2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one dihydrochloride | 152946-64-0

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one dihydrochloride
• 英文别名: 2-amino-6-methyl-5-(4-pyridylthio)-3H-quinazolin-4-one dihydrochloride；nolatrexed dihydrochloride；thymitaq；2-Amino-6-methyl-5-(pyridin-4-ylthio)quinazolin-4(1H)-one hydrochloride；2-amino-6-methyl-5-pyridin-4-ylsulfanyl-3H-quinazolin-4-one;hydrochloride
• CAS: 152946-64-0；152946-68-4
• 化学式: C₁₄H₁₂N₄OS*2ClH
• 分子量: 357.263
• InChiKey: JSVRVYCCSLQAON-UHFFFAOYSA-N

物化性质

• 熔点：
  301-3020C
• 溶解度：
  溶于甲醇、水

计算性质

• 辛醇/水分配系数(LogP)：
  2.78
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  4

制备方法与用途

市场情况

盐酸诺拉曲塞是一种用于治疗肝癌和鼻咽癌的药物，最初由Agouron开发，并于1998年授权给Gilead。2002年，该产品的开发权在韩国被Gilead授权给了LGLifeSciences公司。2015年1月，北京康辰向中国食品药品监督管理总局（CFDA）提交了新药注册申请（NDA），但于2016年5月未获批准。

生物活性

盐酸诺拉曲塞二水合物（Nolatrexed dihydrochloride，简称AG 337）是一种非竞争性的胸苷酸合成酶抑制剂。它通过与该酶的叶酸辅因子结合位点相互作用，在人胸苷酸合成酶中具有11 nM的Ki值。这种药物能够在癌细胞S期诱导细胞周期停滞，并且具有抗癌活性。

靶点

• Ki: 11 nM (Human Thymidylate Synthase)

反应信息

• 作为产物：
  描述：

  methyl 2-amino-6-bromo-5-methylbenzoate 在 copper(I) oxide 、 盐酸 、 potassium carbonate 、 copper(I) bromide 作用下， 以 乙醇 、 二乙二醇二甲醚 、 N,N-二甲基乙酰胺 、 水 为溶剂， 反应 5.0h， 生成 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one dihydrochloride
  参考文献：
  名称：

  A New Method for Synthesis of Nolatrexed Dihydrochloride

  摘要：

  A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate/sodium methoxide. In the final Ullmann reaction potassium carbonate was employed in place of sodium hydride, and the amount of copper catalysts was significantly reduced. Moreover, sodium sulfide solution was utilized to efficiently remove copper under approximately neutral conditions instead of hydrogen sulfide/methanol under strongly acidic conditions. By means of these modifications, nolatrexed dihydrochloride was ensured to be prepared in good yield and high purity.

  DOI：

  10.1021/op9002517

文献信息

• A Large Scale Process for the Preparation of Thymitaq
  作者：Håkan Malmgren、Birthe Bäckström、Ellen Sølver、Johan Wennerberg

  DOI：10.1021/op800181e

  日期：2008.11.21

  The large scale manufacturing of the anticancer agent 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one dihydrochloride (thymitaq) from 6-bromo-5-methylanthranilic acid is described. The chemical route consists of two chemical steps: formation of a bromoquinazolinone and a copper-mediated Ullman-like coupling between 4-mercaptopyridine and the bromoquinazolinone. During process development, sodium hydride was replaced with sodium hydroxide and a method for removal of copper, based on 2,4,6-trimercapto-s-triazine, was developed. A number of purification operations were performed to ensure a product of pharmaceutical quality.
• Org. Process Res. Dev. 2008, 12, 1195-1200
  作者：

  DOI：——

  日期：——
• Chemical Reagents 2011, 33, 1131-1134
  作者：

  DOI：——

  日期：——
• CN104140416
  申请人：——

  公开号：——

  公开（公告）日：——
• A New Method for Synthesis of Nolatrexed Dihydrochloride
  作者：Xueqing Zhao、Fei Li、Weiping Zhuang、Xiaowen Xue、Yuanyang Lian、Jianhui Fan、Dongsheng Fang

  DOI：10.1021/op9002517

  日期：2010.3.19

  A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate/sodium methoxide. In the final Ullmann reaction potassium carbonate was employed in place of sodium hydride, and the amount of copper catalysts was significantly reduced. Moreover, sodium sulfide solution was utilized to efficiently remove copper under approximately neutral conditions instead of hydrogen sulfide/methanol under strongly acidic conditions. By means of these modifications, nolatrexed dihydrochloride was ensured to be prepared in good yield and high purity.