1,3-二(四氢-2-呋喃基)-5-氟尿嘧啶 | 62987-05-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 1,3-二(四氢-2-呋喃基)-5-氟尿嘧啶
• 英文名称: 1,3-bis(tetrahydro-2-furyl)-5-fluorouracil
• 英文别名: N(1),N(3)-Bis(2-tetrahydrofuryl)-5-fluoruracil；1,3-Bis(tetrahydro-2-furanyl)-5-fluoro-2,4-pyrimidinedione；5-fluoro-1,3-bis(oxolan-2-yl)pyrimidine-2,4-dione
• CAS: 62987-05-7
• 化学式: C₁₂H₁₅FN₂O₄
• 分子量: 270.261
• InChiKey: FLMBDTNCANYTCP-UHFFFAOYSA-N

物化性质

• 熔点：
  104-106 °C
• 沸点：
  379.5±52.0 °C(Predicted)
• 密度：
  1.2650 (estimate)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  59.1
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 海关编码：
  2934999090
• 储存条件：
  2-8℃

制备方法与用途

生物活性：Tegadifur 是一种含氟药物，具有抗新陈代谢作用。

类别 有毒物质

毒性分级 中毒

急性毒性 大鼠口服 LD50: 1730 毫克/公斤；小鼠口服 LD50: 2564 毫克/公斤

可燃性危险特性 受热分解，排放有毒氮氧化物和氟化物烟雾

储运特性 应存放在通风低温干燥的库房中，并与氧化剂、酸类分开存放

灭火剂 水、干粉、干砂、二氧化碳、泡沫或1211灭火剂

反应信息

• 作为反应物：
  描述：

  1,3-二(四氢-2-呋喃基)-5-氟尿嘧啶 在 水 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以76%的产率得到替加氟
  参考文献：
  名称：

  一种抗肿瘤药物替加氟的制备方法

  摘要：

  本发明属于有机合成化学领域，具体涉及一种抗肿瘤药物替加氟的制备方法。本发明以5‑氟尿嘧啶和四氢呋喃为原料，加过氧化物，催化剂四烷基碘化铵盐和碱，就能高效合成替加氟。该方法无需无水无氧，高温高压等苛刻条件，不需用到有毒物料与金属催化剂，且物料廉价易得，利于工业化生产。

  公开号：

  CN111925361B
• 作为产物：
  描述：

  3-(2-四氢呋喃基)-5-氟尿嘧啶 以14%的产率得到
  参考文献：
  名称：

  NOMURA HIROAKI; YOSHIOKA YOSHIO; MINAMI ISAO, CHEM. AND PHARM. BULL., 1979, 27, NO 4, 899-906

  摘要：

  DOI：

文献信息

• Studies on antitumor agents. V. Syntheses and antitumor activities of 5-fluorouracil derivatives.
  作者：JUNICHI YAMASHITA、ICHIRO YAMAWAKI、SHUICHI UEDA、MITSUGI YASUMOTO、NORIO UNEMI、SADAO HASHIMOTO

  DOI：10.1248/cpb.30.4258

  日期：——

  Six types of 5-fluorouracil (5-FU) derivatives were synthesized ; namely, 2, 4-di-O-substituted, 2-O-substituted, 4-O-substituted, 1, 3-disubstituted, 1-substituted and 3-substituted compounds. After oral administration of these compounds to rats, the blood levels of 5-FU were determined. Among O-substituted derivatives, a 4-O-substituted derivative was most easily activated to 5-FU and 2-O-substituted derivatives were next most easily activated. Among N-substituted derivatives, acyl and sulfonyl derivatives showed the highest 5-FU releasing abilities and 1-alkoxymethyl substituted derivatives showed low ability. N-Alkyl substituted derivatives were not activated to 5-FU. Several compounds which gave higher blood levels of 5-FU than that obtained with 1-(tetrahydro-2-furyl)-5-fluorouracil (Thf-FU), as well as same related compounds, were selected and their antitumor activities were examined. The 2-O-substituted derivatives, 2-butoxy-5-fluoro-4 (1H)-pyrimidone (11) and 2-benzyloxy-5-fluoro-4 (1H)-pyrimidone (19), were as effective as Thf-FU. The activities of 2, 4-di-O-substituted derivatives, 2, 4-dibutoxy-5-fluoropyrimidine (1) and 2, 4-dibenzyloxy-5-fluoropyrimidine (6), against Ehrlich carcinoma and against sarcoma 180, respectively, were the same as those of Thf-FU. The 1-substituted derivatives, 1-ethoxymethyl-5-fluorouracil (49) and 1-(1-ethoxy-1-phenylmethyl)-5-fluorouracil (50), were found to be as effective as Thf-FU.

  合成了六类氟尿嘧啶（5-FU）衍生物，即2,4-二-O-取代、2-O-取代、4-O-取代、1,3-二取代、1-取代和3-取代的化合物。在大鼠口服这些化合物后，测定了5-FU的血药浓度。在O-取代衍生物中，4-O-取代衍生物最容易被激活为5-FU，其次是2-O-取代衍生物。在N-取代衍生物中，酰基和磺酰基衍生物显示出最高的5-FU释放能力，1-烷氧甲基取代衍生物的释放能力较低。N-烷基取代衍生物未被激活为5-FU。选择了几种在血中5-FU水平高于1-(四氢-2-呋喃基)-5-氟尿嘧啶（Thf-FU）的化合物，以及一些相关化合物，并对其抗肿瘤活性进行了检测。2-O-取代衍生物，2-丁氧基-5-氟-4(1H)-嘧啶酮（11）和2-苄氧基-5-氟-4(1H)-嘧啶酮（19），与Thf-FU一样有效。2,4-二-O-取代衍生物，2,4-二丁氧基-5-氟嘧啶（1）和2,4-二苄氧基-5-氟嘧啶（6），对艾氏癌和肉瘤180的活性与Thf-FU相同。1-取代衍生物，1-乙氧甲基-5-氟尿嘧啶（49）和1-(1-乙氧基-1-苯甲基)-5-氟尿嘧啶（50），发现与Thf-FU一样有效。
• Polysacchocride prodrug of 5-fluorouracil (5-FU) with enhanced target specificity for galectin-3 expressing cancers
  申请人：Tam C. Joemy

  公开号：US20080004237A1

  公开（公告）日：2008-01-03

  This application discloses embodiments of a novel prodrug and its method of synthesis. The prodrug comprises a galactose-containing polysaccharide covalently linked to 5-fluorouracil (5-FU). The galactose residues that are part of the backbone of the galactose-containing polysaccharide mediate the binding between the prodrug and the lectin galectin-3 which is expressed in various cancers. The galactose-containing polysaccharide is isolated from various plant material and covalently bonded to 5-FU. Various formulations (parenteral, or other local or systemic forms) can be used to administer this 5-FU-releasing prodrug to target galectin-3 expressing cancers.

  该应用程序披露了一种新型前药及其合成方法的实施方式。该前药包括一个含半乳糖的多糖，与5-氟尿嘧啶（5-FU）共价连接。作为半乳糖多糖骨架的一部分的半乳糖残基介导了前药与在各种癌症中表达的凝集素galectin-3之间的结合。这种含半乳糖的多糖是从各种植物材料中分离出来并与5-FU共价结合。可以使用各种配方（全身或局部形式）来向靶向表达galectin-3的癌症患者管理这种释放5-FU的前药。
• Novel polysaccharide pro-drug 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer and its preparation methods
  申请人：Tam C. Joemy

  公开号：US20080085871A1

  公开（公告）日：2008-04-10

  This invention describes a novel polysaccharide prodrug of 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer treatment, and its preparation methods. The prodrug is synthesized by chemically linking anti-cancer drug 5-fluorouracil (5-FU) with a specially selected polysaccharide with molecular weight of 10 5 ˜10 7 Da containing galactose residues. Its distinctive characteristics are that it is a prodrug synthesized by chemically linking polysaccharides with 5-FU through different bridge links for the targeted treatment of colorectal cancer; that the polysaccharides in the chemical compound contain galactose residues; and that these polysaccharides are prepared from natural gums or plant materials. Due to these unique characteristics, as an oral preparation, the polysaccharide component of this novel prodrug can protect the active agent 5-FU from absorption (or metabolism) in the upper gastrointestinal tract and deliver a high concentration of the 5-FU to the colorectal area. Upon reaching the colorectal area, the 5-FU-galactose portion of the prodrug will bind to galectin-3, a-galactoside-binding protein implicated in tumor progression by interactions with its ligands, such as TF (Thomsen-Friedenreich, Galb3GalNAc), Tn (GalNAcaThr/Ser), and Sialy-Tn with galactose residues, which are highly expressed among colorectal cancer cells. Finally, the active 5-FU component will be released locally from the polysaccharide via enzymatic hydrolysis from the local bacterial flora, allowing it to actively kill the colorectal cancer cells. In summary, this novel target-specific prodrug can enhance the selectivity of 5-FU and increase its therapeutic effects in the treatment of colorectal cancer. In addition, with this enhanced target specificity, it is possible to maximize the 5-FU efficacy in cancer patients by having either less toxicity with the same or higher therapeutic dose, and/or administer a lower dosage (if so desired) to achieve the same therapeutic effects, but with much less toxicity. Multiple examples of various approaches to synthesize this novel prodrug are enclosed herein along with several animal model experiments to substantiate the claims as stated above.

  这项发明描述了一种新型的多糖前药5-氟尿嘧啶（5-FU），具有增强的靶向特异性，用于结直肠癌治疗，以及其制备方法。该前药是通过化学连接抗癌药物5-氟尿嘧啶（5-FU）与分子量为105˜107Da、含有半乳糖残基的特选多糖进行合成的。其独特特点在于，它是通过不同的桥接链将多糖与5-FU化学连接而合成的前药，用于靶向治疗结直肠癌；化合物中的多糖含有半乳糖残基；这些多糖是从天然树胶或植物材料中制备的。由于这些独特特点，作为口服制剂，这种新型前药的多糖成分可以保护活性成分5-FU不被上消化道吸收（或代谢），并将高浓度的5-FU传递到结直肠区域。到达结直肠区域后，前药的5-FU-半乳糖部分将与半乳糖结合蛋白galectin-3结合，后者通过与其配体的相互作用，如TF（Thomsen-Friedenreich，Galb3GalNAc）、Tn（GalNAcaThr/Ser）和带有半乳糖残基的Sialy-Tn，参与了肿瘤进展，在结直肠癌细胞中高表达。最终，活性的5-FU成分将通过局部细菌群的酶水解从多糖中释放出来，从而能够主动杀死结直肠癌细胞。总之，这种新型靶向特异性前药可以增强5-FU的选择性，并增加其在结直肠癌治疗中的治疗效果。此外，通过增强的靶向特异性，可以通过减少毒性或使用相同或更高的治疗剂量来最大化癌症患者的5-FU疗效，或者以更低剂量（如果需要）来达到相同的治疗效果，但毒性更小。本文附有多种合成这种新型前药的方法示例，以及几个动物模型实验，以证实上述声明。
• Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions
  作者：Aleksandra Zasada、Ewa Mironiuk-Puchalska、Mariola Koszytkowska-Stawińska

  DOI：10.1021/acs.oprd.7b00103

  日期：2017.6.16

  for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the 1,8-diazabicycloundec-7-ene-mediated alkylation of 5-fluorouracil with 2-acetoxytetrahydrofuran at 90 °C, followed by treatment of the prepurified mixture of the alkylation products with aqueous ethanol at 70 °C. The yield of the two-step process is 72%.

  报道了一种制备替加氟（5-氟尿嘧啶的前药）的新方案。该方法包括在90°C下用2-乙酰氧基四氢呋喃进行1，8-二氮杂双环十一烷基-7-烯介导的5-氟尿嘧啶的烷基化反应，然后在70°C下用乙醇水溶液处理烷基化产物的预纯化混合物。两步法的产率为72％。
• Process for producing 5-fluorouracil derivative with a calcium chloride
  申请人：Nikken Chemicals Co., Ltd.

  公开号：US04121037A1

  公开（公告）日：1978-10-17

  5-Fluorouracil derivative having the formula ##STR1## wherein R represents hydrogen atom or 2-tetrahydrofuryl group is produced by reacting more than equi-mole of 2,3-dihydrofuran with 5-fluorouracil in a polar aprotic solvent with a catalytically effective amount of a catalyst selected from the group consisting of metal halides, non-metal halides, tertiary amine salt of inorganic acids and organic acids in neutral or basic condition at 50.degree. to 150.degree. C under pressure.

  具有以下式子的5-氟尿嘧啶衍生物 ##STR1## 其中R代表氢原子或2-四氢呋喃基，是通过在极性无质子溶剂中，在中性或碱性条件下，用金属卤化物、非金属卤化物、无机酸和有机酸的三级胺盐等催化剂的催化下，在50℃到150℃的压力下，将多于等摩尔的2,3-二氢呋喃与5-氟尿嘧啶反应而制得的。