CN1681824A - 制备埃坡霉素衍生物的新方法、新的埃坡霉素衍生物以及用于该方法的新的中间体及其制备方法 - Google Patents
制备埃坡霉素衍生物的新方法、新的埃坡霉素衍生物以及用于该方法的新的中间体及其制备方法 Download PDFInfo
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- CN1681824A CN1681824A CNA038215837A CN03821583A CN1681824A CN 1681824 A CN1681824 A CN 1681824A CN A038215837 A CNA038215837 A CN A038215837A CN 03821583 A CN03821583 A CN 03821583A CN 1681824 A CN1681824 A CN 1681824A
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
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- YSAVZVORKRDODB-UHFFFAOYSA-N Diethyl tartrate Chemical compound CCOC(=O)C(O)C(O)C(=O)OCC YSAVZVORKRDODB-UHFFFAOYSA-N 0.000 claims description 4
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- NJUZHMQXHDCTPO-UHFFFAOYSA-N (7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C NJUZHMQXHDCTPO-UHFFFAOYSA-N 0.000 claims description 3
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- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 2
- 238000006859 Swern oxidation reaction Methods 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- ZFDLFHQAGYPRBY-UHFFFAOYSA-N chloro acetate Chemical compound CC(=O)OCl ZFDLFHQAGYPRBY-UHFFFAOYSA-N 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- 239000012267 brine Substances 0.000 description 22
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
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- PIXFBKFETIBCSY-YJGXYOHVSA-N methyl (2e,5s,6e)-5-[tert-butyl(dimethyl)silyl]oxy-2-[(4s)-5-[tert-butyl(dimethyl)silyl]oxy-4-methylpentyl]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)hepta-2,6-dienoate Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H](C)CCC/C(C(=O)OC)=C\C[C@H](O[Si](C)(C)C(C)(C)C)C(\C)=C\C1=CSC(C)=N1 PIXFBKFETIBCSY-YJGXYOHVSA-N 0.000 description 4
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Abstract
本发明提供了制备式(9)埃坡霉素衍生物及其盐的合成法以及用于合成式(9)化合物的中间体,其中R1为甲基,R2的含义为未取代或取代的芳基、未取代或取代的杂芳基或者与苯核稠合的未取代或取代的杂环基团。
Description
本发明涉及制备埃坡霉素衍生物的新方法,所述埃坡霉素衍生物不仅具有2-甲基-噻唑取代基,而且还具有例如其它杂芳基或芳基取代基或者与苯核稠合的杂环基团,并且在埃坡霉素结构的12位上以甲基作为取代基;本发明还涉及新的埃坡霉素衍生物以及用于该方法的中间体产物及其制备方法。所述中间体本身是新化合物,并且是本发明的一部分。
埃坡霉素(为最初从分枝杆菌纤维堆囊菌(Sorangium cellulosum)中分离出的16-元大环内酯)代表一类具有前景的抗肿瘤药,并且已经发现其可有效对抗多种癌细胞系、包括乳癌细胞系。
这些药物具有与紫杉醇(Taxol)相同的生物学作用机理,并且已经报导其比紫杉醇更有效,所述紫杉醇是目前作为乳癌治疗使用的基础疗法。
埃坡霉素可能的应用是治疗阿耳茨海默氏病、疟疾以及由革兰氏阴性生物体引起的疾病。特别地,埃坡霉素适合用于治疗增殖性疾病。
术语“增殖性疾病”尤其涉及实体瘤疾病、液体瘤如白血病和银屑病。
术语“实体瘤疾病”尤其指乳癌、结肠癌和通常指胃肠道癌(包括胃癌)、肝癌;肺癌,特别是小细胞肺癌和非小细胞肺癌、肾癌、间皮瘤、神经胶质瘤、皮肤鳞状上皮细胞癌、头和颈癌、泌尿生殖器癌如宫颈癌、子宫癌、卵巢癌、睾丸癌、前列腺癌或膀胱癌;何杰金氏病、类癌综合征或卡波西肉瘤。
埃坡霉素衍生物已经例如在WO 97/19086中有描述。这些衍生物从天然埃坡霉素A和B开始制备。
埃坡霉素A的全合成由Schinzer等人在Chem.Eur.J.1996,2,No.11,1477-1482中有描述。埃坡霉素A和B及衍生物的另一合成法由K.C.Nicolaou等人在Angew.Chem.1997,109,170-172和Nature,Vol.387,1997,268-272中有描述。
在Chem.Commun.1997,第2343-2344页中,K.C.Nicolaou等人描述了26-羟基埃坡霉素B以及相关化合物的全合成,该合成包括选择性Wittig烯化反应、醛醇缩合反应和大环内酯化反应作为关键的步骤。通过基于大环内酯化的策略来全合成26-羟基埃坡霉素B及相关化合物已经由K.C.Nicolaou等人在Tetrahedron 54(1998),7127-7166中更详细地进行了描述。
另外在WO 98/25029中,K.C.Nicolaou等人描述并请求保护通过使用固相和溶液相化学合成埃坡霉素A、埃坡霉素B、埃坡霉素类似物和埃坡霉素类似物文库。
本发明的实施方案和目标是克服已知方法的所有缺陷,并提供一种更为简单和经改善的制备上述埃坡霉素和埃坡霉素衍生物及其盐的方法,该方法通过缩短合成途径的序列而在工业规模上是可行的,并且该方法构成了高平均总产率的基础且提供了高纯度的前体和终产物。
制备式9的埃坡霉素衍生物及其盐的合成法:
其中,
R1为甲基,且
R2的含义为未取代或取代的芳基、未取代或取代的杂芳基或者与苯核稠合的未取代或取代的杂环基团。
前缀“低级”指具有不超过且包括最多6个、尤其是不超过且包括最多4个碳原子的基团,所述基团是直链或具有一个或多个支链。
作为未取代或取代的芳基的R2优选为具有6至14个碳原子的芳基,尤其是苯基、萘基、芴基或菲基,其中所述基团为未取代的或者被一个或多个、优选不超过三个、主要是一个或两个取代基取代,尤其是选自以下的那些:氨基;低级烷酰基氨基,尤其是乙酰氨基;卤素,尤其是氟、氯或溴;低级烷基,尤其是甲基或者也可以是乙基或丙基;卤代低级烷基,尤其是三氟甲基;羟基;低级烷氧基,尤其是甲氧基或者也可以是乙氧基;苯基-低级烷氧基,尤其是苄氧基;硝基、氰基、C8-C12烷氧基、尤其是正癸氧基、氨基甲酰基、低级烷基-氨基甲酰基如N-甲基-或N-叔丁基氨基甲酰基、低级烷酰基如乙酰基、苯氧基、卤代-低级烷氧基如三氟甲氧基或1,1,2,2-四氟乙氧基、低级烷氧羰基如乙氧羰基、低级烷硫基如甲硫基、卤代-低级烷硫基如三氟甲硫基、羟基-低级烷基如羟甲基或1-羟甲基、低级烷基磺酰基如甲基磺酰基、卤代-低级烷基磺酰基如三氟甲基磺酰基、苯基磺酰基、二羟基硼(-B(OH)2)、2-甲基-嘧啶-4-基、噁唑-5-基、2-甲基-1,3-二氧戊环-2-基、1H-吡唑-3-基、1-甲基-吡唑-3-基;以及与两个相邻碳原子键合的亚烷基二氧基如亚甲二氧基。
作为芳基的R2尤其是苯基。
卤素尤其是氟、氟、溴或碘,特别是氟或氯。
作为未取代或取代的杂芳基的R2例如是选自下述结构的基团:
作为与苯核稠合的杂环基团的R2是例如选自下式的基团:
新的合成包括下述序列:
a)使式1化合物
其中R2具有上述给出的含义,甲磺酰基可被甲苯磺酰基等替换,
为醇保护基,优选为甲硅烷基保护基,更优选为后面所列的甲硅烷基醚形成基团中的任意基团,最优选为优选选自TES、TBDS和TPS的低级烷基甲硅烷基保护基,
与例如式2的磺内酰胺衍生化合物进行选择性醇醛缩合反应,
其中
为醇保护基,优选为甲硅烷基保护基,更优选为后面所列的甲硅烷基醚形成基团中的任意基团,最优选为优选选自TES、TBDS和TPS的低级烷基甲硅烷基保护基,
该反应在Lewis酸存在下、加入碱、在惰性溶剂中于-50℃至-100℃的较低温度下进行,之后升温至-20℃至+20℃的温度,得到式3化合物:
其中R2具有上述给出的定义。
如上所给出的式2化合物可被如下的式2化合物替换:
为醇保护基,优选为甲硅烷基保护基,更优选为后面所列的甲硅烷基醚形成基团中的任意基团,最优选为优选选自TES、TBDS和TPS的低级烷基甲硅烷基保护基。
式3化合物为新化合物,并且可用作用于该方法序列中下一步骤b)的中间体,以及
b)使所得的上式3化合物在-70至+25℃的温度下、在甲硅烷基-醚形成化合物存在下且在2,6-二甲基吡啶存在下反应,形成式4化合物:
式4化合物为新化合物,并且可用作该方法序列中下一步骤c)的前体,以及
c)通过用在DME中的TBAOH/H2O2或在THF/MeOH/H2O中的LiO2H裂解手性辅助基团而将上述式4化合物转化为羧酸,得到式5化合物:
其中R2和
具有上述给出的定义。
所得式5化合物为新化合物,并且可用作该方法序列中下一步骤d)的另一中间体,以及
d)使以上式5化合物与还原剂在惰性溶剂中反应,裂解甲磺酰基或甲苯磺酰基等,得到式6化合物,
其中R2和
具有上述给出的定义。
所得式6化合物为新化合物,并且可用作用于该方法序列中下一步骤e)的中间体,以及
e)将以上式6的三重保护的三甲硅烷基醚化合物用去甲硅烷基试剂或惰性溶剂中的酸或其混合物如TASF或在THF中的HF·吡啶水解,得到选择性去甲硅烷基化的式7化合物:
其中R2和
具有上述给出的定义。
式7化合物为新化合物,并且可用作该方法序列中下一步骤f)的前体,以及
f)按照M.Yamaguchi等人,Bull.Chem.Soc.Jpn.,1979,52,1989中所描述的条件将所得的式7化合物大环内酯化,得到式8的全保护埃坡霉素衍生物:
所得式8化合物为新化合物,并且可用作该方法序列中下一步骤g)的前体,以及
g)将所得式8化合物用在惰性溶剂中的HF·吡啶于0至30℃的温度下处理,裂解两个甲硅烷基醚保护基,得到式9的埃坡霉素衍生物
其中R1为甲基,R2具有上述的含义,并且任选按照常规方法将式9化合物转化为金属阳离子的盐。
埃坡霉素B向相应的内酰胺的转化在W0 99/02514的流程图21(第31和32页)和实施例3(第48-50页)中有描述。不同与埃坡霉素B的式9化合物向相应的内酰胺化合物的转化也可类似地完成。
在反应步骤a)至g)中所提及的惰性溶剂包括但不局限于甲醇、乙醇、丙醇、二氯甲烷、二氯乙烷、DMF、四氢呋喃(THF)、苯、甲苯、吡啶、乙酸乙酯、丙酮或叔丁基甲基醚(TBME)、己烷或庚烷等及其混合物。
在反应步骤a)至g)中所提及的有机碱包括但不局限于有机胺如未取代或羟基取代的单-、二-或三-烷基胺、尤其是单-、二-或三-低级烷基胺,例如甲胺、二甲胺、二正丙胺、三乙胺、三正丙胺、三正丁胺和二异丙基乙基胺(iPr2Net),例如氮杂环、丫丙啶(ethylene-imine)、吡咯烷、哌啶和吗啉,尤其是4-二甲氨基-吡啶(DMAP)、吡啶、2,6-二甲基吡啶、2,6-二叔丁基吡啶等。
金属有机碱例如是LDA(二异丙氨基锂)、BuLi、仲-BuLi、KHMDS、LiHMDS或NaHMDS。
还原剂例如是DIBAL-H(二异丁基氢化铝)、LiAIH4(氢化铝锂)、三乙基硼氢化锂等。
为有机合成中常用的醇保护基,其应当防止羟基官能团发生不希望的副反应。甲硅烷基-醚形成化合物例如是有机合成中非常常用的标准保护基,优选甲硅烷基保护基为低级烷基甲硅烷基,更优选甲硅烷基保护基选自TMS(三甲基甲硅烷基)、TES(三乙基甲硅烷基)、TPS(三正丙基甲硅烷基)、TBDS(叔丁基二甲基甲硅烷基)、DEIPS(二乙基异丙基甲硅烷基)、IPDMS(二甲基异丙基甲硅烷基)、TDS(己基-二甲基甲硅烷基)、TIPS(三异丙基甲硅烷基)、THP(四氢吡喃基甲硅烷基)等,优选为TES、TPS或TBDMS,最优选为TPS。如果化合物含有多个保护基,则保护基可彼此独立地选择,并且可全部相同、全部不同或者是其任意的组合,优选保护基全部相同,最优选保护基为TPS。
术语“可药用的金属盐”指与钠、钾、钙、镁、铝、铁和锌离子形成的盐。该盐通过常规方法制备。
通过水解裂解式4化合物的二-三甲基硅烷氧基的适合的酸是不会使埃坡霉素结构的环氧环开环的有机弱酸,其例如是稀乙酸、丙酸、羟基乙酸、乳酸、富马酸、琥珀酸、己二酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、马来酸、扁桃酸、氨基酸如谷氨酸或天门冬氨酸,尤其是柠檬酸等。尤其可提及的是在THF中的HF·吡啶或在吡啶中的HF吡啶。
用于方法序列中a)的醛醇缩合反应的手性辅助基团例如是磺内酰胺辅助基团或噁唑烷酮类基团如
尤其是
和其它已知的手性辅助基团。
如下所述更详细地进行所提及的制备式9化合物的方法序列的反应步骤a)至g):
a)使式1化合物与式2化合物例如在TiCl4和Hünig碱(iPr2NET)存在下、在二氯甲烷中于-78℃、之后于0℃的温度下反应,得到新的式3化合物。
b)使所得式3化合物与甲硅烷基-醚形成化合物如TPSCl、TBDMSOTf在2,6-二甲基吡啶存在下、在-20℃至25℃、尤其在-10℃的温度下在惰性溶剂二氯甲烷中反应,形成式4化合物。
c)通过用DME中的TBAOH/H2O2或THF/MeOH/H2O中的LiO2H裂解手性辅助基团而将所得式4化合物转化为羧酸,得到式5化合物。
d)使所得式5化合物与还原剂LiBHET3在惰性溶剂THF中反应,裂解甲磺酰基或甲苯磺酰基等,得到式6化合物
e)将所得式6化合物用去甲硅烷基试剂、尤其是TASF或在惰性溶剂如吡啶或THF中的有机酸、尤其是HF·吡啶水解,得到式7化合物。
f)根据M.Yamaguchi等人所述将所得的式7化合物大环内酯化,例如用Et3N和2,4,6-三氯苯甲酰氯在较低温度如0℃下处理羟酸,之后将反应混合物加入4-DMAP在甲苯中的溶液中并将温度升至约75℃,得到式8化合物。
g)将所得受保护的式8埃坡霉素衍生物用在惰性溶剂吡啶中的HF吡啶处理,在裂解两个甲硅烷基醚保护基(TPS、TES、TBDMS)后,得到式9的埃坡霉素衍生物,其中R1为甲基,R2具有上述含义,
并且任选将其中R1和R2具有式9中指定含义的式9化合物通过常规方法转化为金属阳离子的盐。
该方法序列所使用的式1原料化合物可用作制备新的式9埃坡霉素衍生物的关键中间体,其是新化合物并可通过如下文所给出的包括步骤a)至g)的下述方法序列制备,在所述式1化合物中,R2的含义是未取代或取代的芳基、未取代或取代的杂芳基或者与苯核稠合的未取代或取代的杂环基团。
新开发的合成法包括下述序列:
a)使式X化合物
与PPH3在50℃-150℃的温度、更优选在100℃的温度下反应,之后与KHMDS在惰性溶剂、尤其是THF中于0℃下反应,之后将反应混合物冷却至-50℃至-100℃的温度,并更精确地在-78℃的温度下用CH3CO2Cl处理,得到式XI化合物:
以及,
b)使所得式XI化合物与式XII化合物
在惰性溶剂如甲苯中于20℃-60℃的温度、更精确地在40℃的温度下反应,得到式XIII化合物,
c)将式XIII化合物用还原剂、尤其是DIBALH在惰性溶剂如甲苯中于-50℃至-100℃的温度下、更精确地在-78℃的温度下还原,之后升温至0℃,得到式XIV化合物:
(式XIV和下述化合物的图已简化)
d)使用Sharpless[L(+)-酒石酸二乙酯,Ti(OPr)4,t-BuOOH]条件进行式XIV化合物的环氧化,得到式XV化合物:
所得式XV化合物为新化合物,并且可用作该方法序列中下一步骤e)的前体,以及
e)在三乙胺(Et3N)存在下在惰性溶剂如二氯甲烷中通过加入甲磺酰氯(甲磺酰基可被相应的甲苯磺酰基等替换),将甲磺酰基引入式XV化合物中,得到式XVI化合物:
所得式XVI化合物为新化合物,并且可用作下一步骤f)的中间体,以及
f)将所得的式XVI化合物用在惰性溶剂中的有机酸处理,更准确地用无水乙醇中的对甲苯磺酸吡啶鎓或樟脑磺酸处理,水解一个保护基,得到式XVII化合物:
其中R2具有上述给出的含义,以及
g)使用Swern氧化法氧化,例如通过草酰氯的促进和二甲亚砜的活化使醇基团氧化,通过烷氧基锍盐,在加入碱和分子内重排后得到式1的酮类化合物,该化合物在前述创造性的方法序列中用作原料化合物。
所发明的用于制备式9的埃坡霉素衍生物的创造性的方法序列与其它已知和出版的合成法相比表现出许多优点:
-早期引入环氧可出人意料地避免对合成序列中较后中间体进行的有争议的环氧化步骤,
-观察到甲磺酰基和甲苯磺酰基环氧化结构具有显著的稳定作用。很多步骤可在这些官能团的存在下进行。
-可获得α-支化的醛与乙基酮关键片段之间的高产率和高非对映立体选择性的烯醇钛醛醇缩合反应。
-该醛醇反应可出人意料地耐受甲磺酰基和甲苯磺酰基环氧化结构的存在;
-该醛醇反应允许进行埃坡霉素衍生物的高汇集合成。
-该醛醇反应出人意料地允许使用手性磺内酰胺辅助基作为羧酸保护基,因此避免了在最终的大环内酯步骤之前进行耗时的还原和氧化步骤。
-该发明的方法序列是较任何其它已出版的、文献中已知的合成途径更为短的合成途径,另外还可检测到较高的总产率。
总而言之,所概括的优点突出了所提及工艺序列的创造性。
本发明的第二方面是新的中间体,所述中间体根据所描述的反应制备,并可用于制备式9化合物。
用于药物治疗的式9的埃坡霉素衍生物可通过每种已知的途径施用,所述途径可选自静脉内途径、动脉内途径、皮内途径、皮下途径、口服途径、口腔途径、肌内途径、肛门途径、透皮途径、真皮内途径和intratechal途径等。
还可制备包括可生物降解的微球的缓释制剂,所述微球例如是含聚丙烯酸、聚乙醇酸或其混合物的微球。
本发明的式9化合物可单独或与其它药物活性物质组合使用,例如与其它化疗药物如经典的细胞抑制剂组合使用。当与其它化疗药物组合时,可按照本领域技术人员已知的方法制备两种或多种成分的固定组合(例如含各部分的药盒(kit of parts)),并且本发明的化合物以及任一其它化疗药物可间隔施用,以获得肿瘤治疗的常规作用、额外作用或优选协同作用。
以下非限制性实施例解释了发明人优选的制备所请求保护的本发明化合物的方法,其不应当解释为限制本发明的范围。
实施例1
化合物X
6-苄氧基-己酸(II)(Can.J.Chem.1992,70,1427)
向102.2g(0.90mol)6-己内酯于1.5L甲苯中的溶液中加入250.6g(4.48mol)KOH和113.3ml(0.98mol)苄基氯。将反应混合物在回流温度搅拌20小时。在室温下用1.7L水终止反应。分离水层,将甲苯层用200ml水萃取。将所合并的水相于12℃用300ml HCl(浓)处理,使溶液酸化为pH1.0。在用1.1L醋酸异丙酯分两份萃取后,将所合并的有机萃取液用300ml盐水洗涤并经MgSO4干燥。减压浓缩得到151.2g(76%)黄色油状的酸II。Rf=0.35(SiO2,95∶5 CH2Cl2-CH3OH)。
6-苄氧基-己酰氯(III)
将酸II粗品(110g,0.50mol)溶于320ml甲苯中。向该溶液中加入140μlDMF,之后加入56.7ml(0.66mol)草酰氯。将反应混合物于室温下搅拌过夜并真空中浓缩,得到126g的酰氯III,其可直接用于下一步骤。
(S)-4-苄基-3-(6-苄氧基-己酰基)-噁唑烷-2-酮(V)
将87.7g(0.50mol)的(S)-4-苄基-2-噁唑烷酮IV的溶液溶解于1.4L THF中并冷却至-78℃。加入己基锂(2.5M,在己烷中)(178ml,0.45mol),之后缓慢加入酰氯III(126g,0.50mol)在100ml THF中的溶液。于-78℃搅拌1小时后,将所得溶液温热至0℃。加入饱和的氯化铵水溶液(400ml)以终止反应。分离各层,将有机层用另外100ml饱和氯化铵溶液洗涤。将THF层用200ml 1M NaOH和500ml盐水洗涤两次,经MgSO4干燥并浓缩。将粗品(162.4g)用快速色谱法(200g SiO2,庚烷/TBME=80∶20-60∶20)纯化,得到110.1g(两步产率为58%)的酰胺V。Rf=0.41(SiO2,1∶1己烷-TBME)。
(S)-4-苄基-3-[(S)-6-苄氧基-2-甲基-己酰基]-噁唑烷-2-酮(VI)
将酰胺V(120.1g,0.32mol)的THF(200ml)溶液于-78℃加入372ml(0.37mol)在380ml THF中的NaHMDS(1.0M,在THF中),之后加入CH3l(78.4ml,1.26mol)在70ml THF中的溶液。将反应混合物于-78℃搅拌2小时。加入饱和氯化铵水溶液(670ml)以终止反应。分离各层,将水相用200ml TBME萃取。将合并的有机层用250ml盐水洗涤两次,经MgSO4干燥并在真空中浓缩。以87%de获得产物VI(123.9g),其可直接用于下一步骤。Rf=0.05(SiO2,1∶1庚烷-TBME);
(S)-6-苄氧基-2-甲基-己-1-醇(VII)
于0℃向13.2g(0.35mol)LiAIH4于380ml THF的悬浮液中加入酰胺VI在250ml THF中的溶液。将混合物于0℃搅拌2小时,用14ml H2O、14ml 15%NaOH和25ml H2O终止反应。经过滤除去所沉淀的铝盐。滤液浓缩后,将粗品通过硅胶过滤(570g SiO2、甲苯/EtOAc=90∶10,3L以及甲苯/EtOAc=80∶20,1L)纯化。得到无色油状的产物VII(54.5g,两步为81%)。Rf=0.24(SiO2,1∶1庚烷-TBME);HPLC:87%de(Chiralcel OD,正己烷/i-PrOH=95∶5,1.0ml/min,30℃),tR=10.07min。
[(S)-6-苄氧基-2-甲基-己氧基]-叔丁基-二甲基-硅烷(VIII)
将醇VII(54.4g,0.25mol)溶于100ml DMF中,并用33.3g(0.49mol)咪唑处理,之后于0℃缓慢加入55.4g(0.37mol)叔丁基二甲基甲硅烷基氯在100ml DMF中的溶液。将混合物于20℃搅拌2小时,然后倾倒入240ml冰冷的0.1N HCl中,并用300ml庚烷萃取。将有机层用另外100ml 0.1NHCl、200ml NaHCO3饱和水溶液、200ml盐水洗涤,经MgSO4干燥并真空浓缩。通过过滤(670g SiO2,甲苯)纯化粗产物(81.5g),得到64.8g(79%)无色油。Rf=0.64(SiO2,1∶1庚烷-TBME)。
(S)-6-(叔丁基二甲基硅烷氧基)-5-甲基-己-1-醇(IX)
在环境温度下将64.0g(0.19mol)苄基醚VIII在500ml THF中的溶液经7.0g 20%Pd(OH)2/C氢化(3.5bar)30分钟。过滤除去催化剂,将滤液浓缩,得到无色油状的醇IX(46.9g,100%)。Rf=0.33(SiO2,1∶1庚烷-TBME)。
叔丁基-[(S)-6-碘代-2-甲基-己氧基]-二甲基-硅烷(X)
在室温下将三苯膦(23.91g,91.16mmol)和咪唑(12.45g,182.9mmol)加入到15g(60.9mmol)醇IX在390ml乙腈/甲苯(1∶5)中的溶液中。将混合物冷却至0℃,在10分钟内分4份加入23.13g(91.13mmol)碘。将该不均匀的溶液搅拌90分钟。加入亚硫酸氢钠水溶液(4%,300ml)和100ml甲苯。分离水层,并用甲苯(100ml)再次萃取。将合并的甲苯层通过硅胶过滤并在真空中浓缩。向残余物中加入庚烷(225ml)。将所得悬浮液搅拌10分钟,并在4℃下储存12小时。过滤并浓缩滤液,得到21.05g(97%)浅黄色油状的碘化物X。Rf=0.66(SiO2,7∶3庚烷-AcOEt)。
实施例2
具有TBDMS保护基的醛1
(S)-7-(叔丁基二甲基-硅烷氧基)-6-甲基-2-(三苯基亚膦基(phosphanylidene))-庚酸甲酯(XI)
在氩气和室温下,将碘化物X(15.46g,43.4mmol)和三苯膦(12.52g,45.75mmol)加入甲苯(8ml)中。将所得混合物于100℃加热3小时。然后减压除去甲苯。将THF(400ml)加入残余物(29.67g)中并将溶液冷却至0℃,随后用二(三甲基甲硅烷基)氨基化钾在甲苯中的溶液(0.5M,174ml,86.8mmol)处理。将所得橙色悬浮液于0℃搅拌1小时,然后冷却至-75℃。加入氯甲酸甲酯(3.72ml,48.2mmol)。在于-75℃搅拌1小时后,将该黄色反应混合物温热至-40℃。加入NaHCO3(300ml),之后加入EtOAc(300ml)和水(150ml)。分离各层,将水相用EtOAc(150ml)萃取。将合并的有机层用NaCl饱和水溶液洗涤(2×200ml),经MgSO4干燥并在真空中浓缩。所得的粘稠橙色油状的粗产物XI(27.02g)直接用于下一步骤。
(2E,6E)-(S)-5-(叔丁基二甲基硅烷氧基)-2-[(S)-5-(叔丁基二甲基硅烷氧基)-4-甲基-戊基]-6-甲基-7-(2-甲基-噻唑-4-基)-庚-2,6-二烯酸甲酯(XIII)
在环境温度和氩气下,将内鎓盐(XI)(27g)在甲苯(200ml)中的溶液用醛(XII)(12.7g,39.0mmol)在甲苯(80ml)中的溶液处理。将所得混合物于70℃搅拌5小时。减压除去溶剂。将所得固态残余物(37.8g)加入370ml庚烷中,连续于40℃搅拌30分钟,室温下搅拌2小时30分钟,最后于0℃下搅拌30分钟。将所得悬浮液过滤,滤饼用庚烷(2×60ml)洗涤。收集滤液并在真空中浓缩,得到24.85g黄色油状的Wittig产物XIII,其不经进一步纯化即可用于下一步骤。Rf=0.59(SiO2,1∶1庚烷-AcOEt);1H-NMR(DMSO-d6,300MHz,300K)δ6.90(s,1H,C5”-H),6.77(t,J=7.5Hz,1H,C3-H),6.47(s,1H,C7-H),4.20(dd,J=7.2,5.4Hz,1H,C5-H),3.69(s,3H,CO2CH3),3.40(dd,J=9.9,5.7Hz,1H,C5’-Ha),3.31(dd,J=9.9,6.6Hz,1H,C5’-Hb),2.68(s,3H,C2”-CH3),2.44-2.36和2.28-2.21(两个m,4H,C4-H2和C1’-H2),2.00(s,3H,C6-CH3),1.30-1.15(两个m,4H,C2’-H2,C3’-Ha和C4’-H),1.06-0.99(m,1H,C3’-Hb),0.86(s,9H,SiC(CH3)3),0.85(s,9H,SiC(CH3)3),0.83(d,J=6.6,3H,C5’-CH3),0.05(s,3H,SiCH3),0.01(s,6H,两个SiCH3),-0.01(s,3H,SiCH3)。
(2E,6E)-(S)-5-(叔丁基二甲基硅烷氧基)-2-[(S)-5-(叔丁基二甲基硅烷氧基)-4-甲基-戊基]-6-甲基-7-(2-甲基-噻唑-4-基)-庚-2,6-二烯-1-醇(XIV)
于-78℃向500ml THF中的13.9g(23mmol)烯丙基酯XIII中于10分钟内加入47ml(70mmol)DIBALH(1.5M,在甲苯中)。将反应混合物连续于-78℃搅拌3小时,30分钟内温热至0℃,并于0℃另外搅拌30分钟。之后加入50ml 0.1N HCl水溶液终止反应。分离各层,水层用TBME(2×50ml)洗涤。将合并的萃取液用NaHCO3饱和水溶液(2×50ml)和盐水(50ml)洗涤,经MgSO4干燥并在真空中浓缩。将粗产物通过快速色谱法(SiO2,5∶1庚烷/EtOAc)纯化,得到10.0g(76%)浅黄色油状的烯丙基醇XIV。Rf=0.16(SiO2,3∶1庚烷-AcOEt)。
{(2S,3S)-3-[(E)-(S)-2-(叔丁基二甲基硅烷氧基)-3-甲基-4-(2-甲基-噻唑-4-基)-丁-3-烯基]-2-[(S)-5-(叔丁基二甲基硅烷氧基)-4-甲基戊基]-环氧乙基}-甲醇(XV)
将烯丙基醇(XIV)(3.00g,5.28mmol)溶于51ml CH2Cl2中。于-30℃加入0.59M的L(+)酒石酸二乙酯(4.48ml,2.64mmol)在CH2Cl2中的溶液,之后加入异丙氧基钛(IV)在CH2Cl2中的0.34M溶液(6.21ml,2.11mmol)。将混合物于-30℃搅拌30分钟。然后于5分钟内加入2.11ml(16.6mmol)过氧化氢叔丁基(5.5M,在癸烷中)。将反应混合物于-30℃搅拌24小时。然后加入NaHSO3水溶液(4%,50ml)。分离各层,水层用乙酸乙酯(2×50ml)萃取。将合并的有机萃取液用50ml盐水洗涤,经MgSO4干燥。真空浓缩后,得到3.11g浅黄色油状的环氧醇XV,其不经进一步纯化即可用于下一步骤。Rf=0.22(SiO2,2∶1庚烷-AcOEt);MS(ES+)m/z(%)606(100,[M+Na]+),584(13,[M+H]+)。
甲磺酸(2S,3S)-3-[(E)-(S)-2-(叔丁基二甲基硅烷氧基)-3-甲基-4-(2-甲基-噻唑-4-基)-丁-3-烯基]-2-((S)-5-(叔丁基二甲基硅烷氧基)-4-甲基-戊基)-环氧乙基甲酯(XVI)
于0℃向环氧醇(XV)粗品(3.11g,5.3mmol)于CH2CL2(50ml)中的溶液中加入2.74ml(16.0mmol)N-乙基二异丙胺。将所得混合物于0℃搅拌15分钟。然后逐滴加入甲磺酰氯(0.75ml,8.0mmol)。在于0℃搅拌1小时后,用40ml H2O和40ml TBME淬灭反应溶液。分离各层,水层用TBME(40ml)萃取。将有机萃取液用HCl(0.1N)(40ml)、NaHCO3饱和水溶液(2×40ml)和盐水(40ml)洗涤,经MgSO4干燥。在真空中浓缩,得到3.79g的甲磺酰酯XVI粗品,其不经进一步纯化即可用于下一步骤。纯化。Rf=0.27(SiO2,2∶1庚烷-AcOEt);HRMS m/z 688,3222([M+Na]+,计算C31H59NO6S2Si2为684.3220)。
甲磺酸(2S,3S)-3-[(E)-(S)-2-(叔丁基二甲基硅烷氧基)-3-甲基-4-(2-甲基-噻唑-4-基)-丁-3-烯基]-2-((S)-5-羟基-4-甲基戊基)-环氧乙基甲酯(XVII)
将TBDMS醚XVI粗品(3.79g,5.7mmol)溶于CH2Cl2与CH3OH的混合物(1∶1v/v)(140ml)中,于0℃用1.33g(5.73mmol)的10-樟脑磺酸处理。将反应混合物于0℃搅拌1小时。在去保护后,加入20ml NaHCO3饱和水溶液和20ml TBME。分离各层,水层用TBME(2×20ml)萃取。将合并的有机层用NaHCO3饱和水溶液(2×20ml)和盐水(20ml)洗涤,经MgSO4干燥并减压浓缩。得到黄色油状的粗产物XVII(3.11g),其不经进一步纯化即可用于下一步骤。Rf=0.28(SiO2,1∶1庚烷-AcOEt)。
甲磺酸(2S,3S)-3-[(E)-(S)-2-(叔丁基二甲基硅烷氧基)-3-甲基-4-(2-甲基-噻唑-4-基)-丁-3-烯基]-2-((S)-4-甲基-5-氧代戊基)-环氧乙基甲酯(1)
于0℃将醇XVII(3.11g,5.7mmol)在CH2Cl2(15ml)中的溶液连续用三乙胺(10ml)、DMSO(6ml)和SO3-吡啶(3.6g,22.7mmol)在DMSO(40ml)中的溶液连续处理,其中SO3-吡啶在DMSO中的溶液在5分钟内加入。于0℃搅拌1小时后,将反应混合物用NaHSO4水溶液(10%,20ml)淬灭,用TBME(20ml)稀释。分离各层,水层用TBME(2×20ml)萃取。将合并的有机层用NaHCO3饱和水溶液(2×20ml)和盐水(20ml)洗涤,经MgSO4干燥并减压浓缩。将残余物通过快速色谱法(SiO2,3∶1庚烷/EtOAc)纯化。得到浅黄色油状的醛1(2.20g,基于XIV的四步产率为76%)。Rf=0.39(SiO2,1∶1庚烷-AcOEt)。
实施例3
具有TBDMS保护基的醛XVI’
4-[(E)-(S)-3-(叔丁基二甲基硅烷氧基)-4-{(2S,3R)-3-[(S)-5-(叔丁基二甲基硅烷氧基)-4-甲基-戊基]-3-碘甲基-环氧乙基}-2-甲基-丁-1-烯基]-2-甲基-噻唑(XVI′)
在室温和氩气下将环氧-醇XV′(50mg,86μmol)、三苯膦(34mg,0.13mmol)和咪唑(18mg,0.26mmol)在5∶1v/v甲苯/乙腈(2.4ml)中的溶液用一份碘(33mg,0.13mmol)处理。搅拌30分钟后,判断反应完全(TLC)并进行处理。将反应混合物倾倒入NaHSO4饱和水溶液(5ml)中。分离各层,水层用甲苯(2×2ml)萃取。将合并的有机层用1N HCl(5ml)、NaHCO3饱和水溶液(5ml)和盐水(5ml)洗涤,经MgSO4干燥并在真空中浓缩。将残余物悬浮在庚烷中,过滤除去不溶的三苯膦氧化物。得到浅黄色油状的碘化物XVI’粗品(65mg),其不需要另外纯化。
实施例4
化合物2
1-(10,10-二甲基-3,3-二氧代-6-硫杂-4-氮杂-三环[5.2.1.0]癸-4-基)-3-羟基-4,4-二甲基-庚烷-1,5-二酮(11)
在环境温度、氩气下于聚四氟乙烯烧瓶中,将TBDMS醚(10)(9.21g,18.43mmol)与HF·吡啶复合物(26.3ml,921mmol)混合。将所得反应混合物搅拌2小时,然后通过将其加入搅拌的NaHCO3(78g,在500ml水中)水溶液和200ml TBME中终止反应。分离各层,有机层用盐水(2×200ml)洗涤,经MgSO4干燥并真空浓缩,得到6.80g粗品,其不需其它任何纯化。1-(10,10-二甲基-3,3-二氧代-6-硫杂-4-氮杂-三环[5.2.1.0]癸-4-基)-4,4-二甲基-3-三乙基硅烷氧基-庚烷-1,5-二酮(2)
于0℃向醇(11)粗品(6.80g,17.6mmol)于CH2Cl2(90ml)中的溶液中加入2,6-二甲基吡啶(6.14ml,52.9mmol),之后加入三氟甲磺酸三乙基甲硅烷基酯(7.98ml,35.3mmol)。将所得反应混合物于0℃搅拌30分钟,然后小心加入140ml 1N HCl和150ml TBME来终止反应。分离各层,将有机层连续用100ml NaHCO3饱和水溶液和100ml盐水洗涤,经MgSO4干燥并真空浓缩。粗品通过色谱法(SiO2,4∶6己烷/AcOEt)纯化,得到8.3g纯的TES-醚2。(两步为90%)。Rf=0.62(SiO2,1∶1庚烷-AcOEt);1H-NMR(DMSO-d6,400MHz,300K)δ4.55(t,J=5.2Hz,1H,C3-H),3.86(d,J=14.3Hz,1H,C8‘-Ha),3.83(t,J=6.1Hz,1H,C1‘-H),3.66(d,J=14.2Hz,1H,C8‘-Hb),2.84(dd,J=17.4,4.6Hz,1H,C2-Ha),2.54(m,3H,C2-Hb和C7-H2,部分被DMSO遮掩),2.00-1.92和1.87-1.73(2m,6H,C2‘-H2,C3‘-H和C5‘-H2),1.48-1.20和1.34-1.24(2m,2H,C4‘-H2),1.10(s,3H,C4-CH3),1.07(s,3H,C4-CH3),0.98(s,3H,C9‘-CH3),0.95(s,3H,C9‘-CH3),0.94-0.87(m,12H,Si(CH2CH3)3和C7-H3),0.60-0.45(m,6H,Si(CH2CH3)3);13C-NMR(DMSO-d6,100MHz,300K)δ215.3,169.7,73.1,65.1,52.9,52.7,49.2,48.1,45.1,40,38.8,32.8,32.1,26.7,21.5,20.9,21.0,20.4,8.5,7.6,7.5,5.4;IR(KBr)νmax2958s,2913m,2878s,1702s,1391m,1333s,1312m,1267m,1237m,1219m,1166m,1136s,1087s,743m,539m cm-1;MS(ES+)m/z(%)769(3,[3M+Ca]2+),538(6,[M+K]+),522(100,[M+Na]+),519(17,[2M+Ca]2+),500(5,[M+H]+)。
实施例5
具有TBDMS保护基的化合物6
醛醇产物(3)
在氩气氛下于-78℃将2(750mg,1.50mmol)在CH2Cl2(5.6ml)中的溶液连续用TiCl4在CH2Cl2(3.00ml,1.50mmol)中的0.5M溶液和N-乙基二异丙胺(257μl,1.50mmol)处理,溶液立即变为浓郁的暗红色。在于-78℃搅拌10分钟后,逐滴加入1(900mg,1.65mmol)在CH2Cl2(1.9ml)中的溶液。然后,将反应溶液于-78℃搅拌1小时,然后温热至0℃并另外搅拌15分钟,此时判断反应完全(TLC)。于0℃通过加入磷酸盐缓冲液(pH7,4ml)和用TBME(5ml)稀释来终止反应。将水层用TBME(2×5ml)萃取。将合并的有机萃取液用NaHCO3饱和水溶液(2×4ml)和盐水(4ml)洗涤,竟MgSO4干燥并在真空中浓缩。将残余物通过快速色谱法(50g SiO2,庚烷/AcOEt 2∶1)纯化,得到浅黄色油状的醛醇产物3(1200mg,基于1为70%)。Rf=0.42(SiO2,1∶2庚烷-AcOEt);MS(ES+)m/z(%)1084(5,[M+K]+),1067(100,[M+Na]+),1045(26,[M+Na]+)。
TBDMS醚(4)
在氩气氛下于0℃将3(1.20g,1.15mmol)在CH2Cl2(15ml)中的溶液连续用2,6-二甲基吡啶(0.87ml,7.49mmol)和三氟甲磺酸叔丁基二甲基甲硅烷基酯(1.32ml,5.74mmol)处理。在于0℃搅拌14小时后,通过加入0.1N HCl水溶液(5ml)和CH2Cl2(5ml)对反应进行处理。分离各层,水层用CH2Cl2(2×5ml)萃取。将合并的有机萃取液连续用NaHCO3饱和水溶液(2×5ml)和盐水(5ml)洗涤,经MgSO4干燥并在真空中浓缩。将残余物通过快速色谱法(50g SiO2,庚烷/AcOEt 2∶1)纯化,得到浅黄色油状的化合物16(893mg,67%)。Rf=0.70(SiO2,1∶2庚烷-AcOEt);MS(ES+)m/z(%)1197(12,[M+K]+),1081(100,[M+Na]+),1059(31,[M+H]+),599(75,[M+Ca]2+)。
羧酸(5)
于0℃将4(318mg,0.274mmol)在1,2-二甲氧基乙烷(4.8ml)中的溶液连续用TBAOH(730μl,2.76mmol)和H2O2 30%(280μl,2.74mmol)处理,将所得混合物于0℃搅拌5小时,然后进行处理:加入NH4Cl饱和水溶液(2ml)和TBME(2ml)。分离各层,水层用TBME(2×2ml)萃取。将有机萃取液连续用NaHCO3饱和水溶液(2×2ml)和盐水(2ml)洗涤,合并,经MgSO4干燥并在真空中浓缩。将残余物通过快速色谱法(15g SiO2,庚烷/AcOEt 1∶1,含1%AcOH)纯化,得到浅黄色油状的化合物5(103mg,39%)。Rf=0.41(SiO2,3∶3∶4 CH2Cl2-CH3CN-己烷);MS(ES+)m/z(%)984(100,[M+Na]+),962(12,[M+H]+)。
甲基环氧化物(6)
在环境温度下,将5(78mg,0.081mmol)在THF(1.6ml)中的溶液逐滴用LiBHEt3在THF(970μl,0.97mmol)中的1M溶液处理,将所得混合物于环境温度下搅拌1小时。通过加入NH4Cl(2ml)饱和水溶液和TBME(2ml)来终止反应。分离各层,水层用TBME(2×2ml)萃取。将合并的有机萃取液连续用NaHCO3饱和水溶液(2×2ml)和盐水(2ml)洗涤,经MgSO4干燥并在真空中浓缩。将残余物通过快速色谱法(6g SiO2,庚烷/AcOEt 1∶1,含1%AcOH)纯化,得到浅黄色油状的化合物6(60mg,85%)。Rf=0.56(SiO2,1∶1庚烷/AcOEt,含1%AcOH);MS(ES+)m/z(%)890(100,[M+Na]+),868(50,[M+H]+)。
实施例6
具有一个TES和一个TBDMS保护基的醛1
(2E,6E)-(S)-5-羟基-2-[(S)-5′-羟基-4′-甲基-戊基]-6-甲基-7-(2″-甲基-噻唑-4″-基)-庚-2,6-二烯酸甲酯(12)
于-10℃向含24ml HF·吡啶复合物(839mol)的聚四氟乙烯烧瓶中加入烯丙基酯(XIII)(10.0g,16.8mmol)。将所得混合物于-10℃搅拌10分钟,此时通过原料的消失判断反应完全(TLC)并立即终止。将混合物倾倒入NaHCO3(70g)在水(100ml)和TBME(100ml)中的搅拌的悬浮液中。分离各层,水相用TBME(3×80ml)萃取。将有机萃取液合并,用150ml的0.1N HCl洗涤,经MgSO4干燥,在真空中浓缩,得到二醇(2)粗品(6.34g),其可直接进行下一反应。Rf=0.06(SiO2,1∶1庚烷-AcOEt);1H-NMR(DMSO-d6,300MHz,300K)δ6.90(s,1H,C5“-H),6.75(t,1H,J=7.5Hz,C3-H),6.51(s,1H,C7-H),4.23(t,J=6.3Hz,1H,C3-H),3.65(s,3H,CO2CH3),3.41(dd,J=10.5,6.0Hz,1H,C5‘-Ha),3.34(dd,J=10.5,6.3Hz,1H,C5‘-Hb),2.64(s,3H,C2“-CH3),2.46(t,J=6.9Hz,2H,C4-H2),2.25(t,J=7.2Hz,2H,C1‘-H2),2.00(s,3H,C6-CH3),1.70-1.55和1.53-1.25(2br m,6H,C2‘-H2,C3‘-Ha,C4‘-H,C5-OH和C5‘-OH),1.15-1.00(m,1H,C3‘-Hb),0.85(d,J=6.6Hz,3H,C4‘-CH3)。
(2E,6E)-(S)-6-甲基-7-(2′-甲基-噻唑-4′-基)-2-[(S)-4″-甲基-5″-三乙基硅烷氧基-戊基]-5-三乙基硅烷氧基-庚-2,6-二烯酸甲酯(XIII′)
于0℃将二醇(2)粗品(6.33g,14mmol)在CH2Cl2(150ml)中的溶液连续用N-乙基二异丙胺(23.6ml,138mmol)、4-(N,N-二甲氨基)-吡啶(70mg,0.57mmol)和三乙基氯硅烷(10.9ml,86.1mmol)处理。将所得溶液于环境温度下搅拌过夜。用NaHCO3饱和水溶液(150ml)终止反应,水层用CH2Cl2(3×200ml)萃取。合并有机萃取液,用200ml盐水洗涤,经MgSO4干燥并真空中浓缩。残余物通过快速色谱法(SiO2,20%至30%的己烷/AcOEt梯度洗脱)纯化,得到8.6g(两步为86%)TES保护的二醇(XIII′)。Rf=0.63(SiO2,1∶1庚烷/AcOEt);1H-NMR(DMSO-d6,400MHz,300K)δ7.26(s,δ,C5‘-H),6.73(t,J=7.3Hz,1H,C3-H),6.48(s,1H,C7-H),4.30(t,J=6.7Hz,1H,C5-H),3.65(s,3H,CO2CH3),3.41(dd,J=9.8,5.9Hz,1H,C5“-Ha),3.36(dd,J=9.8,6.3Hz,1H,C5“-Hb),2.66(s,3H,C2‘-CH3),2.45(t,J=6.7Hz,2H,C4-H2),2.30-2.20(br m,2H,C1“-H2),2.04(s,3H,C6-CH3),1.59-1.47(br m,1H,C4“-H),1.45-1.23(br m,3H,C2“-H2和C3“-Ha),1.01-1.00(br m,1H,C3“-Hb),0.98-0.88(m,18H,两个Si(CH2CH3)3),0.83(d,J=6.9Hz,3H,C4“-CH3),0.62-0.52(m,12H,两个Si(CH2CH3)3);IR(膜)νmax 2953s,2934s,2913s,2875s,1713s,1644w,1505w,1459m,1437m,1414w,1376w,1285m,1269m,1241m,1185m,1120m,1072m,1006m,744m,723scm-1;MS(ES+)m/z(%)618(100,[M+Na]+),596(72,[M+H]+)。
(2E,6E)-(S)-6-甲基-7-(2′-甲基-噻唑-4′-基)-2-[(S)-4″-甲基-5″-三乙基硅烷氧基-戊基]-5-三乙基硅烷氧基-庚-2,6-二烯-1-醇(XIV)
于-78℃向烯丙基酯(XIII′)(45.54g,76.4mmol)于THF(250ml)中的溶液中加入DIBAL-H在甲苯中的1.5M溶液(153ml,229mmol)。将所得混合物于-78℃搅拌3小时。通过缓慢加入115ml的2N HCl终止反应,并用100ml的TBME稀释。分离各层,水相用TBME(2×100ml)萃取。将合并的有机层用100ml NaHCO3、之后用100ml盐水洗涤,经MgSO4干燥。在真空中浓缩,得到51.53g烯丙醇粗品,该粗品通过色谱法(SiO2,20%至40%的己烷/AcOEt梯度洗脱)得到32.5g(39%)纯烯丙基醇(XIV)。
Rf=0.47(SiO2,1∶1庚烷/AcOEt);1H-NMR(DMSO-d6,500MHz,300K)δ7.29(s,1H,C5‘-H),6.38(s,1H,C7-H),5.29(t,J=7.1Hz,1H,C3-H),4.60(t,J=5.4Hz,1H,C1-OH),4.10(t,J=6.4Hz,1H,C5-H),3.79(d,J=5.1Hz,2H,C1-H2),3.40(dd,J=9.8,5.9Hz,1H,C5“-Ha),3.33(dd,J=9.8,6.5Hz,1H,C5“-Hb),2.64(s,3H,C2‘-CH3),2.25(t,J=6.8Hz,2H,C4-H2),1.99(s,3H,C6-CH3),2.00-1.90(br m,2H,C1“-H2),1.58-1.46(m,1H,C4“-H),1.43-1.22(m,3H,C3“-Ha和C2“-H2),1.08-0.97(m,1H,C3“-Hb),0.95-0.85(m,18H,两个Si(CH2CH3)3),0.82(d,J=6.7Hz,3H,C4“-CH3),0.58-0.50(m,12H,两个Si(CH2CH3)3);13C-NMR(DMSO-d6,125MHz,300K)δ164.1,152.5,141.1,140.7,119.9,118.4,116.6,78.0,67.3,64.6,35.2,34.4,32.9,28.0,25.4,18.9,16.6,13.7,6.74,6.72,4.3,4.0;IR(膜)νmax 3341s(br),2952s,2932s,2874s,1508m,1458m,1414m,1378w,1238w,1190m,1071s,1016s,883w,829w,743m,728m cm-1;MS(ES+)m/z(%)590(28,[M+Na]+),568(100,[M+H]+)。
{(2S,3S)-3-[(E)-(S)-3’-甲基-4’-(2”-甲基-噻唑-4”-基)-2-三乙基硅烷氧基-丁-3-烯基]-2-[(S)-4-甲基-5-三乙基硅烷氧基-戊基]-环氧乙基}-甲醇(XV)
在干燥烧瓶中和氩气下,将5.00g(8.80mmol)烯丙基醇(4)溶于100mlCH2Cl2中。加入4分子筛(4g),并将混合物温度设置为-30℃。加入L(+)-酒石酸二乙酯(7.46ml,4.40mmol),之后加入异丙氧基钛(IV)(10.35ml,3.52mmol)。将所得混合物于-30℃搅拌1小时,同时溶液逐渐呈现黄绿色。然后加入3.52ml过氧化氢叔丁基(19.36mmol)。将反应于-25℃放置过夜,用100mlNaHSO3终止反应并充分搅拌。滤液用TBME(2×80ml)萃取。将合并的有机层用80ml盐水洗涤,经MgSO4干燥并在真空中浓缩,得到7.24g粗品。通过色谱法(1∶1己烷/AcOEt)纯化,得到5.2g(100%)环氧醇(XV)。Rf=0.38(SiO2,1∶1庚烷/AcOEt);1H-NMR(DMSO-d6,400MHz,300K)δ7.28(s,1H,C5“-H),6.44(s,1H,C4-H),4.30(dd,J=8.2,4.1Hz,1H,C2‘-H),3.46(d,J=12.2Hz,1H,C1-Ha),3.39(dd,J=10.2,6.0Hz,1H,C5‘“-Ha),3.34(dd,J=10.2,6.2Hz,1H,C5‘“-Hb),3.27(d,J=12.2Hz,1H,C1-Hb),2.90(dd,J=7.3,4.6Hz,1H,C3-H),2.63(s,3H,C2“-CH3),1.98(s,3H,C3‘-CH3),1.81(ddd,J=12.3,8.2,4.6Hz,1H,C1‘-Ha),1.68-1.20(4m,7H,C1‘-Hb,C1‘“-H2,C2‘“-H2,C3‘“-Ha,C4‘“-H,),1.08-0.98(m,1H,C3‘“-Hb),0.93-0.83(m,18H,两个Si(CH2CH3)3),0.82(d,J=6.7Hz,3H,C4‘“-CH3),0.59-0.50(m,12H,两个Si(CH2CH3)3);13C-NMR(DMSO-d6,125MHz,300K)δ164.7,152.6,141.2,118.7,117.1,76.3,67.6,63.6,63.6,60.2,57.5,35.5,35.4,33.3,28.7,22.3,19.1,16.8,14.4,13.9,7.1,7.0,4.6,4.3;IR(膜)νmax3403s(br),2954s,2876s,1507m,1459m,1414m,1377m,1239m,1185m,1084s,1007s,976w,802w,744s,676w cm-1;MS(ES)m/z(%)606(52,[M+Na]+),584(100,[M+H]+)。
甲磺酸(2S,3S)-3-[(E)-(S)-3’-甲基-4’-(2”-甲基-噻唑-4”-基)-2-三乙基硅烷氧基-丁-3-烯基]-2-[(S)-4-甲基-5-三乙基硅烷氧基-戊基]-环氧乙基甲酯(XVI)
于0℃向环氧醇(XV)(11.71g,20.0mmol)于CH2Cl2(148ml)中的溶液中加入10.3ml(60.1mmol)N-乙基二异丙胺。将所得混合物于0℃搅拌15分钟。然后加入甲磺酰氯(2.23ml,30.1mmol)。在于0℃搅拌1小时后,将反应溶液用50ml H2O和50ml TBME淬灭。分离各层,水层用TBME(50ml)萃取。将合并的有机萃取液用0.1N HCl(40ml)、NaHCO3饱和水溶液(2×40ml)和盐水(50ml)洗涤,经MgSO4干燥。在真空中浓缩,得到13.7g的环氧甲磺酸酯XVI,其不需要任何其它纯化。Rf=0.55(SiO2,1∶1庚烷-AcOEt);1H-NMR(DMSO-d6,400MHz,300K)δ7.34(s,1H,C5“-H),6.49(s,1H,C4‘-H),4.38(d,J=11.4Hz,1H,C1-Ha),4.34(dd,J=8.2,3.7Hz,1H,C2‘-H),4.07(d,J=11.4Hz,1H,C1-Hb),3.43(dd,J=9.8,5.9Hz,1H,C5‘“-Ha),3.37(dd,J=9.8,6.3Hz,1H,C5‘“-Hb),3.33(s,3H,SO2CH3),3.06(dd,J=7.0,4.6Hz,1H,C3-H),2.66(s,3H,C2“-CH3),2.03(s,3H,C3‘-CH3),1.89(ddd,J=15.2,7.0,3.7Hz,1H,C1‘-Ha),1.77-1.20(5m,7H,C1‘-Hb,C1‘“-H2,C2‘“-H2,C3‘“-Ha,C4‘“-H),1.12-1.03(m,1H,C3‘“-Hb),0.97-0.88(m,18H,两个Si(CH2CH3)3),0.85(d,J=6.6Hz,3H,C4‘“-CH3),0.63-0.50(m,12H,两个Si(CH2CH3)3);13C-NMR(DMSO-d6,125MHz,300K)δ164.2,152.3,140.5,118.6,117.0,75.8,72.1,67.2,60.4,57.8,36.6,35.1,34.6,32.8,28.1,21.7,18.9,16.5,13.6,6.8,6.7,4.3,4.0;MS(ES+)m/z(%)684(100,[M+Na]+),662(54,[M+H]+)。
甲磺酸(2S,3S)-2-[(S)-5’-羟基-4’-甲基-戊基]-3-[(E)-(S)-3”-甲基-4”-(2-甲基-噻唑-4-基)-2-三乙基硅烷氧基-丁-3-烯基]-环氧乙基甲酯(XVII)
将二-TES醚(XVI)(4.89g,7.38mmol)在THF/AcOH/H2O(10∶2∶1v/v/v,115ml)中的溶液于50℃加热15小时。加入460ml NaHCO3饱和水溶液终止反应,并将混合物用TBME(2×250ml)萃取。合并有机层,并用盐水洗涤,经MgSO4干燥并在真空中浓缩,得到4.73g粗品。通过快速色谱法(SiO2,30%至60%的AcOEt/己烷梯度洗脱)纯化,得到3.10g(基于XV两步为79%)的醇(XVII)。Rf=0.15(SiO2,1∶1庚烷-AcOEt)。1H-NMR(DMSO-d6,400MHz,300K)δ7.42(s,1H,C5‘“-H),6.50(s,1H,C4“-H),4.38(d,J=11.3Hz,1H,C1-Ha),4.36(dd,J=8.3,4.6Hz,1H,C2“-H,部分被C1-Ha遮掩),4.07(d,J=11.8Hz,1H,C1-Ha),3.30-3.23(m,1H,C5‘-Ha),3.20(s,3H,SO2CH3),3.22-3.14(m,1H,C5‘-Hb,部分被SO2CH3遮掩),3.06(dd,J=7.1,4.4Hz,1H,C3-H),2.67(s,3H,C2‘“-CH3),2.04(s,3H,C3“-CH3),1.90(ddd,J=14.2,8.3,4.4Hz,1H,C1“-Ha),1.70-1.58(m,1H,C1“-Hb),1.54-1.32(m,6H,C1‘-H2,C2‘-H2,C3‘-Ha,C4‘-H),1.10-0.98(m,1H,C3‘-Hb),0.93(t,J=8.0Hz,9H,Si(CH2CH3)3),0.84(d,J=6.6Hz,3H,C4‘-CH3),0.60(q,J=8.0Hz,6H,Si(CH2CH3)3);13C-NMR(DMSO-d6,100MHz,300K)δ165.1,153.2,141.5,119.4,117.9,76.6,73.3,67.0,61.2,58.6,37.6,36.0,35.5,33.9,29.0,22.6,19.7,17.5,14.9,14.5,7.63,7.58,5.1;IR(膜)νmax 3410s(br),2955s,2876s,1655w,1505w,1459m,1414m,1359s,1270w,1239w,1177s,1081m,1006m,958m,833m,745m,529m cm-1;MS(ES+)m/z(%)586(5,[M+K]+),570(100,[M+Na]+),548(8,[M+H]+)。
甲磺酸(2S,3S)-3-[(E)-(S)-3′-甲基-4′-(2″-甲基-噻唑-4″-基)-2-三乙基硅烷氧基-丁-3-烯基]-2-[(S)-4-甲基-5-氧代-戊基]-环氧乙基甲酯(1)
于0℃向醇(XVII)(2.00g,3.65mmol)于CH2Cl2(10ml)中的溶液中连续加入三乙胺(3.86ml,27.7mmol)、DMSO(6.48ml,91.3mmol)和在DMSO(26ml)中的吡啶·SO3复合物(2.32g,14.6mmol)。将所得溶液于0℃搅拌1小时。将反应用NaHSO4水溶液(40%,120ml)和TBME(150ml)终止。分离各层,有机层用NaHCO3饱和水溶液(2×100ml)洗涤。将水层用TBME(2×100ml)返萃取。合并有机萃取液,用盐水(100ml)洗涤,经MgSO4干燥并在真空中浓缩,得到1.94粗品。通过快速色谱法(SiO2,50%至70%AcOEt/己烷梯度洗脱)纯化,得到1.63g(82%)纯的醛(1)。Rf=0.30(SiO2,1∶1庚烷-AcOEt);1H-NMR(CDCl3,500MHz,300K)δ9.61(d,J=1.7Hz,1H,CHO),6.95(s,1H,C5“-H),6.52(s,1H,C4‘-H),4.33(dd,J=4.4Hz,1H,C2‘-H,部分被C1-Ha遮掩),4.34(d,J=11.4Hz,1H,C1-Ha),4.08(d,J=11.4Hz,1H,C1-Hb),3.11(dd,J=7.8,3.9Hz,1H,C3-H),3.05(s,3H,SO2CH3),2.71(s,3H,C2“-CH3),2.33(m,1H,C4‘“-H),2.02(s,3H,C3‘-CH3),1.99-1.32(6m,8H,C1‘-H2,C1‘“-H2,C2‘“-H2,C3‘“-H2),1.11(d,J=7.1Hz,3H,C4‘“-CH3),0.94(t,J=8.0Hz,9H,Si(CH2CH3)3),0.61(q,J=8.0Hz,6H,Si(CH2CH3)3);13C-NMR(CDCl3,125MHz,300K)δ204.7,164.8,152.8,141.8,119.2,115.8,76.0,72.0,60.7,59.0,46.3,37.8,35.3,30.5,28.3,22.5,19.4,14.1,13.5,7.0,4.9;IR(膜)ν2956s,2876s,2720w,1724s,1658w,1508m,1459m,1414w,1358S,1240w,1177s,1079m,1006m,957m,883w,828m,745m,529m cm-1;MS(ES+)m/z546(100,[M+H]+)。
Claims (34)
1、制备式9的埃坡霉素衍生物及其与金属阳离子的盐的方法:
其中,
R1为甲基,和
R2的含义为未取代或取代的芳基、未取代或取代的杂芳基或者与苯核稠合的未取代或取代的杂环基团,
其特征在于,
a)使式1化合物
其中R2具有上述给出的含义,甲磺酰基可被甲苯磺酰基等替代,
为醇保护基,
与例如式2的磺内酰胺衍生的化合物进行选择性醇醛缩合反应,
该反应在Lewis酸存在下、加入碱、在惰性溶剂中于-50℃至-100℃的较低温度下、随后在-20℃至+20℃的升高温度下进行,得到式3化合物:
其中R2和
具有上述给出的定义,以及
b)使所得以上式3化合物在-70℃至25℃的温度下、在甲硅烷基-醚形成化合物和2,6-二甲基吡啶存在下反应,形成式4化合物:
其中R2和
具有上述给出的定义,以及
c)通过用DME中的TBAOH/H2O2或THF/MeOH/H2O中的LiO2H裂解手性辅助基团而将以上式4化合物转化为羧酸,得到式5化合物:
d)使以上式5化合物与还原剂在惰性溶剂中反应,裂解甲磺酰基或甲苯磺酰基等,得到式6化合物:
其中R2具有上述给出的定义,
e)将上式6化合物用去甲硅烷基试剂或惰性溶剂中的酸或其混合物如TASF或THF中的HF·吡啶水解,得到选择性去甲硅烷基化的式7化合物:
其中R2和
具有上述给出的定义,以及
f)按照M.Yamaguchi等人,Bull.Chem.Soc.Jpn.,1979,52,1989中所描述的条件将所得的式7化合物大环内酯化,得到式8的全保护埃坡霉素衍生物:
g)将所得的式8化合物用惰性溶剂中的HF·吡啶于0℃至30℃的温度下处理,裂解两个甲硅烷基保护基,得到式9的埃坡霉素衍生物:
其中R1为甲基,R2具有上述的含义,
并且任选按照常规方法将其中R1和R2具有式9中所定义的含义的式9化合物转化为金属阳离子的盐。
2、根据权利要求1中步骤a)的方法,其特征在于:使式1化合物与式2化合物例如在TiCl4和
碱(iPr2Net)存在下、在二氯甲烷中于-78℃且之后于0℃的温度下反应,得到新的式3化合物。
3、根据权利要求1中步骤b)的方法,其特征在于:使所得式3化合物与甲硅烷基-醚形成化合物在2,6-二甲基吡啶存在下、在-20℃至20℃、尤其在-10℃的温度下、在惰性溶剂二氯甲烷中反应,形成式4化合物。
4、根据权利要求1中步骤c)的方法,其特征在于:通过用DME中的TBAOH/H2O2或THF/MeOH/H2O中的LiO2H裂解手性辅助基团而将所得式4化合物转化为羧酸,得到式5化合物。
5、根据权利要求1中步骤d)的方法,其特征在于:使所得式5化合物与还原剂LiBHEt3在惰性溶剂THF中反应,裂解甲磺酰基或甲苯磺酰基等,得到式6化合物。
6、根据权利要求1中步骤e)的方法,其特征在于:将所得式6化合物用去甲硅烷基试剂、尤其是TASF或在惰性溶剂如吡啶或THF中的有机酸、尤其是HF·吡啶水解,得到式7化合物。
7、根据权利要求1中步骤f)的方法,其特征在于:根据Yamaguchi等人所述的方法将所得式7化合物大环内酯化,例如用Et3N和2,4,6-三氯苯甲酰氯在较低温度如0℃下处理羟基酸,之后将反应混合物加入到4-DMAP在甲苯中的溶液中并将温度升至约75℃,得到式8化合物。
9、式9化合物及其与金属阳离子的盐:
其中,R1为甲基,R2为未取代或取代的芳基。
10、式9化合物及其与金属阳离子的盐:
其中,R1为甲基,R2为未取代或取代的苯基。
11、式3化合物:
其中R2具有式9中给出的含义。
14、制备新的式4化合物的方法,其特征在于:
使式3化合物
在-70℃至25℃的温度下、在甲硅烷基-醚形成化合物存在下且在2,6-二甲基吡啶存在下反应,形成以上给出的式4化合物。
15、式5化合物:
其中R2具有上述给出的含义。
16、制备新的式5化合物的方法,其特征在于:
通过用DME中的TBAOH/H2O2或THF/MeOH/H2O中的LiO2H裂解手性辅助基团而将式4化合物转化为羧酸,得到式5化合物,
19、式7化合物:
其中R2具有上述给出的定义。
20、制备新的式7化合物的方法,其特征在于:将上式6的三重保护的三甲硅烷基醚化合物用去甲硅烷基试剂、尤其是TASF或者在惰性溶剂如吡啶或THF中的有机酸、尤其是HF·吡啶水解,得到式7化合物。
21、式8化合物:
其中R2具有上述给出的定义。
24、制备式1化合物的方法,其特征在于:
a)使式X化合物
与PPH3在50℃至150℃的温度、更精确地在100℃的温度下反应,之后与KHMDS在惰性溶剂、尤其是THF中于0℃下反应,之后将反应混合物冷却-50℃至-100℃的温度、并更精确地在-78℃的温度下用CH3CO2Cl处理,得到式XI化合物:
以及,
b)使所得式XI化合物与式XII化合物
在惰性溶剂如甲苯中于20℃至60℃的温度、更精确地在40℃的温度下反应,得到式XIII化合物,
c)将式(XIII)化合物用还原剂、尤其是DIBALH在惰性溶剂如甲苯中于-50℃至-100℃的温度下、更精确地在-78℃的温度下还原,之后升温至0℃,得到式XIV化合物:
(式XIV和之后的下述化合物的图已简化)
d)使用Sharpless[L(+)-酒石酸二乙酯,Ti(OPr)4,t-BuOOH]条件进行式XIV化合物的环氧化,得到式XV化合物:
所得式XV化合物为新化合物,并且可用作该方法序列中下一步骤e)的前体,以及
e)在三乙胺(Et3N)存在下在惰性溶剂如二氯甲烷中通过加入甲磺酰氯将甲磺酰基引入式XV化合物(甲磺酰基可被相应的甲苯磺酰基等替代),得到式XVI化合物:
所得式XVI化合物为新化合物,并且可用作下一步骤f)的中间体,以及
f)将所得式XVI化合物用惰性溶剂中的有机酸处理、更准确地用无水乙醇中的对甲苯磺酸吡啶鎓或樟脑磺酸处理,水解一个保护基,得到式XVII化合物:
其中R2具有上述给出的含义,以及
g)使用Swern氧化法氧化,例如通过草酰氯的促进和二甲亚砜的活化使醇基团氧化,通过烷氧基锍盐,在加入碱和分子内重排后,得到式1的酮类化合物,
26、制备式XV化合物的方法,其特征在于:
使用Sharpless[L(+)-酒石酸二乙酯,Ti(OPr)4,t-BuOOH]条件进行以上式XIV化合物的环氧化,得到式XV化合物:
其中R2和
分别具有上述式9和式1中给出的含义。
30、制备式XVII化合物的方法,其特征在于:将所得的式XVI化合物用惰性溶剂中的有机酸处理、更准确地用无水乙醇中的对甲苯磺酸吡啶鎓或樟脑磺酸处理,水解保护基
,得到式XVII化合物。
32、治疗患有癌症疾病和需要该治疗的温血动物的方法,该方法包括向所述温血动物施用足以用于所述治疗的量的根据权利要求9的式9化合物或其可药用盐,其中R2为未取代或取代的芳基。
33、适合用于向温血动物施用以治疗癌症疾病的药物组合物,其包含有效治疗所述癌症疾病的量的根据权利要求9的其中R2为未取代或取代的芳基的式9活性成分以及至少一种可药用载体。
34、式8化合物在制备用于药物治疗的式9化合物中的用途。
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