联苯双酯 | 73536-69-3

• 物质功能分类: 原料药 - 消化系统用药 - 肝病用药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 单宁
• 中文名称: 联苯双酯
• 中文别名: 4,4'-二甲氧基-5,6,5',6'-双亚甲二氧联苯-2,2'-二甲酸二甲酯；右旋糖酐20；4,4"-二甲氧基-5,6,5",6"-双亚甲二氧联苯-2,2"-二甲酸二甲酯
• 英文名称: DDB
• 英文别名: bifendate；bifendatatum；dimethyl 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate；methyl 7-methoxy-4-(7-methoxy-5-methoxycarbonyl-1,3-benzodioxol-4-yl)-1,3-benzodioxole-5-carboxylate
• CAS: 73536-69-3
• 化学式: C₂₀H₁₈O₁₀
• 分子量: 418.357
• InChiKey: JMZOMFYRADAWOG-UHFFFAOYSA-N

物化性质

• 熔点：
  179-181 °C
• 沸点：
  606.9±55.0 °C(Predicted)
• 密度：
  1.390±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  108
• 氢给体数：
  0
• 氢受体数：
  10

ADMET

代谢

Bifendate 已知的代谢物包括甲基 4-(2,3-二羟基-4-甲氧基-6-甲氧羰基苯基)-7-甲氧基-1,3-苯并二氧杂环戊烷-5-羧酸酯和单-O-去甲基化 BDD。

Bifendate has known human metabolites that include methyl 4-(2,3-dihydroxy-4-methoxy-6-methoxycarbonylphenyl)-7-methoxy-1,3-benzodioxole-5-carboxylate and Mono-O-demethylated bdd.

来源:NORMAN Suspect List Exchange

安全信息

• 海关编码：
  2932992000
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存储条件：0-10°C，需置于惰性气体中，避免与空气接触和加热。

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Bifendatatum
Synonyms: 7,7’-Dimethoxy-(4,4’-bi-1,3-benzodioxole)-5,5’-dicarboxylic acid dimethyl ester

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Bifendatatum
CAS number: 73536-69-3

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C20H18O10
Molecular weight: 418.4

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

概述

联苯双酯是我国自主研发的一种治疗肝炎的降酶药物。它具有很高的生物活性，能够显著降低血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平，增强肝脏解毒功能，并有抗肝细胞坏死的作用。该药物对化疗药物如甲氨蝶呤、5-氟尿嘧啶等引起的中毒性肝炎有明显的治疗效果，且毒性极低，无致畸、致突变效应。药理研究表明联苯双酯还具有一定的抗癌活性。临床主要用于迁延性、慢性肝炎患者以及因药物引起的丙氨酸氨基转移酶持续升高的患者。

作用

联苯双酯能够显著降低丙氨酸氨基转移酶（ALT）水平，对由肝炎或药物引起血清丙氨酸氨基转移酶升高患者具有明显的降酶效果，并且不良反应较少。随疗程延长而逐渐提高降酶效果，尤其对单项丙氨酸氨基转移酶高者效果更佳。对HBsAg阴性者的疗效明显优于阳性者。此外，联苯双酯对肝炎的主要症状有一定改善作用，但对肝、脾肿大无显著影响。

用途

1. 慢性迁延性肝炎：用于丙氨酸氨基转移酶长期增高的患者。
2. 单项丙氨酸氨基转移酶升高：适用于无其他肝功能异常者。
3. 化学药物引起的丙氨酸氨基转移酶升高：可用于治疗由化疗药物等引起的肝损伤。

合成方法

联苯双酯的合成首先通过没食子酸与甲醇在浓硫酸催化下回流得到没食子酸甲酯。将该产物溶于硼砂水溶液中，分别滴加硫酸二甲酯及氢氧化钠溶液进行反应，生成3,4-二羟基-5-甲氧基苯甲酸甲酯。再与二氯甲烷、无水碳酸钾和N,N-二甲基甲酰胺回流反应，得到3,4-亚甲二氧基-5-甲氧基苯甲酸甲酯。最后在氯仿中进行溴化，并通过乌尔曼反应制得联苯双酯。

图1展示了联苯双酯的合成路线。

药动学

联苯双酯口服吸收约30%，肝脏首过效应明显，24小时内约70%由粪便排出。滴丸剂的生物利用度是片剂的1.25～2.37倍。

上述概述、作用、药动学及合成方法信息由Chemicalbook的侍艳编辑整理（2015-12-28）。

禁忌

1. 肝硬化患者。
2. 孕妇及哺乳期妇女。

注意事项

1. 少数病人在用药过程中ALT可回升，加大剂量可能使之降低。停药后部分患者ALT反跳，但继续服药仍有效。
2. 个别患者于服药过程中可出现黄疸及病情恶化，应立即停药。
3. 慢性肝炎患者及老年患者慎用。

药物相互作用

肌苷可以减少联苯双酯的降酶反跳现象。

用途

抗肝炎药物，用于慢性迁延性肝炎、慢性活动性肝炎等疾病的治疗。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  7,7-二甲氧基-[4,4]bi[苯并[1,3]二氧代]-5,5-二羧酸	4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-2,2'-dibenzoic acid	105868-34-6	C18H14O10	390.303

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	7,7'-dimethoxy-5'-(methoxycarbonyl)-4,4'-bibenzo[d][1,3]dioxole-5-carboxylic acid	211996-66-6	C19H16O10	404.33
  ——	dimethyl 2',3'-methylenedioxy-2,3,4,4'-tetramethoxy-1,1'-biphenyl-6,6'-dicarboxylate	118503-15-4	C21H22O10	434.4
  5'-(羟甲基)-7,7'-二甲氧基-[4,4'-二苯并[D][1,3]1,3-二氧杂环戊烯E]-5-甲酸甲酯	bicyclol	118159-48-1	C19H18O9	390.347
  ——	Methyl 4-(2,3-dihydroxy-4-methoxy-6-methoxycarbonylphenyl)-7-methoxy-1,3-benzodioxole-5-carboxylate	347885-76-1	C19H18O10	406.346
  7,7-二甲氧基-[4,4]bi[苯并[1,3]二氧代]-5,5-二羧酸	4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-2,2'-dibenzoic acid	105868-34-6	C18H14O10	390.303
  ——	4-[5-(Hydroxymethyl)-7-methoxy-1,3-benzodioxol-4-yl]-7-methoxy-1,3-benzodioxole-5-carboxylic acid	854750-47-3	C18H16O9	376.32
  ——	dimethyl 2,3-acetoxymethylenedioxy-2',3'-methylenedioxy-4,4'-dimethoxy-1,1'-biphenyl-6,6'-dicarboxylate	118503-25-6	C22H20O12	476.394
  ——	methyl 2'-chlorocarbonyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-biphenyl-2-carboxylate	502621-95-6	C19H15ClO9	422.776
  ——	5-(2-ethoxy-4-formylphenyl) 5'-methyl 7,7'-dimethoxy-4,4'-bibenzo[d][1,3]dioxole-5,5'-dicarboxylate	1350363-15-3	C28H24O12	552.491
  ——	(7,7′-dimethoxy-[4,4′-bibenzo[d][1,3]dioxole]-5,5′-diyl)dimethanol	——	C18H18O8	362.336

反应信息

• 作为反应物：
  描述：

  联苯双酯 在 盐酸 、 lithium aluminium tetrahydride 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 16.0h， 生成 N-(6-(4,10-dimethoxy-6H-[1,3]dioxolo[4',5':3,4]benzo[1,2-c][1,3]dioxolo[4',5':5,6]benzo[1,2-e]azepin-7(8H)-yl)hexyl)-2-methoxybenzamide
  参考文献：
  名称：

  具有潜在P-糖蛋白和肿瘤转移抑制剂的6,7-二氢-二苯并[ c，e ]]庚因骨架的联苯菊酯衍生物的合成和生物学评价

  摘要：

  作为先前研究的延续，合成了15个带有6,7-二氢-二苯并[c，e]氮杂pine骨架的联苯菊酯衍生物，并将其评估为P-gp药物多药耐药性（MDR）逆转剂。生物学评估表明，化合物6k和9c通过阻止P-gp介导的药物外排功能，而不是通过降低K562 / A02 MDR细胞中P-gp的表达，比联苯菊酯和维拉帕米（VRP）更有效地逆转P-gp介导的MDR。有趣的是，伤口愈合和小室迁移分析表明6k和9c可以显着减弱MDA-MB-231细胞的迁移。值得注意的是6k和9c可以显着抑制MDA-MB-231细胞的侵袭活性，从而显示出潜在的抗转移活性。初步的机理研究表明，6k和9c的抗转移活性与其对MMP-2和MMP-9的活性和表达的抑制作用有关。这些结果以及MDR逆转结果表明，化合物6k和9c可能是开发具有P-gp和肿瘤转移抑制活性的新型抗癌药的有希望的先导。

  DOI：

  10.1016/j.ejmech.2018.01.019
• 作为产物：
  描述：

  2-溴-3,4-二羟基-5-甲氧基苯甲酸 在 potassium fluoride 、 硫酸 、 铜 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 11.67h， 生成 联苯双酯
  参考文献：
  名称：

  Synthesis and antihepatotoxicity of some Wuweizisu analogues

  摘要：

  A preparation of dimethyl 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (VII) was readily achieved. It provided the advantages of specificity, simplicity, and efficiency in reactions. 6-Phenyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylenedioxy-6,7-dihydro-5H-dibenz(c, e)azepin (X) was successfully synthesized from VII (DDB) and its liver-protective property proved to be more effective than DDB and silymarin in the in vitro test of carbon tetrachloride-induced damage of primary cultured rat hepatocytes.

  DOI：

  10.1016/0223-5234(92)90148-t

文献信息

• Exhaustive Reduction of Esters Enabled by Nickel Catalysis
  作者：Adam Cook、Sekar Prakash、Yan-Long Zheng、Stephen G. Newman

  DOI：10.1021/jacs.0c02405

  日期：2020.5.6

  tolyl-derivatives. This is achieved by an organosilane-mediated ester hydrosilylation reaction and subsequent Ni/NHC catalyzed hydrogenolysis. The resulting conditions provide a direct and efficient alternative to multi-step procedures for this transformation that often require use of hazardous metal hydrides. Applications in the synthesis of -CD3 containing products, derivatization of bioactive molecules, and chemoselective

  我们报告了将未活化的芳基酯直接还原为其相应的甲苯基衍生物的一步程序。这是通过有机硅烷介导的酯氢化硅烷化反应和随后的 Ni/NHC 催化氢解来实现的。由此产生的条件为通常需要使用危险金属氢化物的这种转化的多步骤程序提供了一种直接有效的替代方法。展示了在合成含 -CD3 的产品、生物活性分子的衍生化以及在其他 CO 键存在下进行化学选择性还原中的应用。
• Synthesis, Separation, and Theoretical Studies of Chiral Biphenyl Lignans (- and -DDB)
  作者：Junbiao Chang、Rongfeng Chen、Ruiyun Guo、Chunhong Dong、Kang Zhao

  DOI：10.1002/hlca.200390180

  日期：2003.6

  Two biphenyl lignans, α- and β-DDB (1 and 2, respectively) were efficiently synthesized without contamination by other regio-isomers. The different yields of the Ullmann coupling reactions for the synthesis of 1 and 2 were rationalized by calculating steric hindrance, stability, entropy change, and heat-of-formation values. The enantiomers of 1 and 2 were readily separated by HPLC on a chiral stationary

  有效地合成了两个联苯木脂素α-和β- DDB（分别为1和2），而没有受到其他区域异构体的污染。通过计算位阻，稳定性，熵变和形成热值，可以合理地合成用于1和2合成的Ullmann偶联反应的不同收率。1和2的对映体很容易通过HPLC在手性固定相上分离。根据真实天然产品的棉花效果分配其配置。
• Synthesis and biological evaluation of bifendate–chalcone hybrids as a new class of potential P-glycoprotein inhibitors
  作者：Xiaoke Gu、Zhiguang Ren、Xiaobo Tang、Hui Peng、Yuanfang Ma、Yisheng Lai、Sixun Peng、Yihua Zhang

  DOI：10.1016/j.bmc.2012.02.050

  日期：2012.4

  cancer chemotherapy. To find novel effective P-gp inhibitors, a series of bifendate–chalcone hybrids were synthesized and evaluated. Among them, the most active compound 8g had little intrinsic cytotoxicity (IC50 > 200 μM), and could increase accumulation of Rhodamine 123 in K562/A02 cells more potently than bifendate and verapamil (VRP) by inhibiting P-gp efflux function. And 8g displayed potent chemo-sensitizing

  P-糖蛋白（P-gp）的过表达是成功进行癌症化疗的主要问题之一。为了找到新型有效的P-gp抑制剂，合成并评估了一系列联苯双酯-查尔酮杂化物。其中，活性最高的化合物8g几乎没有内在的细胞毒性（IC 50  > 200μM），并且通过抑制P-gp外排功能，比联苯菊酯和维拉帕米（VRP）更有效地增加了罗丹明123在K562 / A02细胞中的蓄积。和8克显示强效的化学增敏效果和持续了长得多的时间（> 24小时）与VRP（<6小时）进行比较。另外，与VRP不同，8g对P-gp ATPase活性没有刺激，表明它不是P-gp底物。因此，8g 可能代表开发用于癌症化疗的MDR逆转剂的有希望的领先者。
• Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones as P-glycoprotein-mediated multidrug resistance reversal agents
  作者：Xiaobo Tang、Xiaoke Gu、Zhiguang Ren、Yuanfang Ma、Yisheng Lai、Hui Peng、Sixun Peng、Yihua Zhang

  DOI：10.1016/j.bmcl.2012.03.005

  日期：2012.4

  A series of substituted dibenzo[c,e]azepine-5-ones (7a–h) were synthesized and evaluated as P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal agents. The most potent compound 7h could significantly and selectively enhance the chemo-sensitivity of drug-resistant K562/A02 cells to the cytotoxic effect of adriamycin (ADR) in a dose-dependent manner. Further studies indicated that 7h could

  合成了一系列取代的二苯并[ c，e ]氮杂-5-酮（7a – h），并作为P-糖蛋白（P-gp）介导的多药耐药（MDR）逆转剂进行了评估。最有效的化合物7h可以剂量依赖性方式显着和选择性地增强耐药K562 / A02细胞对阿霉素（ADR）细胞毒性作用的化学敏感性。进一步的研究表明，7h可以显着增加若丹明123和ADR在K562 / A02细胞中的细胞内积累，并抑制它们从细胞中的流出。和7H对P-gp的表达水平和蛋白质在K562 / A02细胞的影响很小。这些结果表明7h的抗MDR作用 可能归因于P-gp药物外排功能的抑制，导致药物在K562 / A02细胞中的积累增加，因此该化合物可作为开发P-gp介导的MDR逆转剂的先导。
• Multi-functionalization of gallic acid towards improved synthesis of α- and β-DDB
  作者：Ashraful Alam、Yutaka Takaguchi、Hideyuki Ito、Takashi Yoshida、Sadao Tsuboi

  DOI：10.1016/j.tet.2004.11.083

  日期：2005.2

  The synthesis of mono-, di- and trisubstituted gallic acids and their ester with similar or different groups including different acetal and ketals is described. Regioselective bromination on two ortho-positions of methyl gallate, which is very crucial for many organic syntheses, was achieved in high yield and purity. The α- and β-DDB were synthesized in high overall yield and purity from the regioselective

  描述了具有相似或不同基团（包括不同的缩醛和缩酮）的单，二和三取代的没食子酸及其酯的合成。高产率和高纯度实现了对许多有机合成非常关键的在没食子酸甲酯的两个邻位上的区域选择性溴化。α-和β-DDB是由区域选择性溴代衍生物合成的，具有较高的总收率和纯度。