CN116354823A - 一类化合物的制备方法和应用 - Google Patents
一类化合物的制备方法和应用 Download PDFInfo
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- CN116354823A CN116354823A CN202111615209.5A CN202111615209A CN116354823A CN 116354823 A CN116354823 A CN 116354823A CN 202111615209 A CN202111615209 A CN 202111615209A CN 116354823 A CN116354823 A CN 116354823A
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- substituted
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- alkyl
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Abstract
Description
技术领域
本发明涉及医药化学技术领域,具体涉及一类化合物的制备方法和应用。
背景技术
癌症已成为全球高发疾病之一,乳腺癌根据受体表达类型分为三类:雌激素受体(ER)阳性、HER2阳性和三阴性乳腺癌。其中,雌激素受体阳性患者占全部乳腺癌70%以上,针对ER信号通路的内分泌疗法是目前临床治疗的主要手段之一。常用的治疗药物大多是以ER为靶点,但长期使用内分泌疗法类药物,如他莫昔芬会产生耐药性,在80%的晚期乳腺癌患者中ERα存在高表达。因此使用选择性雌激素受体下调剂(selective estrogenreceptor downregulators,SERDs)来降解ERα,从而在蛋白水平真正阻断ER信号通路,有望克服临床上出现的耐药性问题。
氟维司群是目前唯一被FDA批准的SERD,与雌激素受体结合后会加强泛素化降解使细胞中ERα水平显著下降。它可以抑制他莫昔芬耐药性乳腺癌细胞的增殖,但是口服生物利用度差使其只能通过肌肉注射给药,限制了它的广泛应用。有文献报道各种基于三苯氧胺母核的结构改造化合物,但大多结构复杂,合成难度大。
蛇孢假壳素(ophiobolin)类化合物属于二倍半萜类化合物,具有特征性C5-C8-C5三环母核结构。该类化合物对多种肿瘤细胞具有显著细胞毒活性。文献报道从红树林真菌094102的次级代谢产物中分离鉴定了一系列蛇孢假壳素类衍生物,其中6-epi-ophiobolinG(简称MHO7)表现出良好的雌激素受体降解活性,并可以在ER阳性乳腺癌细胞中抑制ESR1转录合成hnRNA和相应的mRNA,还可以竞争雌二醇与雌激素受体的结合位点,抑制癌细胞的增殖(Pharmacol Res,146(2019)104294)。但仍然存在药效和生物利用度低的问题,进行结构修饰有利于将其开发成为新的抗肿瘤药物。
Crews等首次提出小分子疏水标记诱导HaloTag融合蛋白的降解技术(Nat ChemBiol 7,538–543(2011).)。并接着证明了Boc3-Arg诱导蛋白降解的能力。通过共价抑制剂etacrynic acid与Boc3-Arg连接,靶向降解谷胱甘肽-S-转移酶α1(GST-α1)。类似地,使用微摩尔浓度的与Boc3-Arg偶联的非共价抑制剂甲氧苄氨嘧啶(trimethoprim)可以降解二氢叶酸还原酶。
利用化学结构修饰的方法将疏水标签嵌合到蛇孢假壳素中,合成新型蛇孢假壳素类化合物,制备对ERα降解的新型分子,开发以ERα为靶点的药物。
发明内容
本发明的首要目的在于克服现有技术存在的不足而提供一种蛇孢假壳素类化合物及其应用,所述的蛇孢假壳素类化合物具有抑制ER阳性乳腺癌细胞增殖和靶向ERα降解活性,对三阴乳腺癌和阿霉素耐药乳腺癌也具有明显的抑制生长和转移的作用,且对病毒也有抑制作用,可以作为新的抗癌和抗病毒药物进行开发,具有广泛的应用前景。
本发明另一目的是提供上述蛇孢假壳素类化合物的制备方法。在合成中,利用不同路线高效获得目标化合物,总结出了一条适用性强、产率高的合成路线。
本发明的第三目的是提供上述蛇孢假壳素类化合物作为选择性雌激素受体降解剂在制备抗肿瘤、抗病毒药物中的用途;特别提供了上述蛇孢假壳素类化合物在制备抗乳腺癌药物中的用途。
为了实现上述目的,本发明采用如下技术方案:
本发明提供了式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药:
其中,
R1、R2、R3分别独立选自氢、C1~C8烷基、羟基或卤素;或者R3与R2连接形成双键,R1选自氢、C1~C8烷基、羟基或卤素;
R4、R5、R7、R8、R9、R10分别独立选自氢或C1~C8烷基;
R6选自氢、C1~C8烷基、羟基取代的C1~C8烷基或醛基;
R11、R12分别独立选自氢或C1~C8烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C8烷基;
m为0或1;
R15、R16、R17分别独立选自氢或C1~C8烷基;
R14选自取代或未取代的C1~C14烷基、取代或未取代的C1~C14烯基、取代或未取代的C1~C14炔基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂芳基、取代或未取代的3~6元杂环烷基、-CH=CHR18、金刚烷基、-(CH2)bOC(O)(CH2)cR18、-(CH2CH2O)bC(O)(CH2)cR18;
a为1~8的整数;
b为1~10的整数;
c为1~5的整数;
R18选自金刚烷基、取代或未取代的5~10元芳基、5~10元杂芳基;
所述烷基、烯基、炔基的取代基选自羧基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂环烷基、金刚烷;
所述芳基、杂芳基的取代基选自C1~C8烷基、C1~C8烷氧基、卤素、三氟甲基、硝基、三氟甲氧基、-C(O)CH=CHR19;
所述杂环烷基的取代基为C1~C8烷基;或者同一个碳原子上两个取代基连接形成=O;
所述杂芳基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
所述杂环烷基的杂原子个数为1、2或3个,所述杂原子选自O、S或N。
进一步地,所述化合物为式II所示:
其中,
R1、R2、R3分别独立选自氢、C1~C8烷基、羟基或卤素;或者R3与R2连接形成双键,R1选自氢、C1~C8烷基、羟基或卤素;
R5选自氢或C1~C8烷基;
R6选自氢、C1~C8烷基、羟基取代的C1~C8烷基或醛基;
R11、R12分别独立选自氢或C1~C8烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C8烷基;
m为0或1;
R15、R16、R17分别独立选自氢或C1~C8烷基;
R14选自取代或未取代的C1~C14烷基、取代或未取代的C1~C14烯基、取代或未取代的C1~C14炔基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂芳基、取代或未取代的3~6元杂环烷基、-CH=CHR18、金刚烷基、-(CH2)bOC(O)(CH2)cR18、-(CH2CH2O)bC(O)(CH2)cR18;
a为1~8的整数;
b为1~10的整数;
c为1~5的整数;
R18选自金刚烷基、取代或未取代的5~10元芳基、5~10元杂芳基;
所述烷基、烯基、炔基的取代基选自羧基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂环烷基、金刚烷;
所述芳基、杂芳基的取代基选自C1~C8烷基、C1~C8烷氧基、卤素、三氟甲基、硝基、三氟甲氧基、-C(O)CH=CHR19;
所述杂环烷基的取代基为C1~C8烷基;或者同一个碳原子上两个取代基连接形成=O;
所述杂芳基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
所述杂环烷基的杂原子个数为1、2或3个,所述杂原子选自O、S或N。
进一步地,
R1、R2、R3分别独立选自氢、C1~C3烷基或羟基;或者R3与R2连接形成双键,R1选自C1~C3烷基;
R5选自氢;
R6选自C1~C3烷基、羟基取代的C1~C3烷基或醛基;
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
进一步地,所述化合物为式III所示:
其中,
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式IV所示:
其中,
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
进一步地,所述化合物为式IIIa所示:
其中,
R14选自取代或未取代的C1~C6烷基、-CH=CHR18;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式IIIb所示:
其中,
R14选自取代或未取代的C1~C6烷基、-CH=CHR18;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式IVa所示:
其中,
R14选自-(CH2CH2O)bC(O)(CH2)cR18;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
R18选自金刚烷基;
或者,所述化合物为式IVb所示:
其中,
R14选自-(CH2CH2O)bC(O)(CH2)cR18;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
R18选自金刚烷基。
进一步地,所述化合物为式V所示:
其中,
R11、R12分别独立选自氢或C1~C8烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C8烷基;
m为0或1;
R15、R16、R17分别独立选自氢或C1~C8烷基;
R14选自取代或未取代的C1~C14烷基、取代或未取代的C1~C14烯基、取代或未取代的C1~C14炔基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂芳基、取代或未取代的3~6元杂环烷基、-CH=CHR18、金刚烷基、-(CH2)bOC(O)(CH2)cR18、-(CH2CH2O)bC(O)(CH2)cR18;
a为1~8的整数;
b为1~10的整数;
c为1~5的整数;
R18选自金刚烷基、取代或未取代的5~10元芳基、5~10元杂芳基;
所述烷基、烯基、炔基的取代基选自羧基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂环烷基、金刚烷;
所述芳基、杂芳基的取代基选自C1~C8烷基、C1~C8烷氧基、卤素、三氟甲基、硝基、三氟甲氧基、-C(O)CH=CHR19;
所述杂环烷基的取代基为C1~C8烷基;或者同一个碳原子上两个取代基连接形成=O;
所述杂芳基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
所述杂环烷基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
优选地,
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
进一步地,所述化合物为式Va所示:
其中,
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式Vb所示:
其中,
X为-O-或-NR15-;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式Vc所示:
其中,
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式Vd所示:
其中,
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
进一步地,所述化合物为如下化合物之一:
(1)常温下,原料1与1,3-二甲基咪唑-2-硒酮溶解于溶剂中,加入碘苯二乙酸反应,得化合物2;或者,40~60℃回流条件下,原料1与二氧化硒、过氧叔丁醇、水杨酸在溶剂中反应,得化合物2;
(2)常温下,化合物2与含有羧基的衍生物在缩合剂EDCI和DMAP作用下反应,即得;所述含有羧基的衍生物结构为COOR14;R14如前述式Va所述;
优选地,所述溶剂为二氯甲烷。
1)常温下,原料1与1,3-二甲基咪唑-2-硒酮溶解于溶剂中,加入碘苯二乙酸反应,得化合物2;或者,40~60℃回流条件下,原料1与二氧化硒、过氧叔丁醇、水杨酸在溶剂中反应,得化合物2;
2)室温下,化合物2与卤代物Y-R14以及Ag2O在溶剂中反应,即得;
所述Y-R14中Y为卤素,R14如前述式Vb所述;
优选地,所述溶剂为二氯甲烷。
a)常温下,原料1与1,3-二甲基咪唑-2-硒酮溶解于溶剂中,加入碘苯二乙酸反应,得化合物2;或者,40~60℃回流条件下,原料1与二氧化硒、过氧叔丁醇、水杨酸在溶剂中反应,得化合物2;
b)室温下,化合物2与NH2-R14、三苯基膦、二碘乙烷在溶剂中反应,即得;
所述NH2-R14中,R14如前述式Vb所述;
优选地,所述步骤(1)中,溶剂为二氯甲烷;
和/或,所述步骤(2),中,溶剂为DMF。
(A)50~70℃回流条件下,原料1与末端烯烃衍生物在溶剂中,Grubbs催化剂的作用下反应;
(B)步骤(1)得到的反应物硅胶柱层析分离纯化,利用石油醚和乙酸乙酯体积比1:1的混合溶液作为洗脱剂洗脱,分离得到式Vc和式Vd所示化合物;
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药在制备雌激素受体α降解剂中的用途。
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药在制备抗肿瘤药物和/或抗病毒药物中的用途;
优选地,所述肿瘤为乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、胰腺癌、直肠结肠癌、子宫颈癌、神经胶质瘤、膀胱癌、卵巢癌;
和/或,所述病毒为冠状病毒、HIV病毒、巨细胞病毒、EB病毒、腺病毒、疱疹病毒、人T淋巴细胞病毒、乙肝病毒、甲肝病毒。
本发明还提供了一种药物,它是由前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药为活性成分,加上药学上可接受的辅助性成分或辅料制备而成的制剂;
优选地,所述药物为抗肿瘤药物和/或抗病毒药物;
更优选地,所述肿瘤为乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、胰腺癌、直肠结肠癌、子宫颈癌、神经胶质瘤、膀胱癌、卵巢癌;
和/或,所述病毒为冠状病毒、HIV病毒、巨细胞病毒、EB病毒、腺病毒、疱疹病毒、人T淋巴细胞病毒、乙肝病毒、甲肝病毒。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
本发明中所述化合物的结构均是指能够稳定存在的结构。
本发明中碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(Ca~Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C1~C10烷基是指包含1~10个碳原子的直链或支链烷基;C1~C8烷氧基是指包含1~8个碳原子的烷氧基;C2~C10烯基是指包含2~10个碳原子的烯基;C2~C10炔基是指包含2~10个碳原子的炔基。
本发明中卤素为氟、氯、溴或碘。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。6~10元芳基是指芳基含有6~10个碳原子。
“杂环烷基”是指包含至少一个杂原子的饱和或部分饱和的非芳香性环状基团;包括单个环或多个环(包括稠合、桥连和螺环体系);其中杂原子指氮原子、氧原子、硫原子。杂环烷基基团的实例包括例如,哌啶基、哌嗪基、吗啉基、
本发明提供了一类蛇胞假壳素类化合物结构修饰的方法,此类化合物可以有效抑制多种乳腺癌细胞的增殖活性,其中对三阴乳腺癌细胞和阿霉素耐药细胞均有良好的抑制增殖活性,也能够有效抑制它们的迁移;同时,此类化合物具有良好的雌激素受体α下调活性,显示了此类化合物在癌症治疗,特别是在乳腺癌治疗中的应用前景。此外,研究发现此类化合物对冠状病毒有良好的抑制活性,无明显毒副作用,可作为预防和治疗冠状病毒药物的一种新选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为氟维司群、MHO7及其衍生物处理后MCF-7细胞中ERα的蛋白免疫印迹分析
图2为化合物16a处理MCF-7细胞后ERα的蛋白免疫印迹分析。
图3为化合物16a抑制耐药乳腺癌细胞的迁移结果。
图4为化合物16a抑制三阴乳腺癌细胞的迁移结果。
具体实施方式
原料可以从商业途径获得,或者通过本领域已知的方法制备,或者根据本文提供的方法制备。
除非做出说明,实施例中的化合物可通过以下路线进行合成,具体如下:
路线1:
中间体2的合成:
将原料1(1g,0.272mol)溶于35ml二氯甲烷,缓慢加入1,3-二甲基咪唑-2-硒酮(IMeSe,190mg,0.109mol),室温下搅拌30分钟,然后分批加入碘苯二乙酸(1.75g,0.545mol),添加完毕后室温反应约24h,TLC点板检测反应,原料1大部分反应后停止反应,将反应液浓缩,使用乙酸乙酯和饱和食盐水的混合溶液(1:1,v/v)萃取三次,合并有机相,使用无水硫酸钠干燥1h;最后浓缩,使用硅胶拌样,柱层析分离,未反应完全的原料1可以回收再利用,得中间体370mg(2)。HRMS[ESI]+,Calcd.For C25H35O3[M+H]+,383.2586,found383.2574。
中间体2:1H NMR(400MHz,CDCl3)δ9.29(s,1H),6.84(d,J=4.3Hz,1H),6.12(t,J=11.1Hz,1H),6.06(s,1H),6.03(d,J=12.1Hz,1H),5.13(t,J=10.0Hz,1H),4.16(s,2H),3.41(d,J=3.8Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.7Hz,3H),0.89(s,3H).13CNMR(101MHz,CDCl3)δ207.58,192.99,177.56,157.72,140.04,138.48,138.36,130.28,123.17,119.15,68.45,52.02,49.97,49.12,45.84,45.43,44.28,43.83,32.74,30.88,29.71,27.75,22.91,21.25,17.23,14.09.
化合物X1的合成:
冰浴下,将含有裸露羧基的衍生物(1.5mol)完全溶解于二氯甲烷,随后加入EDCI(1.5mol)和DMAP(0.1mol),搅拌30min,最后缓慢滴加中间体2(1.0mol)的二氯甲烷溶液,室温搅拌3-12h,待TLC板检测中间体2反应完全,停止反应,浓缩反应体系,加入乙酸乙酯和饱和碳酸氢钠溶液的混合溶液(1:1,v/v)萃取三次,合并有机相,加入无水硫酸钠干燥,浓缩,拌样,柱层析分离纯化后可得化合物X1。
实施例1、化合物3a的合成
采用上述合成路线1的方法制备化合物3a,其中含有裸露羧基的衍生物为1-肉桂酸。
收率87%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.75(d,J=16.0Hz,1H),7.56(dd,J=6.6,3.0Hz,3H),7.46–7.37(m,4H),6.84(dd,J=6.7,2.5Hz,1H),6.51(d,J=16.0Hz,1H),6.39(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.06(s,2H),5.36(t,J=10.2Hz,1H),4.85–4.65(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m/z calculated for C34H40O4[M+H]+:513.3005,found513.3001.
实施例2、化合物3b的合成
采用上述合成路线1的方法制备化合物3b,其中含有裸露羧基的衍生物为4-氟肉桂酸。
收率84%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.70(d,J=16.0Hz,1H),7.54(dd,J=8.6,5.5Hz,2H),7.11(t,J=8.6Hz,2H),6.84(dd,J=6.6,2.4Hz,1H),6.43(d,J=16.0Hz,1H),6.17(t,J=11.2Hz,1H),6.05(t,J=1.7Hz,1H),5.44–5.26(m,1H),4.83–4.64(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m/z calculated for C34H39FO4[M+H]+:531.2911,found 531.2907.
实施例3、化合物3c的合成
采用上述合成路线1的方法制备化合物3c,其中含有裸露羧基的衍生物为3-三氟甲基肉桂酸。
收率86%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.78(d,J=9.2Hz,2H),7.72(d,J=6.1Hz,2H),7.67(d,J=7.8Hz,1H),7.55(t,J=7.8Hz,1H),6.84(dd,J=6.6,2.4Hz,1H),6.57(d,J=16.0Hz,1H),6.39(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.06(s,1H),5.37(t,J=10.2Hz,1H),4.84–4.66(m,2H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.89(s,3H).ESI-HRMS:m/z calculated for C35H39F3O4[M+H]+:581.2879,found 581.2863.
实施例4、化合物3d的合成
采用上述合成路线1的方法制备化合物3d,其中含有裸露羧基的衍生物为3,4,5-三氟肉桂酸。
收率76%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),7.56(d,J=15.9Hz,1H),7.24–7.10(m,2H),6.83(dd,J=6.6,2.4Hz,1H),6.50–6.32(m,2H),6.17(t,J=11.2Hz,1H),6.06(s,1H),5.44–5.29(m,1H),4.86–4.64(m,2H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.89(s,3H).ESI-HRMS:m/z calculated for C34H37F3O4[M+H]+:567.2722,found567.2708.
实施例5、化合物3e的合成
采用上述合成路线1的方法制备化合物3e,其中含有裸露羧基的衍生物为3-三氟甲氧基肉桂酸。
收率89%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.70(d,J=16.0Hz,1H),7.46(d,J=7.5Hz,2H),7.39(s,1H),7.24(m,1H),6.84(dd,J=6.5,2.4Hz,1H),6.52(d,J=16.0Hz,1H),6.38(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.06(t,J=1.6Hz,1H),5.37(t,J=10.3Hz,1H),4.84–4.67(m,2H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m/z calculated for C35H39F3O5[M+H]+:597.2828,found 597.2812.
实施例6、化合物3f的合成
采用上述合成路线1的方法制备化合物3f,其中含有裸露羧基的衍生物为4-溴肉桂酸。
收率77%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.67(d,J=16.0Hz,1H),7.60–7.51(m,2H),7.47–7.38(m,2H),6.84(dd,J=6.5,2.4Hz,1H),6.49(d,J=16.0Hz,1H),6.38(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.06(t,J=1.7Hz,1H),5.36(t,J=10.2Hz,1H),4.82–4.66(m,2H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m/zcalculated for C34H39BrO4[M+H]+:591.2110,found 591.2102.
实施例7、化合物3g的合成
采用上述合成路线1的方法制备化合物3g,其中含有裸露羧基的衍生物为3-氯肉桂酸。
收率86%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.67(d,J=16.0Hz,1H),7.54(d,J=1.9Hz,1H),7.45–7.32(m,3H),6.84(dd,J=6.6,2.4Hz,1H),6.51(d,J=16.0Hz,1H),6.38(d,J=11.6Hz,1H),6.18(t,J=11.1Hz,1H),6.10–6.03(m,1H),5.36(t,J=10.2Hz,1H),4.85–4.65(m,2H),3.39(d,J=4.0Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.88(s,3H).ESI-HRMS:m/zcalculated for C34H39ClO4[M+H]+:547.2615,found 547.2619.
实施例8、化合物3h的合成
采用上述合成路线1的方法制备化合物3h,其中含有裸露羧基的衍生物为2-硝基肉桂酸。
收率75%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),8.20(d,J=15.8Hz,1H),8.08(d,J=8.1Hz,1H),7.73–7.64(m,2H),7.58(ddd,J=8.6,6.1,2.7Hz,1H),6.87(dd,J=6.6,2.4Hz,1H),6.53–6.35(m,2H),6.18(t,J=11.2Hz,1H),6.05(s,1H),5.36(t,J=10.3Hz,1H),4.87–4.68(m,2H),3.40(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.89(s,3H).ESI-HRMS:m/zcalculated for C34H39NO6[M+H]+:558.2856,found 558.2831.
实施例9、化合物3i的合成
采用上述合成路线1的方法制备化合物3i,其中含有裸露羧基的衍生物为2-甲基肉桂酸。
收率74%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),8.05(d,J=15.8Hz,1H),7.59(d,J=7.5Hz,1H),7.23(d,J=7.4Hz,3H),6.87–6.81(m,1H),6.48–6.35(m,2H),6.19(t,J=11.2Hz,1H),6.06(s,1H),5.36(t,J=10.2Hz,1H),3.84(s,1H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.89(s,3H).ESI-HRMS:m/z calculated for C35H42O4[M+H]+:527.3161,found527.3145.
实施例10、化合物3j的合成
采用上述合成路线1的方法制备化合物3j,其中含有裸露羧基的衍生物为2-甲氧基肉桂酸。
收率71%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),8.06(d,J=16.1Hz,1H),7.54(dd,J=7.6,1.7Hz,1H),7.42–7.34(m,1H),7.03–6.91(m,2H),6.88(dd,J=6.7,2.4Hz,1H),6.18(t,J=11.2Hz,1H),6.08–6.03(m,1H),5.34(t,J=10.3Hz,1H),4.84–4.64(m,2H),3.91(s,3H),3.38(d,J=4.2Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m/zcalculated for C35H42O5[M+H]+:543.3110,found 543.3102.
实施例11、化合物3k的合成
采用上述合成路线1的方法制备化合物3k,其中含有裸露羧基的衍生物为2,4-二甲氧基肉桂酸。
收率79%,1H NMR(400MHz,CDCl3)δ9.26(s,1H),7.97(d,J=16.0Hz,1H),6.88(d,J=2.5Hz,1H),6.60–6.42(m,3H),6.39(d,J=11.6Hz,1H),6.17(t,J=11.3Hz,1H),6.05(s,1H),5.32(t,J=10.3Hz,1H),4.86–4.59(m,2H),4.14(q,J=7.1Hz,1H),3.88(s,3H),3.86(s,3H),3.38(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.4Hz,3H),0.89(s,3H).ESI-HRMS:m/z calculated forC36H44O6[M+H]+:573.3216,found 573.3221.
实施例12、化合物3l的合成
采用上述合成路线1的方法制备化合物3l,其中含有裸露羧基的衍生物为2,5-二甲氧基肉桂酸。
收率81%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),8.04(d,J=16.1Hz,1H),7.07(d,J=3.1Hz,1H),6.94(dd,J=9.0,3.0Hz,1H),6.88(q,J=5.1,4.1Hz,2H),6.56(d,J=16.2Hz,1H),6.40(d,J=11.6Hz,1H),6.17(t,J=11.2Hz,1H),6.05(s,1H),5.34(t,J=10.3Hz,1H),4.85–4.62(m,1H),3.86(s,3H),3.81(s,3H),3.38(d,J=4.2Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m/z calculated for C36H44O6[M+H]+:573.3216,found573.3211.
实施例13、化合物3m的合成
采用上述合成路线1的方法制备化合物3m,其中含有裸露羧基的衍生物为3,4-二甲氧基肉桂酸。
收率83%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.68(d,J=15.9Hz,1H),7.13(dd,J=8.3,2.0Hz,1H),7.07(d,J=1.9Hz,1H),6.89(d,J=8.3Hz,1H),6.85(dd,J=6.5,2.3Hz,1H),6.39(s,1H),6.36(d,J=5.1Hz,1H),6.17(t,J=11.2Hz,1H),6.05(s,1H),5.35(t,J=10.2Hz,1H),4.81–4.65(m,2H),3.93(s,6H),3.38(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.87(s,3H).ESI-HRMS:m/z calculated for C36H44O6[M+H]+:573.3216,found 573.3217.
实施例14、化合物3n的合成
采用上述合成路线1的方法制备化合物3n,其中含有裸露羧基的衍生物为2,3,4-三甲氧基肉桂酸。
收率85%,1H NMR(400MHz,CDCl3)δ9.26(s,1H),7.94(d,J=16.2Hz,1H),7.30(s,1H),6.86(dd,J=6.5,2.4Hz,1H),6.72(dd,J=8.8,4.1Hz,1H),6.48(d,J=16.1Hz,1H),6.43–6.35(m,1H),6.17(t,J=11.2Hz,1H),6.05(s,1H),5.34(t,J=10.3Hz,1H),4.83–4.62(m,2H),3.97–3.86(m,12H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m/z calculated for C37H46O7[M+H]+:603.3322,found 603.3314.
实施例15、化合物3o的合成
采用上述合成路线1的方法制备化合物3o,其中含有裸露羧基的衍生物为4-吡啶肉桂酸。
收率73%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),8.69(d,J=5.0Hz,2H),7.65(d,J=16.1Hz,1H),7.42(d,J=5.2Hz,2H),6.83(dd,J=6.6,2.4Hz,1H),6.67(d,J=16.1Hz,1H),6.38(d,J=11.6Hz,1H),6.17(t,J=11.3Hz,1H),6.06(d,J=1.7Hz,1H),5.37(t,J=10.3Hz,1H),4.84–4.64(m,2H),3.39(d,J=4.2Hz,1H),2.94(d,J=30.0Hz,2H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m/z calculated for C33H39NO4[M+H]+:514.2957,found 514.2942.
实施例16、化合物3p的合成
采用上述合成路线1的方法制备化合物3p,其中含有裸露羧基的衍生物为3-呋喃肉桂酸。
收率72%,1H NMR(400MHz,CDCl3)δ9.27(s,1H),7.68(s,1H),7.61(s,1H),7.46(d,J=2.9Hz,1H),6.87–6.82(m,1H),6.62(d,J=2.0Hz,1H),6.37(dd,J=13.9,4.7Hz,1H),6.26–6.18(m,1H),6.05(s,1H),5.36(d,J=10.3Hz,1H),4.77–4.64(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=30.0Hz,2H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m/zcalculated for C32H38O5[M+H]+:503.2797,found 503.2786.
实施例17、化合物3q的合成
采用上述合成路线1的方法制备化合物3q,其中含有裸露羧基的衍生物为3-噻吩肉桂酸。
收率69%,1H NMR(400MHz,CDCl3)δ9.26(s,1H),7.53(dd,J=3.1,1.2Hz,1H),7.37(dd,J=5.2,2.9Hz,1H),7.33(dd,J=5.1,1.3Hz,1H),6.84(dd,J=6.5,2.4Hz,1H),6.37(d,J=11.8Hz,1H),6.33(d,J=15.9Hz,1H),6.17(t,J=11.3Hz,1H),6.08–6.03(m,1H),5.35(t,J=10.2Hz,1H),4.79–4.66(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=30.0Hz,2H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.89(s,3H).ESI-HRMS:m/z calculated for C32H48O4S[M+H]+:519.2569,found 519.2537.
实施例18、化合物3r的合成
采用上述合成路线1的方法制备化合物3r,其中含有裸露羧基的衍生物为3,4-亚甲氧基肉桂酸。
收率84%,1H NMR(400MHz,CDCl3)δ9.26(s,1H),7.64(d,J=15.9Hz,1H),7.06(d,J=1.7Hz,1H),7.03(dd,J=8.1,1.7Hz,1H),6.84(d,J=7.9Hz,2H),6.38(d,J=11.8Hz,1H),6.33(d,J=15.9Hz,1H),6.18(t,J=11.2Hz,1H),6.05(s,2H),5.40–5.30(t,1H),4.81–4.62(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=30.0Hz,2H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m/z calculated for C35H40O6[M+H]+:557.2903,found557.2911.
实施例19、化合物3s的合成
采用上述合成路线1的方法制备化合物3s,其中含有裸露羧基的衍生物为苯甲酸。
收率89%,1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.16–8.05(m,2H),7.61(dt,J=12.0,7.3Hz,1H),7.49(q,J=7.3Hz,2H),6.77(dd,J=6.5,2.4Hz,1H),6.44(d,J=11.6Hz,1H),6.18(t,J=11.3Hz,1H),6.06(s,1H),5.35(t,J=10.3Hz,1H),4.97–4.75(m,2H),3.38(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.88(s,3H).ESI-HRMS:m/z calculated for C32H38O4[M+H]+:487.2848,found 487.2834.
实施例20、化合物3t的合成
采用上述合成路线1的方法制备化合物3t,其中含有裸露羧基的衍生物为3,4-二甲氧基苯甲酸。
收率84%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),7.75(dd,J=15.2,11.8Hz,1H),7.40(d,J=8.2Hz,1H),7.09–6.98(m,1H),6.38(d,J=2.3Hz,1H),6.37–6.31(m,2H),6.24–6.15(m,1H),6.07(s,1H),5.81(t,J=10.2Hz,1H),3.81(d,J=2.2Hz,6H),3.38(d,J=4.6Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.5Hz,3H),0.89(s,3H).ESI-HRMS:m/z calculated for C34H42O6[M+H]+:547.3060,found 547.3046.
实施例21、化合物3u的合成
采用上述合成路线1的方法制备化合物3u,其中含有裸露羧基的衍生物为4-氯苯甲酸。
收率79%,1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.02(d,J=8.2Hz,2H),7.45(d,J=8.3Hz,2H),6.80–6.74(m,1H),6.41(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.05(s,1H),5.37(d,J=10.2Hz,1H),5.00–4.75(m,2H),3.38(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.6Hz,3H),0.89(s,3H).ESI-HRMS:m/z calculatedfor C32H47ClO4[M+H]+:521.2459,found 521.2441.
实施例22、化合物3v的合成
采用上述合成路线1的方法制备化合物3v,其中含有裸露羧基的衍生物为6-吲哚甲酸。
收率77%,1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.60(s,1H),7.39–7.33(m,1H),6.73(s,1H),6.68(d,J=7.8Hz,1H),6.46(d,J=11.9Hz,1H),6.19(t,J=11.3Hz,1H),6.06(d,J=8.1Hz,1H),5.33(t,J=10.3Hz,1H),4.99–4.76(m,2H),3.90(d,J=4.6Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.82(s,3H).ESI-HRMS:m/zcalculated for C34H39NO4[M+H]+:526.2957,found 526.2928.
实施例23、化合物3w的合成
采用上述合成路线1的方法制备化合物3w,其中含有裸露羧基的衍生物为7-喹啉甲酸。
收率85%,1H NMR(400MHz,CDCl3)δ9.22(s,1H),9.05(dd,J=4.3,1.7Hz,1H),8.65(d,J=1.9Hz,1H),8.34(ddd,J=19.5,8.7,1.8Hz,2H),8.20(d,J=8.8Hz,1H),7.60–7.49(m,1H),6.81(dd,J=6.5,2.4Hz,1H),6.51–6.44(m,1H),6.26–6.16(m,1H),6.08–6.03(m,1H),5.38(t,J=10.3Hz,1H),5.00–4.86(m,2H),3.38(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m/z calculatedfor C35H39NO4[M+H]+:538.2957,found 538.2937.
实施例24、化合物3x的合成
采用上述合成路线1的方法制备化合物3x,其中含有裸露羧基的衍生物为3,4-二甲氧基苯丙酸。
收率87%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),6.80(dd,J=20.2,8.2Hz,4H),6.33(d,J=11.7Hz,1H),6.16(t,J=11.3Hz,1H),6.08(s,1H),5.36(t,J=10.2Hz,1H),4.61(q,J=12.4Hz,2H),3.89(d,J=4.9,2.0Hz,6H),3.41(d,J=4.2Hz,1H),2.94(t,J=7.7Hz,2H),2.69(t,J=7.8Hz,2H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m/z calculated forC36H46O6[M+H]+:575.3373,found 575.3341.
实施例25、化合物3y的合成
采用上述合成路线1的方法制备化合物3y,其中含有裸露羧基的衍生物为1-金刚烷乙酸。
收率90%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),6.83(dd,J=6.4,2.4Hz,1H),6.33(d,J=11.6Hz,1H),6.16(t,J=11.3Hz,1H),6.06(t,J=1.6Hz,1H),5.34(t,J=10.2Hz,1H),4.58(q,J=12.7Hz,2H),3.40(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.31–2.27(m,1H),2.24(s,2H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,4H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,16H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.87(s,3H).ESI-HRMS:m/z calculated for C37H50NO4[M+H]+:559.3787,found 559.3739.
实施例26、化合物3z的合成
采用上述合成路线1的方法制备化合物3z,其中含有裸露羧基的衍生物为丁二酸酐。
收率89%,1H NMR(400MHz,CDCl3)δ9.17(s,1H),6.88(dd,J=6.8,2.3Hz,1H),6.31(d,J=11.5Hz,1H),6.13(dt,J=23.6,11.2Hz,1H),5.37–5.28(m,1H),4.13(d,J=7.9Hz,2H),3.31(d,J=4.3Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,4H),2.61–2.54(m,4H),2.31–2.27(m,1H),2.24(s,2H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,4H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,16H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.87(s,3H).ESI-HRMS:m/z calculated for C29H38O6[M+H]+:483.2747,found 483.2711.
路线2:
中间体2的合成:
中间体2的合成方法如路线1。
化合物X2的合成:
室温下,将中间体2(1.0mol)溶于二氯甲烷,缓慢加入Ag2O(2.0mol),最后加入不同卤代物(2.0mol),之后室温下搅拌三天,TLC板检测反应进行情况,反应完成后浓缩,柱层析分离纯化得到化合物X2。
实施例27、化合物x2的合成
采用上述合成路线2的方法制备化合物x2,其中卤代物为1-溴辛烷。
收率39%,1H NMR(400MHz,CDCl3)δ9.28(p,J=1.1Hz,1H),6.80(tq,J=7.3,1.8Hz,1H),6.08(p,J=1.6Hz,1H),6.09–6.00(m,2H),5.17(d,J=8.9Hz,1H),3.96(s,2H),3.47(d,J=9.5Hz,1H),3.40(t,J=6.2Hz,2H),2.73–2.60(m,2H),2.08(d,J=1.5Hz,3H),2.05–1.95(m,1H),1.94–1.83(m,2H),1.82–1.70(m,4H),1.57(tt,J=7.7,6.2Hz,2H),1.55–1.47(m,1H),1.49–1.39(m,2H),1.39–1.20(m,12H),1.00(dd,J=12.4,6.7Hz,1H),0.92(dt,J=6.2,1.2Hz,3H),0.90–0.83(m,6H).ESI-HRMS:m/z calculated for C33H51O3[M+H]+:495.3838,found 495.3814.
路线3:
中间体2的合成:
中间体2的合成方法如路线1。
化合物X3的合成:
将中间体2(0.5mol)和三苯基膦(PPh3,0.6mol)溶于无水DMF中,N2氛围下,使用针头缓慢滴加DMF溶解的二碘乙烷(0.6mol)溶液,最后加入不同类型的胺,室温反应12-24h,TLC检测反应情况,反应完成后加入二氯甲烷和饱和食盐水的混合溶液(1:1,v/v),萃取三次,合并有机相,加入无水硫酸钠干燥2h,浓缩,拌样,柱层析分离纯化得到化合物X3。
实施例28、化合物x3的合成
采用上述合成路线3的方法制备化合物x3,其中胺为3,4-二甲氧基苯乙胺。
收率46%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),6.84–6.76(m,2H),6.76(d,J=8.4Hz,1H),6.69(ddt,J=8.4,2.0,1.0Hz,1H),6.08(d,J=1.6Hz,1H),6.08–6.00(m,1H),6.02–5.96(m,1H),5.17(td,J=10.6,7.9,1.8,1.0Hz,1H),3.86(s,6H),3.47(dtt,J=9.7,1.8,0.8Hz,1H),3.22(dt,J=5.0,0.9Hz,2H),2.91(qd,J=5.0,4.1Hz,1H),2.86(td,J=5.5,4.4Hz,2H),2.73–2.60(m,4H),2.08(d,J=1.4Hz,3H),2.05–1.95(m,1H),1.94–1.83(m,2H),1.79–1.71(m,1H),1.70(t,J=1.2Hz,3H),1.55–1.47(m,1H),1.39–1.30(m,1H),1.30–1.20(m,3H),1.00(dd,J=12.4,6.7Hz,1H),0.92(dt,J=6.2,1.2Hz,3H),0.85(s,3H).ESI-HRMS:m/z calculated for C36H47NO5[M+H]+:574.3532,found 574.3515.
路线4:
取两口瓶,放入磁力搅拌子,在105℃下烘烤15min后,趁热装置,无水无氧操作,在通N2下,称取原料1溶于无水二氯甲烷,N2氛围下加入无水二氯甲烷溶解的原料1(1.0mol),随后加入Grubbs II(5%)催化剂和末端烯烃衍生物(3.0mol),最后加入Ti(OAc)4(1%),回流条件下反应12-24h,TLC检测反应进行情况,停止反应,加入二氯甲烷和饱和食盐水的混合溶液(1:1,v/v)萃取三次,合并有机相,加入无水硫酸钠干燥2h,浓缩,拌样,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物X4和X5,化合物X4和X5的质量比为1:1左右。
实施例29~30、化合物4a和4b的合成
采用上述合成路线4的方法制备化合物4a和4b,其中末端烯烃衍生物为丙烯酸正丁酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物4a和4b。
化合物4a:收率41%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),δ7.59(dd,J=15.1,11.7Hz,1H),6.79(dd,J=6.5,2.4Hz,1H),6.12(t,J=11.3Hz,1H),6.06(t,J=1.6Hz,1H),5.97(d,J=15.2Hz,1H),5.71(t,J=10.2Hz,1H),4.20(t,J=6.7Hz,2H),3.37(d,J=4.2Hz,1H).,2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.96(t,J=7.4Hz,3H),0.88(s,3H).13C NMR(101MHz,CDCl3)δ207.43,192.94,177.46,167.41,156.96,147.44,140.19,138.82,130.33,125.66,122.49,77.24,64.41,51.68,49.95,49.05,45.85,45.52,44.14,43.84,33.54,30.95,30.74,29.71,29.37,27.73,22.86,21.49,19.19,17.23,13.77.ESI-HRMS:m/z calculated for C28H38O4[M+H]+:439.2848,found438.2841.
化合物4b:收率45%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),δ7.00–6.88(m,1H),6.80(dd,J=6.6,2.5Hz,1H),6.06(s,1H),5.86(d,J=15.9Hz,1H),4.17(q,J=6.9Hz,1H),3.36(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.96(t,J=7.4Hz,3H),0.88(s,3H).13C NMR(101MHz,CDCl3)δ207.19,192.91,177.30,166.66,156.32,154.37,140.39,130.36,129.53,120.48,114.63,64.49,49.91,49.80,48.96,45.87,45.48,44.15,43.56,36.59,31.14,30.67,29.70,27.62,22.76,20.61,19.21,17.21,13.78.ESI-HRMS:m/zcalculated for C26H37O4[M+H]+:413.2692,found 413.2671.
实施例31~32、化合物5a和5b的合成
采用上述合成路线4的方法制备化合物5a和5b,其中末端烯烃衍生物为丙烯酸正戊酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物5a和5b。
化合物5a:收率43%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),7.59(dd,J=15.2,11.7Hz,1H),6.79(dd,J=6.3,2.5Hz,1H),6.13(d,J=11.2Hz,1H),6.06(s,1H),5.97(d,J=15.2Hz,1H),5.71(t,J=10.2Hz,1H),4.19(t,J=6.7Hz,2H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.38(m,2H)1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.96(t,J=7.4Hz,3H),0.88(s,3H).13C NMR(101MHz,CDCl3)δ192.93,181.84,176.83,157.71,147.55,138.82,128.72,126.32,123.15,109.22,65.26,51.69,49.95,49.06,45.86,45.53,44.15,43.85,38.16,33.54,29.72,28.39,28.13,27.74,22.86,22.36,21.50,17.24,14.01.ESI-HRMS:m/zcalculated for C29H40O4[M+H]+:453.3005,found 453.3001.
化合物5b:收率46%,1H NMR(400MHz,CDCl3)δ9.31(s,1H),6.93(dd,J=15.9,8.2Hz,1H),6.81(dd,J=6.4,2.3Hz,1H),6.07(s,1H),5.87(d,J=15.9Hz,1H),4.17(q,J=6.8Hz,2H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.38(m,2H)1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.96(t,J=7.4Hz,3H),0.88(s,3H).13C NMR(101MHz,CDCl3)δ207.19,192.93,177.28,166.67,156.31,154.37,140.41,130.38,120.49,77.23,64.80,49.92,49.80,48.96,45.88,45.49,44.16,43.57,36.60,31.15,29.71,29.39,28.31,28.11,27.62,22.77,22.37,20.62,17.22,14.00.ESI-HRMS:m/z calculated for C27H38O4[M+H]+:427.2848,found 427.2837.
实施例33~34、化合物6a和6b的合成
采用上述合成路线4的方法制备化合物6a和6b,其中末端烯烃衍生物为丙烯酸正已酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物6a和6b。
化合物6a:收率39%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),δ7.59(dd,J=15.1,11.6Hz,1H),6.79(dd,J=6.4,2.4Hz,1H),6.12(t,J=11.2Hz,1H),6.03(d,J=29.6Hz,1H),5.71(t,J=10.2Hz,1H),4.19(t,J=6.7Hz,2H),3.38(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.38(m,2H)1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.89(t,J=7.4Hz,3H),0.86(s,3H).13C NMR(101MHz,CDCl3)δ207.45,192.93,177.47,167.40,156.95,147.43,140.19,138.81,130.32,125.66,122.50,64.71,51.68,49.94,49.06,45.85,45.52,44.14,43.84,33.54,31.94,31.45,30.95,30.19,29.71,29.38,28.65,27.73,25.63,22.86,22.71,22.56,21.49,17.23,14.14,14.02.ESI-HRMS:m/z calculated for C30H42O4[M+H]+:467.3161,found 467.3157.
化合物6b:收率43%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),6.92(dd,J=15.8,8.2Hz,1H),6.81(dd,J=6.5,2.3Hz,1H),6.06(d,J=2.0Hz,1H),5.86(d,J=15.8Hz,1H),4.23–4.08(m,2H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.38(m,2H)1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.89(t,J=7.4Hz,3H),0.86(s,3H).13C NMR(101MHz,CDCl3)δ207.19,192.92,177.30,166.66,156.32,154.37,140.39,130.36,120.48,64.81,49.91,49.80,48.96,45.87,45.48,44.16,43.57,36.59,31.47,31.14,29.70,28.56,27.61,25.63,22.76,22.54,20.61,17.21,14.03.ESI-HRMS:m/z calculated for C28H40O4[M+H]+:441.3005,found 441.3001.
实施例35~36、化合物7a和7b的合成
采用上述合成路线4的方法制备化合物7a和7b,其中末端烯烃衍生物为丙烯酸正庚酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物7a和7b。
化合物7a:收率38%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),7.59(dd,J=15.2,11.7Hz,1H),6.81–6.78(m,1H),6.12(t,J=11.3Hz,1H),6.06(d,J=1.8Hz,2H),5.97(d,J=15.2Hz,1H),5.71(t,J=10.3Hz,1H),5.08–4.99(m,1H),4.19(t,J=6.8Hz,2H),3.37(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.90(t,J=7.4Hz,3H),0.86(s,3H).13C NMR(101MHz,CDCl3)δ206.80,193.92,178.57,167.12,159.44,148.98,140.92,139.19,130.31,128.72,125.59,121.89,121.24,114.61,66.69,63.90,53.44,49.60,48.24,43.83,32.88,30.95,30.10,26.93,24.53,19.93,17.22,14.12.ESI-HRMS:m/z calculated for C31H44O4[M+H]+:481.3318,found 481.3314.
化合物7b:收率42%,1H NMR(400MHz,CDCl3)δ9.31(s,1H),6.93(dd,J=15.8,8.2Hz,1H),6.81(dd,J=6.5,2.3Hz,1H),6.06(t,J=1.7Hz,1H),5.86(d,J=15.9Hz,1H),4.23–4.08(m,2H),3.37(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.74(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.64–1.58(m,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.90(t,J=7.4Hz,3H),0.94–0.86(m,6H).13C NMR(101MHz,CDCl3)δ207.20,192.93,177.30,166.67,156.33,154.37,140.40,130.37,120.49,64.82,49.91,49.80,48.96,45.88,45.48,44.16,36.60,31.73,31.15,29.71,28.96,28.61,27.62,26.55,26.43,25.93,25.83,25.64,22.77,22.60,20.61,17.22,14.09.ESI-HRMS:m/z calculated for C29H42O4[M+H]+:455.3161,found 455.3143.
实施例37~38、化合物8a和8b的合成
采用上述合成路线4的方法制备化合物8a和8b,其中末端烯烃衍生物为丙烯酸正辛酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物8a和8b。
化合物8a:收率37%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),7.59(dd,J=15.2,11.8Hz,1H),6.84(dd,J=6.6,2.5Hz,1H),6.11(t,J=11.4Hz,1H),6.06(s,2H),5.96(d,J=15.2Hz,1H),5.81–5.75(m,1H),5.10–4.96(m,2H),4.18(t,J=6.8Hz,1H),3.41(d,J=4.2Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,7H).13C NMR(101MHz,CDCl3)δ207.50,193.02,192.92,177.50,167.39,157.31,147.44,144.99,140.19,138.80,130.30,125.65,122.49,113.78,64.71,51.67,50.01,49.96,49.93,49.09,49.05,45.88,45.51,45.36,44.30,44.12,43.84,43.56,37.65,33.53,31.79,30.96,29.70,29.24,29.21,28.69,27.73,27.66,25.96,22.92,22.85,22.65,21.46,17.23,14.11.ESI-HRMS:m/z calculatedfor C32H46O4[M+H]+:495.3474,found 495.3467.
化合物8b:收率45%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),6.92(dd,J=15.8,8.2Hz,1H),6.80(dd,J=6.5,2.3Hz,1H),6.05(s,1H),5.85(d,J=15.8Hz,1H),4.15(q,J=6.9Hz,3H),3.36(d,J=4.1Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,7H).13C NMR(101MHz,CDCl3)δ207.16,192.90,177.29,166.65,156.32,154.36,140.38,130.34,120.47,64.80,49.90,49.79,48.95,45.86,45.47,44.14,43.56,36.58,31.79,31.13,29.24,29.18,28.59,27.61,26.87,26.76,26.20,26.03,25.96,22.75,22.64,20.60,17.20,14.10.ESI-HRMS:m/z calculated for C30H44O4[M+H]+:469.3318,found 469.3311.
实施例39~40、化合物9a和9b的合成
采用上述合成路线4的方法制备化合物9a和9b,其中末端烯烃衍生物为丙烯酸正壬酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物9a和9b。
化合物9a:收率42%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),7.59(dd,J=15.2,11.8Hz,1H),6.84(dd,J=6.6,2.5Hz,1H),6.12(t,J=11.2Hz,1H),6.06(d,J=2.2Hz,2H),5.97(d,J=15.2Hz,1H),5.70(t,J=8.6Hz,1H),5.12–4.98(m,2H),4.18(t,J=6.6Hz,2H),3.37(d,J=4.1Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,5H),1.18(t,J=13.1Hz,2H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,6H).13C NMR(101MHz,CDCl3)δ207.19,192.92,166.38,158.52,156.27,155.30,140.41,130.36,129.53,121.13,120.00,114.63,65.83,62.97,49.91,49.78,48.96,45.84,45.48,44.15,43.54,36.68,31.14,29.71,27.61,22.77,20.57,17.22,14.11.ESI-HRMS:m/z calculatedfor C33H48O4[M+H]+:509.3631,found 509.3634.
化合物9b:收率43%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),6.92(dd,J=15.8,8.2Hz,1H),6.80(dd,J=6.5,2.3Hz,1H),6.06(s,1H),5.86(d,J=15.9Hz,1H),4.15(q,J=6.9Hz,2H),3.36(d,J=4.2Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,5H),1.18(t,J=13.1Hz,2H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,6H).13C NMR(101MHz,CDCl3)δ207.20,192.93,177.30,166.66,156.37,154.37,140.39,130.36,120.49,64.83,49.91,49.79,48.95,45.87,45.49,44.15,43.55,36.61,31.94,31.87,31.15,29.71,29.50,29.31,29.27,28.61,27.62,25.98,22.77,22.69,20.63,17.23,14.14.ESI-HRMS:m/z calculated for C31H46O4[M+H]+:483.3474,found 483.3467.
实施例41~42、化合物10a和10b的合成
采用上述合成路线4的方法制备化合物10a和10b,其中末端烯烃衍生物为丙烯酸正癸酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物10a和10b。
化合物10a:收率36%,1H NMR(400MHz,CDCl3)δ9.31(s,1H),7.65–7.51(m,0H),7.00–6.91(m,1H),6.86–6.82(m,1H),6.80(d,J=2.4Hz,0H),6.07(d,J=1.8Hz,2H),5.90–5.81(m,1H),5.10–5.00(m,1H),4.22–4.14(m,2H),3.38(d,J=4.2Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,7H),1.18(t,J=13.1Hz,2H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,6H).13C NMR(101MHz,CDCl3)13C NMR(101MHz,CDCl3)δ207.24,192.94,177.34,166.67,156.38,154.38,147.44,144.99,140.38,130.36,120.49,64.84,49.91,49.79,48.95,45.86,45.48,44.15,43.55,36.61,31.91,31.14,29.71,29.56,29.54,29.32,29.31,28.61,27.62,25.98,22.77,22.69,20.63,17.23,14.17.ESI-HRMS:m/z calculated for C34H50O4[M+H]+:523.3787,found 523.3763.
化合物10b:收率41%,1H NMR(400MHz,CDCl3)δ9.31(s,1H),6.93(dd,J=15.9,8.2Hz,1H),6.81(dd,J=6.6,2.3Hz,1H),6.07(t,J=1.7Hz,1H),5.86(d,J=15.9Hz,1H),4.16(q,J=6.8Hz,3H),3.37(d,J=4.1Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,9H),1.18(t,J=13.1Hz,2H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,6H).13C NMR(101MHz,CDCl3)δ207.24,192.94,177.34,166.67,156.38,154.38,140.38,130.36,120.49,64.84,49.91,49.79,48.95,45.86,45.48,44.15,43.55,36.61,31.91,31.14,29.71,29.56,29.54,29.32,29.31,28.61,27.62,25.98,22.77,22.69,20.63,17.23,14.15.ESI-HRMS:m/z calculated for C32H48O4[M+H]+:497.3631,found 497.3627.
实施例43~44、化合物11a和11b的合成
采用上述合成路线4的方法制备化合物11a和11b,其中末端烯烃衍生物为丙烯酸三乙二醇甲醚酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物11a和11b。
化合物11a:收率26%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),7.61(dd,J=15.2,11.8Hz,1H),6.87–6.74(m,1H),6.12(t,J=11.2Hz,1H),6.06(s,1H),6.00(d,J=15.2Hz,1H),5.73(t,J=10.1Hz,1H),4.35(t,J=4.9Hz,2H),4.24(t,J=4.8Hz,2H),3.85–3.64(m,8H),3.37(d,J=4.1Hz,1H),3.31(s,3H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.89(s,3H).13C NMR(101MHz,CDCl3)δ207.38,192.93,171.74,167.20,156.89,147.80,140.21,139.31,130.32,125.63,122.06,70.64,70.55,69.33,63.64,62.92,51.67,49.94,49.05,48.84,45.85,45.53,44.13,33.58,30.95,28.62,27.74,22.86,21.52,17.22.ESI-HRMS:m/z calculated for C31H44O7[M+H]+:529.3165,found 529.3153.
化合物11b:收率31%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),6.97(dd,J=15.9,8.1Hz,1H),6.88–6.73(m,1H),6.06(t,J=1.7Hz,1H),5.91(d,J=15.9Hz,1H),4.33(dtd,J=12.1,7.5,4.8Hz,2H),4.25–4.20(m,2H),3.77(t,J=4.9Hz,2H),3.73–3.70(m,2H),3.68(s,4H),3.36(d,J=4.2Hz,1H),3.31(s,3H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.89(s,3H).13C NMR(101MHz,CDCl3)δ207.14,192.91,176.23,171.74,165.41,156.27,155.00,140.42,129.35,121.11,70.64,70.55,69.33,63.64,62.92,51.67,49.94,49.05,48.84,45.85,45.53,44.13,33.58,30.95,28.62,27.74,22.86,21.52,17.22.ESI-HRMS:m/z calculated for C29H42O7[M+H]+:503.3009,found 503.3007.
实施例45~46、化合物12a和12b的合成
采用上述合成路线4的方法制备化合物12a和12b,其中末端烯烃衍生物为丙烯酸金刚烷酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物12a和12b。
化合物12a:收率43%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),7.66–7.56(m,1H),6.79(dd,J=6.5,2.5Hz,1H),6.14(d,J=11.3Hz,1H),6.06(t,J=1.6Hz,1H),5.70(t,J=10.2Hz,1H),5.04(s,1H),3.38(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,5H),δ1.92(m,1H),1.85(s,3H),1.79(s,3H),1.75(m,8H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,3H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.88(s,3H).13C NMR(101MHz,CDCl3)δ207.41,192.93,181.85,177.42,166.69,156.94,147.19,140.20,138.53,130.32,129.31,128.56,126.05,125.67,123.22,51.69,49.94,49.06,45.87,45.50,44.15,43.91,37.41,36.36,33.50,31.96,31.85,31.00,29.70,29.37,27.73,27.28,27.02,22.86,22.70,21.47,17.21.ESI-HRMS:m/z calculated for C34H44O4[M+H]+:517.3318,found 517.3327.
化合物12b:收率47%,1H NMR(400MHz,CDCl3)δ9.31(s,1H),6.94(dd,J=15.8,8.3Hz,1H),6.82(dd,J=6.6,2.4Hz,1H),5.94–5.83(m,1H),5.02(d,J=3.2Hz,1H),3.37(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,5H),δ1.92(m,1H),1.85(s,3H),1.79(s,3H),1.75(m,8H),1.73–1.65(m,1H),1.55(dd,J=11.8,5.0Hz,3H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.88(s,3H).13C NMR(101MHz,CDCl3)δ207.15,192.94,177.25,165.99,156.33,154.03,140.40,130.37,121.11,49.91,49.85,48.96,45.87,45.46,44.17,43.64,37.41,36.57,36.35,36.32,31.95,31.83,31.80,31.22,29.70,29.37,27.60,27.29,27.02,22.78,22.70,20.66,17.20.ESI-HRMS:m/z calculated for C32H42O4[M+H]+:491.3161,found 491.3158.
实施例47~48、化合物13a和13b的合成
采用上述合成路线4的方法制备化合物13a和13b,其中末端烯烃衍生物为丙烯酸丙二醇金刚烷酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物13a和13b。
化合物13a:收率39,1H NMR(400MHz,CDCl3)δ9.29(s,1H),7.60(dd,J=15.3,11.8Hz,1H),6.80(dd,J=6.5,2.5Hz,1H),6.13(d,J=11.3Hz,1H),5.96(d,J=15.2Hz,2H),5.73(t,J=10.2Hz,1H),4.27(t,J=6.3Hz,2H),4.17(t,J=6.3Hz,2H),3.41(d,J=3.8Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,5H),1.97(m,3H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,17H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.86(s,3H).13C NMR(101MHz,CDCl3)δ214.18,192.57,171.64,166.07,156.28,147.92,141.98,138.81,132.26,126.99,122.10,61.79,60.74,51.03,49.95,48.94,46.13,45.38,43.65,42.97,36.35,33.56,33.18,30.77,29.72,29.04,27.61,27.31,22.86,21.74,17.90.ESI-HRMS:m/z calculated for C39H52O6[M+H]+:617.3842,found 617.3840.
化合物13b:收率45%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),6.94(dd,J=15.9,8.2Hz,1H),6.81(dd,J=6.4,2.1Hz,1H),6.06(s,1H),5.86(d,J=15.6Hz,1H),4.26(q,J=6.4Hz,2H),4.18(t,J=6.4Hz,2H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,5H),1.97(m,3H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,17H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.89(s,3H).13C NMR(101MHz,CDCl3)δ207.19,192.89,177.31,171.84,166.36,156.27,154.86,150.09,144.98,140.41,130.35,127.56,120.15,61.18,60.62,50.44,49.91,49.79,49.00,48.95,48.91,45.83,45.49,44.14,43.53,42.39,37.25,36.71,36.61,32.76,31.13,29.69,28.58,27.96,27.60,22.76,20.57,17.21.ESI-HRMS:m/z calculated for C37H50O6[M+H]+:591.3686,found 591.3681.
实施例49~50、化合物14a和14b的合成
采用上述合成路线4的方法制备化合物14a和14b,其中末端烯烃衍生物为丙烯酸辛醇金刚烷酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物14a和14b。
化合物14a:收率36%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),7.59(dd,J=15.2,11.8Hz,1H),6.84(dd,J=6.6,2.5Hz,1H),6.11(t,J=11.4Hz,1H),6.06(s,2H),5.96(d,J=15.2Hz,1H),5.81–5.75(m,1H),5.10–4.96(m,2H),4.18(t,J=6.8Hz,1H),3.41(d,J=4.2Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,3H),δ1.92(m,4H),1.82–1.54(m,18H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,7H).13C NMR(101MHz,CDCl3)δ207.50,193.02,192.92,177.50,167.39,157.31,147.44,144.99,140.19,138.80,130.30,125.65,122.49,113.78,64.71,51.67,50.01,49.96,49.93,49.09,49.05,45.88,45.51,45.36,44.30,44.12,43.84,43.56,37.65,33.53,31.79,30.96,29.70,29.24,29.21,28.69,27.73,27.66,25.96,22.92,22.85,22.65,21.46,17.23.ESI-HRMS:m/z calculated forC44H62O6[M+H]+:687.4625,found 687.4631.
化合物14b:收率38%,1H NMR(400MHz,CDCl3)δ9.31(s,1H),6.95(d,J=8.2Hz,0H),6.81(dd,J=6.5,2.3Hz,1H),6.06(q,J=1.5Hz,1H),5.86(d,J=15.8Hz,1H),4.05(t,J=6.7Hz,2H),3.37(d,J=4.2Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H)2.09(s,3H),2.08–2.03(m,4H),δ1.92(m,1H),1.82–1.54(m,18H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,7H).13C NMR(101MHz,CDCl3)δ207.23,192.93,177.35,172.03,166.65,156.40,154.44,140.38,130.35,120.44,64.73,64.04,49.91,49.78,49.08,48.95,45.85,45.49,44.15,43.53,42.41,42.33,36.75,36.61,32.74,31.14,29.71,29.19,29.10,28.65,28.61,27.62,25.95,25.90,22.77,20.64,17.24.ESI-HRMS:m/z calculated for C42H60O6[M+H]+:661.4468,found 661.4461.
实施例51~52、化合物15a和15b的合成
采用上述合成路线4的方法制备化合物15a和15b,其中末端烯烃衍生物为丙烯酸二乙二醇金刚烷酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物15a和15b。
化合物15a:收率39%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),7.61(dd,J=15.2,11.8Hz,1H),6.79(dd,J=6.5,2.5Hz,1H),6.11(s,1H),6.06(s,1H),6.00(d,J=15.2Hz,1H),5.73(t,J=10.3Hz,1H),4.35(td,J=4.4,2.2Hz,2H),4.25(dd,J=5.7,4.0Hz,2H),3.77(t,J=4.7Hz,2H),3.75–3.73(m,4H),3.41(d,J=3.8Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.87(s,3H).13C NMR(101MHz,CDCl3)δ207.40,192.92,177.43,171.72,167.16,156.87,147.87,140.22,139.37,130.32,125.61,121.97,69.26,69.08,63.58,62.84,51.67,49.94,49.06,48.82,45.85,45.53,45.44,44.13,43.83,42.35,36.73,33.58,32.80,31.44,30.95,29.70,29.66,28.60,27.73,22.85,21.52,17.22.ESI-HRMS:m/z calculated for C40H54O7[M+H]+:647.3948,found647.3931.
化合物15b:收率42%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),7.12–6.92(m,1H),6.81(d,J=5.7Hz,1H),6.06(d,J=2.1Hz,1H),5.88(dd,J=19.8,15.7Hz,1H),4.32(t,J=5.1Hz,2H),4.24(p,J=2.8Hz,2H),3.75(dq,J=15.7,4.6Hz,4H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.87(s,3H).13C NMR(101MHz,CDCl3)δ207.79,195.26,173.50,170.44,167.87,162.33,148.38,148.20,130.81,119.93,69.57,69.27,65.21,63.02,55.46,52.40,47.95,47.15,46.73,44.42,41.93,41.83,40.00,39.90,39.81,37.55,37.33,29.71,29.61,29.50,29.39,27.03,26.60,25.89,21.48,18.28.ESI-HRMS:m/z calculated for C38H52O7[M+H]+:621.3791,found 621.3787.
实施例53~54、化合物16a和16b的合成
采用上述合成路线4的方法制备化合物16a和16b,其中末端烯烃衍生物为丙烯酸三乙二醇金刚烷酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物16a和16b。
化合物16a:收率36%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),7.61(dd,J=15.2,11.8Hz,1H),6.87–6.74(m,1H),6.12(t,J=11.2Hz,1H),6.06(s,1H),6.00(d,J=15.2Hz,1H),5.73(t,J=10.1Hz,1H),4.35(t,J=4.9Hz,2H),4.24(t,J=4.8Hz,2H),3.85–3.64(m,8H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.89(s,3H).13C NMR(101MHz,CDCl3)δ207.38,192.93,177.41,171.74,167.20,156.89,147.80,140.21,139.31,130.32,125.63,122.06,70.64,70.55,69.33,63.64,62.92,51.67,49.94,49.05,48.84,45.85,45.53,44.13,43.83,42.35,36.74,33.58,32.79,30.95,29.71,28.62,27.74,22.86,21.52,17.22.ESI-HRMS:m/z calculated forC42H58O8[M+H]+:691.4210,found691.4211.
化合物16b:收率41%,1H NMR(400MHz,CDCl3)δ9.30(s,1H),6.97(dd,J=15.9,8.1Hz,1H),6.88–6.73(m,1H),6.06(t,J=1.7Hz,1H),5.91(d,J=15.9Hz,1H),4.33(dtd,J=12.1,7.5,4.8Hz,2H),4.25–4.20(m,2H),3.77(t,J=4.9Hz,2H),3.73–3.70(m,2H),3.68(s,4H),3.36(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.06(d,J=6.7Hz,3H),0.86(s,3H).13C NMR(101MHz,CDCl3)δ207.14,192.91,177.27,171.74,166.46,156.27,155.00,140.42,130.35,120.11,70.54,70.50,69.30,69.22,63.53,62.94,49.90,49.76,48.95,48.83,45.86,45.48,44.15,43.53,42.34,36.73,36.62,32.78,31.13,28.61,27.60,22.76,20.56,17.21.ESI-HRMS:m/z calculated for C40H57O8[M+H]+:665.4053,found 665.4051.
实施例55~56、化合物17a和17b的合成
采用上述合成路线4的方法制备化合物17a和17b,其中末端烯烃衍生物为丙烯酸四乙二醇金刚烷酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,分别得到化合物17a和17b。
化合物17a:收率35%,1H NMR(400MHz,CDCl3)δ9.31(s,1H),7.60(dd,J=15.2,11.8Hz,1H),6.85–6.74(m,1H),6.12(t,J=11.2Hz,1H),6.06(s,1H),6.00(d,J=15.2Hz,1H),5.73(t,J=10.1Hz,1H),4.35(t,J=4.9Hz,2H),4.24(t,J=4.8Hz,4H),3.85–3.64(m,10H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.95(d,J=6.7Hz,3H),0.91(s,3H).13C NMR(101MHz,CDCl3)δ207.38,192.93,177.41,171.74,167.20,156.89,147.80,140.21,139.31,130.32,125.63,122.06,73.58,70.64,70.55,69.33,65.35,63.64,62.92,51.67,49.94,49.05,48.84,45.85,45.53,44.13,43.83,42.35,36.74,33.58,32.79,30.95,29.71,28.62,27.74,22.86,21.52,17.22.ESI-HRMS:m/zcalculated for C44H62O9[M+H]+:735.4472,found 735.4461.
化合物17b:收率39%,1H NMR(400MHz,CDCl3)δ9.29(s,1H),6.91(dd,J=15.9,8.1Hz,1H),6.88–6.73(m,1H),6.06(t,J=1.7Hz,1H),5.91(d,J=15.9Hz,1H),4.33(dtd,J=12.1,7.5,4.8Hz,2H),4.25–4.20(m,2H),3.73–3.70(m,2H),3.68(m,10H),3.36(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.03(d,J=6.7Hz,3H),0.89(s,3H).13C NMR(101MHz,CDCl3)δ207.14,192.91,177.27,171.74,166.46,156.27,155.00,140.42,130.35,120.11,73.58,70.54,70.50,69.30,69.22,65.25,63.53,62.94,49.90,49.76,48.95,48.83,45.86,45.48,44.15,43.53,42.34,36.73,36.62,32.78,31.13,28.61,27.60,22.76,20.56,17.21.ESI-HRMS:m/z calculated for C42H60O9[M+H]+:703.4316,found 703.4311.
实施例57、化合物18的合成
取5mL茄形瓶,烘干,放入磁力搅拌子,加入路线4得到的化合物16a(20mg,1equiv.)溶于2mL无水乙醇中,冰浴条件下加入硼氢化钠(6mg,0.8equiv.),持续搅拌1.5h,点TLC板确认反应情况,反应结束后加入1mL水淬灭反应;真空旋出乙醇,加入10mL乙酸乙酯和10mL饱和食盐水,萃取,干燥,浓缩,柱层析分析,展开剂选择石油醚和乙酸乙酯(比例2:1)洗脱,最终得到9mg化合物18。
化合物18a:收率36%,1H NMR(400MHz,CDCl3)δ6.97(dd,J=15.9,8.1Hz,1H),6.88–6.73(m,1H),6.06(t,J=1.7Hz,1H),5.91(d,J=15.9Hz,1H),4.33(dtd,J=12.1,7.5,4.8Hz,2H),4.25–4.20(m,2H),3.77(t,J=4.9Hz,2H),3.73–3.70(m,2H),3.68(s,4H),3.36(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.06(d,J=6.7Hz,3H),0.86(s,3H).13C NMR(101MHz,CDCl3)δ210.28,180.00,166.75,159.07,155.90,137.46,132.24,130.14,119.63,72.26,69.31,67.74,65.26,62.99,53.23,50.78,49.77,48.85,46.34,45.03,43.35,42.34,36.73,36.38,32.80,31.95,31.64,29.73,29.69,29.64,29.40,28.60,22.73,17.17.ESI-HRMS:m/z calculated for C40H58O8[M+H]+:667.4210,found 667.4206.
路线5:
取两口瓶,放入磁力搅拌子,在105℃下烘烤15min后,趁热装置,无水无氧操作,在通N2下,称取原料4溶于无水二氯甲烷,N2氛围下加入无水二氯甲烷溶解的原料4(1.0mol),随后加入Grubbs II(5%)催化剂和末端烯烃衍生物(3.0mol),最后加入Ti(OAc)4(1%),回流条件下反应10h,TLC检测反应进行情况,停止反应,加入二氯甲烷和饱和食盐水的混合溶液(1:1,v/v)萃取三次,合并有机相,加入无水硫酸钠干燥2h,浓缩,拌样,柱层析分离纯化,最后化合物4可以反应完全,得到单一化合物X6。
实施例58、化合物x6的合成
采用上述合成路线5的方法制备化合物x6,其中末端烯烃衍生物为丙烯酸三乙二醇金刚烷酯,硅胶柱层析分离纯化,利用石油醚和乙酸乙酯混合溶液(石油醚和乙酸乙酯的体积比2:1)作为洗脱剂洗脱,得到化合物x6。
收率87%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),7.08(dt,J=16.1,6.2Hz,1H),6.86(tq,J=7.1,1.6Hz,1H),6.08(d,J=1.6Hz,1H),5.88(dt,J=15.9,0.9Hz,1H),4.39–4.32(m,4H),3.77–3.71(m,4H),3.65(s,4H),3.47(d,J=9.5Hz,1H),2.69(dtd,J=9.7,6.7,1.8Hz,1H),2.38(d,J=17.4Hz,1H),2.18–1.93(m,10H),1.80–1.73(m,1H),1.77–1.68(m,2H),1.60–1.47(m,13H),1.50–1.42(m,1H),1.45–1.32(m,1H),1.30–1.24(m,1H),1.27–1.20(m,2H),1.13(dtd,J=12.3,8.7,6.4Hz,1H),1.00(d,J=12.4,6.7Hz,3H),0.88(s,3H).13C NMR(101MHz,CDCl3)δ207.79,195.26,173.50,170.44,167.46,162.33,148.38,148.20,130.81,121.32,70.78,70.69,69.57,69.27,65.21,63.02,55.20,52.40,47.95,46.99,46.73,44.42,41.93,41.83,40.00,39.90,39.81,37.74,37.65,37.55,34.49,33.84,29.71,29.61,29.50,29.39,26.84,26.61,25.89,21.48,14.13.ESI-HRMS:m/zcalculated for C42H56O8[M+H]+:689.4210,found 689.4203.
实施例59、化合物x7的合成
将化合物1(1mmol)溶于二氯甲烷中,冰浴条件下,分批加入mCPBA(1mmol),搅拌30min,TLC点板检测反应,结束反应,加入饱和碳酸氢钠淬灭反应,直接加入硅胶拌样,柱层析分离,得到环氧异构体化合物(2:1)产物。
收率75%,1H NMR(400MHz,CDCl3)δ9.28(s,1H),6.84–6.76(m,1H),6.08(h,J=1.6Hz,1H),5.42(dd,J=3.8,1.9Hz,2H),3.63(tt,J=3.0,1.3Hz,1H),3.47(d,J=9.5Hz,1H),2.69(d,J=9.7Hz,1H),2.08(d,J=1.5Hz,3H),2.06–2.00(m,2H),2.00–1.95(m,1H),1.88(m,1H),1.79–1.70(m,1H),1.51(ddd,J=12.1,7.4,5.7Hz,1H),1.39–1.29(m,1H),1.29–1.20(m,9H),1.00(dd,J=12.4,6.7Hz,1H),0.88–0.82(m,6H).ESI-HRMS:m/zcalculated for C25H34O3[M+H]+:383.2586,found 383.2569.
以下为此发明部分化合物的生物活性评价,主要包括细胞水平和ERα蛋白降解水平两个方面。
试验例1、本发明部分化合物对多种癌细胞的增殖抑制活性
1、实验方法
以MTT法测定化合物对三种乳腺癌细胞(MCF-7、MDA-MB-231、MCF-7/ADR,MCF-7/ADR为对阿霉素耐药的乳腺癌细胞)的细胞毒性:细胞在含10%胎牛血清的有酚红DMEM液体培养基中培养。细胞密度至80%~90%时,消化细胞,并用含10%FCS的无酚红DMEM培养基将细胞悬浮液铺至96孔细胞培养板中。待细胞完全贴壁后,弃去原培养液,每孔加入100μl新鲜的不含10%FCS的DMEM培养基配制的化合物溶液(阳性对照为MHO7和ADR)。药物处理培养48h后,取出培养板,每孔加入20μl 5mg/ml MTT工作液,置于37℃、5%CO2培养箱中孵育4小时。之后吸去每孔液体,然后每孔加入100μl二甲亚砜(DMSO),放在微量搅拌器上震荡10分钟使结晶物充分溶解。在酶标仪上读板,选取490nm处波长为主波长,630nm处波长为参照波长,分析实验结果,并计算出IC50。
2、实验结果
本发明实施例合成的化合物对乳腺癌细胞的抗增殖活性见表1。
表1.本发明化合物对三种乳腺癌细胞的抗增殖活性结果(IC50,μM)a
a IC50值是至少三次独立实验的均值。
从实验结果看,本发明的大部分化合物都表现出了比改造前化合物MHO7天然产物更好的抗乳腺癌细胞增殖活性,同时对耐药细胞也表现出了较好的体外抑制增殖活性,体现出了该系列化合物在抗乳腺治疗中的优良潜力。其中,发现侧链为3个PEG链长的金刚烷基修饰时(16a),化合物的抗乳腺癌细胞增殖活性最好。
试验例2、本发明部分化合物对ERα蛋白降解的活性
1、实验样品及实验方法
被测样品溶液的配置:测试样品为本发明实施例化合物6a、7a、12a、12b、15a、15b、16a、16b、17a、17b。准确称取适量样品,用DMSO配置成所需浓度的溶液,供活性测试。实验用MCF-7细胞购自中国典型培养物保藏中心,使用含10%胎牛血清(FBS)的DMEM高糖培养基于37℃,5%浓度二氧化碳的条件下培养。
1.1MCF-7细胞处理
(1)取处于对数生长期的MCF-7细胞,经0.25%胰蛋白酶消化后用新鲜DMEM高糖培养基配置成细胞悬液,以每孔5×106个细胞左右密度接种于六孔板。
(2)加入含有药物的培养基,使终浓度符合测试组别设置,在37℃,5%浓度二氧化碳的条件下再培养24小时。
1.2细胞总蛋白提取
(1)移去培养基,用PBS清洗一遍,每个六孔板的孔加入1ml PBS,用细胞刮刀将皿底细胞刮散,将细胞悬液转入1.5ml塑料离心管中。
(2)将装有细胞悬液的离心管在4℃以4000rpm转速离心5分钟,弃去上清,每个离心管加入200μl的RIPA裂解液(biosha rp公司),用移液枪吹打,使沉淀溶解,在4℃以12000rpm转速离心15分钟,取上清为总蛋白提取液。
(3)加入6×SDS-PAGE样品缓冲液煮沸10分钟,室温12000×g离心10分钟,取10μl上清进行SDS-PAGE电泳。
1.3Western blot检测
(1)滤纸和膜的准备(在电泳结束前20分钟应开始准备工作)。具体包括:
1)配制足够量的1×转膜液;
2)准备合适大小的滤纸和膜;
3)将膜泡入甲醇中1~2分钟,再放入1×转膜液中;
4)将靠胶一侧滤纸和靠膜一侧的滤纸分别泡在1×转膜液中。
(2)转膜
1)先将黑色海绵铺在电转仪夹子上,上面放好三层滤纸;
2)在靠膜一侧滤纸上铺上膜,再在膜上倒一些转膜液,保持膜的湿润;
3)将胶剥出后切掉浓缩胶,将胶转移到膜上并做好记号标注胶的位;
4)在胶上放置一张靠胶滤纸,倒上一些转膜液,再铺两张靠胶滤纸;
6)装好电转仪,调节为恒压模式,电流400mA,时间1小时。
(3)封闭
将转好的膜放入5%的脱脂奶粉中,室温封闭1小时。
(4)孵育一抗
1)按照抗体说明书推荐比例用TBS与5%脱脂奶粉混合液(混合液比例为3:1)稀释抗体;
2)将膜放入稀释好的抗体中,4℃孵育过夜;
3)用TBST洗3次膜,每次8分钟。
(5)孵育二抗
1)按照1:10000的比例用TBST稀释一抗对应的二抗抗体;
2)将膜放入稀释好的抗体中,室温孵育1小时;
3)用TBST洗3次膜,每次8分钟。
(6)显色
1)将显色液A和B等体积混合;
2)将混合物加到膜表面,摇晃使均匀;
3)将膜用保鲜膜包起来,放入暗室中;
4)在暗室中每18s曝光一次,曝光总时间为30分钟。
2、结果分析
化合物6a、7a、12a、12b、15a、15b、16a、16b、17a、17b显影结果如图1,同时使用Image J软件对显影结果进行灰度分析,以各样品灰度值与空白对照组灰度值之比反应雌激素受体α的蛋白水平变化,与对照临床药物氟维司群相比,化合物6a和16a都显示出了良好的下调MCF-7中ERα蛋白水平的能力,这种能力有一定的浓度依赖性。
图2显示化合物16a在1μM时ERα蛋白下调水平超过90%。
试验例3、本发明化合物体外抗冠状病毒活性
1、病毒株:人冠状病毒OC43(HCoV-OC43)和人冠状病毒229E(HCoV-229E),由中国典型培养物保藏中心CCTCC提供。
2、细胞培养:以Vr1558细胞为例:在长满Vr1558细胞的培养瓶内加0.25%TrypsinEDTA 3ml,37℃消化1~2分钟,弃消化液,加培养液吹打,按1:3传代后于37℃,5%CO2培养,2-3天传代一次,种板时配制成每毫升15万个细胞,接种96孔细胞培养板,每孔0.1ml,37℃,5%CO2培养过夜,细胞长成单层后进行实验。
3、抗HCoV-OC43的活性测定(CPE法)
实验在传代Vr1558细胞中进行,细胞以1.5×104个/孔接种于96孔板中,过夜培养后将100TCID50 HCoV-OC43病毒液感染96孔板内细胞,待测药物用培养液液稀释,于感染同时给药进行测定,待测药物以三倍稀释8个剂量的样品进行实验,每个剂量设2个平行孔,待病毒对照组病变达4+号时观察结果,记录并用Reed-Muench法计算药物对病毒的半数抑制浓度,公式为:IC50=AntiLog(A+D×(B-50)/(50-C))。
其中:A=累积抑制率<50%的药物浓度,B=累积抑制率>50%的抑制率,C=累积抑制率<50%的抑制率,D=log稀释倍数。
4、抗HCoV-229E的活性测定(CPE法)
实验在传代Vr740细胞中进行,Vr740细胞1.5×104个/孔接种于96孔板中,过夜培养后将100TCID50 HCoV-229E病毒液感染96孔板内Vr740细胞,待测药物用维持液稀释,于感染同时给药进行测定,待测药物以三倍稀释8个剂量的样品进行实验,每个剂量设2个平行孔,待病毒对照组病变达4+号时观察结果,记录并用Reed-Muench法计算药物对病毒的半数抑制浓度,公式为:IC50=AntiLog(A+D×(B-50)/(50-C))及选择指数(SI=IC50/TC50)。其中:A=累积抑制率<50%的药物浓度,B=累积抑制率>50%的抑制率,C=累积抑制率<50%的抑制率,D=log稀释倍数。
CC50表示化合物细胞毒的抑制率(%)=[1-(E-N)/(P-N)]×100,其中“E”代表给药组的OD值,“P”代表未给药组的OD值,“N”代表空白组OD值。化合物的半数抑制浓度(CC50)作为该化合物细胞毒性的指标。
5、筛选结果
MHO7及本发明化合物对于两种人冠状病毒的抑制作用体外筛选结果见表2。受试药物:MHO7、化合物3m以及化合物16a三个化合物。
表2.本发明化合物抗人冠状病毒活性的结果
从表2中可以看出,化合物3m和16a对于两种冠状病毒都具有很好的抑制活性,且优于母核化合物MHO7。此外,化合物均表现出良好的选择性,CC50均大于100μg/ml,无明显毒副作用,可作为预防和治疗冠状病毒药物的一种新选择。
试验例4、化合物抑制乳腺癌细胞迁移
1、实验材料和试剂
乳腺癌细胞株:MDA-MB-231、MCF-7/ADR,购自武汉大学典型培养物保藏中心;
2、实验方法
取对数生长期细胞种于孔板中,待细胞长至70%以上,进行细胞划痕并进行化合物16a(0~2μM)干预,分别在给药前后拍照计算划痕面积,处理24小时后,进行transwell实验检测细胞侵袭的能力。
3、统计学分析
采用IBM SPSS 22.0软件进行统计学处理,所有计量数据以均值±标准差表示。
4、实验结果
根据图3和图4结果可知,经过24小时后,对照组(0μM)的划痕面积与0小时相比明显减小,即细胞愈合面积增大,而化合物16a能抑制MCF-7/ADR及MDA-MB-231细胞的迁移,降低细胞相对愈合面积。
综上,本发明提供了一类蛇胞假壳素类化合物结构修饰的方法,此类化合物可以有效抑制多种乳腺癌细胞的增殖活性,其中对三阴乳腺癌细胞和阿霉素耐药细胞均有良好的抑制增殖活性,也能够有效抑制它们的迁移;同时,此类化合物具有良好的雌激素受体α下调活性,显示了此类化合物在癌症治疗,特别是在乳腺癌治疗中的应用前景。此外,研究发现此类化合物对冠状病毒有良好的抑制活性,无明显毒副作用,可作为预防和治疗冠状病毒药物的一种新选择。
Claims (15)
1.式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药:
其中,
R1、R2、R3分别独立选自氢、C1~C8烷基、羟基或卤素;或者R3与R2连接形成双键,R1选自氢、C1~C8烷基、羟基或卤素;
R4、R5、R7、R8、R9、R10分别独立选自氢或C1~C8烷基;
R6选自氢、C1~C8烷基、羟基取代的C1~C8烷基或醛基;
R11、R12分别独立选自氢或C1~C8烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C8烷基;
m为0或1;
R15、R16、R17分别独立选自氢或C1~C8烷基;
R14选自取代或未取代的C1~C14烷基、取代或未取代的C1~C14烯基、取代或未取代的C1~C14炔基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂芳基、取代或未取代的3~6元杂环烷基、-CH=CHR18、金刚烷基、-(CH2)bOC(O)(CH2)cR18、-(CH2CH2O)bC(O)(CH2)cR18;
a为1~8的整数;
b为1~10的整数;
c为1~5的整数;
R18选自金刚烷基、取代或未取代的5~10元芳基、5~10元杂芳基;
所述烷基、烯基、炔基的取代基选自羧基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂环烷基、金刚烷;
所述芳基、杂芳基的取代基选自C1~C8烷基、C1~C8烷氧基、卤素、三氟甲基、硝基、三氟甲氧基、-C(O)CH=CHR19;
所述杂环烷基的取代基为C1~C8烷基;或者同一个碳原子上两个取代基连接形成=O;
所述杂芳基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
所述杂环烷基的杂原子个数为1、2或3个,所述杂原子选自O、S或N。
2.根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药,其特征在于:所述化合物为式II所示:
其中,
R1、R2、R3分别独立选自氢、C1~C8烷基、羟基或卤素;或者R3与R2连接形成双键,R1选自氢、C1~C8烷基、羟基或卤素;
R5选自氢或C1~C8烷基;
R6选自氢、C1~C8烷基、羟基取代的C1~C8烷基或醛基;
R11、R12分别独立选自氢或C1~C8烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C8烷基;
m为0或1;
R15、R16、R17分别独立选自氢或C1~C8烷基;
R14选自取代或未取代的C1~C14烷基、取代或未取代的C1~C14烯基、取代或未取代的C1~C14炔基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂芳基、取代或未取代的3~6元杂环烷基、-CH=CHR18、金刚烷基、-(CH2)bOC(O)(CH2)cR18、-(CH2CH2O)bC(O)(CH2)cR18;
a为1~8的整数;
b为1~10的整数;
c为1~5的整数;
R18选自金刚烷基、取代或未取代的5~10元芳基、5~10元杂芳基;
所述烷基、烯基、炔基的取代基选自羧基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂环烷基、金刚烷;
所述芳基、杂芳基的取代基选自C1~C8烷基、C1~C8烷氧基、卤素、三氟甲基、硝基、三氟甲氧基、-C(O)CH=CHR19;
所述杂环烷基的取代基为C1~C8烷基;或者同一个碳原子上两个取代基连接形成=O;
所述杂芳基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
所述杂环烷基的杂原子个数为1、2或3个,所述杂原子选自O、S或N。
3.根据权利要求2所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药,其特征在于:
R1、R2、R3分别独立选自氢、C1~C3烷基或羟基;或者R3与R2连接形成双键,R1选自C1~C3烷基;
R5选自氢;
R6选自C1~C3烷基、羟基取代的C1~C3烷基或醛基;
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
4.根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药,其特征在于:所述化合物为式III所示:
其中,
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式IV所示:
其中,
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
5.根据权利要求4所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药,其特征在于:所述化合物为式IIIa所示:
其中,
R14选自取代或未取代的C1~C6烷基、-CH=CHR18;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式IIIb所示:
其中,
R14选自取代或未取代的C1~C6烷基、-CH=CHR18;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式IVa所示:
其中,
R14选自-(CH2CH2O)bC(O)(CH2)cR18;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
R18选自金刚烷基;
或者,所述化合物为式IVb所示:
其中,
R14选自-(CH2CH2O)bC(O)(CH2)cR18;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
R18选自金刚烷基。
6.根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药,其特征在于:所述化合物为式V所示:
其中,
R11、R12分别独立选自氢或C1~C8烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C8烷基;
m为0或1;
R15、R16、R17分别独立选自氢或C1~C8烷基;
R14选自取代或未取代的C1~C14烷基、取代或未取代的C1~C14烯基、取代或未取代的C1~C14炔基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂芳基、取代或未取代的3~6元杂环烷基、-CH=CHR18、金刚烷基、-(CH2)bOC(O)(CH2)cR18、-(CH2CH2O)bC(O)(CH2)cR18;
a为1~8的整数;
b为1~10的整数;
c为1~5的整数;
R18选自金刚烷基、取代或未取代的5~10元芳基、5~10元杂芳基;
所述烷基、烯基、炔基的取代基选自羧基、取代或未取代的5~10元芳基、取代或未取代的5~10元杂环烷基、金刚烷;
所述芳基、杂芳基的取代基选自C1~C8烷基、C1~C8烷氧基、卤素、三氟甲基、硝基、三氟甲氧基、-C(O)CH=CHR19;
所述杂环烷基的取代基为C1~C8烷基;或者同一个碳原子上两个取代基连接形成=O;
所述杂芳基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
所述杂环烷基的杂原子个数为1、2或3个,所述杂原子选自O、S或N;
优选地,
R11、R12分别独立选自氢或C1~C3烷基;或者R11与R12连接形成双键;
n为0或1;
R13选自氢或C1~C3烷基;
m为0或1;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
7.根据权利要求6所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药,其特征在于:所述化合物为式Va所示:
其中,
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式Vb所示:
其中,
X为-O-或-NR15-;
R15选自氢或C1~C3烷基;
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式Vc所示:
其中,
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
或者,所述化合物为式Vd所示:
其中,
R14选自取代或未取代的C1~C12烷基、C1~C4烯基、C1~C4炔基、取代或未取代的苯基、萘基、-CH=CHR18、/>金刚烷基、-(CH2)bOC(O)(CH2)cR18或-(CH2CH2O)bC(O)(CH2)cR18;
a为1、2或3;
b为1、2、3、4、5、6、7或8;
c为1、2或3;
所述苯基的取代基选自C1~C3烷基、C1~C3烷氧基、卤素、三氟甲基、硝基、三氟甲氧基或-C(O)CH=CHR19;
13.权利要求1~8任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药在制备雌激素受体α降解剂中的用途。
14.权利要求1~8任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药在制备抗肿瘤药物和/或抗病毒药物中的用途;
优选地,所述肿瘤为乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、胰腺癌、直肠结肠癌、子宫颈癌、神经胶质瘤、膀胱癌、卵巢癌;
和/或,所述病毒为冠状病毒、HIV病毒、巨细胞病毒、EB病毒、腺病毒、疱疹病毒、人T淋巴细胞病毒、乙肝病毒、甲肝病毒。
15.一种药物,它是由权利要求1~8任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药为活性成分,加上药学上可接受的辅助性成分或辅料制备而成的制剂;
优选地,所述药物为抗肿瘤药物和/或抗病毒药物;
更优选地,所述肿瘤为乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、胰腺癌、直肠结肠癌、子宫颈癌、神经胶质瘤、膀胱癌、卵巢癌;
和/或,所述病毒为冠状病毒、HIV病毒、巨细胞病毒、EB病毒、腺病毒、疱疹病毒、人T淋巴细胞病毒、乙肝病毒、甲肝病毒。
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