CN108558813B - 一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途 - Google Patents

一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途 Download PDF

Info

Publication number
CN108558813B
CN108558813B CN201810293506.4A CN201810293506A CN108558813B CN 108558813 B CN108558813 B CN 108558813B CN 201810293506 A CN201810293506 A CN 201810293506A CN 108558813 B CN108558813 B CN 108558813B
Authority
CN
China
Prior art keywords
dimethoxy
nmr
reaction
phenyl
hydroxyacetophenone
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.)
Active
Application number
CN201810293506.4A
Other languages
English (en)
Other versions
CN108558813A (zh
Inventor
阮班锋
葛为为
程慧洁
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.)
Hefei University of Technology
Original Assignee
Hefei University of Technology
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 Hefei University of Technology filed Critical Hefei University of Technology
Priority to CN201810293506.4A priority Critical patent/CN108558813B/zh
Publication of CN108558813A publication Critical patent/CN108558813A/zh
Application granted granted Critical
Publication of CN108558813B publication Critical patent/CN108558813B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

本发明公开了一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途，其中含有类黄酮的白藜芦醇类衍生物的结构由以下通式(1)或通式(2)表示：

Description

一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途
技术领域
本发明涉及一种白藜芦醇类衍生物，具体地说是一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途。
背景技术
白藜芦醇，又称3,4',5-三羟基二苯乙烯，是一种含有芪类结构的非类黄酮多酚，天然存在的白藜芦醇具有反式和顺式两种异构体，反式异构体比顺式异构体更稳定。
白藜芦醇是具有生物学多效性的多酚类物质之一。除了作为植物抗毒素，用于植物自我保护之外，白藜芦醇还具有抗菌、抗癌、抗炎、抗过敏、降血脂、抗氧化等多种药理活性。在这些药理活性中，白藜芦醇的抗炎作用引起了人们的广泛兴趣。研究表明，白藜芦醇对急性、慢性炎症均有良好的治疗作用，其抗炎机制可能与抑制炎症信号转导通路，减少炎症细胞因子生成，干扰花生四烯酸代谢相关。
类黄酮(Flavonoid)是广泛分布在自然界一种多酚类化合物，存在于水果，蔬菜，豆类以及茶叶等食源性植物中。泛指两个或多个具有酚羟基的苯环通过中央三碳原子相互连结而成的一类化合物。研究发现，类黄酮化合物具有抗癌，抗微生物，抗病毒，抗炎，免疫调节和抗血栓等活性。在这些生物活性中，类黄酮的抗炎能力早已通过使用粗制植物提取物在中药中使用得以证明。
发明内容
本发明依据药物的拼合原理和基于结构的药物分子设计理念，在白藜芦醇所具有的二苯乙烯分子骨架上引入类黄酮结构结构，旨在提供一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途。生物活性测试结果表明本发明含有类黄酮的白藜芦醇类衍生物能够抑制LPS刺激的RAW264.7释放NO。
本发明含有类黄酮的白藜芦醇类衍生物，其结构由以下通式(1)或通式(2)表示：
Figure GDA0003062293980000011
Figure GDA0003062293980000021
通式(1)中，R1选自H、4-CH3、5-CH3、5-OCH3、4-F、5-F、3-Cl、4-Cl、5-Cl、4-Br、5-Br或4，5-CH3；R2选自Me、Et或N-buty。
通式(2)中，R3选自H、4-CH3、5-CH3、4，5-CH3、5-OCH3、4，5-OCH3、4-F、5-F、3-Cl、4-Cl、5-Cl、4-Br、5-Br；R4选自Me、Et、N-buty或benzyl。
进一步地，通式(1)中化合物的结构式优选为如下F1-F18的结构；通式(2)中化合物的结构式优选为如下H1-H22的结构。
Comp.no R<sub>2</sub> R<sub>1</sub> Comp.no R<sub>2</sub> R<sub>1</sub>
F1 Me H F10 Me 4-Br
F2 Me 4-CH<sub>3</sub> F11 Me 5-Br
F3 Me 5-CH<sub>3</sub> F12 Me 4，5-CH<sub>3</sub>
F4 Me 5-OCH<sub>3</sub> F13 Et H
F5 Me 4-F F14 Et 5-OCH<sub>3</sub>
F6 Me 5-F F15 Et 5-Br
F7 Me 3-Cl F16 N-buty H
F8 Me 4-Cl F17 N-buty 5-OCH<sub>3</sub>
F9 Me 5-Cl F18 N-buty 5-Br
Figure GDA0003062293980000022
Figure GDA0003062293980000031
结合效果，优选基团为R2＝-CH3、R1＝5-OCH3；R4＝-CH3、R3＝5-OCH3。
本发明含有类黄酮的白藜芦醇类衍生物的制备方法之一，包括如下步骤：
Figure GDA0003062293980000032
步骤a、称取(E)-3,5-二甲氧基-4'-羟基苯乙烯(A，1mmol)于50mL圆底烧瓶中，加入15mL丙酮溶解，加入四丁基溴化铵(TBAB，1.2mmol)、无水K2CO3(1.2mmol)，搅拌5min后加入溴代烷(1mmol)，保持回流反应，TLC监测，反应完全后抽滤，干燥，经柱层析分离(洗脱液为乙酸乙酯和石油醚，1:6，v/v)得B2-3；
所述溴代烷的结构式为：R2′-Br，其中R2′选自乙基或正丁基。
其中B2-3的结构式为
Figure GDA0003062293980000033
B2-3中R2′选自乙基或正丁基。
步骤b、先向N,N-二甲基甲酰胺中加入B1-3，然后于冰浴中缓慢滴加三氯氧磷，B1-3与三氯氧磷的摩尔比为1:1，滴加完毕后恢复至室温反应，1h后停止反应，随后将反应液逐滴加入到冰水与乙酸乙酯的混合溶液中，冰水与乙酸乙酯的体积比为5:1，再分次加入碳酸钠固体直至无气泡产生，搅拌过夜后析出淡黄色固体，抽滤、干燥，最后柱层析(二氯甲烷：石油醚＝1:2，v/v)，分离得C1-3。
所述B1-3为B1、B2-3中的一种；其中B1的结构式为：
Figure GDA0003062293980000041
所述C1-3的结构式为：
Figure GDA0003062293980000042
步骤c、称取取代羟基苯乙酮(1mmol)、C1-3(1mmol)、吡咯烷(1mmol)于50mL圆底烧瓶中，加入10mL乙醇做溶剂，40℃反应36h，反应结束，有黄色固体析出，抽滤，由乙酸乙酯重结晶得到产物D1-18；
所述取代羟基苯乙酮结构式为：
Figure GDA0003062293980000043
其中R1选自H、4-CH3、5-CH3、5-OCH3、4-F、5-F、3-Cl、4-Cl、5-Cl、4-Br、5-Br或4，5-CH3。
所述D1-18的结构式为：
Figure GDA0003062293980000044
其中R1选自H、4-CH3、5-CH3、5-OCH3、4-F、5-F、3-Cl、4-Cl、5-Cl、4-Br、5-Br或4，5-CH3。
步骤d、取上步产物D1-18(0.5mmol)于50mL圆底烧瓶中，加入10mL甲醇溶解，再加入NaOH固体(2.5mmol)，用移液枪取30％的H2O2溶液(2.5mmol)逐滴加入到混合溶液中，40℃条件下反应48h，随后停止反应；取一个100mL烧杯，加入50mL冰水，然后将反应液逐滴加入其中，滴加稀盐酸，不停搅拌，同时监测溶液的pH值，保持在5-6之间，析出固体后抽滤、干燥、柱层析分离(乙酸乙酯：石油醚＝1:3，v/v)，得到产物F1-18。
本发明含有类黄酮的白藜芦醇类衍生物的制备方法之二，包括如下步骤：
Figure GDA0003062293980000051
步骤a、称取(E)-3,5-二甲氧基-4'-羟基苯乙烯(A，1mmol)于50mL圆底烧瓶中，加入15mL丙酮溶解，加入四丁基溴化铵(TBAB，1.2mmol)、无水K2CO3(1.2mmol)，搅拌5min后加入溴代烷(1mmol)，保持回流反应，TLC监测，反应完全后抽滤，干燥，经柱层析得B2-4。
其中B2-4的结构式为：
Figure GDA0003062293980000052
B2-4中R4′选自乙基、正丁基或苄基。
所述溴代烷的结构式为：R4′-Br，其中R4′选自乙基、正丁基或苄基。
步骤b、先向N,N-二甲基甲酰胺中加入B1-4，然后于冰浴中缓慢滴加三氯氧磷，B1-4与三氯氧磷的摩尔比为1:1，滴加完毕后恢复至室温反应，1h后停止反应，随后将反应液逐滴加入到冰水与乙酸乙酯的混合溶液中，冰水与乙酸乙酯的体积比为5:1，再分次加入碳酸钠固体直至无气泡产生，搅拌过夜后析出淡黄色固体，抽滤、干燥，最后柱层析分离(二氯甲烷：石油醚＝1:2，v/v)，得到C1-4。
B1-4为B1、B2-4中的一种，其中B1的结构式为：
Figure GDA0003062293980000061
C1-4的结构式为：
Figure GDA0003062293980000062
步骤c、称取取代羟基苯乙酮(1mmol)、C1-4(1mmol)、吡咯烷(1mmol)于50mL圆底烧瓶中，加入10mL乙醇做溶剂，40℃反应36h，反应结束，有黄色固体析出，抽滤，由乙酸乙酯重结晶得到产物D1-22。
D1-22的结构式为：
Figure GDA0003062293980000063
其中R3选自H、4-CH3、5-CH3、4，5-CH3、5-OCH3、4，5-OCH3、4-F、5-F、3-Cl、4-Cl、5-Cl、4-Br、5-Br。
步骤d、取上步产物D1-22(0.5mmol)和单质碘(0.005mmol)于反应管中，加入二甲基亚砜(1mL/mmol)溶解，130℃下反应4～6h，TLC监测反应，待反应完成后，将反应液逐滴加入装有冰水混合物的100mL的烧杯中搅拌，析出淡黄色固体，抽滤、干燥、通过柱层析分离(乙酸乙酯：石油醚＝1:3，v/v)，得到产物H1-22。
所述取代羟基苯乙酮结构式为：
Figure GDA0003062293980000071
其中R3选自H、4-CH3、5-CH3、4，5-CH3、5-OCH3、4，5-OCH3、4-F、5-F、3-Cl、4-Cl、5-Cl、4-Br、5-Br。
本发明含有类黄酮的白藜芦醇类衍生物的用途，是在制备具有抑制LPS刺激的RAW264.7释放NO作用的单胺氧化酶抑制剂中的应用。
通过生物活性测试结果表明本发明含有类黄酮的白藜芦醇类衍生物能够有效的抑制LPS刺激的RAW264.7释放NO。
具体实施方式
通过以下实施例进一步详细说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
实施例1：(E)-3-(2,4-二甲氧基-6-((E)-4-甲氧基苯乙烯基)苯基)-1-(2-羟基苯基)丙-2-烯-1-酮(F1)的制备
Figure GDA0003062293980000072
a、先向N,N-二甲基甲酰胺中加入白藜芦醇三甲醚(B1)，然后于冰浴中缓慢滴加三氯氧磷，白藜芦醇三甲醚与三氯氧磷的摩尔比为1:1，滴加完毕后恢复至室温反应，1h后停止反应，随后将反应液逐滴加入到冰水与乙酸乙酯的混合溶液中，冰水与乙酸乙酯的体积比为5:1，再分次加入碳酸钠固体直至无气泡产生，搅拌过夜后析出淡黄色固体，抽滤、干燥，最后柱层析(二氯甲烷：石油醚＝1:2，v/v)，分离得(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯甲醛(C1)。
b、称取2-羟基苯乙酮(1mmol,132μL)、(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯甲醛(C1,1mmol,298mg)、吡咯烷(1mmol,85μL)于50mL圆底烧瓶中，加入10mL乙醇做溶剂，40℃反应，TLC监控。36h后，反应结束，有黄色固体析出，抽滤，由乙酸乙酯重结晶得到产物D1。产物为黄色固体粉末，收率84％，熔点：127-129℃。1H NMR(600MHz,CDCl3):δ13.06(s,1H),8.29(d,J＝15.4Hz,1H),7.78(d,J＝8.0Hz,1H),7.72(d,J＝15.5Hz,1H),7.49(d,J＝8.4Hz,2H),7.44(t,J＝7.7Hz,1H),7.35(d,J＝16.0Hz,1H),7.00(d,J＝8.3Hz,1H),6.95(d,J＝16.0Hz,1H),6.91(d,J＝8.3Hz,2H),6.80(t,J＝7.6Hz,1H),6.73(s,1H),6.45(s,1H),3.93(s,3H),3.91(s,3H),3.84(s,3H).13C NMR(151MHz,CDCl3):δ197.07(s),166.17(s),164.65(s),163.69(s),162.38(s),144.85(s),142.06(s),138.49(s),134.75(s),132.39(s),132.28(s),130.69(s),128.05(s),125.69(s),123.03(s),121.30(s),121.08(s),118.44(s),116.92(s),106.64(s),100.31(s),58.46(s),58.15(s),58.01(s).
c、取上步产物D1(0.5mmol，160mg)于50mL圆底烧瓶中，加入10mL甲醇溶解后，再加入NaOH固体(2.5mmol，200mg)，用移液枪取30％的H2O2溶液(2.5mmol，140μL)逐滴加入到混合溶液中。40℃条件下反应48h，随后停止反应。取一个100mL烧杯，加入50mL冰水，然后将反应液逐滴加入其中，滴加稀盐酸，不停搅拌，同时监测溶液的pH值，保持在5-6之间，析出固体后抽滤、干燥、柱层析得到产物F1。产物为白色固体粉末，收率是76％，熔点230-232℃。1HNMR(600MHz,DMSO):δ8.85(s,1H),8.15(d,J＝8.0Hz,1H),7.74(t,J＝7.7Hz,1H),7.60(d,J＝8.4Hz,1H),7.46(t,J＝7.5Hz,1H),7.30(d,J＝8.6Hz,2H),7.25(d,J＝16.2Hz,1H),7.03(s,1H),6.84(d,J＝8.6Hz,2H),6.74(d,J＝16.2Hz,1H),6.61(s,1H),3.89(s,3H),3.72(t,J＝20.0Hz,6H).13C NMR(151MHz,DMSO):δ175.66(s),164.97(s),162.31(s),161.96(s),158.47(s),148.85(s),143.43(s),141.68(s),136.50(s),133.97(s),132.35(s),131.01(s),128.08(s),127.54(s),125.75(s),125.28(s),121.55(s),117.30(s),114.78(s),104.04(s),100.93(s),59.01(s),58.66(s),58.19(s).MS(ESI):431.1483.(C26H22O6,[M+H]+).
实施例2：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-7-甲基-4H-苯并吡喃-4-酮(F2)的制备
Figure GDA0003062293980000081
本实施例的制备方法同实施例1，不同的是步骤b中以4-甲基-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D2，再按照实施例1从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-7-甲基-4H-苯并吡喃-4-酮F2。F2为白色固体粉末，收率78％，熔点：210-213℃。1H NMR(600MHz,DMSO):δ8.77(s,1H),8.02(d,J＝8.2Hz,1H),7.40(s,1H),7.32-7.23(m,4H),7.02(s,1H),6.84(d,J＝8.6Hz,2H),6.71(d,J＝16.2Hz,1H),6.60(s,1H),3.89(s,3H),3.71(t,J＝14.1Hz,6H),2.42(s,3H).13C NMR(101MHz,DMSO):δ172.37(s),161.80(s),159.18(s),158.83(s),155.49(s),145.24(s),144.25(s),140.12(s),138.50(s),130.77(s),129.23(s),127.85(s),125.93(s),124.72(s),122.64(s),119.93(s),117.87(s),100.88(s),97.79(s),114.18(s),111.76(s),55.85(s),55.51(s),55.05(s),21.15(s).MS(ESI):445.1645.(C27H24O6,[M+H]+).
实施例3：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-6-甲基-4H-苯并吡喃-4-酮(F3)的制备
Figure GDA0003062293980000091
本实施例的制备方法同实施例1，不同的是步骤b中以5-甲基-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D3，再按照实施例1从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-7-甲基-4H-苯并吡喃-4-酮F3。F3为白色固体粉末，收率44％，熔点：201-204℃。1H NMR(600MHz,DMSO):δ8.80(s,1H),7.93(s,1H),7.56(d,J＝8.6Hz,1H),7.49(d,J＝8.5Hz,1H),7.28(d,J＝8.5Hz,2H),7.25(d,J＝16.2Hz,1H),7.02(s,1H),6.84(d,J＝8.3Hz,2H),6.69(d,J＝16.2Hz,1H),6.60(s,1H),3.89(s,3H),3.70(d,J＝13.1Hz,6H),2.44(s,3H).13C NMR(101MHz,CDCl3):δ172.94(s),162.46(s),159.59(s),159.29(s),154.69(s),144.74(s),139.83(s),139.54(s),134.80(s),134.32(s),131.18(s),129.63(s),128.04(s),124.57(s),123.31(s),121.01(s),118.44(s),114.09(s),111.35(s),101.26(s),98.00(s),56.03(s),55.73(s),55.43(s),20.98(s).MS(ESI):445.1642.(C27H24O6,[M+H]+).
实施例4：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-6-甲氧基-4H-苯并吡喃-4-酮(F4)的制备
Figure GDA0003062293980000092
本实施例的制备方法同实施例1，不同的是步骤b中以5-甲氧基-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D4，再按照实施例1从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-6-甲氧基-4H-苯并吡喃-4-酮F4。F4为白色固体粉末，收率89％，熔点：188-191℃。1H NMR(600MHz,DMSO):δ8.81(s,1H),7.56(d,J＝9.1Hz,1H),7.48(d,J＝2.7Hz,1H),7.34(dd,J＝9.1,2.7Hz,1H),7.29(d,J＝8.4Hz,2H),7.25(d,J＝16.2Hz,1H),7.02(s,1H),6.84(d,J＝8.4Hz,2H),6.69(d,J＝16.2Hz,1H),6.60(s,1H),3.88(d,J＝8.5Hz,6H),3.70(d,J＝14.7Hz,6H).13C NMR(101MHz,DMSO):δ172.09(s),161.82(s),159.19(s),158.83(s),155.84(s),150.32(s),145.61(s),139.86(s),138.53(s),130.79(s),129.22(s),127.83(s),123.18(s),122.70(s),122.63(s),120.05(s),114.18(s),111.75(s),103.96(s),100.92(s),97.80(s),55.86(s),55.69(s),55.51(s),55.05(s).MS(ESI):461.1591.(C27H24O7,[M+H]+).
实施例5：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-氟-3-羟基-4H-苯并吡喃-4-酮(F5)的制备
Figure GDA0003062293980000101
本实施例的制备方法同实施例1，不同的是步骤b中以4-氟-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D5，再按照实施例1从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-氟-3-羟基-4H-苯并吡喃-4-酮F5。F5为白色固体粉末，收率63％，熔点：236-239℃。1H NMR(600MHz,DMSO):δ8.94(s,1H),8.20(dd,J＝8.9,6.5Hz,1H),7.58(dd,J＝9.7,2.1Hz,1H),7.37–7.34(m,1H),7.33(d,J＝8.6Hz,2H),7.26(d,J＝16.2Hz,1H),7.03(d,J＝1.6Hz,1H),6.84(d,J＝8.7Hz,2H),6.74(d,J＝16.2Hz,1H),6.60(d,J＝1.7Hz,1H),3.89(s,3H),3.71(d,J＝13.5Hz,6H).13C NMR(101MHz,CDCl3):δ172.46(s),167.96(s),164.28(s),162.62(s),159.67(s),159.29(s),157.37(s),145.24(s),139.81(s),139.62(s),131.43(s),129.57(s),128.17(s),123.16(s),118.43(s),114.13(s),110.84(s),105.15(s),104.90(s),101.34(s),97.95(s),56.01(s),55.56(s),55.30(s).MS(ESI):449.1392.(C26H21FO6,[M+H]+).
实施例6：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-氟-3-羟基-4H-苯并吡喃-4-酮(F6)的制备
Figure GDA0003062293980000111
本实施例的制备方法同实施例1，不同的是步骤b中以5-氟-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D6，再按照实施例1从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-氟-3-羟基-4H-苯并吡喃-4-酮F6。F6为白色固体粉末，收率68％，熔点：190-193℃。1H NMR(600MHz,DMSO):δ8.99(s,1H),7.80(dd,J＝22.0,16.1Hz,1H),7.72(dd,J＝8.9,3.7Hz,1H),7.64(t,J＝7.1Hz,1H),7.32(d,J＝8.3Hz,2H),7.26(d,J＝16.2Hz,1H),7.01(d,J＝26.2Hz,1H),6.82(t,J＝16.7Hz,2H),6.72(d,J＝16.2Hz,1H),6.61(s,1H),3.89(s,3H),3.70(d,J＝15.6Hz,6H).13C NMR(101MHz,DMSO):δ171.91(s),161.93(s),159.20(s),158.84(s),157.16(s),151.85(s),146.32(s),140.04(s),138.63(s),130.92(s),129.21(s),127.95(s),123.16(s),122.56(s),121.74(s),121.20(s),114.14(s),111.44(s),109.12(s),100.95(s),97.78(s),55.88(s),55.52(s),55.05(s).MS(ESI):449.1392.(C26H21FO6,[M+H]+).
实施例7：(E)-8-氯-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮(F7)的制备
Figure GDA0003062293980000112
本实施例的制备方法同实施例1，不同的是步骤b中以3-氯-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D7，再按照实施例1从而得到目标化合物(E)-8-氯-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮F7。E7为白色固体粉末，收率55％，熔点：208-210℃。1H NMR(600MHz,DMSO):δ9.07(s,1H),8.11(d,J＝8.0Hz,1H),7.92(d,J＝7.7Hz,1H),7.45(t,J＝7.9Hz,1H),7.34(d,J＝8.5Hz,2H),7.27(d,J＝16.2Hz,1H),7.04(s,1H),6.84(d,J＝8.5Hz,2H),6.79(d,J＝16.2Hz,1H),6.63(s,1H),3.90(s,3H),3.74(s,3H),3.70(s,3H).13C NMR(151MHz,DMSO):δ175.28(s),165.16(s),162.33(s),162.18(s),153.80(s),149.10(s),143.72(s),141.98(s),136.44(s),134.08(s),132.43(s),131.14(s),127.87(s),127.27(s),126.80(s),125.84(s),125.06(s),117.26(s),114.39(s),104.34(s),101.12(s),59.17(s),58.69(s),58.21(s).MS(ESI):465.1097.(C26H21ClO6,[M+H]+).
实施例8：(E)-7-氯-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮(F8)的制备
Figure GDA0003062293980000121
本实施例的制备方法同实施例1，不同的是步骤b中以4-氯-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D8，再按照实施例1从而得到目标化合物(E)-7-氯-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮F8。F8为白色固体粉末，收率48％，熔点：209-210℃。1H NMR(600MHz,DMSO):δ8.98(s,1H),8.14(d,J＝8.7Hz,1H),7.82(d,J＝1.5Hz,1H),7.50(dd,J＝8.6,1.7Hz,1H),7.33(d,J＝8.7Hz,2H),7.25(d,J＝16.2Hz,1H),7.03(d,J＝1.7Hz,1H),6.84(d,J＝8.7Hz,2H),6.73(t,J＝12.4Hz,1H),6.60(d,J＝1.8Hz,1H),3.89(s,3H),3.71(d,J＝13.0Hz,6H).13C NMR(101MHz,CDCl3):δ172.52(s),162.63(s),159.67(s),159.30(s),156.40(s),145.31(s),140.07(s),139.63(s),139.52(s),131.48(s),129.54(s),128.08(s),126.88(s),125.40(s),123.10(s),120.08(s),118.62(s),114.13(s),110.80(s),101.33(s),97.93(s),56.00(s),55.56(s),55.30(s).MS(ESI):465.1102.(C26H21ClO6,[M+H]+).
实施例9：(E)-6-氯-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮(F9)的制备
Figure GDA0003062293980000122
本实施例的制备方法同实施例1，不同的是步骤b中以5-氯-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D9，按照实施例1从而得到目标化合物(E)-6-氯-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮F9。F9为白色固体粉末，收率60％，熔点：189-192℃。1H NMR(600MHz,CDCl3):δ8.27(s,1H),7.60(d,J＝9.0Hz,1H),7.45(d,J＝8.9Hz,1H),7.26(d,J＝4.7Hz,3H),7.06(d,J＝16.0Hz,1H),6.91(s,1H),6.80(d,J＝8.2Hz,2H),6.77(d,J＝16.1Hz,1H),6.50(s,1H),3.93(s,3H),3.78(d,J＝6.5Hz,6H).13C NMR(101MHz,CDCl3):δ172.35(s),162.65(s),159.68(s),159.27(s),154.65(s),145.45(s),140.02(s),139.63(s),133.60(s),131.45(s),130.34(s),129.51(s),128.04(s),124.74(s),123.08(s),122.35(s),120.41(s),114.13(s),110.78(s),101.36(s),97.93(s),56.01(s),55.57(s),55.31(s).MS(ESI):465.1101.(C26H21ClO6,[M+H]+).
实施例10：(E)-7-溴-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮(F10)的制备
Figure GDA0003062293980000131
本实施例的制备方法同实施例1，不同的是步骤b中以4-溴-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D10，按照实施例1从而得到目标化合物(E)-7-溴-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮F10。F10为白色固体粉末，收率76％，熔点：202-205℃。1H NMR(600MHz,DMSO):δ9.03(s,1H),8.05(d,J＝8.6Hz,1H),7.94(d,J＝1.3Hz,1H),7.63(dd,J＝8.6,1.1Hz,1H),7.33(d,J＝8.6Hz,2H),7.25(d,J＝16.2Hz,1H),7.01(d,J＝1.5Hz,1H),6.83(d,J＝8.6Hz,2H),6.73(d,J＝16.2Hz,1H),6.59(d,J＝1.6Hz,1H),3.88(s,3H),3.70(d,J＝11.5Hz,6H).13C NMR(101MHz,CDCl3):δ172.60(s),162.64(s),159.68(s),159.30(s),156.34(s),145.17(s),140.09(s),139.63(s),131.49(s),129.54(s),128.08(s),127.76(s),126.89(s),123.09(s),121.71(s),120.41(s),114.13(s),110.78(s),101.32(s),97.93(s),56.01(s),55.56(s),55.31(s).MS(ESI):509.0590.(C26H21BrO6,[M+H]+).
实施例11：(E)-6-溴-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮(F11)的制备
Figure GDA0003062293980000141
本实施例的制备方法同实施例1，不同的是步骤b中以5-溴-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D11，按照实施例1从而得到目标化合物(E)-6-溴-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮F11。F11为白色固体粉末，收率82％，熔点：201-204℃。1H NMR(600MHz,DMSO):δ9.08(s,1H),8.22(d,J＝2.4Hz,1H),7.88(dd,J＝8.9,2.4Hz,1H),7.61(d,J＝8.9Hz,1H),7.33(d,J＝8.7Hz,2H),7.26(d,J＝16.2Hz,1H),7.03(d,J＝1.7Hz,1H),6.84(d,J＝8.7Hz,2H),6.72(d,J＝16.2Hz,1H),6.60(d,J＝1.8Hz,1H),3.89(s,3H),3.70(d,J＝11.1Hz,6H).13C NMR(101MHz,CDCl3):δ171.92(s),162.65(s),159.68(s),159.28(s),155.08(s),145.54(s),140.10(s),139.63(s),136.28(s),131.45(s),129.51(s),128.04(s),123.07(s),122.89(s),120.62(s),117.74(s),114.13(s),110.79(s),101.36(s),97.93(s),56.01(s),55.57(s),55.31(s).MS(ESI):511.0572.(C26H21BrO6,[M+H]+).
实施例12：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-6,7-二甲基-4H-苯并吡喃-4-酮(F12)的制备
Figure GDA0003062293980000142
本实施例的制备方法同实施例1，不同的是步骤b中以4,5-甲基-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D12，按照实施例1从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-3-羟基-6,7-二甲基-4H-苯并吡喃-4-酮F12。F12为白色固体粉末，收率66％，熔点：214-217℃。1H NMR(600MHz,CDCl3):δ8.03(s,1H),7.27(d,J＝6.3Hz,1H),7.26(s,1H),7.25(s,2H),7.06(d,J＝16.0Hz,1H),6.91(s,1H),6.82–6.77(m,3H),6.50(d,J＝1.4Hz,1H),3.92(d,J＝8.1Hz,3H),3.77(d,J＝3.9Hz,6H),2.39(d,J＝7.5Hz,6H).13C NMR(101MHz,CDCl3):δ172.88(s),162.39(s),159.57(s),159.31(s),155.16(s),144.27(s),144.00(s),139.68(s),139.50(s),133.84(s),131.09(s),129.67(s),128.05(s),124.83(s),123.36(s),119.38(s),118.67(s),114.08(s),111.52(s),101.20(s),98.00(s),56.02(s),55.54(s),55.29(s),20.55(s),19.39(s).MS(ESI):459.1803.(C28H26O6,[M+H]+).
实施例13：(E)-2-(2-(4-乙氧基苯乙烯基)-4,6-二甲氧基苯基)-3-羟基-4H-苯并吡喃-4-酮(F13)的制备
Figure GDA0003062293980000151
a、称取(E)-3,5-二甲氧基-4'-羟基苯乙烯(A,1mmol,256mg)于50mL圆底烧瓶中，加入15mL丙酮溶解，加入四丁基溴化铵(TBAB,1.2mmol,386mg)、无水K2CO3(1.2mmol,165mg)，搅拌5min后加入溴乙烷(1mmol,109mg)，保持回流反应，TLC监测，反应完全后抽滤，干燥，经柱层析(乙酸乙酯：石油醚＝1：5)，得(E)-1-(4-乙氧基苯乙烯基)-3,5-二甲氧基苯(B2)。1H NMR(600MHz,CDCl3):δ7.44(d,J＝8.5Hz,2H),7.05(d,J＝16.2Hz,1H),6.93-6.88(m,3H),6.66(s,2H),6.39(s,1H),4.06(q,J＝7.0Hz,2H),3.83(s,6H),1.43(t,J＝7.0Hz,2H).13C NMR(151MHz,CDCl3):δ163.65(s),161.46(s),142.42(s),132.46(s),131.47(s),130.44(s),129.14(s),117.37(s),107.03(s),102.29(s),66.16(s),57.99(s),17.47(s).
b、先向N,N-二甲基甲酰胺中加入(E)-1-(4-乙氧基苯乙烯基)-3,5-二甲氧基苯(B2)，然后于冰浴中缓慢滴加三氯氧磷，B2与三氯氧磷的摩尔比为1:1，滴加完毕后恢复至室温反应，1h后停止反应，随后将反应液逐滴加入到冰水与乙酸乙酯的混合溶液中，冰水与乙酸乙酯的体积比为5:1，再分次加入碳酸钠固体直至无气泡产生，搅拌过夜后析出淡黄色固体，抽滤、干燥，最后柱层析(二氯甲烷：石油醚＝1:2)，分离得(E)-2-(4-乙氧基苯乙烯基)-4,6-二甲氧基苯甲醛(C13)。
c、称取2-羟基苯乙酮(1mmol)、(E)-2-(4-乙氧基苯乙烯基)-4,6-二甲氧基苯甲醛(C13)(1mmol)、吡咯烷(1mmol)于50mL圆底烧瓶中，加入10mL乙醇做溶剂，40℃反应，TLC监控。36h后，反应结束，有黄色固体析出，抽滤，由乙酸乙酯重结晶得到产物D13。产物为黄色固体粉末，收率87％，熔点：155-157℃。1H NMR(600MHz,DMSO):δ12.47(s,1H),8.11(d,J＝15.5Hz,1H),7.84(d,J＝7.4Hz,1H),7.73(d,J＝15.5Hz,1H),7.54(d,J＝8.6Hz,2H),7.50(t,J＝7.7Hz,1H),7.38(d,J＝16.1Hz,1H),7.07(d,J＝16.0Hz,1H),6.96(d,J＝8.3Hz,1H),6.93(d,J＝8.6Hz,2H),6.89(t,J＝7.5Hz,1H),6.82(d,J＝2.0Hz,1H),6.61(d,J＝1.9Hz,1H),4.04(q,J＝6.9Hz,2H),3.93(s,3H),3.88(s,3H),1.32(t,J＝7.0Hz,3H).13CNMR(101MHz,DMSO):δ193.70(s),162.03(s),161.53(s),161.05(s),158.62(s),141.99(s),138.70(s),135.80(s),132.42(s),129.88(s),129.22(s),128.15(s),124.23(s),122.98(s),121.04(s),119.14(s),117.76(s),114.65(s),114.31(s),104.30(s),97.77(s),63.07(s),56.04(s),55.55(s),14.59(s).
d、取上步产物D13(0.5mmol)于50mL圆底烧瓶中，加入10mL甲醇溶解后，再加入NaOH固体(2.5mmol，200mg)，用移液枪取30％的H2O2溶液(2.5mmol，140μL)逐滴加入到混合溶液中。40℃条件下反应48h，随后停止反应。取一个100mL烧杯，加入50mL冰水，然后将反应液逐滴加入其中，滴加稀盐酸，不停搅拌，同时监测溶液的pH值，保持在5-6之间，析出固体后抽滤、干燥、柱层析得到产物F13。F13为白色固体粉末，收率77％，熔点：244-247℃。1HNMR(600MHz,CDCl3):δ8.31(d,J＝7.9Hz,1H),7.66(dd,J＝11.4,4.2Hz,1H),7.50(d,J＝8.5Hz,1H),7.43(t,J＝7.5Hz,1H),7.26(s,1H),7.24(s,1H),7.07(d,J＝16.1Hz,1H),6.92(d,J＝2.0Hz,1H),6.81(d,J＝16.2Hz,1H),6.78(d,J＝8.7Hz,2H),6.51(d,J＝2.0Hz,1H),6.29(s,1H),3.99(q,J＝7.0Hz,2H),3.93(s,3H),3.79(s,3H),1.38(t,J＝7.0Hz,3H).13CNMR(101MHz,CDCl3):δ173.15(s),162.51(s),159.31(s),159.01(s),156.42(s),145.02(s),139.93(s),139.63(s),133.32(s),131.35(s),129.45(s),128.06(s),125.54(s),124.38(s),123.14(s),121.55(s),118.69(s),114.64(s),111.22(s),101.30(s),97.96(s),63.47(s),56.02(s),55.55(s),14.79(s).MS(ESI):445.1642.(C27H24O6,[M+H]+).
实施例14：(E)-2-(2-(4-乙氧基苯乙烯基)-4,6-二甲氧基苯基)-3-羟基-6-甲氧基-4H-苯并吡喃-4-酮(F14)的制备
Figure GDA0003062293980000161
本实施例的制备方法同实施例13，不同的是步骤c中以5-甲氧基-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D14，按照实施例13从而得到目标化合物(E)-2-(2-(4-乙氧基苯乙烯基)-4,6-二甲氧基苯基)-3-羟基-6-甲氧基-4H-苯并吡喃-4-酮F14。F14为白色固体粉末，收率81％，熔点：220-223℃。1H NMR(600MHz,CDCl3):δ7.63(d,J＝3.0Hz,1H),7.44-7.42(m,1H),7.27(dd,J＝9.2,3.1Hz,1H),7.24(d,J＝8.7Hz,2H),7.05(d,J＝16.1Hz,1H),6.91(d,J＝2.1Hz,1H),6.78(dd,J＝12.4,3.6Hz,3H),6.50(d,J＝2.1Hz,1H),6.28(s,1H),3.99(q,J＝7.0Hz,2H),3.93(d,J＝6.1Hz,6H),3.78(s,3H),1.38(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ172.71(s),162.47(s),159.29(s),159.00(s),156.41(s),151.58(s),144.80(s),139.62(s),139.54(s),131.28(s),129.44,128.03(s),124.15(s),123.14(s),121.94(s),120.16(s),114.63(s),111.27(s),103.82(s),101.26(s),97.95(s),63.46(s),56.02(s),56.00(s),55.55(s),14.79(s).MS(ESI):475.1747.(C28H26O7,[M+H]+).
实施例15：(E)-2-(2-(4-乙氧基苯乙烯基)-4,6-二甲氧基苯基)-3-羟基-6-溴-4H-苯并吡喃-4-酮(F15)的制备
Figure GDA0003062293980000171
本实施例的制备方法同实施例13，不同的是步骤a中以5-溴-2-羟基苯乙酮替换2-羟基苯乙酮，得到中间体D15，按照实施例13从而得到目标化合物(E)-2-(2-(4-乙氧基苯乙烯基)-4,6-二甲氧基苯基)-3-羟基-6-溴-4H-苯并吡喃-4-酮F15。F15为白色固体粉末，收率78％，熔点：200-205℃。1H NMR(600MHz,CDCl3):δ8.44(d,J＝2.4Hz,1H),7.73(dd,J＝9.0,2.4Hz,1H),7.39(d,J＝8.9Hz,1H),7.24(d,J＝9.0Hz,2H),7.06(d,J＝16.0Hz,1H),6.90(d,J＝2.1Hz,1H),6.79(d,J＝8.7Hz,2H),6.76(d,J＝16.1Hz,1H),6.50(d,J＝2.1Hz,1H),6.22(s,1H),4.00(q,J＝7.0Hz,2H),3.93(s,3H),3.78(s,3H),1.38(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ171.91(s),162.65(s),159.27(s),159.08(s),155.09(s),145.48(s),140.05(s),139.67(s),136.28(s),131.53(s),129.33(s),128.04(s),127.98(s),122.91(s),122.86(s),120.63(s),117.74(s),114.66(s),110.75(s),101.35(s),97.90(s),63.49(s),56.01(s),55.57(s),14.78(s).MS(ESI):525.0729.(C27H23BrO6,[M+H]+).
实施例16：(E)-3-(2,4-二甲氧基-6-((E)-4-丁氧基氧基苯乙烯基)苯基)-1-(2-羟基苯基)丙-2-烯-1-酮(F16)的制备
Figure GDA0003062293980000181
本实施例的制备方法同实施例13，不同的是步骤a中以溴丁烷代替溴乙烷，得到中间体B3，按照实施例13从而得到目标化合物(E)-3-(2,4-二甲氧基-6-((E)-4-丁氧基氧基苯乙烯基)苯基)-1-(2-羟基苯基)丙-2-烯-1-酮F16。F16为淡黄色固体粉末，收率89％，熔点：195-201℃。1H NMR(600MHz,CDCl3):δ8.64(d,J＝2.4Hz,1H),7.83(d,J＝9.0,2.4Hz,1H),7.59(d,J＝8.9Hz,1H),7.34(s 2H),7.06(d,J＝16.0Hz,1H),6.97(d,J＝2.1Hz,1H),6.79(d,J＝8.7Hz,2H),6.66(d,J＝16.1Hz,1H),6.50(d,J＝2.1Hz,1H),6.22(s,1H),4.00(q,J＝7.0Hz,2H),3.93(s,3H),3.78(d,J＝6.2,2H),2.86(d,J＝9.8 2H),2.78(d,J＝9.02H),1.38(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ171.91(s),162.65(s),159.27(s),159.08(s),155.09(s),145.48(s),140.05(s),139.67(s),136.28(s),131.53(s),129.33(s),128.04(s),127.98(s),122.91(s),122.86(s),120.63(s),117.74(s),114.66(s),110.75(s),101.35(s),97.90(s),63.49(s),56.01(s),55.57(s),53.12(s),49.57(s),14.78(s).MS(ESI):472.1929.(C29H28O6,[M+H]+).
实施例17：(E)-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-3-羟基-6-甲氧基-4H-苯并吡喃-4-酮(F17)的制备
Figure GDA0003062293980000182
本实施例的制备方法同实施例14，不同的是步骤a中以溴丁烷代替溴乙烷，得到中间体B3，按照实施例13从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-3-羟基-6-甲氧基-4H-苯并吡喃-4-酮F17。F17为淡黄色固体粉末，收率79％，熔点：208-209℃。1H NMR(600MHz,CDCl3):δ8.77(d,J＝2.4Hz,1H),7.90(d,J＝8.6,2.4Hz,1H),7.68(d,J＝6.0Hz,1H),7.56(s 2H),7.11(d,J＝16.0Hz,1H),6.92(d,J＝2.1Hz,1H),6.61(d,J＝8.7Hz,2H),6.54(d,J＝16.1Hz,1H),6.49(d,J＝2.1Hz,1H),6.34(s,1H),4.56(q,J＝7.0Hz,2H),3.99(s,3H),3.45(s,3H),3.18(d,J＝6.2,2H),2.87(d,J＝9.8 2H),2.75(d,J＝9.0 2H),1.54(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ176.91(s),165.65(s),159.87(s),159.18(s),155.29(s),144.98(s),140.75(s),139.87(s),137.28(s),133.13(s),129.83(s),128.74(s),126.98(s),123.41(s),122.86(s),121.63(s),118.54(s),114.86(s),110.05(s),101.25(s),98.90(s),64.49(s),56.51(s),52.57(s),50.12(s),48.02(s),44.57(s),14.78(s).MS(ESI):502.2011.(C30H30O7,[M+H]+).
实施例18：(E)-6-溴-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮(F18)的制备
Figure GDA0003062293980000191
本实施例的制备方法同实施例15，不同的是步骤a中以溴丁烷代替溴乙烷，得到中间体E16，按照实施例13从而得到目标化合物(E)-6-溴-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-3-羟基-4H-苯并吡喃-4-酮F18。F18为淡黄色固体粉末，收率75％，熔点：210-211℃。1H NMR(600MHz,CDCl3):δ8.82(d,J＝3.2Hz,1H),8.09(d,J＝6.6,2.4Hz,1H),7.89(d,J＝8.2Hz,1H),7.78(s,2H),7.52(d,J＝16.0Hz,1H),7.08(d,J＝3.4Hz,1H),6.78(d,J＝8.0Hz,2H),6.67(d,J＝16.1Hz,1H),6.54(d,J＝2.1Hz,1H),6.42(s,1H),4.88(q,J＝7.0Hz,2H),3.89(s,3H),3.56(s,3H),2.87(d,J＝9.8 2H),2.70(d,J＝9.0 2H),1.67(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ181.91(s),162.65(s),157.27(s),156.08(s),155.09(s),140.48(s),139.05(s),138.67(s),137.28(s),130.53(s),128.63(s),128.94(s),127.08(s),121.91(s),120.86(s),120.13(s),118.74(s),115.16(s),110.65(s),105.35(s),98.90(s),66.19(s),57.11(s),55.27(s),53.62(s),52.12(s),15.28(s).MS(ESI):551.0829.(C29H27BrO6,[M+H]+).
实施例19：(E)-3-(2,4-二甲氧基-6-((E)-4-甲氧基氧基苯乙烯基)苯基)-1-(2-苯基)丙-2-烯-1-酮(H1)的制备
Figure GDA0003062293980000192
a、先向N,N-二甲基甲酰胺中加入B1，然后于冰浴中缓慢滴加三氯氧磷，B1与三氯氧磷的摩尔比为1:1，滴加完毕后恢复至室温反应，1h后停止反应，随后将反应液逐滴加入到冰水与乙酸乙酯的混合溶液中，冰水与乙酸乙酯的体积比为5:1，再分次加入碳酸钠固体直至无气泡产生，搅拌过夜后析出淡黄色固体，抽滤、干燥，最后柱层析(二氯甲烷：石油醚＝1:2)，分离得C1。
b、称取取代羟基苯乙酮(1mmol)、C1(1mmol)、吡咯烷(1mmol)于50mL圆底烧瓶中，加入10mL乙醇做溶剂，40℃反应36h后，反应结束，有黄色固体析出，抽滤，由乙酸乙酯重结晶得到产物D1。
c、取上步中间体产物D1(0.5mmol)和单质碘(0.005mmol)于反应管中，加入二甲基亚砜(1mL/mmol)溶解后。130℃条件下反应4～6h，TLC监测反应，待反应完成后，将反应液逐滴加入装有冰水混合物的100mL的烧杯中搅拌，析出淡黄色固体，抽滤、干燥、通过柱层析(乙酸乙酯：石油醚＝1:3)得到产物H1。H1为白色固体粉末，收率90％，熔点：193-197℃。1HNMR(600MHz,CDCl3):δ8.27(d,J＝8.2Hz,1H),7.65(t,J＝7.8Hz,1H),7.28(d,J＝8.4Hz,1H),7.02(d,J＝16.2Hz,1H),6.89(d,J＝16.2Hz,1H),6.87(s,1H),6.80(d,J＝7.2Hz,2H),6.42(d,J＝7.2Hz,H),3.89(s,3H),3.72(t,J＝5.2Hz,6H).13C NMR(151MHz,CDCl3):δ173.36(s),163.97(s),162.31(s),160.96(s),157.47(s),146.85(s),142.56(s),141.89(s),135.75(s),133.61(s),132.11(s),130.51(s),127.14(s),127.04(s),124.85(s),128.08(s),120.15(s),115.78(s),113.98(s),103.94(s),100.63(s),57.61(s),57.46(s),56.89(s).MS(ESI):415.1440.(C26H23O5,[M+H]+)
实施例20：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-甲基-4H-苯并吡喃-4-酮(H2)的制备
Figure GDA0003062293980000201
本实施例的制备方法同实施例19，不同的是步骤b中以4-甲基-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D2，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-甲基-4H-苯并吡喃-4-酮H2。H2为白色固体粉末，收率61％，熔点：186-189℃。1H NMR(600MHz,CDCl3):δ8.66(d,J＝8.2Hz,1H),7.56(s,1H),7.32(d,J＝6.2,2H),7.23(s,1H),7.02(s,2H),6.91(d,J＝16.1Hz,1H),6.84(d,J＝8.6Hz,2H),6.71(d,J＝16.2Hz,1H),6.60(s,1H),3.91(s,3H),3.87(t,J＝14.1Hz,6H),2.61(s,3H).13CNMR(101MHz,CDCl3):δ175.27(s),162.78(s),160.29(s),159.73(s),156.29(s),147.14(s),145.65(s),142.22(s),139.47(s),131.87(s),130.13(s),128.89(s),126.93(s),124.89(s),123.64(s),120.73(s),118.87(s),99.87(s),98.79(s),113.18(s),110.76(s),56.85(s),55.81(s),55.95(s),20.95(s).MS(ESI):429.1697.(C27H25O5,[M+H]+)
实施例21：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-甲基-4H-苯并吡喃-4-酮(H3)的制备
Figure GDA0003062293980000211
本实施例的制备方法同实施例19，不同的是步骤b中以5-甲基-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D3，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-甲基-4H-苯并吡喃-4-酮H3。H3为白色固体粉末，收率59％，熔点：187-192℃。1H NMR(600MHz,CDCl3):δ8.23(s,1H),7.78(d,J＝8.6Hz,2H),7.56(d,J＝8.5Hz,1H),7.27(d,J＝8.5Hz,2H),7.20(d,J＝16.2Hz,1H),7.11(s,1H),6.89(d,J＝7.6Hz,2H),6.71(d,J＝16.2Hz,1H),6.65(s,1H),3.88(s,3H),3.65(d,J＝13.1Hz,6H),2.64(s,3H).13CNMR(101MHz,CDCl3):δ168.94(s),161.46(s),158.79(s),156.89(s),154.56(s),143.94(s),136.73(s),135.54(s),134.79(s),134.12(s),130.98(s),128.93(s),128.14(s),125.17(s),122.81(s),120.91(s),117.94(s),113.89(s),110.95(s),100.96(s),98.80(s),58.03(s),54.73(s),52.43(s),22.98(s).MS(ESI):429.1694(C27H25O5,[M+H]+)
实施例22：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6,7-二甲基-4H-苯并吡喃-4-酮(H4)的制备
Figure GDA0003062293980000221
本实施例的制备方法同实施例19，不同的是步骤b中以4,5-二甲基-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D4，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6,7-二甲基-4H-苯并吡喃-4-酮H4。H4为白色固体粉末，收率72％，熔点：203-207℃。1H NMR(600MHz,CDCl3):δ8.03(s,1H),7.32(d,J＝6.3Hz,1H),7.27(s,1H),7.26(s,2H),7.08(d,J＝16.0Hz,1H),6.93(s,1H),6.89–6.78(m,3H),6.61(d,J＝6.7Hz,1H),3.89(s,3H),3.78(d,J＝3.9Hz,6H),2.41(d,J＝7.5Hz,6H).13C NMR(101MHz,CDCl3):δ179.68(s),163.59(s),158.97(s),157.81(s),156.16(s),145.27(s),145.00(s),138.98(s),137.50(s),135.64(s),130.29(s),128.97(s),128.15(s),123.83(s),122.66(s),109.98(s),107.67(s),106.88(s),103.62(s),101.30(s),99.00(s),57.02(s),56.54(s),56.19(s),21.65(s),20.19(s).MS(ESI):443.1854.(C28H27O5,[M+H]+)
实施例23：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮(H5)的制备
Figure GDA0003062293980000222
本实施例的制备方法同实施例19，不同的是步骤b中以5-甲氧基-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D5，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮H5。H5为淡黄色固体粉末，收率66％，熔点：168-170℃。1H NMR(600MHz,DMSO):δ8.30(s,1H),7.32(d,J＝9.1Hz,1H),7.11(d,J＝2.7Hz,1H),7.04(dd,J＝7.9,2.7Hz,1H),6.98(d,J＝8.4Hz,2H),6.90(d,J＝16.2Hz,1H),6.81(s,1H),6.75(d,J＝6.8Hz,2H),6.68(d,J＝16.1Hz,1H),6.57(s,1H),3.54(d,J＝8.5Hz,6H),3.41(d,J＝14.7Hz,6H).13C NMR(101MHz,DMSO):δ178.09(s),164.72(s),161.29(s),159.73(s),156.44(s),149.82(s),146.91(s),141.76(s),140.53(s),131.79(s),129.02(s),125.83(s),122.48(s),120.70(s),117.63(s),115.05(s),114.28(s),112.05(s),100.96(s),98.92(s),96.80(s),57.86(s),55.09(s),53.51(s),45.05(s).MS(ESI):445.1650.(C27H25O6,[M+H]+)
实施例24：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6,7-二甲氧基-4H-苯并吡喃-4-酮(H6)的制备
Figure GDA0003062293980000231
本实施例的制备方法同实施例19，不同的是步骤b中以2-羟基-4,5-二甲氧基苯乙酮代替2-羟基苯乙酮，得到中间体D6，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6,7-二甲氧基-4H-苯并吡喃-4-酮H6。H6为淡黄色固体粉末，收率42％，熔点：188-192℃。1H NMR(600MHz,DMSO):δ8.09(s,1H),7.62(d,J＝8.2Hz,1H),7.12(d,J＝6.2Hz,1H),6.78(d,J＝8.4Hz,2H),6.90(d,J＝16.2Hz,1H),6.79(s,1H),6.58(d,J＝6.8Hz,2H),6.43(d,J＝16.1Hz,1H),6.37(s,1H),3.78(s,3H),3.54(d,J＝8.5Hz,6H),3.41(d,J＝14.7Hz,6H).13C NMR(101MHz,DMSO):δ178.09(s),164.72(s),161.29(s),159.73(s),156.44(s),149.82(s),146.91(s),141.76(s),140.53(s),131.79(s),129.02(s),125.83(s),122.48(s),120.70(s),117.63(s),115.05(s),114.28(s),112.05(s),100.96(s),98.92(s),96.80(s),57.86(s),55.09(s),53.51(s),42.05(s),39.67(s).MS(ESI):475.1760.(C28H27O7,[M+H]+)
实施例25：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-氟-4H-苯并吡喃-4-酮(H7)的制备
Figure GDA0003062293980000232
本实施例的制备方法同实施例19，不同的是步骤b中以4-氟-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D7，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-氟-4H-苯并吡喃-4-酮H7。H7为淡黄色固体粉末，收率78％，熔点：186-191℃。1H NMR(600MHz,DMSO):δ8.34(d,J＝5.6,1H),7.80(s,1H),7.31(dd,J＝8.9,3.7Hz,1H),7.01(t,J＝6.9Hz,1H),6.91(d,J＝6.3Hz,2H),6.86(d,J＝16.2Hz,1H),6.71(s,1H),6.52(t,J＝16.0Hz,2H),6.41(d,J＝6,3Hz,1H),6.21(s,1H),3.75(s,3H),3.62(d,J＝15.6Hz,6H).13C NMR(101MHz,DMSO):δ185.91(s),174.63(s),165.87(s),155.84(s),150.16(s),147.85(s),145.32(s),139.04(s),137.53(s),129.72(s),127.91(s),125.95(s),123.96(s),123.56(s),120.94(s),118.90(s),115.64(s),113.64(s),108.12(s),102.95(s),98.70(s),53.88(s),50.52(s),45.65(s).MS(ESI):433.1449.(C26H22FO5,[M+H]+)
实施例26：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-氟-4H-苯并吡喃-4-酮(H8)的制备
Figure GDA0003062293980000241
本实施例的制备方法同实施例19，不同的是步骤b中以5-氟-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D8，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-氟-4H-苯并吡喃-4-酮H8。H8为白色固体粉末，收率59％，熔点：216-220℃。1H NMR(600MHz,DMSO):δ8.39d,J＝6.3 1H),7.96(t,J＝8.3,16.1Hz,1H),7.72(dd,J＝8.9,3.7Hz,1H),7.64(t,J＝7.1Hz,1H),7.32(d,J＝8.3Hz,2H),7.26(d,J＝16.2Hz,1H),7.01(d,J＝26.2Hz,1H),6.82(t,J＝16.7Hz,2H),6.72(d,J＝16.2Hz,1H),6.61(s,1H),3.89(s,3H),3.70(d,J＝15.6Hz,6H).13C NMR(101MHz,DMSO):δ171.91(s),161.93(s),159.20(s),158.84(s),157.16(s),151.85(s),146.32(s),140.04(s),138.63(s),130.92(s),129.21(s),127.95(s),123.16(s),122.56(s),121.74(s),121.20(s),114.14(s),111.44(s),109.12(s),100.95(s),97.78(s),55.88(s),55.52(s),55.05(s).MS(ESI):433.1441.(C26H22FO5,[M+H]+)
实施例27：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-8-氯-4H-苯并吡喃-4-酮(H9)的制备
Figure GDA0003062293980000251
本实施例的制备方法同实施例19，不同的是步骤b中以3-氯-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D9，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-8-氯-4H-苯并吡喃-4-酮H9。H9为白色固体粉末，收率58％，熔点：231-234℃。1H NMR(600MHz,DMSO):δ8.45d,J＝6.3 1H),7.97(d,J＝8.3,16.1Hz,1H),7.66(d,J＝8.3,,1H),7.62(t,J＝7.1Hz,1H),7.42(d,J＝3.2Hz,2H),7.43(d,J＝16.2Hz,1H),7.23(d,J＝6.1Hz,1H),6.83(d,J＝16.7Hz,2H),6.70(s,1H),6.59(s,1H),3.78(s,3H),3.68(d,J＝8.4Hz,6H).13C NMR(101MHz,DMSO):δ182.91(s),167.63(s),160.16(s),159.864(s),158.06(s),152.75(s),148.02(s),141.24(s),139.53(s),131.52(s),128.91(s),128.05(s),122.16(s),121.56(s),120.74(s),120.20(s),115.14(s),112.14(s),108.62(s),100.35(s),96.78(s),57.12(s),54.82(s),52.05(s).MS(ESI):449.1147.(C26H22ClO5,[M+H]+)
实施例28：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-氯-4H-苯并吡喃-4-酮(H10)的制备
Figure GDA0003062293980000252
本实施例的制备方法同实施例19，不同的是步骤b中以4-氯-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D10，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-氯-4H-苯并吡喃-4-酮H10。H10为白色固体粉末，收率68％，熔点：221-225℃。1H NMR(600MHz,CDCl3):δ8.23d,J＝7.2 1H),7.88(d,J＝11.3Hz,1H),7.64(s1H),7.54(d,J＝6.2Hz,1H),7.28(d,J＝8.3Hz,2H),7.18(d,J＝16.1Hz,1H),7.09(d,J＝6.1Hz,2H),6.88(d,J＝16.0Hz,1H),6.45(s,1H),6.33(s,1H),3.89(s,3H),3.59(s,3H),3.45(s,3H).13C NMR(101MHz,CDCl3):δ187.51(s),175.63(s),168.26(s),159.84(s),158.16(s),156.15(s),149.12(s),145.14(s),140.43(s),133.62(s),129.91(s),128.25(s),122.46(s),120.86(s),119.74(s),118.20(s),115.64(s),112.04(s),109.62(s),99.35(s),95.78(s),58.12(s),52.82(s),50.05(s).MS(ESI):471.0970.(C26H21ClO5Na,[M+Na]+)
实施例29：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-氯-4H-苯并吡喃-4-酮(H11)的制备
Figure GDA0003062293980000261
本实施例的制备方法同实施例19，不同的是步骤b中以5-氯-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D11，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-氯-4H-苯并吡喃-4-酮H11。H11为白色固体粉末，收率71％，熔点：227-229℃。1H NMR(600MHz,CDCl3):δ8.33d,J＝5.6 1H),7.67(d,J＝8.3Hz,1H),7.77(s 1H),7.68(d,J＝3.5Hz,1H),7.34(d,J＝6.8Hz,2H),7.23(d,J＝16.1Hz,1H),7.11(s,2H),6.56(d,J＝16.0Hz,1H),6.23(s,1H),6.15(s,1H),3.67(s,3H),3.45(s,3H),3.34(s,3H).13C NMR(101MHz,CDCl3):δ179.51(s),170.73(s),168.66(s),160.24(s),158.56(s),154.65(s),148.12(s),146.34(s),137.73(s),134.62(s),128.93(s),127.85(s),124.46(s),119.86(s),113.84(s),110.78(s),108.64(s),100.04(s),98.62(s),78.35(s),74.78(s),46.88(s),45.82(s),41.65(s).MS(ESI):471.0970.(C26H21ClO5Na,[M+Na]+)
实施例30：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-溴-4H-苯并吡喃-4-酮(H12)的制备
Figure GDA0003062293980000262
本实施例的制备方法同实施例19，不同的是步骤b中以4-溴-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D12，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-7-溴-4H-苯并吡喃-4-酮H12。H12为白色固体粉末，收率75％，熔点：219-220℃。1H NMR(600MHz,CDCl3):δ8.13(s,1H),7.87(d,J＝6.3Hz,1H),7.83(s,1H),7.57(d,J＝8.0Hz,1H),7.34(s,2H),7.13(d,J＝16.1Hz,1H),7.09(s,2H),6.76(d,J＝16.0Hz,1H),6.03(s,1H),5.98(s,1H),3.71(s,3H),3.56(s,3H),3.22(s,3H).13C NMR(101MHz,CDCl3):δ181.51(s),172.87(s),169.16(s),161.34(s),159.46(s),154.35(s),150.32(s),147.64(s),134.73(s),130.12(s),128.23(s),126.55(s),124.36(s),118.86(s),113.54(s),111.78(s),109.74(s),101.02(s),99.32(s),86.35(s),79.28(s),56.88(s),55.12(s),40.25(s).MS(ESI):515.0465.(C26H21BrO5Na,[M+Na]+)
实施例31：(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮(H13)的制备
Figure GDA0003062293980000271
本实施例的制备方法同实施例19，不同的是步骤b中以5-溴-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D13，按照实施例19从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-甲氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮H13。H13为白色固体粉末，收率88％，熔点：225-229℃。1H NMR(600MHz,CDCl3):δ8.33(s,1H),7.92(d,J＝3.2Hz,1H),7.46(s,1H),7.29(d,J＝11.2Hz,1H),7.10(s,2H),6.71(d,J＝16.1Hz,1H),6.67(s,2H),6.36(d,J＝16.0Hz,1H),6.02(s,1H),5.89(s,1H),3.66(s,3H),3.36(s,3H),3.20(s,3H).13C NMR(101MHz,CDCl3):δ180.51(s),176.87(s),162.96(s),160.34(s),158.96(s),154.15(s),151.32(s),148.34(s),136.73(s),131.12(s),129.53(s),126.65(s),125.16(s),119.86(s),113.44(s),110.78(s),106.74(s),101.32(s),98.32(s),85.35(s),77.28(s),55.84(s),53.42(s),50.25(s).MS(ESI):515.0465.(C26H21BrO5Na,[M+Na]+)
实施例32：(E)-3-(2,4-二甲氧基-6-((E)-4-乙氧基苯乙烯基)苯基)-1-(2-苯基)丙-2-烯-1-酮(H14)的制备
Figure GDA0003062293980000281
a、称取(E)-3,5-二甲氧基-4'-羟基苯乙烯(A,1mmol)于50mL圆底烧瓶中，加入15mL丙酮溶解，加入四丁基溴化铵(TBAB,1.2mmol)、无水K2CO3(1.2mmol)，搅拌5min后加入溴代乙烷(1mmol)，保持回流反应，TLC监测，反应完全后抽滤，干燥，经柱层析得B2。
b、先向N,N-二甲基甲酰胺中加入B1，然后于冰浴中缓慢滴加三氯氧磷，B2与三氯氧磷的摩尔比为1:1，滴加完毕后恢复至室温反应，1h后停止反应，随后将反应液逐滴加入到冰水与乙酸乙酯的混合溶液中，冰水与乙酸乙酯的体积比为5:1，再分次加入碳酸钠固体直至无气泡产生，搅拌过夜后析出淡黄色固体，抽滤、干燥，最后柱层析(二氯甲烷：石油醚＝1:2)，分离得C2。
c、称取2-羟基苯乙酮(1mmol)、C2(1mmol)、吡咯烷(1mmol)于50mL圆底烧瓶中，加入10mL乙醇做溶剂，40℃反应36h后，反应结束，有黄色固体析出，抽滤，由乙酸乙酯重结晶得到产物D2。
d、取上步产物中间体产物D2(0.5mmol)和单质碘(0.005mmol)于反应管中，加入二甲基亚砜(1mL/mmol)溶解后。130℃条件下反应4～6h，TLC监测反应，待反应完成后，将反应液逐滴加入装有冰水混合物的100mL的烧杯中搅拌，析出淡黄色固体，抽滤、干燥、通过柱层析(乙酸乙酯：石油醚＝1:3)得到产物H14。H14为白色固体粉末，收率93％，熔点：178-180℃。1H NMR(600MHz,CDCl3):δ8.13(d,J＝3.2Hz,1H),7.96(s,1H),7.56(s,1H),7.32(d,J＝10.2Hz,1H),7.15(s,2H),6.82(d,J＝16.1Hz,1H),6.56(s,2H),6.42(d,J＝16.1Hz,1H),6.11(s,1H),5.92(s,1H),3.56(s,3H),3.23(s,3H),3.01(dd,2H),1.58(t,J＝3.2Hz 3H).13C NMR(101MHz,CDCl3):δ181.53(s),174.57(s),163.46(s),161.24(s),159.74(s),153.45(s),150.46(s),149.20(s),137.93(s),130.56(s),128.78(s),125.93(s),123.59(s),118.05(s),111.97(s),109.64(s),106.89(s),100.98(s),96.83(s),84.96(s),74.95(s),54.43(s),52.34(s),50.29(s),42.89(s)MS(ESI):451.1516.(C27H24O5Na,[M+Na]+)
实施例33：(E)-2-(2,4-二甲氧基-6-(4-乙氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮(H15)的制备
Figure GDA0003062293980000291
本实施例的制备方法同实施例32，不同的是步骤b中以5-甲氧基-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D15，按照实施例30从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-乙氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮H15。H15为白色固体粉末，收率83％，熔点：167-169℃。1H NMR(600MHz,CDCl3):δ8.03(d,J＝3.1Hz,1H),7.86(s,1H),7.55(s,1H),7.31(d,J＝8.2Hz,1H),7.18(s,2H),6.80(d,J＝16.1Hz,1H),6.61(s,2H),6.51(d,J＝16.1Hz,1H),6.34(s,1H),6.21(s,1H),3.53(d,J＝3.2Hz 6H),3.23(s,3H),3.01(dd,2H),1.58(t,J＝3.2Hz,3H).13C NMR(101MHz,CDCl3):δ180.24(s),175.23(s),165.85(s),161.97(s),149.74(s),143.45(s),139.56(s),128.97(s),126.43(s),124.56(s),120.78(s),118.93(s),113.59(s),107.05(s),102.97(s),100.64(s),98.89(s),86.98(s),84.83(s),80.96(s),67.95(s),45.43(s),42.34(s),40.89(s),40.09(s),35.27(s).MS(ESI):481.1622.(C28H26O6Na,[M+Na]+)。
实施例34：(E)-2-(2,4-二甲氧基-6-(4-乙氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮(H16)的制备
Figure GDA0003062293980000292
本实施例的制备方法同实施例32，不同的是步骤b中以5-溴-2-羟基苯乙酮代替2-羟基苯乙酮，得到中间体D16，按照实施例30从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-乙氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮H16。H16为白色固体粉末，收率88％，熔点：243-244℃。1H NMR(600MHz,CDCl3):δ8.13(d,J＝3.7Hz,1H),7.81(d,J＝6.2Hz,1H),7.65(s,1H),7.24(d,J＝8.1Hz,1H),7.10(s,2H),6.82(d,J＝16.0Hz,1H),6.57(s,2H),6.47(d,J＝16.2Hz,1H),6.24(s,1H),6.19(s,1H),3.45(s,3H),3.21(s,3H),3.02(dd,2H),1.62(t,J＝3.2Hz,3H).13C NMR(101MHz,CDCl3):δ179.64(s),175.13(s),163.45(s),162.97(s),152.85(s),150.45(s),149.43(s),126.34(s),125.83(s),123.78(s),121.53(s),119.53(s),115.73(s),108.25(s),103.52(s),101.47(s),100.89(s),98.25(s),91.33(s),83.32(s),75.95(s),52.55(s),49.43(s),47.16(s),39.96(s),.MS(ESI):529.0621.(C27H23BrO5Na,[M+Na]+)
实施例35：(E)-3-(2,4-二甲氧基-6-((E)-4-丁氧基苯乙烯基)苯基)-1-(2-苯基)丙-2-烯-1-酮(H17)的制备
Figure GDA0003062293980000301
本实施例的制备方法同实施例32，不同的是步骤a中以溴丁烷代替溴乙烷，得到中间体B3，按照实施例30从而得到目标化合物(E)-3-(2,4-二甲氧基-6-((E)-4-丁氧基苯乙烯基)苯基)-1-(2-苯基)丙-2-烯-1-酮H17。H17为淡黄色固体粉末，收率89％，熔点：167-169℃。1H NMR(600MHz,CDCl3):δ8.31(d,J＝2.4Hz,1H),7.82(d,J＝9.0,2.4Hz,1H),7.61(d,J＝8.9Hz,1H),7.32(s,1H),7.01(d,J＝16.0Hz,1H),6.87(d,J＝2.1Hz,1H),6.79(d,J＝8.7Hz,2H),6.66(d,J＝16.1Hz,1H),6.50(d,J＝2.1Hz,1H),6.22(s,1H),4.00(q,J＝7.0Hz,2H),3.93(s,3H),3.78(d,J＝6.2,2H),2.86(d,J＝9.8 2H),2.78(d,J＝9.0 2H),1.38(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ181.21(s),172.65(s),159.27(s),149.08(s),145.09(s),140.47(s),139.05(s),135.67(s),130.28(s),129.53(s),123.33(s),120.63(s),120.34(s),119.38(s),116.91(s),114.83(s),110.74(s),100.66(s),100.15(s),99.85(s),97.30(s),66.49(s),57.01(s),55.17(s),53.54(s),48.57(s),44.78(s).MS(ESI):457.2016.(C29H29O5,[M+H]+)
实施例36：(E)-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮(H18)的制备
Figure GDA0003062293980000311
本实施例的制备方法同实施例33，不同的是步骤a中以溴丁烷代替溴乙烷，得到中间体B3，按照实施例33从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮H18。H18为淡黄色固体粉末，收率78％，熔点：169-171℃。1H NMR(600MHz,CDCl3):δ8.13(d,J＝3.2Hz,1H),7.87(d,J＝8.6,1H),7.67(d,J＝6.1Hz,1H),7.57(s2H),7.01(d,J＝16.0Hz,1H),6.90(d,J＝3.1Hz,1H),6.63(d,J＝6.7Hz,1H),6.53(d,J＝16.1Hz,1H),6.45(d,J＝2.1Hz,1H),6.35(s,1H),4.71(q,J＝7.0Hz,2H),3.92(s,3H),3.71(s,3H),3.31(d,J＝6.1,2H),2.80(d,J＝9.8 2H),2.71(d,J＝9.0 2H),1.64(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ186.21(s),171.65(s),162.87(s),160.24(s),157.29(s),143.98(s),141.75(s),139.82(s),135.28(s),134.13(s),129.36(s),128.94(s),127.18(s),124.41(s),123.45(s),122.63(s),119.54(s),114.86(s),110.05(s),101.75(s),99.90(s),65.49(s),56.51(s),52.57(s),50.12(s),48.02(s),44.57(s),14.78(s).MS(ESI):487.2115.(C30H31O6,[M+H]+)。
实施例37：(E)-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮(H19)的制备
Figure GDA0003062293980000312
本实施例的制备方法同实施例34，不同的是步骤a中以溴丁烷代替溴乙烷，得到中间体B3，按照实施例34从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-丁氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮H19。H19为淡黄色固体粉末，收率79％，熔点：265-267℃。1HNMR(600MHz,CDCl3):δ8.12(d,J＝3.2Hz,1H),8.02(d,J＝6.6,2.4Hz,1H),7.85(d,J＝8.2Hz,1H),7.78(s,2H),7.62(d,J＝16.0Hz,1H),7.08(d,J＝3.4Hz,1H),6.78(d,J＝8.0Hz,1H),6.67(d,J＝16.1Hz,1H),6.54(d,J＝2.1Hz,1H),6.42(s,1H),4.88(q,J＝7.0Hz,2H),3.89(s,3H),3.56(s,3H),2.87(d,J＝9.8 2H),2.70(d,J＝9.0 2H),1.67(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ181.91(s),162.65(s),157.27(s),156.08(s),155.09(s),140.48(s),139.05(s),138.67(s),137.28(s),130.53(s),128.63(s),128.94(s),127.08(s),121.91(s),120.86(s),120.13(s),118.74(s),115.16(s),110.65(s),105.35(s),98.90(s),66.19(s),57.11(s),55.27(s),53.62(s),52.12(s),15.28(s).MS(ESI):557.0834.(C29H27BrO5Na,[M+Na]+)
实施例38：(E)-3-(2,4-二甲氧基-6-((E)-4-苄氧基苯乙烯基)苯基)-1-(2-苯基)丙-2-烯-1-酮(H20)的制备
Figure GDA0003062293980000321
本实施例的制备方法同实施例32，不同的是步骤a中以苄基溴代替溴乙烷，得到中间体B4，按照实施例30从而得到目标化合物(E)-3-(2,4-二甲氧基-6-((E)-4-苄氧基苯乙烯基)苯基)-1-(2-苯基)丙-2-烯-1-酮H20。H20为淡黄色固体粉末，收率92％，熔点：156-157℃。1H NMR(600MHz,CDCl3):δ8.14(d,J＝3.1Hz,1H),7.83(d,J＝9.0,2.4Hz,2H),7.59(d,J＝8.9Hz,2H),7.34(s 2H),7.06(d,J＝16.0Hz,1H),6.97(d,J＝2.1Hz,3H),6.79(d,J＝8.7Hz,2H),6.66(d,J＝16.1Hz,1H),6.50(d,J＝2.1Hz,1H),6.22(s,1H),4.00(s,2H),3.93(s,3H),3.38(s,3H).13C NMR(101MHz,CDCl3):δ181.91(s),162.65(s),160.27(s),159.48(s),157.09(s),156.48(s),152.05(s),151.67(s),145.28(s),140.05(s),139.67(s),136.28(s),131.53(s),129.33(s),128.04(s),127.98(s),122.91(s),122.86(s),120.63(s),117.74(s),114.66(s),110.75(s),101.35(s),97.90(s),63.49(s),56.01(s),55.57(s).MS(ESI):491.1853.(C32H27O5,[M+H]+)
实施例39：(E)-2-(2,4-二甲氧基-6-(4-苄氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮(H21)的制备
Figure GDA0003062293980000331
本实施例的制备方法同实施例33，不同的是步骤a中以苄基溴代替溴乙烷，得到中间体B4，按照实施例33从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-苄氧基苯乙烯基)苯基)-6-甲氧基-4H-苯并吡喃-4-酮H21。H21为淡黄色固体粉末，收率76％，熔点：231-232℃。1H NMR(600MHz,CDCl3):δ8.14(d,J＝2.9Hz,1H),7.93(d,J＝8.0,2.4Hz,2H),7.69(d,J＝3.2Hz,2H),7.36(s,2H),7.17(d,J＝16.0Hz,1H),6.94(d,J＝3.1Hz,3H),6.76(d,J＝8.7Hz,2H),6.71(d,J＝16.1Hz,1H),6.48(d,J＝2.1Hz,1H),6.21(s,1H),3.78(s,2H),3.56(s,3H),3.42(s,3H).13C NMR(101MHz,CDCl3):δ181.67(s),163.72(s),160.62(s),158.98(s),157.19(s),156.36(s),152.17(s),150.81(s),145.28(s),140.05(s),138.82(s),136.28(s),131.53(s),129.33(s),128.04(s),127.98(s),122.91(s),122.86(s),120.63(s),117.74(s),114.66(s),110.75(s),101.35(s),97.90(s),66.52(s),56.91(s),53.61(s),45.91.MS(ESI):521.1959.(C33H29O6,[M+H]+)。
实施例40：(E)-2-(2,4-二甲氧基-6-(4-苄氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮(H22)的制备
Figure GDA0003062293980000332
本实施例的制备方法同实施例34，不同的是步骤a中以苄基溴代替溴乙烷，得到中间体B4，按照实施例34从而得到目标化合物(E)-2-(2,4-二甲氧基-6-(4-苄氧基苯乙烯基)苯基)-6-溴-4H-苯并吡喃-4-酮H22。H22为淡黄色固体粉末，收率78％，熔点：259-260℃。1HNMR(600MHz,CDCl3):δ8.23(d,J＝3.2Hz,1H),7.91(d,J＝6.2,2H),7.67(d,J＝2.4Hz,2H),7.38(s,2H),7.22(d,J＝16.2Hz,1H),6.84(d,J＝2.2Hz,3H),6.58(d,J＝8.1Hz,2H),6.42(d,J＝16.0Hz,1H),6.31(d,J＝2.4Hz,1H),6.20(s,1H),3.67(s,2H),3.31(s,3H).13C NMR(101MHz,CDCl3):δ182.69(s),164.92(s),161.82(s),157.54(s),157.01(s),156.36(s),152.17(s),150.81(s),145.28(s),140.05(s),138.92(s),136.28(s),131.53(s),129.33(s),128.14(s),127.26(s),122.73(s),122.86(s),121.63(s),117.52(s),114.74(s),110.16(s),101.54(s),100.83(s),67.62(s),55.73(s),50.96(s).MS(ESI):591.0778.(C32H25BrO5Na,[M+Na]+)
实施例41：白藜芦醇丙烯酸(酚)酯类衍生物对LPS刺激的RAW264.7释放NO的影响
以LPS刺激小鼠RAW 264.7细胞为炎症细胞模型，采用Griess法测定细胞上清液中NO含量，检测了白藜芦醇类黄酮类类衍生物对LPS刺激的RAW264.7释放NO的影响。
取对数生长期的细胞以7×104个/孔接种于24孔板中，培养24h。实验共分3分组，弃去原先培养基。空白对照组用500μL新培养基培养细胞，LPS刺激组同样加入500μL新培养基，给药组加入含有40μM化合物的培养基500μL。1h后，LPS刺激组和给药组均给予0.5μLLPS刺激，空白对照组不加LPS。干预24h后,收集各孔细胞上清液，用Griess法检测并计算NO细胞浓度
(11)初步构效关系分析与讨论
通过Griess法检测并计算NO细胞浓度，我们测定了40个含有类黄酮的白藜芦醇衍生物对LPS刺激的RAW264.7释放NO的影响，活性结果见表1。
表1本发明所列含类黄酮类的白藜芦醇类衍生物抗炎活性(IC50,μM)
Figure GDA0003062293980000341
Figure GDA0003062293980000351
a Antiinflammatory activity was measured by the Griess method.Valuesare the average of three independent experiments run in triplicate.Variationwas generally 5-10％.
由表1可以看出，复筛所选的化合物除了F8、F10、F16、H10、H11、H12、H19、H22外，其他化合物均表现出了较好的NO抑制率。

Claims (4)

1.一种含有类黄酮的白藜芦醇类衍生物，其特征在于其结构如下所示：
Figure FDA0003062293970000011
2.一种权利要求1所述的含有类黄酮的白藜芦醇类衍生物的制备方法，其特征在于包括如下步骤：
步骤a、称取(E)-3,5-二甲氧基-4'-羟基苯乙烯1mmol于50mL圆底烧瓶中，加入15mL丙酮溶解，加入四丁基溴化铵1.2mmol、无水K2CO31.2mmol，搅拌5min后加入溴代烷1mmol，保持回流反应，TLC监测，反应完全后抽滤，干燥，经柱层析分离得B2-3；
所述溴代烷的结构式为：R2′-Br，其中R2′选自正丁基；
所述B2-3的结构式为：
Figure FDA0003062293970000012
步骤b、先向N,N-二甲基甲酰胺中加入B2-3，然后于冰浴中缓慢滴加三氯氧磷，滴加完毕后恢复至室温反应，1h后停止反应，随后将反应液逐滴加入到冰水与乙酸乙酯的混合溶液中，再分次加入碳酸钠固体直至无气泡产生，搅拌过夜后析出淡黄色固体，抽滤、干燥，最后柱层析分离得C1-3；
所述C1-3的结构式为：
Figure FDA0003062293970000013
R2为正丁基；
步骤c、称取取代羟基苯乙酮1mmol、C1-31mmol、吡咯烷1mmol于50mL圆底烧瓶中，加入10mL乙醇做溶剂，40℃反应36h，反应结束，有黄色固体析出，抽滤，由乙酸乙酯重结晶得到产物D17-18；
所述取代羟基苯乙酮结构式为：
Figure FDA0003062293970000021
其中R1选自5-OCH3或5-Br；
所述D17-18的结构式为：
Figure FDA0003062293970000022
步骤d、取上步产物D17-180.5mmol于50mL圆底烧瓶中，加入10mL甲醇溶解，再加入NaOH固体2.5mmol，用移液枪取30％的H2O2溶液2.5mmol滴加入到混合溶液中，40℃条件下反应48h，随后停止反应；将反应液滴加至冰水混合液中，滴加稀盐酸，不停搅拌，同时监测溶液的pH值，保持在5-6之间，析出固体后抽滤、干燥、柱层析分离，得到目标产物。
3.根据权利要求2所述的制备方法，其特征在于：
步骤b中，B2-3与三氯氧磷的摩尔比为1:1，冰水与乙酸乙酯的体积比为5:1。
4.一种权利要求1所述的含有类黄酮的白藜芦醇类衍生物的用途，其特征在于：是在制备具有抑制LPS刺激的RAW264.7释放NO作用的单胺氧化酶抑制剂中的应用。
CN201810293506.4A 2018-03-30 2018-03-30 一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途 Active CN108558813B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810293506.4A CN108558813B (zh) 2018-03-30 2018-03-30 一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810293506.4A CN108558813B (zh) 2018-03-30 2018-03-30 一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途

Publications (2)

Publication Number Publication Date
CN108558813A CN108558813A (zh) 2018-09-21
CN108558813B true CN108558813B (zh) 2021-07-23

Family

ID=63534002

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810293506.4A Active CN108558813B (zh) 2018-03-30 2018-03-30 一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途

Country Status (1)

Country Link
CN (1) CN108558813B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041204A (zh) * 2019-04-10 2019-07-23 合肥工业大学 一种白藜芦醇硝基乙烯类化合物及其制备方法和用途
CN110105316B (zh) * 2019-06-18 2022-10-21 合肥工业大学 一种白藜芦醇-苯酞杂合类化合物及其制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015104298A2 (de) * 2014-01-07 2015-07-16 Analytical Services Polyphenol-konjugate
CN104892556A (zh) * 2015-05-29 2015-09-09 合肥工业大学 一类二苯乙烯香豆素类衍生物及其制备方法与用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015104298A2 (de) * 2014-01-07 2015-07-16 Analytical Services Polyphenol-konjugate
CN104892556A (zh) * 2015-05-29 2015-09-09 合肥工业大学 一类二苯乙烯香豆素类衍生物及其制备方法与用途

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
1H and 13C NMR spectral assignments of flavone derivatives.;Beom Soo Kim等;《Magn. Reson. Chem.》;20161023;第55卷;第359-366页 *
白藜芦醇衍生物的合成及抗炎活性评价;程慧洁;《合肥工业大学硕士学位论文》;20170731;参见全文，特别是第14-41、44-63、66-67页 *
白藜芦醇衍生物的设计合成及活性评价;葛为为;《合肥工业大学硕士学位论文》;20180301;参见全文，特别是第14-38页 *
程慧洁.白藜芦醇衍生物的合成及抗炎活性评价.《合肥工业大学硕士学位论文》.2017,全文，特别是第14-15、44-63、66-67页. *
黄酮类衍生物的合成;钟国琛等;《合成化学》;20110831;第19卷(第4期);第561-563页 *

Also Published As

Publication number Publication date
CN108558813A (zh) 2018-09-21

Similar Documents

Publication Publication Date Title
Yadav et al. Antimalarial activity of newly synthesized chalcone derivatives in vitro
CA2584485C (en) Stilbenes and chalcones for the prevention and treatment of cardiovascular diseases
Robinson et al. Synthesis and biological evaluation of aromatic enones related to curcumin
Kamal et al. Synthesis and anticancer activity of 4β-alkylamidochalcone and 4β-cinnamido linked podophyllotoxins as apoptotic inducing agents
EP1670484A1 (en) Nitric oxide donating derivatives for the treatment of cardiovascular disorders
CN108558813B (zh) 一种含有类黄酮的白藜芦醇类衍生物及其制备方法和用途
Park et al. Total synthesis of chiricanine A, arahypin-1, trans-arachidin-2, trans-arachidin-3, and arahypin-5 from peanut seeds
Reddy et al. Bis-chalcone analogues as potent NO production inhibitors and as cytotoxic agents
Kim et al. Pyranoflavanones and pyranochalcones from the fruits of Amomum tsao-ko
Letcher et al. Chemical constituents of the combretaceae. Part III. Substituted phenanthrenes, 9, 10-dihydrophenanthrenes, and bibenzyls from the heartwood of Combretum psidioides
Liang et al. Synthesis and in vitro and in vivo antitumour activity study of 11-hydroxyl esterified bergenin/cinnamic acid hybrids
WO1994020456A1 (en) Stilbene derivative and stilbene analog derivative, and use thereof
Saito et al. Synthesis and structure–activity relationship studies of furan-ring fused chalcones as antiproliferative agents
CN101066912B (zh) 一种反式多羟基二苯乙烯的制备方法
Master et al. Design and synthesis of low molecular weight compounds with complement inhibition activity
Yuan et al. Synthesis and biological evaluation of novel 1-aryl, 5-(phenoxy-substituted) aryl-1, 4-pentadien-3-one derivatives
Ko et al. Structure-activity relationship studies on chalcone derivatives: potent inhibition of platelet aggregation
CN107417532B (zh) 一种白藜芦醇丙烯酸酚酯类衍生物及其制备方法和用途
CN101485651B (zh) 二氢查尔酮衍生物及其应用
Khrimian et al. Absolute configurations of stink bug-and plant-produced sesquipiperitols via synthesis of all stereoisomers
Schroeder et al. Synthesis of a coumarin-based analogue of Schweinfurthin F
CN106946828B (zh) 东莨菪内酯酚醚衍生物及其制备方法和应用
Opletalová et al. Synthesis and biological evaluation of (E)-3-(nitrophenyl)-1-(pyrazin-2-yl) prop-2-en-1-ones
Harmalkar et al. Total synthesis of gramistilbenoids A, B, and C
CN106146394B (zh) 3，4-二羟基苯乙醇烟酸酯及其制备方法和应用

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