (en) 1992-12-29
PL163946B1 (pl) 1994-05-31
AU5515090A (en) 1990-12-20
YU97590A (en) 1991-10-31
EP0400971A3 (en) 1992-01-02
PT94187A (pt) 1991-02-08
DE69032512T2 (de) 1999-03-25
MX9203429A (es) 1992-07-01
NO902404D0 (no) 1990-05-30
AU630696B2 (en) 1992-11-05
JPH0386860A (ja) 1991-04-11
CA2016951A1 (en) 1990-11-30
RU2097374C1 (ru) 1997-11-27
SG43234A1 (en) 1997-10-17
JPH0830050B2 (ja) 1996-03-27
PL164539B1 (pl) 1994-08-31
HU208003B (en) 1993-07-28
DE69032512D1 (de) 1998-09-03
FI102176B (fi) 1998-10-30
NZ233663A (en) 1992-09-25
IE901707L (en) 1990-11-30
CA2016951C (en) 1998-05-12
BG61074B2 (bg) 1996-10-31
HU903245D0 (en) 1990-10-28
ES2122957T3 (es) 1999-01-01
KR0130387B1 (ko) 1998-04-09
IE62678B1 (en) 1995-02-22
IL94426A0 (en) 1991-03-10
HUT57199A (en) 1991-11-28
NO174099B (no) 1993-12-06
EG19555A (en) 1995-09-30
CN1057049A (zh) 1991-12-18
OA09740A (en) 1993-11-30
PL285404A1 (en) 1991-02-11
JPH0770057A (ja) 1995-03-14
CN1086512A (zh) 1994-05-11
FI102176B1 (fi) 1998-10-30
NO174099C (no) 1994-03-16

Similar Documents

Publication Publication Date Title
CN1064958C (zh) 紫杉酚中间体的制备方法
CN1043528C (zh) 用噁嗪酮制备紫杉酚的方法
CN1058714C (zh) 金属醇盐的制备方法
KR0130463B1 (ko) 신규 β-락탐을 사용하는 탁솔 제조방법
JP3394284B2 (ja) 金属アルコキシド及びオキサジノンを用いたタキサン誘導体の半合成
US5015744A (en) Method for preparation of taxol using an oxazinone
FR2696464A1 (fr) Nouveau procédé d'estérification de la baccatine III et de la désacétyl-10 baccatine III.
CN1108653A (zh) 2-脱苯甲酰基-2-酰基紫杉醇衍生物及其制备方法
HU226369B1 (en) Process for preparing substituted isoserine-esters using metal alkoxides and beta-lactams
CN1942460A (zh) 紫杉烷衍生物的一锅合成及其向太平洋紫杉醇和多烯紫杉醇的转化
CN1221412A (zh) 1－脱氧浆果赤霉素ⅲ,1－脱氧紫杉醇和1－脱氧紫杉醇类似物及其制备方法
CN1158126A (zh) 制备紫杉醇及其衍生物的方法
CN1075315A (zh) 用金属烷氧化物和β-内酰胺半合成紫杉烷衍生物的方法
CZ287206B6 (cs) Způsob výroby derivátů taxolu a beta-laktam jako výchozí látka pro výrobu těchto derivátů

Legal Events

Date Code Title Description
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C06 Publication
PB01 Publication
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CX01 Expiry of patent term

Granted publication date: 20010425