CN112961041B - 儿茶酚类化合物及其制备方法和应用 - Google Patents

儿茶酚类化合物及其制备方法和应用 Download PDF

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CN112961041B
CN112961041B CN202110099768.9A CN202110099768A CN112961041B CN 112961041 B CN112961041 B CN 112961041B CN 202110099768 A CN202110099768 A CN 202110099768A CN 112961041 B CN112961041 B CN 112961041B
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祝诗发
曹同祥
王永东
黄志鹏
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GENIFARM (GUANGZHOU) TECHNOLOGY Inc
Xinyuan Guangzhou Pharmaceutical Research Co ltd
South China University of Technology SCUT
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Xinyuan Guangzhou Pharmaceutical Research Co ltd
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Abstract

本发明提供儿茶酚类化合物及其制备方法和应用。该类儿茶酚类化合物具有式(Ⅰ)或式(Ⅲ)结构。本发明还公开所述儿茶酚类化合物的制备方法，该方法原料来源广泛，操作简单，路线简短，无需金属催化，成本低，有潜在工业化的价值。本发明所述儿茶酚类化合物具备抑制PC3人***癌细胞增殖的活性，因此可以用于制备抗***癌药物。

Description

儿茶酚类化合物及其制备方法和应用
技术领域
本发明属于药物化学领域，具体涉及儿茶酚类化合物及其制备方法和应用。
背景技术
儿茶酚类化合物是一类带有邻二羟基骨架的化合物或其衍生物，其广泛存在于自然界，例如茶、果、豆类中的茶多酚、单宁，动物体内的肾上腺素和去甲肾上腺素，细菌中的铁载体(Enterobactin)，昆虫中的N-乙酰多巴胺等等。
Figure BDA0002915280680000011
儿茶酚类化合物由于其独特的结构，具有独特的生物活性，目前研究主要有清除机体内的自由基、抗氧化、延缓机体衰老、预防心血管***疾病、防癌、以及抗菌等生物活性功能。儿茶酚经过进一步修饰改性后还可应用在食品、化妆品、、分析化学、纳米技术和材料科学等领域。
现有的儿茶酚类化合物主要依赖于传统的合成方法制备，即以儿茶酚的苯环为骨架，再对苯环进行化学修饰。这些方法往往需要苛刻的反应条件、昂贵的试剂或对环境有害的金属催化剂，而且具有操作过程繁琐、反应区域选择性不高等缺点，极大地限制了对儿茶酚类衍生物的研究。
发明内容
本发明目的在于提供一系列新的儿茶酚类化合物。该儿茶酚类化合物具有新的母核结构，并且具有抑制PC3人***癌细胞增殖的活性。
本发明的另一目的在于提供所述儿茶酚类化合物的制备方法。
本发明的另一目的在于提供所述儿茶酚类化合物在制备抗***癌药物中的应用。
本发明上述目的通过如下技术方案予以实现：
儿茶酚类化合物，具有式(Ⅰ)或式(Ⅲ)结构：
Figure BDA0002915280680000021
其中，Ar选自苯环、吡啶环或二茂铁，R1选自甲醛基、甲羧基或其衍生的酯基、氰基、甲酰氧基；R2、R3独立选自氢、C1～6直链或支链烷基；R4选自C1～6直链或支链烷基或炔丙基；R5选自氢或卤素；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基、氰基、酯基、丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基；Z为-C(O)-、-N＝C-或-C＝C-。
作为一种具体的实现方式，所述儿茶酚类化合物(Ⅰ)可以是具有式(Ⅰ-Ⅰ)的结构：
Figure BDA0002915280680000022
其中，Ar选自苯环、吡啶环或二茂铁，R4选自C1～6直链或支链烷基或炔丙基；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基、氰基、酯基、丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基。
作为一种具体的实现方式，所述儿茶酚类化合物(Ⅰ)可以是具有式(Ⅰ-Ⅱ)的结构：
Figure BDA0002915280680000031
其中，Ar选自苯环、吡啶环或二茂铁，R2、R3独立选自C1～6直链或支链烷基；R4选自C1～6直链或支链烷基或炔丙基；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基、氰基、酯基、丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基。
作为一种具体的实现方式，所述儿茶酚类化合物可以是具有式(Ⅰ)的结构，且其中，Ar选自苯环、吡啶环或二茂铁，R1选自羧基、氰基、甲酰氧基；R2、R3独立选自C1～6直链或支链烷基；R4选自C1～6直链或支链烷基或炔丙基，R5为氢；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基、氰基、酯基、丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基。
作为一种优选方案，所述儿茶酚类化合物更优选具有式(Ⅰ)的结构，且其中，Ar选自苯环，R1选自甲醛基；R2、R3为氢或甲基；R4选自甲基，R5为氢或甲氧基；所述苯环上的取代基为-CF3、-F、-Br或丙烯酸乙酯基。具有这种结构的儿茶酚类化合物，表现出更好的抑制PC3人***癌细胞增殖的活性。
取代基定义和一般术语
本发明使用的术语“烷基”，表示含有1至6个碳原子，饱和的直链、支链或环状的一价烃基基团。在一实施方案中，烷基基团含有1-6个碳原子；在另一实施方案中，烷基基团含有1-3个碳原子。
术语“卤素”指氟、氯、溴、碘。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。
更具体优选的，作为发明可以制备的儿茶酚类化合物，部分列举如下：
Figure BDA0002915280680000041
本发明还提供上述儿茶酚类化合物的制备方法。
式(Ⅰ-Ⅰ)所述儿茶酚类化合物的制备，包括以下步骤：
S1.将式(Ⅱ)所述吡喃酮衍生物和醇类物质R4OH在第一溶剂中混合搅拌，加入醋酸碘苯反应；
S2.S1.反应结束后，除去第一溶剂，残余物加入第二溶剂后加热反应，得到式(Ⅰ-Ⅰ)所述儿茶酚类化合物；
所述第一溶剂为甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、二氯乙烷、乙腈中的一种或几种混合；
所述第二溶剂为乙腈、二氯乙烷、四氢呋喃、乙醇、异丙醇中的一种或几种混合；
Figure BDA0002915280680000051
优选地，当醇类物质R4OH与第一溶剂的成分不相同时，S1.中，式(Ⅱ)所述吡喃酮衍生物、醇类物质R4OH、醋酸碘苯的摩尔比优选为1:2～10:1～2。
优选地，当醇类物质R4OH与第一溶剂的成分相同时，S1.中，式(Ⅱ)所述吡喃酮衍生物、醋酸碘苯的摩尔比优选为1:1～2。
优选地，S1.中，反应温度优选为-30～60℃。
更优选地，S1.中，反应温度优选为-20～30℃。
优选地，S1.中，反应时间优选为0.1～2小时。
更优选地，S1.中，反应时间优选为0.3～1小时。
优选地，S2.中，反应温度优选为80～150℃。
优选地，S2.中，反应时间优选为1～12小时。
优选地，式(Ⅱ)所述吡喃酮衍生物通过如下方法制备：
Figure BDA0002915280680000061
S3.麦芽酚的羟基上引入保护基TBS，得到化合物M1；
S4.化合物M1与芳香醛ArCHO反应，得到化合物M2；
S5.化合物M2脱水反应，得到带烯键的化合物M3；
S6.化合物M3进行脱TBS保护，得到式(Ⅱ)所述吡喃酮衍生物。
优选地，S3.的反应可以如下进行：麦芽酚与咪唑在二氯甲烷中混合后加入TBSCl，反应后分离得到化合物M1。
优选地，S4.的反应可以如下进行：化合物M1溶于四氢呋喃中，-78℃加入LiHMDS，搅拌均匀后，加入芳香醛ArCHO继续反应，反应结束得到化合物M2。
优选地，S5.的反应可以如下进行：化合物M2与三乙胺在二氯甲烷中混合，0℃加入MsCl反应合适时间，然后加入DBU继续反应4h，反应结束得到化合物M3。
优选地，S6.的反应可以如下进行：化合物M3溶于二氯甲烷中，加入少量盐酸溶液，搅拌反应完全，反应结束后得到式(Ⅱ)所述吡喃酮衍生物。
式(Ⅰ-Ⅱ)所述儿茶酚类化合物的制备方法，包括以下步骤：
对式(Ⅰ-Ⅰ)所述儿茶酚类化合物进行烷基化，得到式(Ⅰ-Ⅱ)所述儿茶酚类化合物。
通常，这种烷基化是将式(Ⅰ-Ⅰ)所述儿茶酚类化合物与碱在有机溶剂中搅拌，然后加入烷基碘化物来实现。
另外，对式(Ⅰ-Ⅱ)所述儿茶酚类化合物的醛基进行官能化，得到Ar选自苯环、吡啶环或二茂铁，R1选自羧基、氰基、甲酰氧基R2、R3独立选自C1～6直链或支链烷基；R4选自C1～6直链或支链烷基或炔丙基，R5为氢的式(Ⅰ)所述儿茶酚类化合物。
式(Ⅲ)所述儿茶酚类化合物通过如下方法制备：
S7.制备3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛；
S8.对3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛的醛基进行修饰，得到式(Ⅲ)所述儿茶酚类化合物。
修饰的方法，可以参照现有技术，或按如下方法：
当Z＝-C＝C-时，将(甲氧基甲基)三苯基氯化磷加入无水四氢呋喃，在0℃下氮气保护下加入叔丁醇钾，搅拌，然后加入3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛进行反应。反应结束后进行后处理，取乙酸乙酯萃取物除去溶剂后得到残余物。残余物溶解于二氯甲烷，加入三氟甲磺酸持续反应、分离，得1,2,3-三甲氧基菲。
当Z＝-N＝C-时，往3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛中，加入醋酸铵、二氧化锰、醋酸和六氟异丙醇。加热至110℃反应。冷却至室温后分离得7,8,9-三甲氧基菲啶。
当Z＝-C(O)-时，取四乙基溴化铵、过硫酸钾，氮气保护下加入3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛和二氯乙烷。加热至120℃反应。冷却到室温后分离得1,2,3-三甲氧基-9H-芴-9-酮。本发明所述儿茶酚类化合物具备抑制PC3人***癌细胞增殖的活性，因此，所述儿茶酚类化合物可以用于制备抗***癌药物。
与现有技术相比，本发明具有如下有益效果：
本发明提供一系列新的儿茶酚类化合物，该类儿茶酚类化合物具备抑制PC3人***癌细胞增殖的活性，因此可以用于制备抗***癌药物。本发明还公开所述儿茶酚类化合物的制备方法，该方法原料来源广泛，操作简单，路线简短，无需金属催化，成本低，有潜在工业化的价值。
具体实施方式
如无特殊说明，本发明所用原料、试剂及溶剂，均为商业购买未经任何处理。为了更清楚地说明本发明，下面结合实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
Figure BDA0002915280680000071
3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-1)的制备
取原料(E)-3-羟基-2-苯乙烯基-4H-吡喃-4-酮(43mg，0.2mmol，1.0eq.)加入甲醇(2ml)，加入PIDA(65mg,1.0eq.)室温搅拌0.5小时。减压除去甲醇，残余物加入二氯乙烷(2ml)，加热130℃反应4小时。冷却后除去溶剂，经柱层析分离得到3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-1)。
浅黄色固体,m.p.＝115.2-118.3℃,Rf＝0.2(PE/EA＝1/1),29.3mg,产率60％；1HNMR(400MHz,CDCl3)δ12.14(s,1H),9.69(s,1H),7.51–7.40(m,5H),7.43–7.32(m,3H),6.51(s,1H),5.65(s,1H),4.00(s,3H).13C NMR(101MHz,CDCl3)δ196.09,152.10,150.36,140.23,137.52,132.36,130.14,128.40,128.19,113.31,105.61,56.41,56.38.IR(KBr,cm-1)3449,1627,1487,1348,1276,1117,1031,836,745,588.HRMS(ESI)m/z:[M+H]+Calcdfor C4H13O3 245.0810；found:245.0808.
实施例2
Figure BDA0002915280680000081
3,4-二羟基-5-甲氧基-4'-硝基-[1,1'-联苯]-2-甲醛(I-2)的制备
以(E)-3-羟基-2-(4-硝基苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得3,4-二羟基-5-甲氧基-4'-硝基-[1,1'-联苯]-2-甲醛(I-2)。
黄色固体,m.p.＝182.5-183.7℃,Rf＝0.21(PE/EA＝1/1),39.3mg,产率68％；1HNMR(400MHz,Acetone-d6)δ12.06(s,1H),9.69(s,1H),8.34(d,J＝8.7Hz,2H),7.77(d,J＝8.7Hz,2H),6.76(s,1H),4.01(s,3H).13C NMR(101MHz,Acetone-d6)δ195.26,153.09,151.46,147.59,144.66,136.81,134.19,131.48,123.25,112.99,106.30,55.97.IR(KBr,cm-1)3458,1633,1508,1402,1342,1244,1159,1102,843,602；HRMS(ESI)m/z:[M+Na]+Calcdfor C14H11NO6Na 312.0479；found:312.0472.
实施例3
Figure BDA0002915280680000082
3,4-二羟基-5-甲氧基-4'-(三氟甲基)-[1,1'-联苯]-2-甲醛(I-3)的制备
以(E)-3-羟基-2-(4-三氟甲基苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得3,4-二羟基-5-甲氧基-4'-(三氟甲基)-[1,1'-联苯]-2-甲醛(I-3)。黄色固体,m.p.＝157.5-158.6℃,Rf＝0.16(PE/EA＝1/1),42.5mg,产率68％；1H NMR(500MHz,CDCl3)δ12.01(s,1H),9.55(s,1H),7.64(d,J＝7.9Hz,2H),7.41(s,2H),6.40(s,1H),5.61(s,1H),3.92(s,3H).13C NMR(126MHz,CDCl3)δ195.26,152.10,150.54,141.22,138.32,132.98,130.47,130.44(q,J＝32.7Hz),125.37(q,J＝3.6Hz),123.97(q,J＝272.2Hz),113.17,105.70,56.47.19F NMR(471MHz,CDCl3)δ-62.62.IR(KBr,cm-1)3450,2982,1637,1405,1325,1200,1124,1018,833,734,584；HRMS(ESI)m/z:[M+Na]+Calcd for C15H11F3O3Na335.0502；found:335.0504.
实施例4
Figure BDA0002915280680000091
3,4-二羟基-5-甲氧基-4'-氰基-[1,1'-联苯]-2-甲醛(I-4)的制备
以(E)-3-羟基-2-(4-氰基苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得3,4-二羟基-5-甲氧基-4'-氰基-[1,1'-联苯]-2-甲醛(I-4)。
黄色固体,m.p.＝214.3-216.0℃,Rf＝0.15(PE/EA＝1/1),38.2mg,产率71％；1HNMR(400MHz,CDCl3)δ12.09(s,1H),9.64(s,1H),7.78(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),6.48(s,1H),5.65(s,1H),4.02(s,3H).13C NMR(101MHz,CDCl3)δ194.85,152.07,150.65,142.30,137.67,133.27,132.18,130.84,118.32,112.98,112.24,105.66,56.55.IR(KBr,cm-1)3224,1639,1551,1395,1267,1198,971,819,750,657；HRMS(ESI)m/z:[M+H]+Calcd for C15H12NO4 270.0763；found:270.0763.
实施例5
Figure BDA0002915280680000101
3,4-二羟基-5-甲氧基-4'-(甲磺酰基)-[1,1'-联苯]-2-甲醛(I-5)的制备
以(E)-3-羟基-2-(4-(甲磺酰基)苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得3,4-二羟基-5-甲氧基-4'-(甲磺酰基)-[1,1'-联苯]-2-甲醛(I-5)。
黄色固体,m.p.＝224.1-225.9℃,Rf＝0.12(PE/EA＝1/1),44.5mg,产率69％；1HNMR(500MHz,DMSO-d6)δ11.77(s,1H),9.64(s,1H),9.11(s,1H),8.00(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),6.67(s,1H),3.93(s,3H),3.28(s,3H).13C NMR(126MHz,DMSO-d6)δ195.22,153.71,151.67,143.35,140.44,136.87,134.08,131.53,127.30,113.29,107.03,56.72,44.02.IR(KBr,cm-1)3450,1633,1399,1385,1304,1195,1090,956,680,587,540；HRMS(ESI)m/z:[M+H]+Calcd for C15H15O6S 323.0579；found:323.0586.
实施例6
Figure BDA0002915280680000102
2'-甲酰-3'，4'-二羟基-5'-甲氧基-[1,1'-联苯]-4-羧酸甲酯(I-6)的制备
以(E)-3-羟基-2-(4-(甲酸甲酯基)苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2'-甲酰-3'，4'-二羟基-5'-甲氧基-[1,1'-联苯]-4-羧酸甲酯(I-6)。
黄色固体,m.p.＝165.0-166.7℃,Rf＝0.15(PE/EA＝1/1),36.3mg,产率60％；1HNMR(400MHz,CDCl3)δ12.11(s,1H),9.66(s,1H),8.13(d,J＝8.0Hz,2H),7.46(d,J＝7.9Hz,2H),6.51(s,1H),5.69(s,1H),4.02(s,3H),3.98(s,3H).13C NMR(101MHz,CDCl3)δ195.44,166.61,152.08,150.53,142.13,138.81,132.89,130.19,129.94,129.62,113.14,105.60,56.48,52.33.IR(KBr,cm-1)3675,2951,1720,1636,1496,1279,1106,869,780,586；HRMS(ESI)m/z:[M+H]+Calcd for C16H15O6303.0865；found:303.0873.
实施例7
Figure BDA0002915280680000111
4'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-7)的制备
以(E)-3-羟基-2-(4-氟苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得4'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-7)。
黄色固体,m.p.＝137.1-138.5℃,Rf＝0.2(PE/EA＝1/1),30.4mg,产率58％；1HNMR(400MHz,CDCl3)δ12.10(s,1H),9.64(s,1H),7.33(dd,J＝8.5,5.4Hz,2H),7.15(t,J＝8.6Hz,2H),6.46(s,1H),5.58(s,1H),3.99(s,3H).13C NMR(101MHz,CDCl3)δ195.71,162.77(d,J＝248.5Hz),152.08,150.39,138.99,133.49(d,J＝3.4Hz),132.49,131.71(d,J＝8.1Hz),115.45(d,J＝21.6Hz),113.37,105.66,56.42.19F NMR(376MHz,CDCl3)δ-113.56.IR(KBr,cm-1)3445,1634,1517,1496,1356,1275,1159,834,749,592；HRMS(ESI)m/z:[M+Na]+Calcd for C14H11FO4Na285.0534；found:285.0529.
实施例8
Figure BDA0002915280680000112
4'-氯-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-8)的制备
以(E)-3-羟基-2-(4-氯苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得4'-氯-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-8)。
黄色固体,m.p.＝129.6-131.2℃,Rf＝0.2(PE/EA＝1/1),30.7mg,产率55％；1HNMR(400MHz,CDCl3)δ12.09(s,1H),9.65(s,1H),7.43(d,J＝8.3Hz,2H),7.29(d,J＝8.3Hz,2H),6.45(s,1H),5.61(s,1H),3.99(s,3H).13C NMR(101MHz,CDCl3)δ195.55,152.10,150.46,138.72,135.94,134.52,132.64,131.34,128.64,113.23,105.58,56.42.IR(KBr,cm-1)3446,1635,1486,1399,1355,1275,1124,827,751,586；HRMS(ESI)m/z:[M+H]+Calcdfor C14H12ClO4 279.0420；found:279.0420.
实施例9
Figure BDA0002915280680000121
4'-溴-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-9)的制备
以(E)-3-羟基-2-(4-溴苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得4'-溴-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-9)。
黄色固体,m.p.＝143.8-144.9℃,Rf＝0.22(PE/EA＝1/1),38.8mg,产率60％；1HNMR(400MHz,CDCl3)δ12.11(s,1H),9.67(s,1H),7.61(d,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,2H),6.47(s,1H),5.59(s,1H),4.01(s,3H).13C NMR(101MHz,CDCl3)δ195.52,152.08,150.47,138.71,136.42,132.65,131.64,131.61,122.66,113.17,105.51,56.46.IR(KBr,cm-1)3444,1635,1510,1484,1396,1275,1159,1124,863,720,585；HRMS(ESI)m/z:[M+H]+Calcd for C14H12BrO4 322.9915；found:322.9912.
实施例10
Figure BDA0002915280680000122
4'-碘-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-10)的制备
以(E)-3-羟基-2-(4-碘苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得4'-碘-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-10)。
黄色固体,m.p.＝163.9-165.9℃,Rf＝0.2(PE/EA＝1/1),37.8mg,产率51％；1HNMR(500MHz,CDCl3)δ12.01(s,1H),9.57(s,1H),7.70(d,J＝8.0Hz,2H),7.02(d,J＝8.0Hz,2H),6.37(s,1H),5.61(s,1H),3.90(s,3H).13C NMR(126MHz,CDCl3)δ195.54,152.15,150.49,138.79,137.55,137.01,132.65,131.85,113.09,105.48,94.21,56.45.IR(KBr,cm-1)3446,2973,1635,1509,1394,1277,1159,1005,822,749,585；HRMS(ESI)m/z:[M+Na]+Calcd for C14H11IO4Na 392.9594；found:392.9587.
实施例11
Figure BDA0002915280680000131
4'-甲基-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-11)的制备
以(E)-3-羟基-2-(4-甲基苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得4'-甲基-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-11)。
黄色固体,m.p.＝98.2-99.8℃,Rf＝0.2(PE/EA＝1/1),16.0mg,产率31％；1H NMR(400MHz,CDCl3)δ12.11(s,1H),9.68(s,1H),7.24(s,4H),6.47(s,1H),5.57(s,1H),3.97(s,3H),2.42(s,3H).13C NMR(101MHz,CDCl3)δ196.16,152.12,150.36,140.31,138.14,134.61,132.24,130.02,129.09,113.39,105.57,56.34,21.15.IR(KBr,cm-1)2919,1633,1521,1446,1354,1268,1123,843,744,592；HRMS(ESI)m/z:[M+Na]+Calcd for C15H14O4Na281.0784；found:281.0780.
实施例12
Figure BDA0002915280680000132
3,4-二羟基-4'，5-二甲氧基-[1,1'-联苯]-2-甲醛(I-12)的制备
以(E)-3-羟基-2-(4-甲氧基苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得4'-甲氧基-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-12)。
黄色固体,m.p.＝110.0-112.3℃,Rf＝0.18(PE/EA＝1/1),8.4mg,产率15％；1HNMR(500MHz,CDCl3)δ12.12(s,1H),9.68(s,1H),7.28(d,J＝8.6Hz,2H),6.98(d,J＝8.5Hz,2H),6.47(s,1H),5.50(s,1H),3.98(s,3H),3.87(s,3H).13C NMR(126MHz,CDCl3)δ196.17,159.71,152.10,150.30,140.03,132.07,131.27,129.80,113.88,113.43,105.50,56.36,55.43.IR(KBr,cm-1)3449,1633,1496,1399,1246,1122,1030,785,658,582；HRMS(ESI)m/z:[M+Na]+Calcd for C15H14O5Na297.0733；found:297.0730.
实施例13
Figure BDA0002915280680000141
2'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-13)的制备
以(E)-3-羟基-2-(2-氟苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-13)。
黄色固体,m.p.＝126.3-128.5℃,Rf＝0.2(PE/EA＝1/1),28.3mg,产率54％；1HNMR(400MHz,CDCl3)δ12.04(s,1H),9.60(d,J＝2.9Hz,1H),7.50–7.40(m,1H),7.35(td,J＝7.5,1.7Hz,1H),7.27(t,J＝8.0Hz,1H),7.19(t,J＝9.0Hz,1H),6.50(s,1H),5.61(s,1H),4.00(s,3H).13C NMR(101MHz,CDCl3)δ195.52,159.66(d,J＝246.5Hz),152.15,150.29,132.97,132.81,132.16(d,J＝2.3Hz),130.45(d,J＝7.9Hz),125.00(d,J＝15.7Hz),124.37(d,J＝3.7Hz),115.82(d,J＝22.3Hz),113.34,106.33,56.42.19F NMR(376MHz,CDCl3)δ-114.82.IR(KBr,cm-1)3440,2945,1639,1511,1487,1356,1261,1127,803,586；HRMS(ESI)m/z:[M+Na]+Calcd for C14H11FO4Na 285.0534；found:285.0533.
实施例14
Figure BDA0002915280680000142
2'-氯-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-14)的制备
以(E)-3-羟基-2-(2-氯苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2'-氯-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-14)。
黄色固体,m.p.＝162.9-164.3℃,Rf＝0.18(PE/EA＝1/1),41.8mg,产率75％；1HNMR(400MHz,CDCl3)δ11.97(s,1H),9.45(s,1H),7.54–7.48(m,1H),7.38(ddt,J＝13.5,6.9,3.8Hz,3H),6.44(s,1H),5.60(s,1H),3.99(s,3H).13C NMR(101MHz,CDCl3)δ195.45,152.07,150.09,136.44,136.25,133.93,132.86,132.03,129.82,129.68,126.79,113.32,105.94,56.47.IR(KBr,cm-1)2943,1635,1508,1352,1253,1161,1054,773,586；HRMS(ESI)m/z:[M+Na]+Calcd for C14H11ClO4Na301.0238；found:301.0239.
实施例15
Figure BDA0002915280680000151
2'-溴-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-15)的制备
以(E)-3-羟基-2-(2-溴苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2'-溴-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-15)。
黄色固体,m.p.＝155.6-158.3℃,Rf＝0.2(PE/EA＝1/1),45.2mg,产率70％；1HNMR(400MHz,CDCl3)δ11.96(s,1H),9.44(s,1H),7.69(d,J＝8.0Hz,1H),7.42(t,J＝7.2Hz,1H),7.38–7.26(m,3H),6.42(s,1H),5.65(s,1H),3.99(s,3H).13C NMR(101MHz,CDCl3)δ195.46,152.04,150.04,138.24,138.20,132.84,131.94,129.95,127.34,124.25,113.22,105.85,56.48.IR(KBr,cm-1)3375,3010,1633,1471,1350,1222,1125,1030,746,619,588；HRMS(ESI)m/z:[M+H]+Calcd for C14H11BrO4 344.9733；found:344.9733.
实施例16
Figure BDA0002915280680000152
3'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-16)的制备
以(E)-3-羟基-2-(3-氟苯乙烯基)-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得3'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-16)。
黄色固体,m.p.＝124.9-126.3℃,Rf＝0.2(PE/EA＝1/1),34.1mg,产率65％；1HNMR(400MHz,CDCl3)δ12.09(s,1H),9.67(s,1H),7.42(q,J＝7.8Hz,1H),7.18–7.08(m,4H),6.48(s,1H),5.62(s,1H),4.00(s,3H).13C NMR(101MHz,CDCl3)δ195.61,162.50(d,J＝248.0Hz),152.04,150.41,139.69,138.59(d,J＝2.0Hz),132.72,129.94(d,J＝8.7Hz),126.06(d,J＝2.7Hz),117.08(d,J＝22.0Hz),115.18(d,J＝20.9Hz),113.18,105.55,56.43.19F NMR(376MHz,CDCl3)δ-112.44.IR(KBr,cm-1)2945,1637,1483,1267,1143,1029,793,744,590,524；HRMS(ESI)m/z:[M+Na]+Calcd for C14H11FO4Na 285.0534；found:285.0529.
实施例17
Figure BDA0002915280680000161
2’-氯-3,4-二羟基-5-甲氧基-5’-硝基-[1,1’-联苯]-2-甲醛(I-17)的制备
以(E)-2-(2-氯-5-硝基苯乙烯基)-3-羟基-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2’-氯-3,4-二羟基-5-甲氧基-5’-硝基-[1,1’-联苯]-2-甲醛(I-17)。黄色固体,m.p.＝189.3-192.1℃,Rf＝0.1(PE/EA＝1/1),30.4mg,产率47％；1H NMR(400MHz,CDCl3)δ11.90(s,1H),9.41(s,1H),8.30–8.22(m,2H),7.73–7.66(m,1H),6.42(s,1H),5.71(s,1H),4.00(s,3H).13C NMR(101MHz,CDCl3)δ194.12,152.23,150.40,146.39,141.07,137.94,133.73,133.64,130.67,126.70,124.56,112.96,105.97,56.63.IR(KBr,cm-1)3443,1640,1525,1445,1346,1278,1130,911,763,587；HRMS(ESI)m/z:[M+H]+Calcd forC14H11ClNO6 324.0271；found:324.0270.
实施例18
Figure BDA0002915280680000162
2'-溴-3,4-二羟基-5-甲氧基-5'-硝基-[1,1'-联苯]-2-甲醛(I-18)的制备
以(E)-2-(2-溴-5-硝基苯乙烯基)-3-羟基-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2’-溴-3,4-二羟基-5-甲氧基-5’-硝基-[1,1’-联苯]-2-甲醛(I-18)。黄色固体,m.p.＝179.4-180.4℃,Rf＝0.1(PE/EA＝1/1),35.3mg,产率48％；1H NMR 500MHz,DMSO-d6)δ10.08(s,1H),8.57(d,J＝2.2Hz,1H),8.19(d,J＝5.4Hz,1H),8.10–8.01(m,1H),7.98(d,J＝8.7Hz,1H),7.46(s,1H),7.46(s,1H),6.44(d,J＝5.4Hz,1H).13C NMR(126MHz,DMSO-d6)δ173.70,155.40,147.94,145.26,144.55,137.18,135.01,130.79,127.48,124.46,122.14,121.94,113.93.IR(KBr,cm-1)3440,1640,1524,1444,1347,1277,1164,1037,837,761,586；HRMS(ESI)m/z:[M+H]+Calcd for C14H11BrNO6 367.9766；found:367.9768.
实施例19
Figure BDA0002915280680000171
4’-氯-3,4-二羟基-5-甲氧基-3’-硝基-[1,1’-联苯]-2-甲醛(I-19)的制备
以(E)-2-(4-氯-3-硝基苯乙烯基)-3-羟基-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得4’-氯-3,4-二羟基-5-甲氧基-3’-硝基-[1,1’-联苯]-2-甲醛(I-19)。黄色固体,m.p.＝174.7-177.3℃,Rf＝0.1(PE/EA＝1/1),40.1mg,产率62％；1H NMR(400MHz,CDCl3)δ12.07(s,1H),9.66(s,1H),7.94–7.89(m,1H),7.67(d,J＝8.2Hz,1H),7.53(d,J＝8.2Hz,1H),6.49(s,1H),5.69(s,1H),4.03(s,3H).13C NMR(101MHz,CDCl3)δ194.39,152.16,150.74,147.87,137.60,135.71,134.50,133.52,131.85,127.09,126.50,113.02,105.84,77.35,56.64.IR(KBr,cm-1)3450,1632,1519,1354,1153,1047,838,751,605；HRMS(ESI)m/z:[M+H]+Calcd for C14H11ClNO3 324.0271；found:324.0272.
实施例20
Figure BDA0002915280680000172
5’-氯-3,4-二羟基-5-甲氧基-2’-硝基-[1,1’-联苯]-2-甲醛(I-20)的制备
以(E)-2-(5-氯-2-硝基苯乙烯)-3-羟基-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得5’-氯-3,4-二羟基-5-甲氧基-2’-硝基-[1,1’-联苯]-2-甲醛(I-20)。黄色固体,m.p.＝157.4-158.8℃,Rf＝0.1(PE/EA＝1/1),51.8mg,产率80％；1H NMR(400MHz,CDCl3)δ11.84(s,1H),9.48(s,1H),8.01(d,J＝8.7Hz,1H),7.59(dd,J＝8.7,1.8Hz,1H),7.43(d,J＝1.9Hz,1H),6.34(s,1H),5.72(s,1H),3.94(s,3H).13C NMR(101MHz,CDCl3)δ193.82,152.00,150.47,147.68,138.99,134.04,133.51,133.00,132.92,129.73,125.84,113.48,104.89,56.56.IR(KBr,cm-1)3443,2978,1640,1525,1344,1278,1130,899,753,589；HRMS(ESI)m/z:[M+H]+Calcd for C14H11ClNO6 324.0271；found:324.0266.
实施例21
Figure BDA0002915280680000181
2'-溴-5'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-21)
以(E)-2-(2-溴-5-氟苯乙烯基)-3-羟基-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2'-溴-5'-氟-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-21)。黄色固体,m.p.＝172.1-174.7℃,Rf＝0.18(PE/EA＝1/1),42.9mg,产率63％；1H NMR(500MHz,CDCl3)δ11.91(s,1H),9.43(s,1H),7.63(dd,J＝8.7,5.3Hz,1H),7.10(dd,J＝8.5,2.8Hz,1H),7.05(td,J＝8.4,2.8Hz,1H),6.39(s,1H),5.69(s,1H),3.98(s,3H).13C NMR(126MHz,CDCl3)δ194.97,161.51(d,J＝249.6Hz),152.07,150.14,140.03(d,J＝7.9Hz),136.91,134.09(d,J＝8.2Hz),133.20,119.08(d,J＝22.9Hz),118.63(d,J＝3.6Hz),117.23(d,J＝22.1Hz),112.95,105.69,56.50.19F NMR(376MHz,CDCl3)δ-114.20.IR(KBr,cm-1)3434,2974,1629,1508,1443,1337,1252,1186,1122,919,720；HRMS(ESI)m/z:[M+Na]+Calcd forC14H10BrFO4Na 362.9639；found:362.9644.
实施例22
Figure BDA0002915280680000182
2'-溴-4'-氯-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-22)的制备
以(E)-2-(2-溴-4-氯苯乙烯基)-3-羟基-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2'-溴-4'-氯-3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-22)。黄色固体,m.p.＝92.7-93.6℃,Rf＝0.20(PE/EA＝1/1),45.8mg,产率64％；1H NMR(400MHz,CDCl3)δ11.92(s,1H),9.42(s,1H),7.70(d,J＝1.8Hz,1H),7.39(dd,J＝8.2,1.7Hz,1H),7.27(d,J＝7.6Hz,1H),6.37(s,1H),5.65(s,1H),3.97(s,3H).13C NMR(101MHz,CDCl3)δ194.97,152.06,150.16,136.90,136.80,135.18,133.12,132.52,132.47,127.66,124.70,113.16,105.88,56.48.IR(KBr,cm-1)2975,1641,1470,1354,1279,1162,1042,867,767,588；HRMS(ESI)m/z:[M+Na]+Calcd for C14H10BrClO4Na 378.9343；found:378.9334.
实施例23
Figure BDA0002915280680000191
2,3-二羟基-4-甲氧基-6-(吡啶-3-基)苯甲醛(I-23)的制备
以(E)-2-(3-吡啶基)-3-羟基-4H-吡喃-4-酮盐酸盐代替实施例1的原料，其余操作一致，得2,3-二羟基-4-甲氧基-6-(吡啶-3-基)苯甲醛(I-23)。
棕色固体,m.p.＝185.6-187.9℃,Rf＝0.1(PE/EA＝1/2),18.6mg,产率38％；1HNMR(500MHz,DMSO-d6)δ11.77(s,1H),9.63(s,1H),9.07(s,1H),8.65(s,1H),8.63(d,J＝4.2Hz,1H),7.89(d,J＝7.8Hz,1H),7.49(dd,J＝7.7,4.9Hz,1H),6.66(s,1H),3.93(s,3H).13C NMR(126MHz,DMSO-d6)δ195.13,153.87,151.74,150.46,149.22,138.01,135.10,133.92,123.63,113.50,107.24,56.73.IR(KBr,cm-1)2961,1631,1508,1478,1397,1188,1049,860,712,633；HRMS(ESI)m/z:[M+H]+Calcd for C13H12NO4 246.0763；found:246.0763.
实施例24
Figure BDA0002915280680000192
2,3-二羟基-4-甲氧基-6-二茂铁基-苯甲醛(I-24)的制备
以(E)-3-羟基-2-二茂铁基-4H-吡喃-4-酮代替实施例1的原料，其余操作一致，得2,3-二羟基-4-甲氧基-6-二茂铁基-苯甲醛(I-24)。
棕色固体,m.p.＝172.7-175.8℃,Rf＝0.18(PE/EA＝1/1),5.6mg,产率8％；1H NMR(400MHz,CDCl3)δ12.21(s,1H),10.26(s,1H),6.97(s,1H),5.44(s,1H),4.46(t,J＝1.7Hz,2H),4.38(t,J＝1.8,0.6Hz,2H),4.17(s,5H),4.05(s,3H).13C NMR(126MHz,CDCl3)δ195.94,151.74,150.19,137.09,131.47,113.92,106.57,84.32,71.07,69.87,68.90,56.18.IR(KBr,cm-1)3451,1632,1470,1399,1276,1128,821,743,584；HRMS(ESI)m/z:[M+H]+Calcd for C18H17FeO4 353.0473；found:353.0474.
实施例25
Figure BDA0002915280680000201
5-乙氧基-3,4-二羟基-[1,1'-联苯]-2-甲醛(I-25)的制备
取原料(E)-3-羟基-2-苯乙烯基-4H-吡喃-4-酮(43mg，0.2mmol，1.0eq.)加入乙醇(2ml)，加入PIDA(65mg,1.0eq.)室温搅拌0.5小时。减压除去乙醇，残余物加入二氯乙烷(2ml)，加热130℃反应4小时。冷却后除去溶剂，经柱层析分离得到3,4-二羟基-5-乙氧基-[1,1'-联苯]-2-甲醛(I-25)。
黄色固体,m.p.＝135.6-137.4℃,Rf＝0.2(PE/EA＝1/1),33.5mg,产率65％；1HNMR(400MHz,CDCl3)δ12.14(s,1H),9.68(s,1H),7.37(s,2H),6.50(s,1H),5.62(s,1H),4.25(q,J＝6.8Hz,2H),1.52(t,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)δ196.04,151.48,150.49,140.13,137.59,132.42,130.14,128.38,128.15,113.23,106.31,65.02,14.77.IR(KBr,cm-1)3445,1626,1486,1422,1337,1219,1117,987,785,590.HRMS(ESI)m/z:[M+Na]+Calcd for C15H14O4Na 281.0784；found:281.0780.
实施例26
Figure BDA0002915280680000202
3,4-二羟基-5-异丙氧基-[1,1'-联苯]-2-甲醛(I-26)的制备
取原料(E)-3-羟基-2-苯乙烯基-4H-吡喃-4-酮(43mg，0.2mmol，1.0eq.)加入异丙醇(2ml)，加入PIDA(65mg,1.0eq.)室温搅拌0.5小时。加热130℃反应4小时。冷却后除去溶剂，经柱层析分离得到3,4-二羟基-5-异丙氧基-[1,1'-联苯]-2-甲醛(I-26)。
黄色固体,m.p.＝125.7-127.2℃,Rf＝0.22(PE/EA＝1/1),29.9mg,产率55％；1HNMR 1H NMR(400MHz,CDCl3)δ12.16(s,1H),9.68(s,1H),7.49–7.43(m,3H),7.40–7.33(m,2H),6.49(s,1H),5.57(s,1H),4.77(dq,J＝11.8,5.9Hz,1H),1.45(s,3H),1.44(s,3H).13CNMR(101MHz,CDCl3)δ195.95,150.77,150.51,139.93,137.63,133.05,130.14,128.37,128.11,113.12,107.39,72.00,22.19.IR(KBr,cm-1)3446,1622,1445,1421,1264,1174,1003,741,590.HRMS(ESI)m/z:[M+Na]+Calcd for C15H16O4Na 295.0941；found:295.0938.
实施例27
Figure BDA0002915280680000211
3,4-二羟基-5-(炔丙基氧基)-[1,1'-联苯]-2-甲醛(I-27)的制备
取原料(E)-3-羟基-2-苯乙烯基-4H-吡喃-4-酮(43mg，0.2mmol，1.0eq.)加入炔丙醇(2ml)，加入PIDA(65mg,1.0eq.)室温搅拌0.5小时。加热130℃反应4小时。冷却后除去溶剂，经柱层析分离得到3,4-二羟基-5-(炔丙基氧基)-[1,1'-联苯]-2-甲醛(I-27)。
黄色固体,m.p.＝88.7-91.2℃,Rf＝0.2(PE/EA＝1/1),16.0mg,产率30％；1H NMR(400MHz,CDCl3)δ12.16(s,1H),9.69(s,1H),7.49–7.42(m,3H),7.38–7.34(m,2H),6.62(s,1H),5.61(s,1H),4.88(d,J＝2.4Hz,2H),2.58(t,J＝2.4Hz,1H).13C NMR(101MHz,CDCl3)δ196.20,150.76,149.75,139.71,137.32,132.97,130.17,128.45,128.24,113.71,107.33,56.93.IR(KBr,cm-1)3446,1630,1484,1397,1277,1166,1112,1026,741,565；HRMS(ESI)m/z:[M+Na]+Calcd for C16H12O4Na291.0628；found:291.0623.
实施例28
Figure BDA0002915280680000221
3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(I-28)的制备
取按实施例1制得的3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛(I-1)(0.8g，1.0eq.)加入碳酸钾(2.27g，5.0eq.)、乙腈(20ml)、碘甲烷(1.39g，3.0eq.)，加热至75℃反应4小时。反应冷却至室温，过滤后除去溶剂，残余物经柱层析分离得到3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(I-28)。
无色液体，Rf＝0.2(PE/EA＝8/1),794mg,产率89％；1H NMR(500MHz,CDCl3)δ9.93(s,1H),7.41(q,J＝5.2Hz,3H),7.31(d,J＝7.6Hz,2H),6.64(s,1H),4.00(s,3H),3.93(s,6H).13C NMR(126MHz,CDCl3)δ190.23,156.97,155.34,142.76,141.69,139.06,129.55,128.19,127.89,121.84,109.87,62.24,61.15,56.20.IR(KBr,cm-1)3446,2939,2848,1688,1585,1485,1339,1251,1124,1013,778,703；HRMS(ESI)m/z:[M+H]+Calcd for C16H17O4273.1123；found:273.1117.
实施例29
Figure BDA0002915280680000222
3,4,5-三甲氧基-[1,1'-联苯]-2-羧酸(I-29)的制备
取按实施例28制得的3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(165mg,1.0eq.)、磷酸二氢钾(330mg,4.0eq.)、1,1,2-三甲基乙烯((0.4mL)，加入叔丁醇/水(3mL/1mL)，滴入亚氯酸钠(164mg,3.0eq.)，室温搅拌3小时。反应结束后加入饱和氯化铵溶液(10ml)，用乙酯萃取(5*10ml)。有机相合并后经饱和食盐水洗涤，硫酸钠干燥。除去溶剂后经柱层析分离得3,4,5-三甲氧基-[1,1'-联苯]-2-羧酸(I-29)。粘稠液体，Rf＝0.1(PE/EA＝1/2),168.1mg,产率96％；1H NMR(500MHz,CDCl3)δ7.42–7.34(m,5H),6.66(s,1H),3.98(s,3H),3.92(s,3H),3.90(s,3H).13C NMR(126MHz,CDCl3)δ171.38,154.65,151.45,141.25,140.09,136.87,128.40,128.26,127.66,119.84,109.44,62.12,61.02,56.17.IR(KBr,cm-1)3439,2982,1699,1594,1348,1251,1110,1024,783,703,585；HRMS(ESI)m/z:[M+Na]+Calcd forC16H16O5Na 311.0890；found:311.0886.
实施例30
Figure BDA0002915280680000231
2-氰基-3,4,5-三甲氧基-[1,1'-联苯](I-30)的制备
取按实施例28制得的3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(55mg,1.0eq.)溶于二氯甲烷(2ml)，室温加入二氯化铁(2.6mg,0.1eq.)、过硫酸钾(82mg,1.5eq.)、碘化钠(1.5mg,0.05eq.)和氨水(0.8ml)，50℃搅拌18小时。将反应倒入水(10ml)中，二氯甲烷(3*10ml)萃取。有机相合并后经饱和食盐水洗涤，硫酸钠干燥。除去溶剂后经柱层析分离得2-氰基-3,4,5-三甲氧基-[1,1'-联苯](I-30)。
无色液体，m.p.＝107.5-108.3℃,Rf＝0.25(PE/EA＝5/1),46mg，收率85％；1H NMR(500MHz,CDCl3)δ7.52(d,J＝7.1Hz,2H),7.45(dt,J＝13.7,7.0Hz,3H),6.71(s,1H),4.09(s,3H),3.94(s,3H),3.91(s,3H).13C NMR(126MHz,CDCl3)δ157.20,156.40,142.59,140.90,138.17,128.69,128.67,128.65,116.06,108.73,98.82,61.92,61.22,56.32.IR(KBr,cm-1)3686,3056,2304,1589,1353,1263,1197,1118,950,903,850；HRMS(ESI)m/z:[M+H]+Calcd for C16H16NO3 270.1126；found:270.1124
实施例31
Figure BDA0002915280680000232
2-甲酰氧基-3,4,5-三甲氧基-[1,1'-联苯](I-31)的制备
取按实施例28制得的3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(31mg,1.0eq.)，加入二氯甲烷(2ml)、间氯过氧苯甲酸(29.5mg,1.5eq.)，室温搅拌4小时。加入水(5ml)，乙酸乙酯(3*5ml)萃取，有机相合并后经饱和食盐水洗涤，硫酸钠干燥。除去溶剂后经柱层析分离得2-甲酰氧基-3,4,5-三甲氧基-[1,1'-联苯](I-31)。无色液体,Rf＝0.2(PE/EA＝5/1),31.1mg,收率95％；1H NMR(500MHz,CDCl3)δ8.09(s,1H),7.43–7.33(m,5H),6.67(s,1H),3.95(s,3H),3.92(s,3H),3.88(s,3H).13C NMR(126MHz,CDCl3)δ159.40,151.66,145.74,142.15,136.96,133.95,130.24,129.05,128.96,128.41,127.71,108.16,61.19,61.12,56.23.IR(KBr,cm-1)3462,2943,1961,1746,1578,1413,1255,1184,1041,956,845；HRMS(ESI)m/z:[M+Na]+Calcd for C16H16O5Na 311.0890；found:311.0885.
实施例32
Figure BDA0002915280680000241
3,3'-(5'-甲酰基-2'，3'，4'-三甲氧基-[1,1'-联苯]-2,6-二基)-二丙烯酸二乙酯(I-32)的制备
取按实施例28制得的3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(55mg,0.2mmol，1.0eq.)，氮气保护下加入丙烯酸乙酯(88μl,0.8mmol)、乙酸钯(4.5mg,0.02mmol)、L-叔亮氨酸(10.6mg,0.08mmol)、碳酸银(223m g,0.8mmol)、六氟异丙醇(2ml)和醋酸(0.5ml)。60℃反应72小时，反应结束后加入二氯甲烷稀释，经短硅胶过滤后蒸除溶剂，残余物经柱层析分离得3,3'-(5'-甲酰基-2'，3'，4'-三甲氧基-[1,1'-联苯]-2,6-二基)-二丙烯酸二乙酯(I-32)。
粘稠液体,Rf＝0.2(PE/EA＝5/1),54.3mg,收率68％；1H NMR(400MHz,CDCl3)δ10.03(s,0H),7.72(d,J＝7.8Hz,1H),7.44(t,J＝7.9Hz,1H),7.25(d,J＝15.9Hz,1H),6.39(s,0H),6.30(d,J＝15.9Hz,1H),4.16(q,J＝7.1Hz,2H),4.07(s,1H),4.00(s,1H),3.87(s,1H),1.25(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ188.64,166.52,157.88,157.43,141.97,141.42,135.34,133.83,128.11,127.56,122.47,120.11,110.52,62.55,61.20,60.43,56.37,14.20.IR(KBr,cm-1)3503,2978,1713,1632,1557,1330,1251,1172,1069,913,795；HRMS(ESI)m/z:[M+Na]+Calcd for C26H28O8Na 491.1676；found:491.1676.
实施例33
Figure BDA0002915280680000251
6-溴-3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(I-33)的制备
取按实施例28制得的3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(55mg,0.2mmol)，加入乙腈(2ml)、NBS(72mg,0.4mmol)。反应室温搅拌24小时。蒸除溶剂，残余物经柱层析分离得6-溴-3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(I-33)。
粘稠液体,Rf＝0.2(PE/EA＝8/1),43.9mg,收率62％；1H NMR(400MHz,CDCl3)δ9.74(s,1H),7.51–7.40(m,3H),7.25–7.16(m,2H),4.05(s,3H),4.01(s,3H),4.00(s,3H).13CNMR(101MHz,CDCl3)δ189.96,155.09,154.68,146.78,141.37,137.48,129.78,128.21,128.16,126.35,115.26,62.39,61.35,61.18.IR(KBr,cm-1)3525,3362,2938,1698,1464,1337,1245,1111,1003,783,699；HRMS(ESI)m/z:[M+Na]+Calcd for C16H15BrO4Na373.0046；found:373.0047.
实施例34
Figure BDA0002915280680000252
1,2,3-三甲氧基菲(III-1)的制备
(甲氧基甲基)三苯基氯化磷(139mg,0.4mmol)加入无水四氢呋喃(2ml)，在0℃下氮气保护下加入叔丁醇钾(139mg,0.4mmol)。继续搅拌1小时，随后加入按实施例28制得的3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(55mg,0.2mmol)。反应结束后加入饱和氯化铵溶液(10ml)，乙酸乙酯(3*5ml)萃取，有机相合并后经饱和食盐水洗涤，硫酸钠干燥。除去溶剂后残余物溶解于二氯甲烷(2ml)，加入三氟甲磺酸(0.05ml)继续反应24小时。蒸除溶剂，残余物经柱层析分离得1,2,3-三甲氧基菲(III-1)。
无色液体,m.p.＝75.6-76.7℃,Rf＝0.25(PE/EA＝8/1),30.0mg,收率55％；1H NMR(400MHz,CDCl3)δ8.53(d,J＝8.2Hz,1H),8.02(d,J＝9.1Hz,1H),7.86(d,J＝8.0Hz,1H),7.83(s,1H),7.65(d,J＝9.0Hz,1H),7.60(t,J＝7.6Hz,2H),7.55(t,J＝6.8Hz,1H),4.08(s,3H),4.07(s,3H),4.01(s,3H).13C NMR(101MHz,CDCl3)δ153.07,148.95,141.34,132.09,129.57,128.73,127.22,126.24,126.21,124.86,124.74,122.56,122.01,120.26,99.39,61.65,61.22,61.08,56.03.IR(KBr,cm-1)3461,2981,2869,1640,1495,1281,1071,913,820,765,559；HRMS(ESI)m/z:[M+H]+Calcd for C17H17O3 269.1174；found:269.1172.
实施例35
Figure BDA0002915280680000261
7,8,9-三甲氧基菲啶(III-2)的制备
取按实施例28制得的3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(55mg,0.2mmol)，加入醋酸铵(23.3mg,0.3mmol)、二氧化锰(52.7mg,0.6mmol)、醋酸(48.6mg,0.8mmol)和六氟异丙醇。加热至110℃36小时。冷却至室温后用短硅胶柱过滤，蒸除溶剂，残余物经柱层析分离得7,8,9-三甲氧基菲啶(III-2)。
无色液体,m.p.＝98.7-100.2℃,Rf＝0.3(PE/EA＝2/1),47.8mg,收率88％；1H NMR(500MHz,CDCl3)δ9.49(s,1H),8.40(d,J＝8.2Hz,1H),8.17(d,J＝8.2Hz,1H),7.71–7.66(m,1H),7.64(s,1H),7.60(t,J＝7.6Hz,1H),4.13(s,3H),4.10(s,3H),4.00(s,3H).13C NMR(126MHz,CDCl3)δ157.16,150.39,147.51,144.15,141.19,130.29,129.82,128.46,126.61,123.42,122.05,116.40,97.76,62.03,61.27,56.15.IR(KBr,cm-1)3378,2942,1709,1599,1479,1374,1277,1116,956,884,832；HRMS(ESI)m/z:[M+Na]+Calcd forC16H15NO3Na 292.0944；found:292.0944.
实施例36
Figure BDA0002915280680000262
1,2,3-三甲氧基-9H-芴-9-酮(III-3)的制备
取四乙基溴化铵(4.2mg,0.1eq.)、过硫酸钾(109mg,2.0eq.)，氮气保护下加入3,4,5-三甲氧基-[1,1'-联苯]-2-甲醛(55mg,0.2mmol)和二氯乙烷(2ml)。反应加热至120℃36小时。冷却到室温后蒸除溶剂，残余物经柱层析分离得1,2,3-三甲氧基-9H-芴-9-酮(III-3)。
黄色固体,m.p.＝100.2-102.4℃,Rf＝0.25(PE/EA＝8/1),26.3mg,收率48％；1HNMR(400MHz,CDCl3)δ7.60(d,J＝7.4Hz,4H),7.48–7.39(m,3H),7.29–7.22(m,5H),6.85(s,4H),4.14(s,11H),4.01(s,12H),3.88(s,11H).13C NMR(101MHz,CDCl3)δ190.53,159.22,153.56,142.87,142.06,142.03,135.18,133.84,128.76,123.65,119.34,118.10,99.97,62.14,61.41,56.47.IR(KBr,cm-1)3446,2938,1702,1607,1479,1244,1122,973,761,636,573；HRMS(ESI)m/z:[M+H]+Calcd for C16H14O4 271.0967；found:271.0966.
其他实施例以(E)-3-羟基-2-苯乙烯基-4H-吡喃-4-酮为原料制备3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛，改变氧化剂的用量和反应温度、时间，其余操作同实施例1，具体如表1所示。
表1
实施例 S1反应条件 S2反应条件 收率(％)
37 PIDA(1.0eq.)，-30℃，2h 120℃，12h 22
38 PIDA(1.2eq.)，-20℃，2h 120℃，12h 42
39 PIDA(2.0eq.)，-20℃，2h 120℃，12h 37
40 PIDA(1.0eq.)，-20℃，0.3h 130℃，4h 61
41 PIDA(1.0eq.)，28℃，0.3h 130℃，4h 63
42 PIDA(1.0eq.)，28℃，0.3h 100℃，8h 60
43 PIDA(1.0eq.)，60℃，0.1h 130℃，4h 50
44 PIDA(1.0eq.)，28℃，0.3h 150℃，1h 58
45 PIDA(1.0eq.)，28℃，0.3h 80℃，12h 49
以(E)-3-羟基-2-苯乙烯基-4H-吡喃-4-酮为原料制备3,4-二羟基-5-甲氧基-[1,1'-联苯]-2-甲醛，改变醇的类型、比例、溶剂，其余操作同实施例1，具体如表2所示。
表2
Figure BDA0002915280680000271
Figure BDA0002915280680000281
实施例48～53中，醇同时作为第一溶剂中的混合成分，其用量记载在第一溶剂中。
实施例54
吡喃酮衍生物(II)的合成
3-羟基-2-苯乙烯基-4H-吡喃-4-酮
Figure BDA0002915280680000282
(1)取麦芽酚(0.1mol，1.0eq.)和咪唑(0.25mol，2.5eq.)，加入二氯甲烷(200ml)，加入TBSCl(0.11mol，1.1eq.)。室温搅拌至TLC监测反应完全。反应液经短硅胶过滤后旋除溶剂，经柱层析分离得到化合物M1(22.1g，92％)。
(2)取化合物M1(0.96g,4mmol,1.0eq.)，加入干燥的四氢呋喃(12ml)，冷却至-78℃，加入LiHMDS(4.4mmol,1.1eq.,1M in THF)，反应45分钟，随后加入苯甲醛(4.4mmol，1.1eq.)继续反应6小时。反应结束后用饱和氯化铵溶液(10ml)淬灭，用乙酸乙酯(2*10ml)萃取，有机相合并后经饱和食盐水洗涤，柱层析分离得到化合物M2(1.16g，84％)。
(3)取化合物M2(1.04g，3mmol，1.0eq.)、三乙胺(2.5eq.)加入干燥的二氯甲烷(15ml)，0℃下加入MsCl(1.05eq.)。反应在室温搅拌3小时后加入DBU(3.0eq.)。继续反应4小时，反应结束后将反应液加入到饱和氯化铵溶液中(20ml)淬灭，用乙酸乙酯(2*15ml)萃取，有机相合并后经饱和食盐水洗涤，柱层析分离得到化合物M3(0.8g，85％)。
(4)取M3(0.75g，1.0eq.)加入干燥二氯甲烷(15ml)，加入浓盐酸(0.5ml)，室温搅拌10分钟，除去溶剂后残余物加入四氢呋喃(3ml)，所得浆液超声5分钟，过滤即可得(E)-3-羟基-2-苯乙烯基-4H-吡喃-4-酮(0.38g，78％)。
1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.12(d,J＝5.3Hz,1H),7.64(d,J＝7.4Hz,2H),7.40(t,J＝7.2Hz,2H),7.34(t,J＝6.9Hz,1H),7.26(s,2H),6.40(d,J＝5.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ173.50,154.98,146.51,143.16,136.17,132.02,129.42,129.37,127.65,116.05,113.80.
更多实施例
吡喃酮衍生物(II)的制备以不同的芳基醛代替实施例37中的苯甲醛，其余操作一致，可以制备得到一系列吡喃酮衍生物，具体结构和表征数据如表3所示。
表3
Figure BDA0002915280680000291
Figure BDA0002915280680000301
Figure BDA0002915280680000311
Figure BDA0002915280680000321
Figure BDA0002915280680000331
Figure BDA0002915280680000341
Figure BDA0002915280680000351
实施例77
测试儿茶酚类化合物(100uM与10uM)对PC3人***细胞增殖的影响
(1)细胞处理：收集人***细胞PC3，胰酶消化，200g离心5min，弃上清，PBS清洗一次，培养基重悬细胞，计数并调整为2×104/mL，以100μl/孔将细胞种于96孔板中。
(2)药物处理：使用培养基将10mM的母液稀释为100μm与10μm处理细胞，每个浓度2个复孔，培养基稀释DMSO作为对照，37℃，5％CO2培养72h。
(3)MTT检测：待测孔加入100μL 5mg/mL的MTT溶液，于培养箱中孵育1.5h，显微镜下观察有蓝紫色甲瓒结晶，吸弃上清液，每孔加入100μl DMSO溶解结晶，平板震荡10min，使用酶标仪测量550nm处吸光值，计算细胞的相对成活率。
选取部分儿茶酚类化合物作为检测代表，具体结果见表4，其中恩杂鲁胺Enzalutamide为对照样品。
表4
Figure BDA0002915280680000361
Figure BDA0002915280680000371
由上可见，本发明代表性儿茶酚类化合物表现出对PC3人***癌细胞的抑制作用，大部分优于对照品恩杂鲁胺的效果，具有重大的药物研发潜力，可作为先导化合物用于新型抗***癌药物的研发。
实施例78
在实施例77的实验结果基础上，挑选在低浓度下活性表现更佳的儿茶酚类化合物(I-3,I-13,I-21,I-32)深入测试其对PC3人***细胞增殖的影响
(1)细胞处理：收集人***细胞PC3，胰酶消化，200g离心5min，弃上清，PBS清洗一次，培养基重悬细胞，计数并调整为2×104/mL，以100μL/孔将细胞种于96孔板中。
(2)药物处理：使用培养基将10mM的母液稀释为800μM，加入第一列待处理细胞中，使用排枪轻轻混匀，以2倍梯度稀释到3.125μM，每个浓度3个复孔，培养基稀释DMSO作为对照，37℃，5％CO2培养72h。
(3)MTT检测：待测孔加入100μL 5mg/mL的MTT溶液，于培养箱中孵育1.5h，显微镜下观察有蓝紫色甲瓒结晶，吸弃上清液，每孔加入100μl DMSO溶解结晶，平板震荡10min，使用酶标仪测量550nm处吸光值，计算细胞的相对成活率。
具体结果见表5。
表5
Figure BDA0002915280680000381
Figure BDA0002915280680000391
由表可见，儿茶酚类化合物(I-3,I-13,I-21,I-32)对PC3人***癌细胞的具有明显的抑制作用，其IC50在12.5～25uM左右，具有重大的药物研发潜力，可作为先导化合物用于新型抗***癌药物的研发。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (9)

1.儿茶酚类化合物，其特征在于，具有式(Ⅰ)结构：
Figure FDA0003577219940000011
其中，Ar选自苯环，R1选自甲醛基、氰基、甲酰氧基；R2、R3独立选自氢、C1～6直链或支链烷基；R4选自C1～6直链或支链烷基；R5选自氢或卤素；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基、丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基。
2.根据权利要求1所述儿茶酚类化合物，其特征在于，所述儿茶酚类化合物具有式(Ⅰ-Ⅰ)的结构：
Figure FDA0003577219940000012
其中，Ar选自苯环R4选自C1～6直链或支链烷基；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基。
3.根据权利要求1所述儿茶酚类化合物，其特征在于，所述儿茶酚类化合物具有式(Ⅰ-Ⅱ)的结构：
Figure FDA0003577219940000013
其中，Ar选自苯环R2、R3独立选自C1～6直链或支链烷基；R4选自C1～6直链或支链烷基；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基、丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基。
4.根据权利要求1所述儿茶酚类化合物，其特征在于，所述儿茶酚类化合物具有式(Ⅰ)的结构，其中，Ar选自苯环，R1选自氰基、甲酰氧基；R2、R3独立选自C1～6直链或支链烷基；R4选自C1～6直链或支链烷基，R5为氢；所述Ar上的任意一个或多个氢可以被取代基取代，所述取代基独立选自硝基、丙烯酸乙酯基、卤素、直链或支链被一个或多个卤素取代或非取代的C1～6烷基或烷氧基。
5.权利要求2所述儿茶酚类化合物的制备方法，其特征在于，包括以下步骤：
S1.将式(Ⅱ)所述吡喃酮衍生物和醇类物质R4OH在第一溶剂中混合搅拌，加入醋酸碘苯反应；
S2.S1.反应结束后，除去第一溶剂，残余物加入第二溶剂后加热反应，得到式(Ⅰ-Ⅰ)所述儿茶酚类化合物；
所述第一溶剂为甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、二氯乙烷、乙腈中的一种或几种混合；
所述第二溶剂为乙腈、二氯乙烷、四氢呋喃、乙醇、异丙醇中的一种或几种混合；
Figure FDA0003577219940000021
6.根据权利要求5所述儿茶酚类化合物的制备方法，其特征在于，式(Ⅱ)所述吡喃酮衍生物通过如下方法制备：
Figure FDA0003577219940000022
S3.麦芽酚的羟基上引入保护基TBS，得到化合物M1；
S4.化合物M1与芳香醛ArCHO反应，得到化合物M2；
S5.化合物M2脱水反应，得到带烯键的化合物M3；
S6.化合物M3进行脱TBS保护，得到式(Ⅱ)所述吡喃酮衍生物。
7.权利要求3所述儿茶酚类化合物的制备方法，其特征在于，包括以下步骤：
对式(Ⅰ-Ⅰ)所述儿茶酚类化合物进行烷基化，得到式(Ⅰ-Ⅱ)所述儿茶酚类化合物。
8.权利要求4所述儿茶酚类化合物的制备方法，其特征在于，包括以下步骤：
对式(Ⅰ-Ⅱ)所述儿茶酚类化合物的醛基进行官能化，得到权利要求4所述儿茶酚类化合物。
9.权利要求1-4任一项所述儿茶酚类化合物在制备抗***癌药物中的应用。
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