5-苯甲基嘧啶-2,4(1H,3H)-二酮 | 18493-83-9

• 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: 5-苯甲基嘧啶-2,4(1H,3H)-二酮
• 英文名称: 5-benzyluracil
• 英文别名: 5-benzyl-1H-pyrimidine-2,4-dione
• CAS: 18493-83-9
• 化学式: C₁₁H₁₀N₂O₂
• 分子量: 202.213
• InChiKey: RPZOVLGFKOOIRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-苯甲基嘧啶-2,4(1H,3H)-二酮 在 乙醇 、 硫酸 、 氨 、 水 、 三氯氧磷 作用下， 生成 4-氨基-5-苄基-2(1H)-嘧啶酮
  参考文献：
  名称：

  Goldberg, Bulletin de la Societe Chimique de France, 1951, p. 895,898

  摘要：

  DOI：
• 作为产物：
  描述：

  5-benzyl-6-methanesulphonyloxy-2,4-(1H,3H)-pyrimidinedione 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 乙醇 、 水 为溶剂， 反应 6.0h， 以85%的产率得到5-苯甲基嘧啶-2,4(1H,3H)-二酮
  参考文献：
  名称：

  Candiani, Ilaria; Cabri, Walter; Bedeschi, Angelo, Heterocycles, 1992, vol. 34, # 5, p. 875 - 879

  摘要：

  DOI：

文献信息

• Process for preparing uracil derivatives
  申请人：Farmitalia Carlo Erba S.r.l.

  公开号：US05286861A1

  公开（公告）日：1994-02-15

  The present invention relates to a novel process for preparing uracil derivatives useful as intermediates in the synthesis of uridines having antiviral or antitumor activity or useful as coadjuvants in antiviral therapy, characterized by converting a compound of the formula II into its mesylate derivative of the formula III which is the reduced to give the desired compound of the formula I: ##STR1## in which R.sub.1 is H, halogen, alkyl, aryl or aralkyl.

  本发明涉及一种新型制备尿嘧啶衍生物的方法，该方法可用作合成具有抗病毒或抗肿瘤活性的尿苷中间体，或者作为抗病毒治疗的辅助剂，其特征在于将式II的化合物转化为其式III的甲磺酸酯衍生物，然后还原得到所需的式I的化合物：##STR1## 其中R.sub.1为H、卤素、烷基、芳基或芳基烷基。
• NOVEL HETEROCYCLIC COMPOUNDS AND USE THEREOF IN MEDICINE AND IN COSMETICS
  申请人：GALDERMA RESEARCH & DEVELOPMENT

  公开号：US20180050992A1

  公开（公告）日：2018-02-22

  The invention relates to novel heterocyclic compounds of general formula (I), as well as their pharmaceutically acceptable salts, and their enantiomers. The invention also relates to the use thereof as a medicinal product, preferably in the prevention and/or treatment of inflammatory diseases with a neurogenic component or use thereof as a cosmetic. The compounds of the present invention act as antagonists of the CGRP-R receptor.

  这项发明涉及一般式(I)的新型杂环化合物，以及它们的药用盐和对映体。该发明还涉及将其用作药物产品，优选用于预防和/或治疗具有神经源性成分的炎症性疾病，或将其用作化妆品。本发明的化合物作为CGRP-R受体的拮抗剂。
• Synthesis of variants of 5-benzylacyclouridine and 5-benzyloxybenzylacyclouridine
  作者：Shih-Hsi Chu、Zhi-Hao Chen、Zum-Yao Weng、Elizabeth C. Rowe、Edward Chu、Ming-Yu Wang Chu

  DOI：10.1002/jhet.5570230609

  日期：1986.11

  A number of variations and derivatives of BAU (5-benzylacyclouridine) and BBAU (5-benzyloxybenzylacy-clouridine), potent inhibitors of uridine phosphorylase were synthesized for evaluation as potential cancer chemotherapeutic agents. (“Acyclo” = 2′-hydroxymethoxymethyl-). These included a modification of the methylene group at N-1, esters of the terminal hydroxyl of the acyclo group, and extension

  合成了尿嘧啶磷酸化酶的有效抑制剂BAU（5-苄基环尿苷）和BBAU（5-苄氧基苄基-氯尿苷）的多种变体和衍生物，以评估其作为潜在的癌症化学治疗剂的能力。（“ Acyclo” ＝ 2'-羟基甲氧基甲基-）。这些包括在N-1处的亚甲基的修饰，无环基团的末端羟基的酯和在尿嘧啶碱基的5位的苄基链的延伸。BBBAU是细胞培养中非常好的FUdR增强剂。
• Pyrimidine Acyclic Nucleotide Analogues with Aromatic Substituents in C-5 Position
  作者：Marcela Krečmerová、Antonín Holý、Milena Masojídková

  DOI：10.1135/cccc20070927

  日期：——

  NH₂-protected 5-phenylcytosine and its derivatives 2a-2d were treated with (2S)-2-[(trityloxy)methyl]oxirane (3) followed by etherification with diisopropyl [(tosyloxy)methyl]phosphonate (5) in the presence of sodium hydride. The intermediary phosphonate esters 6 were debenzoylated and subsequently transformed to free phosphonic acids, i.e. (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenylcytosine (5-phenyl-HPMPC) derivatives (8a-8d) by the action of bromotrimethylsilane and subsequent hydrolysis. Deamination of these compounds with 3-methylbutyl nitrite afforded corresponding (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenyluracil (5-phenyl-HPMPU) derivatives (9a-9d). R-Enantiomers 14 and 15 were prepared analogously starting from (2R)-2-[(trityloxy)methyl]oxirane. 5-Benzyl-, 5-[(1-naphthyl)methyl]- and 5-[(2-naphthyl)methyl]HPMPU (24a-24c) and -HPMPC (25a-25c) were synthesized from appropriate 5-arylmethyl-4-methoxypyrimidin-2(1H)-ones similarly as described for 5-phenyl derivatives. Antiviral activity was found for (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenyluracil (9a) (HSV-1 and HSV-2) and (R)-1-[3-hydroxy2-(phosphonomethoxy)propyl]-5-phenylcytosine (14) (cytomegalovirus and varicella-zoster virus), both tested in cell cultures. Some of the 5-phenyluracil derivatives possessed inhibitory activity against thymidine phosphorylase from SD-lymphoma.

  NH₂保护的5-苯基胞嘧啶及其衍生物2a-2d与(2S)-2-[(三苄氧基)甲基]环氧乙烷(3)反应，随后在钠氢化物存在下与二异丙基[(对甲苯磺酰氧基)甲基]膦酸酯(5)醚化。中间体膦酸酯6被去苄酰化，随后转化为自由膦酸，即(5-苯基-HPMPC)衍生物8a-8d，通过溴三甲基硅烷的作用和随后的水解。这些化合物经过3-甲基丁基亚硝酸酯的去氨基化处理，得到相应的(5-苯基-HPMPU)衍生物9a-9d。类似地，从(2R)-2-[(三苄氧基)甲基]环氧乙烷开始，制备了R-对映体14和15。通过适当的5-芳基甲基-4-甲氧基嘧啶-2(1H)-酮合成了5-苄基、5-[(1-萘基)甲基]和5-[(2-萘基)甲基]HPMPU(24a-24c)和-HPMPC(25a-25c)，类似于5-苯基衍生物的合成方法。在细胞培养中测试后，发现(S)-1-[3-羟基-2-(膦甲氧基)丙基]-5-苯基尿嘧啶(9a) (HSV-1和HSV-2)和(R)-1-[3-羟基2-(膦甲氧基)丙基]-5-苯基胞嘧啶(14) (巨细胞病毒和水痘-带状疱疹病毒)具有抗病毒活性。一些5-苯基尿嘧啶衍生物对SD-淋巴瘤的胸苷磷酸酶具有抑制活性。
• Preparation of 5-Benzyluracil and 5-Benzylcytosine Nucleosides as Potential Inhibitors of Uridine Phosphorylase
  作者：Marcela Krečmerová、Hubert Hřebabecký、Antonín Holý

  DOI：10.1135/cccc19960627

  日期：——

  Reaction of 3,4,6-tri-O-acetyl-2-deoxyglucopyranosyl bromide (1) with silylated 5-benzyluracil and subsequent ammonolysis afforded α- and β-anomers of 5-benzyl-1-(2-deoxy-D-glucopyranosyl)uracil (2 and 3). Under catalysis with tin tetrachloride, silylated 5-benzyluracil reacted with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose to give 2',3',5'-tri-O-benzoyl-5-benzyluridine (10), which was converted into the 4-thio derivative 11 by reaction with Lawesson reagent. Debenzoylation of compound 11 afforded 5-benzyl-4-thiouridine (12), whereas its reaction with methyl iodide and deblocking gave 4-methylthiopyrimidine nucleoside 14. Amonolysis of derivative 12 at elevated temperature afforded 5-benzylcytidine (15). This reacted with thionyl chloride at room temperature to give cyclic sulfite 16 which on heating at 100 °C in dimethylformamide was converted into 5-benzyl-2,2'-cyclocytidine (17). Mild alkaline hydrolysis of compound 17 afforded 1-(β-D-arabinofuranosyl)-5-benzylcytosine (18). With boiling thionyl chloride, compound 15 formed 2',3'-cyclic sulfite 19 which on alkaline hydrolysis gave 5-benzyl-5'-chloro-5'-deoxycytidine (20). Compound 20 was reduced with tributylstannane to 5-benzyl-5'-deoxycytidine (21). Reaction of silylated 5-benzyluracil with 2-deoxy-3,5-bis(O-p-toluoyl)-D-ribofuranosyl chloride, catalyzed with mercury(II) bromide, afforded 5-benzyl-2'-deoxy-3',5'-bis(O-p-toluoyl)uridine (22) and its α-anomer 23. With Lawesson reagent, compound 22 gave 5-benzyl-4-thiouracil derivative 24 which was ammonolyzed to give 5-benzyl-2'-deoxycytidine (25). Analogously, compound 23 was converted into 5-benzyl-2-deoxy-α-cytidine (27). 5'-O-Benzoyl-5-benzyluridine (29) was converted into the 2,2'-anhydro derivative 30 which on reaction with hydrogen chloride afforded 3'-chloro-3'-deoxynucleoside 31. This compound was reduced with tributylstannane and the obtained 2'-deoxynucleoside 32 on treatment with thionyl chloride gave a mixture of erythro- and threo-3'-chloro-2',3'-dideoxynucleosides (33 and 34, respectively) which were reduced to 5'-O-benzoyl-5-benzyl-2',3'-dideoxyuridine (35). Compound 35 reacted with Lawesson reagent under formation of 4-thiouracil derivative 36 and this was deblocked to 5-benzyl-4-thio-2',3'-dideoxyuridine (37). On heating with ammonia, compound 37 was converted into 5-benzyl-2',3'-dideoxycytidine (38). Reaction of 4-thiouracil derivative with methyl iodide and subsequent hydrazinolysis afforded 4-hydrazino derivative 40 which was heated with silver oxide in ethanol to give a mixture of anomeric 5-benzyl-1-(2,3-dideoxyribofuranosyl)-2(1H)-pyrimidinones (42).

  3,4,6-三-O-乙酰基-2-脱氧葡萄糖吡喃溴化物（1）与硅化的5-苄基尿嘧啶反应，随后进行氨解作用，得到5-苄基-1-(2-脱氧-D-葡萄糖吡喃基)尿嘧啶的α-和β-异构体（2和3）。在锡四氯化物催化下，硅化的5-苄基尿嘧啶与1-O-乙酰基-2,3,5-三-O-苯甲酰-D-核糖呋喃糖发生反应，得到2',3',5'-三-O-苯甲酰-5-苄基尿苷（10），它通过与Lawesson试剂反应转化为4-硫衍生物11。化合物11的去苯甲酰化得到5-苄基-4-硫尿苷（12），而它与甲基碘和去保护处理后得到4-甲硫嘧啶核苷（14）。将衍生物12在高温下进行氨解作用得到5-苄基胞嘧啶（15）。这与亚硫酰氯在室温下反应形成环状亚硫酸酯（16），然后在二甲基甲酰胺中加热至100°C，转化为5-苄基-2,2'-环胞嘧啶（17）。化合物17的温和碱水解得到1-(β-D-阿拉伯呋喃糖基)-5-苄基胞嘧啶（18）。用沸腾的亚硫酰氯处理化合物15形成2',3'-环状亚硫酸酯（19），在碱性水解后得到5-苄基-5'-氯-5'-脱氧胞嘧啶（20）。化合物20经三丁基锡烷还原得到5-苄基-5'-脱氧胞嘧啶（21）。硅化的5-苄基尿嘧啶与2-脱氧-3,5-双（O-p-对甲苯酰）-D-核糖呋喃糖氯化物，汞(II)溴化物催化，得到5-苄基-2'-脱氧-3',5'-双（O-p-对甲苯酰）尿苷（22）及其α-异构体23。用Lawesson试剂，化合物22得到5-苄基-4-硫尿嘧啶衍生物24，氨解后得到5-苄基-2'-脱氧胞嘧啶（25）。类似地，化合物23转化为5-苄基-2-脱氧-α-胞嘧啶（27）。5'-O-苯甲酰-5-苄基尿苷（29）转化为2,2'-脱水衍生物30，与氯化氢反应得到3'-氯-3'-脱氧核苷（31）。该化合物经三丁基锡烷还原，得到2'-脱氧核苷（32），经亚硫酰氯处理得到一混合物，包括erythro-和threo-3'-氯-2',3'-脱氧核苷（33和34），进一步还原为5'-O-苯甲酰-5-苄基-2',3'-脱氧尿苷（35）。化合物35与Lawesson试剂反应，形成4-硫尿嘧啶衍生物36，解保护后得到5-苄基-4-硫-2',3'-脱氧尿苷（37）。与氨一起加热，化合物37转化为5-苄基-2',3'-脱氧胞嘧啶（38）。4-硫尿嘧啶衍生物与甲基碘反应，随后进行酰肼解作用得到4-叠氮衍生物40，它与乙醇中的氧化银加热形成5-苄基-1-(2,3-脱氧核糖呋喃基)-2(1H)-嘧啶酮异构体的混合物（42）。