CN112961041A - 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

Info

Publication number
CN112961041A
CN112961041A CN202110099768.9A CN202110099768A CN112961041A CN 112961041 A CN112961041 A CN 112961041A CN 202110099768 A CN202110099768 A CN 202110099768A CN 112961041 A CN112961041 A CN 112961041A
Authority
CN
China
Prior art keywords
formula
alkyl
compound
catechol
biphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202110099768.9A
Other languages
English (en)
Other versions
CN112961041B (zh
Inventor
祝诗发
曹同祥
王永东
黄志鹏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GENIFARM (GUANGZHOU) TECHNOLOGY Inc
Xinyuan Guangzhou Pharmaceutical Research Co ltd
South China University of Technology SCUT
Original Assignee
GENIFARM (GUANGZHOU) TECHNOLOGY Inc
Xinyuan Guangzhou Pharmaceutical Research Co ltd
South China University of Technology SCUT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GENIFARM (GUANGZHOU) TECHNOLOGY Inc, Xinyuan Guangzhou Pharmaceutical Research Co ltd, South China University of Technology SCUT filed Critical GENIFARM (GUANGZHOU) TECHNOLOGY Inc
Priority to CN202110099768.9A priority Critical patent/CN112961041B/zh
Publication of CN112961041A publication Critical patent/CN112961041A/zh
Application granted granted Critical
Publication of CN112961041B publication Critical patent/CN112961041B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/44—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C07D221/12—Phenanthridines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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人前列腺癌细胞增殖的活性，因此可以用于制备抗前列腺癌药物。

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、预防心血管系统疾病、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人前列腺癌细胞增殖的活性。
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前列腺癌药物中的应用。
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人前列腺癌细胞增殖的活性。
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人前列腺癌细胞增殖的活性，因此，所述儿茶酚类化合物可以用于制备抗前列腺癌药物。
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人前列腺癌细胞增殖的活性，因此可以用于制备抗前列腺癌药物。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人前列腺细胞增殖的影响
(1)细胞处理：收集人前列腺细胞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人前列腺癌细胞的抑制作用，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前列腺癌药物的研发。
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人前列腺细胞增殖的影响
(1)细胞处理：收集人前列腺细胞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人前列腺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前列腺癌药物的研发。
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 (10)

1.儿茶酚类化合物，其特征在于，具有式(Ⅰ)或式(Ⅲ)结构：
Figure FDA0002915280670000011
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-。
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 FDA0002915280670000012
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。
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 FDA0002915280670000021
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。
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、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。
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 FDA0002915280670000022
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 FDA0002915280670000031
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.根据权利要求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.根据权利要求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.根据权利要求1所述儿茶酚类化合物的制备方法，其特征在于，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。
10.权利要求1-4任一项所述儿茶酚类化合物在制备抗前列腺癌药物中的应用。
CN202110099768.9A 2021-01-25 2021-01-25 儿茶酚类化合物及其制备方法和应用 Active CN112961041B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110099768.9A CN112961041B (zh) 2021-01-25 2021-01-25 儿茶酚类化合物及其制备方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110099768.9A CN112961041B (zh) 2021-01-25 2021-01-25 儿茶酚类化合物及其制备方法和应用

Publications (2)

Publication Number Publication Date
CN112961041A true CN112961041A (zh) 2021-06-15
CN112961041B CN112961041B (zh) 2022-06-21

Family

ID=76271715

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110099768.9A Active CN112961041B (zh) 2021-01-25 2021-01-25 儿茶酚类化合物及其制备方法和应用

Country Status (1)

Country Link
CN (1) CN112961041B (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113563163A (zh) * 2021-07-07 2021-10-29 南京伊派森化学科技有限公司 一种5-溴-1，2，3-三甲氧基苯的合成方法
CN113582908A (zh) * 2021-09-08 2021-11-02 华南理工大学 一类基于苯氰基的近紫外有机电致发光材料及其制备方法与在制备oled中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1129102A (zh) * 1994-09-21 1996-08-21 辉瑞大药厂 用作肿瘤坏死因子释放抑制剂的儿茶酚二醚化合物
CN1633287A (zh) * 2002-02-15 2005-06-29 恩多研究公司 联苯衍生物及其作为抗雄激素试剂的应用
US20090137687A1 (en) * 2003-02-28 2009-05-28 Oxigene, Inc. Compositions and Methods With Enhanced Therapeutic Activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1129102A (zh) * 1994-09-21 1996-08-21 辉瑞大药厂 用作肿瘤坏死因子释放抑制剂的儿茶酚二醚化合物
CN1633287A (zh) * 2002-02-15 2005-06-29 恩多研究公司 联苯衍生物及其作为抗雄激素试剂的应用
US20090137687A1 (en) * 2003-02-28 2009-05-28 Oxigene, Inc. Compositions and Methods With Enhanced Therapeutic Activity

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BOWDEN, BRUCE F.等: "Constituents of Eupomatia species. VII. Dienone-phenol and dienol-benzene rearrangements in the eupodienone-1 series", 《AUSTRALIAN JOURNAL OF CHEMISTRY》 *
CAS REG: "CAS号：854235-49-7", 《STN》 *
D.A.HORTON等: "he Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures", 《CHEM. REV.》 *
HAILONG ZHANG等: "Non-symmetrical diarylcarboxylic acids via rhodium(I)-catalyzed regiospecific crossdehydrogenation coupling of aromatic acids: twofold direct C–H bond activations in water.", 《RSC ADVANCES》 *
JIAN FAN等: "Expeditious synthesis of phenanthridines through a Pd/MnO2-mediated C–H arylation/oxidative annulation cascade from aldehydes, aryl iodides and amino acids.", 《CHEM. COMMUN.》 *
JUNG-CHIH WAN等: "Novel Syntheses of Fluorenones via Nitrile-Directed Palladium-Catalyzed C-H and Dual C-H Bond Activation.", 《ORGANIC LETTERS》 *
LIANGBIN HUANG等: "Iridium-Catalyzed ortho-Arylation of Benzoic Acids with Arenediazonium Salts.", 《ANGEW. CHEM. INT. ED.》 *
OZEKI, SHOJI: "Alkaloids of Zephyranthes candida.III. Structure of nerinine.", 《YAKUGAKU ZASSHI》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113563163A (zh) * 2021-07-07 2021-10-29 南京伊派森化学科技有限公司 一种5-溴-1，2，3-三甲氧基苯的合成方法
CN113582908A (zh) * 2021-09-08 2021-11-02 华南理工大学 一类基于苯氰基的近紫外有机电致发光材料及其制备方法与在制备oled中的应用
CN113582908B (zh) * 2021-09-08 2023-09-26 华南理工大学 一类基于苯氰基的近紫外有机电致发光材料及其制备方法与在制备oled中的应用

Also Published As

Publication number Publication date
CN112961041B (zh) 2022-06-21

Similar Documents

Publication Publication Date Title
CN112961041B (zh) 儿茶酚类化合物及其制备方法和应用
CN109970755B (zh) 取代的水杨醛衍生物的合成
CN103113293B (zh) 多取代喹啉衍生物及其制备方法
CN111057070A (zh) 一种巴洛沙韦关键中间体的合成方法
CN111303026A (zh) 一种恩诺沙星的丙烯酮衍生物及其制备方法和应用
CN112142660A (zh) 一种简便高效合成4-芳基丁酸衍生物的方法
CN112824391A (zh) 一种加替沙星的丙烯酮衍生物及其制备方法和应用
CN111646974A (zh) 一种n-甲基加替沙星的丙烯酮衍生物及其制备方法和应用
CN111303189A (zh) 一种芦氟沙星的丙烯酮衍生物及其制备方法和应用
CN112824415A (zh) 一种氧氟沙星的丙烯酮衍生物及其制备方法和应用
CN108191800A (zh) 一种微波辐射下水相中铜催化2-炔苯酚衍生物合成含硒苯并[b]呋喃衍生物的方法
CN110143927B (zh) 一种苯并咪唑查尔酮类衍生物及其制备方法和应用
Miranda et al. Potassium fluoride: A convenient, non-covalent support for the immobilization of organocatalysts through strong hydrogen bonds
CN111592509B (zh) 一种铜催化合成芳基(3-砜基苯并呋喃-2-基)甲酮化合物的方法
RU2282633C1 (ru) СПОСОБ ПОЛУЧЕНИЯ 1,11-ДИАЛКИЛ-3,5-ДИГИДРОФУРО[2',3':3,4]ЦИКЛОГЕПТА[c]ИЗОХРОМЕНОВ
CN110526866B (zh) 一种2-喹啉酮类化合物的合成方法
CN112824408A (zh) 一种莫西沙星的丙烯酮衍生物及其制备方法和应用
CN111646937A (zh) 一种 n-乙酰基环丙沙星的丙烯酮衍生物及其制备方法和应用
CN115806502B (zh) 一种α-酰胺酮衍生物及其制备方法和应用
CN111484420B (zh) 合成三芳基甲烷衍生物的方法及其所得三芳基甲烷衍生物
CN112824396A (zh) 一种n-乙酰基洛美沙星的丙烯酮衍生物及其制备方法和应用
CN111393453A (zh) 一种左氧氟沙星的丙烯酮衍生物及其制备方法和应用
CN108358898B (zh) 一种具有抗癌活性的对萘醌衍生物及其合成方法
CN115322192B (zh) 吡咯并[3,4-b]吡啶类衍生物及其合成方法与应用
CN116283632B (zh) 一类β-氨基-α-卤代/硒代羧酸酯及其合成方法和用途

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant