CN101143858B - 一种选择性酰化紫杉烷c(10)和c(2')位羟基的方法 - Google Patents
一种选择性酰化紫杉烷c(10)和c(2')位羟基的方法 Download PDFInfo
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- CN101143858B CN101143858B CN200610047743A CN200610047743A CN101143858B CN 101143858 B CN101143858 B CN 101143858B CN 200610047743 A CN200610047743 A CN 200610047743A CN 200610047743 A CN200610047743 A CN 200610047743A CN 101143858 B CN101143858 B CN 101143858B
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- taxol
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 45
- 229940123237 Taxane Drugs 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 13
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- 230000010933 acylation Effects 0.000 title claims description 8
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- 239000003054 catalyst Substances 0.000 claims abstract 3
- 238000006243 chemical reaction Methods 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
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- 229910052751 metal Inorganic materials 0.000 claims description 5
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- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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Abstract
本发明涉及一种制备紫杉醇及其它紫杉烷的方法。该方法通过使用三氟甲磺酸盐作为催化剂，选择性酰化10-去乙酰-紫杉烷类化合物C(10)和C(2’)位的羟基来实现。所制得C(10)和C(2’)位羟基酰化的紫杉烷，可以作为制备紫杉醇及其它紫杉烷的重要中间体。
Description
技术领域：
本发明涉及一种紫杉醇及其它紫杉烷的制备方法，尤其涉及在三氟甲磺酸盐催化的条件下，通过一步选择性酰化反应将10-去乙酰-紫杉烷类化合物转化为C(10)和C(2’)位羟基酰化的紫杉烷，而后者可以作为制备紫杉醇及其类似物的重要中间体。
背景技术：
紫杉醇(Paclitaxel，式II，1)和多烯紫杉醇(Docetaxel)，当前作为临床一线用药而广泛应用于不同种类肿瘤的治疗。
1.R＝Ac紫杉醇(Paclitaxel) 3.10-去乙酰-巴卡亭III
2.R＝H 10-去乙酰-紫杉醇
式II紫杉醇，10-去乙酰-紫杉醇和10-去乙酰-巴卡亭III
通过红豆杉属植物提取，植物细胞培养，生物合成，真菌发酵以及化学半合成等手段可获得大量10-去乙酰-紫杉烷类化合物，如10-去乙酰-紫杉醇(式II，2)，10-去乙酰-巴卡亭III(10-DAB，式II，3)等。通过酰化C(10)位的羟基即可得到有极高抗癌活性的紫杉醇(Taxol)或其它紫杉烷类化合物。目前针对该类紫杉烷的酰化工作主要集中在以下两个方面：
(一)采用缚酸剂催化酰化10-去乙酰-紫杉醇(烷)
Rao等人(J.Heterocycl.Chem.，1997，34，pp.675)利用高碘酸盐氧化裂解C(7)位木糖基，在吡啶作为缚酸剂的条件下将C(10)和C(2’)位的羟基乙酰化后，再用苯肼脱去C(7)位上的残余基团，从而得到C(2’)位乙酰化的紫杉醇，使用二甲胺选择性水解C(2’)位乙酰基即得到紫杉醇(US5200534；US5367086)。
Sisti等人(US5914411)将10-去乙酰巴卡亭III溶解在THF反应体系中，向其中加入锂盐活化C(10)位的羟基，再加入TEA作缚酸剂，乙酰氯作为酰化剂，选择性的得到了巴卡亭III。在其随后的专利(US6048990，US6066749)中，他们将该方法扩展到当C(2’)位羟基被保护后，选择性乙酰化C(10)位羟基，得到C(2’)位羟基被保护的紫杉醇。
Chattopadhyay等人(US5856532)将得到10-去乙酰紫杉烷化合物，硅醚保护其C(7)和C(2’)位的羟基后，再在吡啶存在的条件下乙酰化C(10)位羟基，最后脱硅醚保护基得到目标产物。
Fang等人(化学快报，8(10)，1997，pp.847)发现7-表-10-去乙酰-紫杉醇中C(7)羟基在吡啶，乙酰氯的条件下很难被乙酰化.因此，他们用三乙基氯硅烷保护C(2，)位羟基，在吡啶催化下乙酰化C(10)位羟基，脱去C(2’)位硅醚保护基后，得到7-表-紫杉醇.
(二)采用Lewis酸催化酰化10-去乙酰-紫杉醇(烷)
Holton等人(Tetrahedron Letters，1998，39，pp.2883)发现，在有Lewis酸，如三氯化铈，氯化锌，氯化锡等存在的情况下，对于10-去乙酰巴卡亭III或C(2’)位羟基被保护后的紫杉醇，C(10)位的羟基可优先于C(7)位的羟基被选择性酰化(CN125196C，WO1999/009021，US6706896)。但在其研究工作中，并没有涉及到以C(2’)位存在自由羟基的紫杉烷为原料，酰化C(2’)位羟基的问题。
Damen等人(Tetrahedron Letters，1998，39，pp.6081)发现，在稀土元素的三氟甲磺酸盐催化下，采用乙酸酐可以将10-DAB选择性的乙酰化为巴卡亭III。若采用其他酸酐，通过选择性酰化10-DAB的C(10)位羟基，可得到不同的衍生物(EP0875508，US5874595，JP10298171)。然而在其研究工作中，并没有涉及到C(13)位存在侧链的紫杉烷，也没有涉及到在该反应条件下C(1)，C(7)，C(10)，C(2’)位各羟基之间的选择性酰化问题。
唐丁宁等人(CN1640871A，WO2005/073209)发现当反应体系中含有氯化稀土，氢氧化稀土，氯氧化稀土，或稀土元素的硫酸盐复盐时，可采用乙酸酐来选择性乙酰化10-去乙酰-紫杉醇C(10)和C(2’)位羟基，再脱去C(2’)位乙酰基即可得到紫杉醇。
IIIB族金属元素的三氟甲磺酸盐是近年来开发的一类新型酰化反应催化剂(Yamamoto et al.，J.Am.Chem.Soc.，1995，117，4413)。对于在C(1)，C(7)，C(10)，C(2’)位存在多个羟基的紫杉烷，考察其对各羟基酰化反应的催化活性仍是一件亟待解决的工作。
技术内容：
本发明的目的在于提供一种将10-去乙酰紫杉烷类化合物转化为C(10)和C(2’)位羟基酰化的紫杉醇或其它紫杉烷的制备方法。本发明尤其涉及紫杉烷在C(1)，C(10)和C(2’)位均含有羟基，C(7)位可含也可不含自由羟基时，使用酰化剂选择性的与C(10)和C(2’)位羟基反应。
本发明的具体实施是通过以IIIB族金属元素的三氟甲磺酸盐作为催化剂，于惰性有机溶剂中与10-去乙酰-紫杉醇(烷)原料混合，在酸酐作为酰化剂的条件下，这些催化剂可以选择性的活化C(10)和C(2’)位羟基，从而使C(10)和C(2’)位羟基先于C(1)和C(7)位羟基位酰化。同时，当C(1)和C(7)位羟基被保护或为其它基团所取代时，采用本发明的方法，也可以得到C(10)和C(2’)位羟基酰化的紫杉烷。而后者可以通过碱性条件下选择性水解C(2’)位酰基得到紫杉醇或其它紫杉烷。
该选择性酰化反应优选在醚类溶剂中进行，如四氢呋喃，乙醚等。但在二氯甲烷，氯仿，乙酸乙酯等紫杉烷的良溶剂中反应也可发生，只是反应时间略有延长。该反应体系优选为严格除水的溶剂，当体系中的水分超过一定量时，可降低反应速度，甚至导致反应无法进行。
该选择性酰化反应所采用的催化剂，来自于元素周期表中IIIB族金属元素的三氟甲磺酸盐。优选自三氟甲磺酸钪，三氟甲磺酸镱，三氟甲磺酸铒，三氟甲磺酸镧，三氟甲磺酸铷，三氟甲磺酸钐，三氟甲磺酸镝。
该选择性酰化反应在室温下即可顺利进行，但适当升温有利于反应尽快达到平衡，一般优选在-80℃至100℃进行.
所述10-去乙酰-紫杉烷具有如下通式I的结构
式I
其中R1为-H，-OR，-OSi(R)3或-COR；R2和R3可以相同也可以不同，为-H，-R或-OR；其中R为H，C1至C20的直链、支链或环型烃基，芳基，芳烷基，及上述三种烃基的取代物，取代基包括羟基，C1至C8的烷氧基，缩醛、缩酮，卤素，硝基和氨基。
特别的，本文所指的缩醛和缩酮部分具有结构通式
其中X1，X2，X3，X4代指氢或烃基，且烃基可被本文所定义的任何取代基所取代，该部分可以包括从糖类或取代糖类如葡萄糖或木糖制成的缩醛或缩酮(KoppakaV.Rao，J.Heterocyclic Chem.34，676(1997))，当该部分被作为C(7)位羟基的保护基进入本发明紫杉烷中时，X1或X2代指紫杉烷部分。
可用于该选择性酰化反应的酰化剂包括各种酸酐，例如，乙酸酐，氯乙酸酐，三氟乙酸酐，苯甲酸酐等，所述酸酐的结构具有结构通式
其中R’为C1至C20的直链、支链或环型烃基，芳基，及上述三种烃基的卤代物。
本发明的工艺流程及化学反应通式如式III所示。
其中R1，R2，R3，R’定义同前。
式III
本发明所涉及的紫杉烷原料可以是天然产物来源的在C(10)，C(2’)位同时含有羟基的10-去乙酰-紫杉烷类化合物单体或其混合物。同时，经由生物合成，化学半合成或全合成手段获得的在上述位置含有羟基的紫杉烷也可以采用本发明对C(10)和C(2’)位羟基进行选择性酰化。
附图说明：
图1为10-去乙酰-紫杉醇的LC-MS谱图，10-去乙酰-紫杉醇的负离子信号：[M-H]-at m/z 810.4；
图2为2’-乙酰基-紫杉醇的LC-MS谱图，2’-乙酰基-紫杉醇的负离子信号：[M-H]-at m/z 894.9；
图3为紫杉醇的LC-MS谱图，紫杉醇的负离子信号：[M-H]-at m/z 852.3；
图4为10-去乙酰-三尖杉宁碱的LC-MS谱图，10-去乙酰-三尖杉宁碱的负离子信号：[M-H]-at m/z788.3；
图5为三尖杉宁碱的LC-MS谱图，三尖杉宁碱的负离子信号：[M-H]-atm/z830.4；
图6为10-去乙酰-7-木糖-紫杉醇的LC-MS谱图；10-去乙酰-7-木糖-紫杉醇的负离子信号：[M-H]-at m/z 942.5。
具体实施方式：
下列实施例是为了进一步说明本发明，而不是要限制其范围。
实施例1采用多种三氟甲磺酸盐催化酰化10-去乙酰-紫杉醇制取2’-乙酰基-紫杉醇
称取10-去乙酰-紫杉醇(含量90％，LC-MS谱图见图1)的样品溶于反应溶剂中，加入催化当量的IIIB族金属元素的三氟甲磺酸盐，充分混合后，缓慢滴加约3当量的乙酸酐，室温下搅拌，TLC检测反应完全后，加入饱和NaHCO3溶液熄灭反应。反应后料液用乙酸乙酯萃取，无水硫酸钠干燥，真空旋蒸得2’-乙酰基-紫杉醇(LC-MS谱图见图2)。所采用的各种催化剂，催化剂量，反应溶剂，反应时间及收率见表1。
表1多种三氟甲磺酸盐催化酰化10-去乙酰-紫杉醇
实施例2从10-去乙酰-紫杉醇制取紫杉醇
称取10-去乙酰-紫杉醇(含量77％，LC-MS谱图见图1)的样品1g，溶于20ml四氢呋喃，加入0.07g三氟甲磺酸镱充分混合后，缓慢滴加0.35ml乙酸酐，室温下反应1.5个小时，加入饱和NaHCO3溶液25ml熄灭反应.反应后料液用乙酸乙酯萃取，无水硫酸钠干燥，真空旋蒸得1.05g白色固体.将其溶于50ml0.1％的二甲胺甲醇溶液中，室温下反应1h后，用乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得0.95g白色固体.该物质经硅胶柱层析后得0.61g紫杉醇(含量90％，收率67.8％，LC-MS谱图见图3).
实施例3从10-去乙酰-三尖杉宁碱制取三尖杉宁碱
称取10-去乙酰-三尖杉宁碱(含量85％，LC-MS谱图见图4)的样品1g，溶于20ml四氢呋喃，加入0.08g三氟甲磺酸镱充分混合后，缓慢滴加0.35ml乙酸酐，室温下反应1.5个小时，加入饱和NaHCO3溶液25ml熄灭反应。反应后料液用乙酸乙酯萃取，无水硫酸钠干燥，真空旋蒸得0.93g白色固体。将其溶于50ml0.1％的二甲胺甲醇溶液中，室温下反应1h后，用乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得0.86g白色固体。该物质经硅胶柱层析后得到0.77g三尖杉宁碱(含量90％，收率77.4％，LC-MS谱图见图5)。
实施例4从10-去乙酰-7-木糖-紫杉醇制取紫杉醇
称取10-去乙酰-7-木糖-紫杉醇(含量90％，LC-MS谱图见图6)的样品1g，溶于50ml甲醇/水(4∶1)中，加入0.9g高碘酸钠和3ml0.5M硫酸后，室温下反应5个小时。加入50ml水熄灭反应，反应后料液用乙酸乙酯萃取，无水硫酸钠干燥，真空旋蒸得0.98g白色固体。将其溶于20ml四氢呋喃，加入0.08g三氟甲磺酸镱后，缓慢滴加0.3ml乙酸酐，室温下反应1个小时，加入饱和NaHCO3溶液25ml熄灭反应，乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得1.03g白色固体。将其溶于20ml甲醇/水(4∶1)中，加入3ml乙酸和0.5ml苯肼，50℃下反应3个小时后，加入50ml水熄灭反应，乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得0.95g白色固体。将其溶于50ml0.1％的二甲胺甲醇溶液中，室温下反应1h后，用乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得0.92g白色固体。该物质经硅胶柱层析后得到0.53g紫杉醇(含量90％，收率58.6％，LC-MS谱图见图3)。
实施例5从10-去乙酰-紫杉醇制取10-苯甲酰-10-去乙酰紫杉醇
称取10-去乙酰紫杉醇(含量77％，LC-MS谱图见图1)的样品1g，溶于20ml四氢呋喃，0.08g三氟甲磺酸镱充分混合后，加入0.5g苯甲酸酐，50℃下反应3个小时，加入饱和NaHCO3溶液25ml熄灭反应。反应后料液用乙酸乙酯萃取，无水硫酸钠干燥，真空旋蒸得0.91g白色固体。将其溶于50ml0.1％的二甲胺甲醇溶液中，室温下反应1h后，用乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得0.87g白色固体。该物质经硅胶柱层析后得到0.72g 10-苯甲酰-10-去乙酰紫杉醇(含量85％，收率69.3％)。
实施例6从10-去乙酰-7-O-Troc-紫杉醇制取10-三氟乙酰-10-去乙酰-7-O-Troc-紫杉醇
称取10-去乙酰-7-O-Troc-紫杉醇(含量78％)的样品0.5g，溶于10ml四氢呋喃，加入0.03g三氟甲磺酸镧充分混合后，加入0.3g三氟乙酸酐，20℃下反应0。5个小时，加入饱和NaHCO3溶液15ml熄灭反应。反应后料液用乙酸乙酯萃取，无水硫酸钠干燥，真空旋蒸得0.52g白色固体。该物质溶于25ml0.1％的二甲胺甲醇溶液中，室温下反应1h后，用乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得0.49g白色固体。该物质经硅胶柱层析后得到0.37g10-三氟乙酰-10-去乙酰-7-O-Troc-紫杉醇(含量85％，收率74.4％)。
实施例7从10-去乙酰-7-O-TES-紫杉醇制取10-丙酰-10-去乙酰-7-O-TES-紫杉醇
称取10-去乙酰-7-O-TES-紫杉醇(含量80％)的样品0.5g，溶于10ml四氢呋喃，加入0.03g三氟甲磺酸钪，充分混合后，加入1.0ml丙酸酐，30℃下反应1.5个小时，加入饱和NaHCO3溶液15ml熄灭反应.反应后料液用乙酸乙酯萃取，无水硫酸钠干燥，真空旋蒸得0.57g白色固体.该物质溶于25ml0.1％的二甲胺甲醇溶液中，室温下反应1h后，用乙酸乙酯萃取料液，无水硫酸钠干燥，真空旋蒸得0.52g白色固体.该物质经硅胶柱层析后得到0.38g10-丙酰-10-去乙酰-7-O-TES-紫杉醇(含量80％，收率71.5％).
Claims (5)
1.一种选择性酰化紫杉烷C(10)和C(2’)位羟基的方法，其特征在于：
——反应体系中含有催化当量的IIIB族金属元素的三氟甲磺酸盐作为催化剂；
——使用不少于2摩尔底物当量的酸酐作为酰化剂，处理具有如下结构通式(式I)的10-去乙酰-紫杉烷类化合物，从而得到C(10)和C(2’)位酰化的紫杉烷；
式I
其中R1为-H，-OR，-OSi(R)3或-OCOR；R2与R3相同或者不同，为-H，-R或-OR；所述的R为H，C1至C20的直链、支链或环型烃基，芳基，芳烷基，或者上述三种烃基的取代物，取代基包括羟基，C1至C8的烷氧基，缩醛、缩酮，卤素，硝基或氨基；
——反应过程于惰性有机溶剂中进行。
2.按照权利要求1所述选择性酰化紫杉烷C(10)和C(2’)位羟基的方法，其特征在于：所述催化剂选自三氟甲磺酸钪，三氟甲磺酸镱，三氟甲磺酸铒，三氟甲磺酸镧，三氟甲磺酸铷，三氟甲磺酸钐，三氟甲磺酸镝。
3.按照权利要求1所述选择性酰化紫杉烷C(10)和C(2’)位羟基的方法，其特征在于：所述酸酐的结构具有结构通式
其中R’为C1至C20的直链、支链或环型烃基，芳基，及上述三种烃基的卤代物。
4.按照权利要求1所述选择性酰化紫杉烷C(10)和C(2’)位羟基的方法，其特征在于：所述惰性有机溶剂选自四氢呋喃，乙醚，乙酸乙酯，二氧六环，氯仿，二氯甲烷中的一种或一种以上的混合体系。
5.按照权利要求1所述选择性酰化紫杉烷C(10)和C(2’)位羟基的方法，其特征在于：所述反应温度为-80℃至100℃。
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| CN111848623B (zh) * | 2019-04-25 | 2021-11-12 | 中国科学院大连化学物理研究所 | 一种手性磷酸催化合成含氟的手性缩酮胺的方法 |
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| US5874595A (en) * | 1997-05-02 | 1999-02-23 | Pharmachemie B.V. | Method for the preparation of baccatin III and derivatives thereof from 10-deacetylbaccatin III |
| CN1640817A (zh) * | 2004-01-13 | 2005-07-20 | 中国科学院过程工程研究所 | 一种制备磷酸锆的方法 |
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| US5874595A (en) * | 1997-05-02 | 1999-02-23 | Pharmachemie B.V. | Method for the preparation of baccatin III and derivatives thereof from 10-deacetylbaccatin III |
| CN1640817A (zh) * | 2004-01-13 | 2005-07-20 | 中国科学院过程工程研究所 | 一种制备磷酸锆的方法 |
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| .具有抗癌活性的水溶性紫杉醇前体药物的合成.国外医药.植物药分册7(1992) 6.1992,7(1992)(6),263. |
| Kazuaki Ishihara, Manabu Kubota, Hideki Kurihara, HisashiYamamoto.Scandium Trifluoromethanesulfonate as an Extremely ActiveAcylation Catalyst.Jounal of the American Chemical society117(1995) 15.1995,117(1995)(15),4413-4414. |
| Kazuaki Ishihara, Manabu Kubota, Hideki Kurihara, HisashiYamamoto.Scandium Trifluoromethanesulfonate as an Extremely ActiveAcylation Catalyst.Jounal of the American Chemical society117(1995) 15.1995,117(1995)(15),4413-4414. * |
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