CN1058714C - 金属醇盐的制备方法 - Google Patents

金属醇盐的制备方法 Download PDF

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CN1058714C
CN1058714C CN92112482A CN92112482A CN1058714C CN 1058714 C CN1058714 C CN 1058714C CN 92112482 A CN92112482 A CN 92112482A CN 92112482 A CN92112482 A CN 92112482A CN 1058714 C CN1058714 C CN 1058714C
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R·A·霍尔顿
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Abstract

一种具有下列通式的金属醇盐:
其中T1为氢或羟基保护基,Z为-OT2,或-OCOCH3,T2为氢或羟基保护基,M选自IA,IIA族和过渡金属。该化合物可用来制备具有生物活性的浆甲赤霉素III和10-去乙酰基浆果赤霉素III衍生物。

Description

金属醇盐的制备方法
本申请是1991年9月23日申请,美国专利申请为07/763,805的部分继续。
本发明是针对新的金属醇盐,它们可用来制备具有生物活性的浆果赤霉素III和10-去乙酰基浆果赤霉素III衍生物如紫杉酚,taxotere和其他紫杉烷衍生物。
紫杉烷族萜类,包括紫杉酚,已经在生物和化学领域引起相当大的兴趣。紫杉酚是个有希望的癌症化疗剂,具有广谱的抗白血病和肿瘤抑制活性。紫杉酚具有如下结构:
Figure C9211248200031
由于这种有希望的活性,在法国和美国,紫杉酚目前正在进行临床试验。
用作临床试验的紫杉酚目前由短叶紫杉(Western Yew)的皮中提供。然而,在这些生长缓慢的长绿植物中,仅含极少量的紫杉酚,这导致人们相当大的关注,以求解紫杉酚的供求矛盾。因而,近年来化学家花费大量精力研究一条制备紫杉酚的可行合成路线。但到目前为止尚无令人满意的结果。
一种已提出的合成路线是针对从市售化学品合成四环紫杉烷核。紫杉酚的同族化合物紫杉素的一种合成方法已经由Holton等在JACS  110,6558(1988)上报导。尽管这个方法有所进步,然而,紫杉酚的最后全合成很可能是多步的,冗长的和昂贵的过程。
制备紫杉酚的另一方法已经由Greene等在JACS  110,5917(1988)中描述,它包括使用一种紫杉酚同族化合物,10-去乙酰基浆果赤霉素III,其具有如式II所示的结构:
Figure C9211248200041
10-去乙酰基浆果赤霉素较紫杉酚容易得到,因为它可由浆果紫杉的针叶中获得。按照Greene  等人的方法。通过连接C-10乙酰基和通过一种β-酰氨基羧酸单元与C-13醇进行酯化作用来连接C-13β-酰氨基酯侧链来由10-去乙酰基浆果赤霉素转化成紫杉酚。尽管这种方法需要较少步骤,但是β-酰氨基羧酸单元的合成却在低产率的多步反应下进行,而且,偶合反应耗时长,产率低。然而,这种偶合反应在所有期望的紫杉酚或具有生物活性的紫杉酚衍生物的合成中是必需的关键步骤,因为Wani等人在JACS  932325(1971)的研究中显示β-酰氨基酯侧链在C13位的存在对抗肿瘤活性是必需的。
最近,Colin等人在美国专利4,814,470中报导式III所示紫杉酚衍生物,它具有较紫杉酚(I)更强的生物活性:
Figure C9211248200051
R′表示氢或乙酰基,R″和R_其中之一表示氢而另一个表示叔丁氧羰基氨基,以及它们的立体异构形式,及其它们的混合物。
根据Colin等人的美国专利4,418,470,通式III的产品可通过叔丁基N-氯氨基甲酸钠与通式(IV)的化合物反应:
Figure C9211248200061
其中R′表示乙酰基或2,2,2-三氯乙氧羰基,接着由氢来取代2,2,2-三氯乙氧羰基或基团而制得。然而,Denis等人在美国专利4,924,011中报导这个反应所产生的是异构体的混合物。这种混合物必须被分离,结果是用于制备通式(IV)化合物的浆果赤霉素III或10-去乙酰基浆果赤霉素III不能全部被转化成通式(III)的产物。
为了改进Colin等人的方法,Denis等人公开了一种制备通式(V)的浆果赤霉素III或10-去乙酰基浆果赤霉素衍生物的不同方法:
Figure C9211248200071
其中R′表示氢或乙酰基,在该方法中,一种如下通式的酸:其中R1为羟基保护基,与通式(VII)的紫杉烷衍生物缩合:
Figure C9211248200073
其中R2为乙酰基,羟基保护基,R3为羟基保护基,然后合适时将保护基R1、R3、R2用氢取代。然而,这种方法需要相对苛刻的条件,转化率低,产率不是最隹。
合成紫杉酚和其它潜在抗肿瘤试剂中主要的困难就是缺乏C-13位氧被活化的浆果赤霉素III和10-去乙酰基浆果赤霉素衍生物。开发这样的衍生物使β-酰氨基酯侧链的连接物的产率提高,因而,使具有一组改性的母核取代基或改性的C-13侧链的紫杉酚及其他相关抗肿瘤试剂的合成变得容易。
在合成紫杉酚中遇到的另一个主要困难是在C-13位连接β-酰氨基酯侧链的已知方法通常不能满足非对映选择。因此,侧链前体必须被制成选择性活性形式以便在连接过程中获得所需的非对映体。
因此,本发明的目的之一就是提供可以高产率连接β-酰氨基酯侧链的活性浆果赤霉素III和10-去乙酰基浆果赤霉素III衍生物,提供可免除费用昂贵、耗时的分离前体化合物成各自异构形式的过程,使侧链前体的外消旋混合物直接使用的衍生物,以及提供可制备在侧链有较大变化的紫杉烷类衍生物。
因而,本发明主要针对具有如下通式的金属醇盐:
Figure C9211248200081
其中T1是氢或羟基保护基,Z是-OT2,或-OCOCH3,T2是氢或羟基保护基,M是金属,优选的是Li,Mg,Na,K或Ti。
本发明的其他目的和特点将在下文中部分地表明和指明。
金属醇盐(1)是活化的浆果赤霉素III和/或10-去乙酰基浆果赤霉素III衍生物,它们在紫杉酚,taxotere和其他具有生物活性的紫杉烷衍生物的制备过程中具有特殊的用途。按照本发明,原料醇结构如下
Figure C9211248200091
其中T1和Z定义如上,所得金属醇盐与β-内酰胺(2)反应形成β-酰氨基酯中间体。然后再将中间体转化成具有生物活性的紫杉烷衍生物。β-内酰胺具有如下通式:
Figure C9211248200092
其中:R1为-OR5,-SR7,或NR8R9
R2为氢,烷基,链烯基,炔基,芳基,或杂芳基;
R3和R4独立地为氢,烷基,链烯基,炔基,芳基,杂芳基,或酰基,然而其条件为R3和R4不能都是酰基;
R5为-COR10,-COOR10,-COSR10,-CONR8R10,-SO2R11,或POR12R13
R6为烷基,烷烯基,炔基,芳基,杂芳基,或羟基保护基团;
R7为烷基,链烯基,炔基,芳基,杂芳基,或巯基保护基团;
R8为氢,烷基,链烯基,炔基,芳基,或杂芳基;
R9为氨基保护基团;
R10为烷基,链烯基,炔基,芳基,或杂芳基;
R11为烷基,链烯基,炔基,芳基,杂芳基,-OR10,或-NR8R14
R12和R13独立地为烷基,链烯基,炔基,芳基,杂芳基,-OR10,或-NR8R14
R14为氢,烷基,链烯基,炔基,芳基,或杂芳基。
按照本发明,β-内酰胺(2)中R5优选的是-COR10,其中R10为芳基,对位取代苯基,或低级烷氧基,而最优选的是苯基,甲氧基,乙氧基,叔丁氧基(“tBuO”;(CH3)3CO-)或
Figure C9211248200101
其中X为Cl,Br,F,CH3O-,或NO2-。优选的R2和R4为氢或低级烷基。优选的R3为芳基,最优选的为萘基,苯基,
Figure C9211248200102
Figure C9211248200111
其中X如前定义,Me为甲基而Ph为苯基。R1优先选择-OR6,-SR7或-NR8R9,其中,R6,R7和R9分别为羟基,巯基,和氨基保护基,而R6为氢,烷基,链烯基,炔基,芳基,或杂芳基。R1最优选的是-OR6,其中R6为三乙基甲硅烷基(“TES”),1-乙氧乙基(“EE”)或2,2,2-三氯乙氧甲基。
β-内酰胺的烷基,无论单独存在还是与上文定义的各种取代基结合,其优选的是在主链上有一到六个碳原子而最多有15个碳原子的低级烷基。它们可以是直链的或支链的,包括甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,芳基,己基等。
β-内酰胺的链烯基,无论单独存在还是与上文定义的各种取代基结合,其优选的是主链含二到六个碳原子最多有15个碳原子的低级链烯基。它们可以是直链或支链的,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-内酰胺的炔基,无论单独存在还是与上文定义的各种取代基结合,其优选的是主链含二到六个碳原子最多有15个碳原子的低级炔基。它们可以是直链的或支链的,包括乙炔基,丙炔基,丁炔基,异丁炔基,芳基,己炔基等。
上述β-内酰胺的芳基部分,无论单独存在还是与各种取代基结合,其含有6到15个碳原子,包括苯基,α-萘基或β-萘基等。取代基包括链烷氧基,被保护的羟基,卤素,烷基,芳基,链烯基,酰基,酸基,硝基,氨基,酰氨基等。最优选的芳基是苯。
如上所述,β-内酰胺(2)的R1可以是-OR6,其中R6为烷基,酰基,乙氧乙基(“EE”)。三乙基甲硅烷基(“TES”),2,2,2-三氯乙氧甲基,或其它羟基保护基团如缩醛和醚类,即,甲氧甲基(“MOM”),苄氧甲基;酯类,如乙酸酯类,碳酸酯类,如碳酸甲酯;以及烷基和芳基甲硅烷基如三乙基甲硅烷基,三甲基甲硅烷基,二甲基-叔丁基甲硅烷基,二甲基芳基甲硅烷基,二甲基杂芳基甲硅烷基,和三异丙基甲硅烷基等。各种羟基保护基和它们的合成可在“有机合成中的保护基团”(Protective Groups inOrganic Synthsis),T.W.Green,John Wiley和Sons,1981.中查找。选择的羟基保护基团应该是在足够温和的条件下容易除去,如,在48%HF,乙腈,吡啶,或0.5%HCl/水/乙醇,和/或锌,乙酸等不影响酯键或紫杉酚中间体的其他取代基的条件下。
同样如上所述,R7可以是巯基保护基,R9可以是氨基保护基。巯基保护基包括半硫缩醛如1-乙氧乙基和甲氧甲基,硫酯,或硫代碳酸酯。氨基保护基包括氨基甲酸酯,例如,2,2,2-三氯乙基氨基甲酸酯或叔丁基氨基甲酸酯。各种巯基和氨基保护基也可在上面指出的T.W.Greene的书中查找。
β-内酰胺(2)可以象流程A和B阐明的那样从容易得到的物质来制备:流程A
Figure C9211248200131
流程B
Figure C9211248200132
反应试剂:(a)三乙氨基,CH2Cl2,25℃,18小时;(b)4当量硝酸高价铈铵,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(催化剂),0℃,1.5小时;(e)正丁基锂,乙醚,-78℃,10分钟;苯甲酰氯,-78℃,1小时;(f)二异丙氨基化锂,THF,-78℃到-50℃;(g)六甲基二硅叠氮化锂,THF,-78℃到0℃;(h)THF,-78℃到25℃,12小时。
起始物质容易得到。流程A中,α-酸基乙酰氯可由羟基乙酸制备,然后,在叔胺存在下,它可与由醛和对甲氧基苯胺制备的亚胺进行环缩合形成1-对-甲氧苯基-3-酸基-4-芳基氮杂环丁烷-2-酮。对甲氧苯基可通过硝酸高价铈铵的氧化作用除去,而酸基可在与本领域熟知的相似的标准条件下还原得到3-羟基-4-芳基氮杂环丁烷-2-酮。 3-羟基可由1-乙氧乙基保护,也可由各种标准的保护基团如三乙基甲硅烷基或其他三烷基(或芳基)甲硅烷基保护。在流程B中,乙基-α-三乙基甲硅烷基氧乙酸酯可容易地由羟基乙酸制备。
外消旋β-内酰胺可以通过相应的2-甲氧基-2-(三氟甲基)苯基乙酸酯的重结晶作用而在保护之前,先被分解成纯对映体。然而在下文描述的连接β-酰氨基酯侧链的反应却有高度非对映选择的优点,因而可允许使用外消旋的侧链前体混合物。
流程A中的3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮和流程B中的3-(1-三乙基甲硅烷基)-4-苯基氮杂环丁烷-2-酮可在-78℃或更低的温度下通过用一种碱,优选的是正丁基锂,和一种酰氯,磺酰氯,氧膦基氯,磷酰氯或氯甲酸烷基酯处理而转化成β-内酰胺(2)。
优选地,金属醇盐可通过具有二到四个环的紫杉烷母核和C-13羟基的醇与一种有机金属化合物在合适的溶剂中反应而制得。最优选的醇是被保护的浆果赤霉素III,特别是7-0-三乙基甲硅烷基浆果赤霉素III(它可按Greenr等在JACS  110,5917(1988)  中描述的方法或其它方法制得)或7,10-双-O-三乙基甲硅烷基浆果赤霉素III。
按照Green等的报告,10-去乙酰基浆果赤霉素III可按照下列反应流程转变成7-O-三乙基甲硅烷基-10-去乙酰基浆果赤霉素III:按照报告仔细完善的条件,10-去乙酰基浆果赤霉素III可与20当量(C2H5)3SiCl在23℃氩气氛中,在50ml吡啶/毫摩尔10-去乙酰基浆果赤霉素III存在下反应20小时得到纯化后产率为84-86%的反应产物,7-三乙基甲硅烷基-10-去乙酰基浆果赤霉素III(4a)。
然后,按Greene等在JACS  110,5917到5918(1988)的报告,用5当量的CH3COCl和25ml吡啶/mmol 4a  在0℃,氩气氛存在下乙酸化反应产物(4a)48小时得到产率为86%的7-O-三乙基甲硅烷基浆果赤霉素III(4b)。
另外,可用一种酸不稳定的羟基保护基团来保护7-三乙基甲硅烷基-10-去乙酰基浆果赤霉素的C-10位氧。例如,在0℃,THF中,先用正丁基锂,然后用三乙基甲硅烷基氯(1.1mol当量)处理(4a)得到产率为95%的7.10-双-O-三乙基甲硅烷基浆果赤霉素III(4c)。(4a)也可由过量乙基乙烯基醚和催化量甲磺酸处理得到产率为90%的7-O-三乙基甲硅烷基-10-(1-乙氧基乙基)浆果赤霉素III(4d)。这些制备过程可由下列反应流程说明。
Figure C9211248200161
7-O-三乙基甲硅烷基浆果赤霉素III衍生物(4b,4c或4d)在溶剂如四氢呋喃(THF)中与有机金属化合物如正丁基锂反应生成13-O-锂-7-O-三乙基甲硅烷基浆果赤霉素III衍生物的金属醇盐(5b,5c或5d),如下列反应流程所示:
Figure C9211248200181
(22b)Z=-OCOCH3(22c)Z=-OSi(C2H5)3(22d)Z=-OEE
按下面反应式,13-O-锂-7-O-三乙基甲硅烷基浆果赤霉素III衍生物(5b,5c或5d)与β-内酰胺(2)反应得到C-7和C-2′位羟基被三乙基甲硅烷基保护的中间体(6b,6c或6d)。然后在温和的条件下水解三乙基甲硅烷基乙氧基乙基,使酯键或紫杉烷取代基不受干扰。
  5b-d                   (2)                        6 b-d
                                                   b,Z=-OCOCH3
                                                   c,Z=-OSi(C2H5)3
                                                   d,Z=-OEE其中T1为羟基保护基;M为金属;Ph为苯基;Ac为乙酰基;而R1到R5如前文所定义。
金属醇盐(3)中的金属取代基M为IA,IIA,IIIA族,镧系或锕系元素或过渡元素,IIIA,IVA,VA或VIA族金属。优选的是IA,IIA或过渡元素金属,最优选的是锂、镁、钠、钾或钛。
不论是将醇转变为金属醇盐还是最后合成紫杉烷衍生物,都可在同一反应器中进行。优选的是,形成金属醇盐后再将β-内酰胺加到反应器中。
有机金属化合物正丁基锂优选地用来将浆果赤霉素III或10-去乙酰基浆果赤霉素III转化成相应的金属醇盐,其他提供金属取代基来源的化合物如二异丙基氨基锂,其他氨基化锂或镁,溴化乙基镁,溴化甲基镁,其他有机锂化合物,其他有机镁化合物,有机钠,有机钛或有机钾也可使用。有机金属化合物容易买到,或者用通常方法包括用金属还原有机卤化物来制备。例如,按下述方法丁基溴可在乙醚中与金属锂反应得到正丁基锂溶液:
对于反应混合物来说,虽然THF为优选的溶剂,但其他醚类溶剂,如二甲氧基乙烷,或芳香族溶剂也是合适的。对反应物溶解度太小的某些溶剂,包括一些卤代溶剂和一些直链烃是不合适的。其他溶剂由于其他的原因也是不合适的。例如,由于不相容性,酯类不适用于某些有机金属化合物如正丁基锂。
虽然本发明公开的反应方案对紫杉酚,taxotere,和这里例举的其他紫杉烷衍生物比较理想,但该方案也可修改而用于将β-内酰胺或四环金属醇盐制备或其他化合物。因而,β-内酰胺和四环金属醇盐可从天然或非天然来源获得,由它们可制备本发明期望的其他合成的紫杉酚,紫杉酚衍生物,10-去乙酰基紫杉酚,及其对映体与非对映体。
本发明的方法也有高度非对映选择的重要优点,因而,侧链前体的外消旋混合物也可被使用。由于不需要将外消旋β-内酰胺解析成纯非对映体,因此可节省大量费用。也由于上述制备过程所需侧链前体减少。例如,减少至60-70%,因而也节省大量费用。
下列实施例是用来说明本发明的。实施例1
从外消旋β-内酰胺制备2′-乙氧基乙基-7-三乙基甲硅烷基紫杉酚以及随后制备紫杉酚:
在-78℃下,向7-三乙基甲硅烷基浆果赤霉素III(20mg,0.028mmol)的1ml THF溶液中滴加0.17ml的0.164MnBuLi的己烷溶液。在-78℃30分钟后,将顺-1-苯甲酰-3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮(47.5mg,0.14mmol)的1ml THF溶液滴加到混合物中。将该溶液缓慢加热(超过1.5小时)到0℃然后在0℃下搅拌1小时并加入1ml 10%的AcOH的THF溶液。将混合物在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分配。通过快速色谱纯化蒸发有机层后的残留物得到23mg(80%)(2′R,3′S)-2′-乙氧基乙基-7-三乙基甲硅烷基紫杉酚和3.5mg(13%)2′,3′-表(2′S,3′R)-2′-乙氧基乙基-7-三乙基甲硅烷基紫杉酚。
将5mg(2′R,3′S)-2′-乙氧乙基-7-三乙基甲硅烷基紫杉酚试样溶解在2ml乙醇中,并加入0.5ml 0.5%HCl水溶液。将混合物在0℃搅拌30小时,并用50ml乙酸乙酯稀释。溶液用20ml饱和碳酸氢钠水溶液萃取,用硫酸钠干燥并浓缩,通过快速色谱纯化残留物得到4.5mg(约90%)紫杉酚,它与可靠样品在各方面完全相同。
将5mg  2′,3′-表(2′S,3′R)-2′-乙氧基乙基-7-三乙基甲硅烷基紫杉酚试样溶解在2ml乙醇中并加入0.5ml 0.5%HCl水溶液,将混合物在0℃搅拌30小时并用50ml乙酸乙酯稀释。溶液用20ml饱和碳酸氢钠水溶液萃取,用硫酸钠干燥并浓缩。用快速色谱纯化残留物,得到4.5mg(约90%)2′,3′-表紫杉酚。实施例2
从外消旋β-内酰胺制备2′,7-(双)三乙基甲硅烷基紫杉酚及随后制备紫杉酚
在-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(100mg0.143mmol)的1ml THF溶液中滴加0.087ml 1.63M的nBuLi己烷溶液。在-45℃保存1小时后,将顺-1-苯甲酰基-3-乙基甲硅烷氧基-4-苯基氮杂环丁烷-2-酮(274mg,0.715mmol)的1ml THF溶液滴加到混合物中。将该溶液缓慢加热到0℃并再在0℃下放置1小时。加入1ml 10%AcOH的THF溶液。将混合物在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分配。通过快速色谱和重结晶纯化蒸发有机层后的残留物得到131mg(85%)(2′R,3′S)-2′,7-(双)三乙基甲硅烷基紫杉酚和15mg(10%)2′,3′-表(2′S,3′R)-2′,7-(双)三乙基甲硅烷基紫杉酚。
0℃下,向121.3mg(0.112 mmol)(2′R,3′S)-2′,7-(双)三乙基甲硅烷基紫杉酚的6ml乙腈和0.3ml吡啶溶液中加入0.9ml 48%HF水溶液。将此混合物在0℃搅拌8小时,然后在25℃保存6小时。将混合物在饱和碳酸氢钠水溶液和乙酸乙酯间分配中。蒸发乙酸乙酯溶液得到113mg残留物,用快速色谱和重结晶纯化后得到94mg(98%)紫杉酚,它与可靠样品在各方面完全相同。
0℃下,向5mg(2′R,3′S)-2′,7-(双)三乙基甲硅烷基紫杉酚的0.5ml乙腈和0.03ml吡啶的溶液中加入0.09ml 48%HF水溶液。将此混合物在0℃下搅拌8小时,然后在25℃保存6小时。将混合物在饱和碳酸氢钠水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得到5mg残留物,用快速色谱和重结晶纯化得到4.6mg(约95%)2′,3′-表紫杉酚。实施例3
制备taxotere
在-45℃下,向7,10-双-三乙基甲硅烷基浆果赤霉素III(200mg,0.248ml)的2ml THF溶液中滴加0.174ml 1.63M正丁基锂的己烷溶液,-45℃下保存0.5小时后,在该混合物中滴加顺-1-(叔丁氧羰基)-3-三乙基甲硅烷氧基-4-苯基氮杂环丁烷-2-酮(467mg,1.24mmol)的2ml THF溶液。将此溶液加热到0℃并在此温度下保存1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分配。蒸发有机层得到残留物,通过硅胶过滤纯化残留物得到280mg 2′,7,10-三-三乙基甲硅烷基taxotere粗品。
在0℃下,向280mg上述反应获得的粗产品的12ml乙腈和0.6ml吡啶溶液中,加入1.8ml 48%HF水溶液。在0℃下,将此混合物搅拌3小时,然后在25℃下搅拌13小时,并将其分配在饱和碳酸氢钠水溶液和乙酸乙酯之间。蒸发乙酸乙酯溶液得到215mg残留物,将其通过快速色谱纯化并用甲醇/水使其重结晶,得到190mg(95%)taxotere,所有分析结果和光谱数据与美国专利4,814,470中报告的taxotere一致。实施例4其中Np2
Figure C9211248200232
制备3′-去苯基-3′-(2-萘基)紫杉酚
在-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml THF溶液中滴加0.174ml 1.63M的正丁基锂的己烷溶液。-45℃保存0.5小时后,在该混合物中滴加顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(2-萘基)氮杂环丁烷-2-酮(620mg,1.43mmol)的2ml THF溶液。将此溶液加热到0℃并在此温度下保持1小时,然后加入1ml10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40的乙酸乙酯/己烷之间。通过硅胶过滤来纯化蒸发有机层所得残留物,得到320mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(2-萘基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向32.0mg(0.283mmol)上述反应所得混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液,0℃下将此混合物搅拌3小时,然后在25℃下搅拌13小时,并分配到饱碳酸氢钠水溶液和乙酸乙酯之间。蒸发乙酸乙酯溶液得到255mg残留物,用快速色谱纯化并将其用甲醇/水重结晶得到116mg(64%)3′-去苯基-3′-(2-萘基)紫杉酚。m.p164-165℃;[α]25 N4-52.6°(c 0.005,CHCl3).1H NMR(CDCl3,300MHz)δ8.14(d,J=7.3Hz,2H,苯甲酸酯邻位),7.96(m,1H,芳族),7.90(m,1H,芳族),7.85(m,2H,芳族),7.76(m,2H,芳族),7.60(m,3H,芳族),7.52(m,4H,芳族),7.41(m,2H,芳族),7.01(d,J=8.8Hz,1H,NH),6.27(s,1H,H10),6.26(dd,J=9.2,9.2Hz,1H,H13),5.97(dd,J=8.8,25Hz,1H,H3′),5.68(d,J=7.1Hz,1H,H2β),4.93(m,1H,H5),4.92(m,1H,H2′),4.39(m,1H,H7),4.30(d,J=8.5Hz,1H,H20α),4.20(d,J=8.5Hz,1H,H20β),3.81(d,J=7.1Hz,1H,H3),3.60(d,J=5Hz,1H,2′OH),2.48(m,1H,H5α),2.45(br,1H,7OH),2.39(s,3H,4Ac),2.30(m,2H,H14),2.24(s,3H,10Ac),1.83(m,1H,H6β),1.82(br s,3H,Me18),1.68(s,1H,1OH),1.68(s,3H,Me19),1.24(s,3H,Me17),1.14(s,3H,Me15)实施例5
Figure C9211248200251
其中Np1
Figure C9211248200252
制备3′-去苯基-3′-(1-萘基)紫杉酚。
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml THF溶液中滴加0.174ml 1.63M正丁基锂的己烷溶液。-45℃保存0.5小时后,在该混合物中滴加顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(1-萘基)氮杂环丁烷-2-酮(620mg,1.43mmol)的2ml THF溶液。该溶液被加热到0℃并保持1小时,然后加入1ml 10%的AcOH的HF溶液。将混合物分配到饱和NaHCO3水溶液和60/40的乙酸乙酯/己烷之间。通过硅胶过滤纯化蒸发有机层所得残留物得到(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(1-萘基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向325mg(0.287mol)上述反应所得混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液。将此混合物在0℃下搅拌3小时,25℃下搅拌13小时将其分配到饱和碳酸氢钠水溶液和乙酸乙酯之间。蒸发乙酸乙酯溶液得到260mg残留物,用快速色谱纯化并由甲醇/水重结晶得到166mg(64%)3′-(1-萘基)紫杉酚。m.p.164-165℃:[α]25 4A-52 6°(c 0.005,CHCl3).1H NMR(CDCl3,300MHz)δ6.11(d,J=7.1Hz,2H,苯甲酸酯邻位),8.11(m,3H,芳族),7.91(m,3H,芳族),7.70(m,2H,芳族),7.63-7.46(m,7H,芳族),6.75(d,J=8.8Hz,1H,NH),6.52(dd,J=8.8,1.6Hz,1H,H3′),6.27(s,1H,H10),6.27(dd,J=9.1,9.1Hz,1H,H13),5.68(d,J=7.1Hz,1H,H2β),4.85(dd,J=7.6,2.2Hz,1H,H5),4.97(dd,J=1.6Hz,1H,H2′),4.39(m,1H,H7),4.24(d,J=8.5Hz,1H,H20α),4.17(d,J=8.5Hz,1H,H20β),3.80(d,J=7.1Hz,1H,H3),3.65(br,1H,2′OH),2.55(m,1H,H6α),2.48(br,1H,7OH),2.41(s,3H,4Ac),2.38(m,1H,H14),1.96(s,3H,10Ac),1.86(m,1H,H6β),1.80(br s,3H,Me18),1.76(s,1H,1OH),1.69(s,3H,Me19),1.28(s,3H,Me17),1.16(s,3H,Me16).实施例6
Figure C9211248200271
制备3′-去苯基-3′-(4-甲氧基苯基)紫杉酚
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml THF溶液中滴加0.174ml,1.63M,nBuLi的己烷溶液。-45℃保存0.5小时后,将顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(4-甲氧基苯基)氮杂环丁烷-2-酮(590mg,1.43mmol)的2ml THF溶液滴加到上述混合物中。将该溶液加热到0℃并在该温度下保持1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中,通过硅胶过滤纯化蒸发有机层所得残留物得到320mg(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(4-甲氧基苯基)紫杉酚和少量(2′S,3′P)异构体的混合物。
0℃下,向上述反应所得的320mg(2.88mmol)混合物的18ml乙腈和0.93吡啶溶液中加入2.8ml 48%HF水溶液。将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并将其分配到饱和碳酸氢钠水溶液和乙酸乙酯中。蒸发乙酸乙酯溶液得到255mg残留物用快速色谱纯化并由甲醇/水重结晶得到172mg(68%)的3′-去苯基-3′-(4-甲氧基苯基)紫杉酚。m.p.174-176℃:[α]25 N4  -48.96°(c 0.06,CHCl3).1H NMR(CDCl3,300MHz)δ8.12(d,J=7.1Hz,2H,苯甲酸酯邻位),7.72(m,2H,芳族),7.59(m,1H,芳族),7.53-7.36(m,8H,芳族),6.96(d,J=8.8Hz,1H,NH),6.90(m,2H,芳族),6.26(s,1H,H10),6.21(dd,J=9.3,9.3Hz,1H,H13),5.70(dd,J=8.8,2.7Hz,1H,H3′),5.66(d,J=6.8Hz,1H,H2β),4.93(dd,J=9.9,2.2Hz,1H,H5),4.74(dd,J=5.5,2.7Hz,1H,H2′),4.39(m,1H,H7),4.29(d,J=8.8Hz,1H,H20α),4.18(d,J=8.8Hz,1H,H20β),3.78(d,J=6.8Hz,1H,H3),3.78(s,3H,ArOMe),3.67(d,J=5.5Hz,1H,2′OH),2.61(m,1H,H6α),2.50 (d,J=4.4Hz,1H,7OH),2.37(s,3H,4Ac),2.31(m,2H,H14),2.22(s,3H,10Ac),1.84(m,1H,H6β),1.79(br  s,3H,Me18),1.79(s,1H,1OH),1.67(s,3H,He19).1.22(s,3H,Me17),1.13(s,3H,Me16).实施例7
制备3′-去苯基-3′-(4-氯苯基)紫杉酚
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286ml)的2ml THF溶液中滴加0.174ml 1.63M的nBuli的己烷溶液。-45℃保存0.5小时后,在该混合物中滴加顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(4-氯苯基)氮杂环丁烷-2-酮的2ml THF溶液。将此溶液加热到0℃并在此温度下保持1小时然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层所得残留物,得到320mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(4-氯苯基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向320mg上述反应得到混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液。将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并在将其分配到饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯所得255mg残留物,得到158mg(62%)3′-去苯基-3′-(4-氯苯基)紫杉酚,并将其用甲醇/水重结晶。m.p.173-175℃;[α]25 N4  -50.8°(c 0.01,CHCl3).1H NMR(COCl3,300MHz)δ8.13(d,J=7.1Hz,2H,苯甲酸酯邻位),7.72(d,J=8.2HZ,2H,苯酰胺  邻位),7.65-7.35(m,1OH,芳族),6.97(d,J=8.8Hz,1H,NH),6.27(s,1H,H10),6.25(dd,J=8.3,8.3Hz,1H,H13),5.78(dd,J=8.8,2.2Hz,1H,H3′),5.67(d,J=7.1Hz,1H,H2β),4.95(dd,J8.8,2.2Hz,1H,H5),4.77(br s,1H,H2),4.40(m,1H,H7),4.31(d,J=8.2Hz,1H,H20α),4.19(d,J=8.2Hz,1H,H20β),3.80(d,J=7.1Hz,1H,H3),3.51(br s,1H,2′OH),2.54(m,1H,H6α),2.38(s,3H,4Ac),2.32(m,2H,H14),2.24(s,3H,10Ac),1.85(m,1H,H63),1.80(br s,3H,Me18),1.68(s,3H,Me19),1.23(s,3H,Me17),1.14(s,3H,Me16).实施例8
Figure C9211248200301
制备3′-去苯基-3′-(4-溴苯基)紫杉酚-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml THF溶液中滴加0.174ml 1.63M的nBuLi的己烷溶液。在-45℃保存0.5小时后,在此混合物中滴加顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(4-溴苯基)氮杂环丁烷-2-酮(660mg,1.43mmol)的2mlTHF溶液。将此溶液加热到0℃并保持1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层所得残留物,得到330mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(4-溴苯基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向330mg(0.284mmol)上述反应所得混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液。将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并将其分配到饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得265mg残留物,得到186mg(64%)3′-去苯基-3′-(4-溴苯基)紫杉酚,并将其用甲醇/水重结晶。m.p. 170-172℃:[α]25 N4 -50.94°(c 0.01,CHCl3).1H NMR(CDCl3,300MHz)δ8.12(d,J=7.2Hz,2H,苯甲酸酯邻位),7.71(m,2H,芳族),7.61(m,1H,芳族),7.50-7.47(m,6H,芳族),7.38(M,3H,芳族),7.04(d,J=8.8Hz,1H,NH),6.27(s,1H,6.10),6.23(dd,J=8.2,8.2Hz,1H,H13),5.75(dd,J=8.8,2.2Hz,1H,H3′),5.66(d,J=7.4Hz,1H,H2β),4.94(dd,J=9.1,1.7Hz,1H,H5),4.75(dd,J=2.2Hz,1H,H2′),4.38(m,1H,H7),4.29(d,J=8.2Hz,1H,H20α),4.18(d,J=8.2Hz,1H,H20β),3.79(d,J=7.1Hz,1H,H3),3.7(br,1H,2′OH),2.53(m,1H,H6α),2.38(br,1H,7OH),2.37(s,3H,4Ac),2.30(m,2H,H14),2.23(s,3H,10Ac),1.87(m,1H,H6β),1.8C (br s,3H,Me18),1.80(s,1H,1OH),1.67(s,3,Me15),1.22(s,3H,Me17),1.13(s,3H,Me16).实施例9
Figure C9211248200321
制备3′-去苯基-3′-(3,4-亚甲基二氧苯基)紫杉酚
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml THF溶液中滴加0.174ml 1.63M的nBuLi的己烷溶液。-45℃下保持0.5小时后,在此混合物中加入顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(3,4-亚甲基二氧苯基)氮杂环丁烷-2-酮(610mg,1.43mmol)的2ml THF溶液。将此溶液加热到0℃并保持1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层得到的残留物,得到320mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(3,4-亚甲基二氧苯基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向320mg(0.284mmol)上述反应所得混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液。将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并将其分配到饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得113mg残留物,得到165mg(64%)3′-去苯基-3′-(3,4-亚甲基二氧苯基)紫杉酚,并将其在甲醇/水中重结晶。m.p.178-180℃;[α]15 N4  -46.6°(c  0.005,CHCl3).1H NMR(CDCl3,300MHz)δ8.14(d,J=7.2Hz,2H,苯甲酸酯邻位),7.72(m,2H,芳族),7.15(m,1H,芳族),7.50(m,2H,芳族),7.38(m,2H,芳族),7.0(m,1H,芳族),6.94(m,2H,芳族),6.88(d,J=9.1Hz,1H,NH),6.83(m,1H,芳族),6.28(s,1H,H10),6.23(dd,J=9.1,9.1Hz,1H,H13),5.97(s,2H,亚甲基),5.69(dd,J=9.1,2.5Hz,1H,H3′),5.68(d,J=6.9Hz,1H,H2β),4.95(dd,J=9.6,2.2Hz,1H,H5),4.72(dd,J=2.5Hz,1H,H2′),4.41(m,1H,H7),4.31(d,J=8.4Hz,1H,H20α),4.20(d,J=8.4Hz,1H,H20β),3.81(d,J=6.9Hz,1H,H3),3.60(br,1H,2′OH),2.56(m,1H,H6α),2.4 3(d,J=4.1Hz,1H,7OH),2.39(s,3H,4Ac),2.31(m,2H,H14),2.24(s,3H,10Ac),1.88(m,1H,H6β),1.82(br s,3H,Me18),1.69(s,1H,1OH),1.68(s,3H,Me19),1.24(s,3H,Me17),1.15(s,3H,Me16).实施例10
制备3′-去苯基-3′-(3,4-二甲氧基苯基)紫杉酚
-45℃下向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml THF溶液中滴加0.174ml 1.63M的nBuli的己烷溶液,-45℃下保存0.5小时后,在此混合液中滴加顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(3,4-二甲氧基苯基)氮杂环丁烷-2-酮(630mg,1.43mmol)的2ml THF溶液。将此溶液加热到0℃并在此温度下保持1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层所得残留物,得到330mg含(2′R, 3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(3,4-二甲氧基苯基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向33mg(0.286mmol)上述反应所得混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液。将此混合物在0℃下搅拌3小时,在25℃搅拌13小时,并将其分配到饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得260mg残留物,得到175mg(67%)3′-去苯基-3′-(3,4-二甲氧基苯基)紫杉酚并将其用甲醇/水重结晶。m.p.165-167℃;[α]25 N4 -42.0°(c 0.005,CHCl3).1H NMR(CDCl3,300MHz)δ8.12(d,J=8.3Hz,2H,苯甲酸酯邻位),7.73(d,J=8.2Hz,2H,苯酰胺 邻位),7.65-7.35(m,6H,芳族),7.1-7.0(m,2H,芳族),6.94(d,J=8.8Hz,1H,NH),6.88(d,J=3.3Hz,2H,芳族),6.27(s,1H,H10),6.21(dd,J=9.3,9.3Hz,1H,H13),5.69(m,2H,H3,H2β),4.94(dd,Hz,J=9.9,2.2Hz,1H,H5),4.77(d,J=2.8Hz, 1H,H2′),4.39(dd,J=11.0,6.6Hz,1H,H7),4.30(d,J=8.5Hz,1H,H20α),4.19(d,J=8.5Hz,1H,H20β),3.88(s,3H,ArOMe),3.87(s,3H,ArOMe),3.80(d,J=7.1Hz,1H,H3),3.59(d,J=4.4Hz,1H,2′CH),2.54(m,1H,H6α),2.38(s,3H,4Ac),2.36(m,2H,H14α,H14β),2.23(s,3H,10Ac),1.86(m,1H,H6β),1.80(br s,3H,Me18),1.68(s,3H,Me19),1.23(s,3H,Me17),1.14(s,3H,Me16)实施例11
Figure C9211248200351
制备N-去苯基甲酰基-N-乙氧羰基紫杉酚
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(155mg,0.221mmol)的2ml THF溶液中滴加0.136ml 1.63M的nBuLi的己烷溶液。-45℃保存0.5小时后,在此混合液中滴加顺-1-乙氧羰基-3-三乙基甲硅烷氧基-4-苯基氮杂环丁烷-2-酮(386mg,1.11mmol)的2ml THF溶液。将此溶液加热到0℃并在此温度下保持1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层所得的残留物,得到252mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-N-去苯甲酰基-N-乙氧羰基紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向252mg(0.112mmol)上述反应得到的混合物的12ml乙腈和0.6ml吡啶溶液中加入1.8ml 48%HF水溶液。将此混合物在0℃下搅拌3小时,在25℃下搅拌13小时,并将其分配在饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得216mg残留物,得到155mg(85%)N-去苯甲酰基-N-乙氧羰基紫杉酚,并将其在甲醇/水中重结晶。m.p.161.5-162.5℃;[α]25 N4 -62.2°(c 51,CHCl3).1H NMR(COCl3,300MHz)δ8.12(d,J=7.7Hz,2H,苯甲酸酯邻位),7.65-7.3(m,8H,芳族),6.28(m,1H,H10)6.27(m,1H,H13),5.67(d,J=7.1Hz,1H,H2β),5.53(d,J=9.3Hz,1H,H3′),5.29(d,J=9.3Hz,1H,NH),4.94(dd,J=9.3,2.2Hz,1H,H5),4.64(dd,J=5.0,2.8Hz,1H,H2′),4.41(m,1H,H7),4.29(d,J=8.5Hz,1H,H20α),4.17(d,J=8.5Hz,1H,H20β),4.01(q,J=7.1Hz,2H,COOCH2CH3),3.79(d,J=7.1Hz,1H,H3),3.45(d,J=5Hz,1H,2′CH),2.54(m,1H,H6α),2.47(d,J=3.9Hz 1H,7OH),2.36(s,3H,4Ac),2.24(s,3H,10Ac),2.22(m,2H,H14α,H14β),1.87(-,1H,H6α),1.83(br s,3H,Me18 ),1.77(s,1H,1OH),1.68(s,3H,Me19),1.27(s,3H,Me17),1.15(s,3H,Me16),1.14(s,J=7.1Hz,2H,CCCCH2CH3).实施例12
制备3′-去苯基-3′-(4-硝基苯基)紫杉酚
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml  THF溶液中滴加0.174ml 1.63M的nBuLi的己烷溶液。-45℃保存0.5小时后,在此混合物中滴加顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(4-硝基苯基)氮杂环丁烷-2-酮(610mg,1.43mmol)的2mlTHF溶液。将此溶液加热到0℃在此温度下保持1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层所得残留物,得到320mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(4-硝基苯基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向320mg(0.284ml)上述反应所得混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液。将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并将其分配在碳酸氢钠饱和水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得255mg残留物,得到147mg(57%)3′-去苯基-3′-(4-硝基苯基)紫杉酚,并将其用甲醇/水重结晶。m.p. 188-190℃:[α]25 N4,-63.7°(c 0.01,CHCl3).1H NMR(CDCl3,300MHz)δ8.26(d,J=8.8Hz,2H,苯甲酸酯邻位),8.20(m,2H,芳族),7.73(m,4H,芳族),7.60(m,1H,芳族),7.52(m,4H,芳族),7.41(m,1H,芳族),7.15(d,J=8.8Hz,1H,NH),6.25(s,1H,H10)6.26(dd,J=9.3,9.3Hz,1H,H13),5.93(dd,J=8.8,2.8Hz,1H,H3′),5.66(d,J=6.6Hz,1H,H2β),4.94(dd,J=9.3,1.7Hz,1H,H5),4.82(dd,J=3.9,2.8Hz,1H,H2′),4.38(m,1H,H7),4.30(d,J=8.8Hz,1H,H20α),4.19(d,J=3.9Hz,1H,H20β),3.86(d,J=3.9Hz,1H,2′OH),3.79(d,J=6.6Hz,1H,H3),2.55(m,1H,H6α),2.46(d,J=3.8Hz,1H,7OH),2.61(s,3H,4Ac),2.38(m,2H,H14),2.23(s,3H,10Ac),1.82(m,1H,H6β),1.80(br s,3H,Me18),1.74(s,1H,1OH),1.68(s,3H,Me19),1.21(s,3H,Me17),1.13(s,3H,Me15).实施例13
Figure C9211248200391
制备N-去苯甲酰基-N-甲氧羰基紫杉酚
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(100mg,0.143mmol)的1ml THF溶液中滴加0.087ml 1.63M的nBuLi的己烷溶液。-45℃保存0.5小时后,在此混合液中加入顺-1-甲氧基羰基-3-三乙基甲硅烷氧基-4-苯基氮杂环丁烷-2-酮(252mg,0.715mmol)的1ml THF溶液。将此溶液加热到0℃并恒温1小时,然后加入1ml 10%AcOH的THF溶液。将此混合物分配到饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层残留物,得到129mg含(2′R,3′S)-2,7-(双)三乙基甲硅烷基-N-去苯甲酰基-N-甲氧羰基紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向129mg(0.112mmol)上述反应中得到的混合物的6ml乙腈和0.3ml吡啶溶液中加入0.9ml 48%HF水溶液。将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并分配到饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得的108mg残留物,得到90mg(76%)N-去苯甲酰基-N-甲氧羰基紫杉酚,并将其用甲醇/水重结晶。m.p. 169-171℃;[α]25 N4-63.7°(c 1.1,CHCl3).1H NMR(CDCl3,300MHz)δ 8.12(d,J=7.1Hz,2H,苯甲酸酯邻位),7.65-7.3m,6H,芳族),6.28(m,2H,H10,H13),5.66(d,J=7.1Hz,1H,H2β),5.58(d,J=9.4Hz,1H,H3′),5.30(d,J=9.4Hz,1H,NH),4.93(dd,J=9.3,1.7Hz,1H,H5),4.65(br s,1H,H2′),4.40(m,1H,H7),4.29(d,J=8.8Hz,1H,H20α ),4.17(d,J=8.8Hz,1H,H20β),3.75(d,J=7.1Hz,1H,H3),3.58(s,3H,COOMe),3.34(d,J=5Hz,1H,2′OH),2.54(m,1H,H6α),2.47(d,J=3.8Hz 1H,7OH),2.36(s,3H,4Ac),2.24(s,3H,10Ac),2.22(m,2H,H14α,H14β),1.88(m,1H,H6α),1.82(br s,3H,Me16),1.73(s,1H,1OH),1.68(s,3H,Me19),1.27(s,3H,Me17),1.14(s,3H,Me16).实施例14
Figure C9211248200401
制备3′-去苯基-3′-(4-氟苯基)紫杉酚
-45℃下,向7-三乙基甲硅烷基浆果赤霉素III(200mg,0.286mmol)的2ml THF溶液中滴加0.174ml 1.63M的nBuLi的己烷溶液。-45℃下放置0.5小时后,在此混合液中滴加顺-1-苯甲酰基-3-三乙基甲硅烷氧基-4-(4-氟苯基)氮杂环丁烷-2-酮(570mg,1.43mmol)的2mlTHF溶液。将其加热到0℃并恒温1小时。然后加入1ml 10%AcOH的THF溶液。将此混合物分配在饱和NaHCO3水溶液和60/40的乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层所得的残留物,得到315mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(4-氟苯基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向315mg(0.28mmol)上述反应所得混合物的18ml乙腈和0.93ml吡啶溶液中加入2.8ml 48%HF水溶液将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并将其分配在饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得250mg残留物,得到160mg(64%)3′-去苯基-3′-(4-氟苯基)紫杉酚,并将其在甲醇/水中重结晶。m.p.171-173℃;[α]25 N4-49.0°(c 0.005,CHCl3).1H NMR(CDCl3,300MHz)δ8.13(d,J=7.5Hz,2H,苯甲酸酯邻位c),7.25(m,2H,芳族),7.61(m,1H,芳族),7.50(m,4H,芳族),7.43(m,2H,芳族),7.10(m,2H,芳族),6.96(d,J=8.7Hz,1H,NH1,6.27(s,1H,H10),6.25(dd,J=8.7,8.7Hz,1H,H13),5.79(dd,J=8.7,2.4Hz,1H,H3′),5.67(d,J=7.1Hz,1H,H2β),4.45(dd,J=7.9Hz,1H,H5),4.76(dd,J=4.8,2.4Hz,1H,H2′),4.39(m,1H,H7),4.31(d,J=8.9Hz,1H,H20α), 4.20(d,J=8.9Hz,1H,H20β),3.80(d,J=7.1Hz,1H,H3),3.57(d,J=4.8Hz,1H,2′OH),2.58(m,1H,H6a),2.43(d,J=4.3Hz,1H,7OH),2.38(s,3H,4Ac),2.30(m,2H,H14),2.24(s,3H,10Ac),1.85(m,1,H6β),1.80(br s,3H,Me19),1.69(s,1H,1OH),1.55(s,3H,Me19),1.23(s,3H,Me17),1.14(s,3H,Me16).实施例15
Figure C9211248200421
制备3′-去苯基-3′-(2-噻吩基)紫杉酚
-45℃下,向7-三乙基甲硅烷基赤浆果霉素III(100mg,0.143mmol)的1ml THF溶液中滴加0.087ml,1.63M的nBuLi的己烷溶液。-45℃下放置0.5小时后在此混合液中滴加顺-1-(4-苯基甲酰基)-3-三乙基甲硅烷氧基-4-(2-噻吩基)氮杂环丁烷-2-酮(277mg,0.715mmol)的1ml THF溶液。将其加热到0℃并恒温1小时,然后加入1ml10%AcOH的THF溶液。将此混合物分配在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷中。通过硅胶过滤纯化蒸发有机层所得残留物,得到169mg含(2′R,3′S)-2′,7-(双)三乙基甲硅烷基-3′-去苯基-3′-(2-噻吩基)紫杉酚和少量(2′S,3′R)异构体的混合物。
0℃下,向169mg上述反应所得混合物的6ml乙腈和0.3ml吡啶溶液中加入0.9ml 48%HF水溶液。将此混合物在0℃搅拌3小时,在25℃搅拌13小时,并将其分配在饱和碳酸氢钠水溶液和乙酸乙酯中。通过快速色谱纯化蒸发乙酸乙酯溶液所得140mg残留物,得到93mg(76%)3′-去苯基-3′-(2-噻吩基)紫杉酚,并将其在甲醇/水中重结晶。m.p.173-175℃;[α]25 N4  -42.1°(c 0.515,CHCl3).1H NMR(COCl3,300MHz)δ8.14(d,J=7.1Hz,2H,苯甲酸酯邻位,7.72(d,J=8.7Hz,2H,苯酰胺 邻位),7.65-7.35(m,6H,芳族),7.31(dd,J=5.5,1.1Hz,1H,噻吩基),7.19(dd,J=3.9,1.1Hz,1H,噻吩基),7.03(dd,J=5.5,3.9Hz,1H,噻吩基),6.96(d,J=8.8Hz,1H,NH),6.28(s,1H,H10),6.24(dd,J=8.8,7.7Hz,1H,H13),5.05(dd,J=8.8,1.7Hz,1H,H3′),5.68(d,J=7.1Hz,1H,H2),4.95(dd,J=9.3,1.7Hz,1H,H5),4.73(d,J=2.2Hz,1H,H2′),4.40(dd,J=11.0,6.6Hz,1H,H7),4.31(d,J=8.5Hz,1H,H20α),4.20(d,J=8.5Hz,1H,H20β),3.81(d,J=7.1Hz,1H,H3),3.72(br,s,1H,2′OH),2.54(m,1H,H6α),2.41(s,3H,4Ac),2.37(m,2H,H14α,H14β),2.23(s,3H,10Ac),1.98(m,1H,H6α),1.82(b=s,3H,Mel8),1.68(s,3H,Me19),1.23(s,3HMe17), 1.14(s,3H,Me16).
鉴于上述,本发明的几种目的显然可以实现。
由于上述物质和方法可产生不破坏本发明范围的各种变化。因此,上述所有内容是说明本发明的而不是限制本发明。

Claims (5)

1.一种制备下式金属醇盐的方法:其中T1是羟基保护基,Z是-OT2,T2是羟基保护基,M是一种选自IA,IIA族或过渡金属元素的金属,Ac是乙酰基且Ph是苯基,该方法包括使一种醇与一种选自IA,IIA族或过渡金属元素的金属有机化合物反应,该醇具有以下通式
其中T1和Z定义如上,
2.权利要求1的方法,其中有机金属化合物是正丁基锂、二异丙基氨化锂或溴化乙基镁。
3.权利要求1的方法,其中M是Li,Mg,Na,K或Ti。
4.权利要求1的方法,其中M是Li。
5.权利要求1的方法,其中T1和T2独立地选自1-乙氧基乙基和三烷基甲硅烷基。
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