Propanoic acid, 2,2-dimethyl-, 4-[[[(4-fluorophenyl)methyl]amino]carbonyl]-1,6-dihydro-1-methyl-2-[1-methyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-5-pyrimidinyl ester | 1172131-65-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Propanoic acid, 2,2-dimethyl-, 4-[[[(4-fluorophenyl)methyl]amino]carbonyl]-1,6-dihydro-1-methyl-2-[1-methyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-5-pyrimidinyl ester
• 英文别名: [4-[(4-fluorophenyl)methylcarbamoyl]-1-methyl-6-oxo-2-[2-(phenylmethoxycarbonylamino)propan-2-yl]pyrimidin-5-yl] 2,2-dimethylpropanoate
• CAS: 1172131-65-5
• 化学式: C₂₉H₃₃FN₄O₆
• 分子量: 552.603
• InChiKey: JZLRFHKDRQZPBJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Propanoic acid, 2,2-dimethyl-, 4-[[[(4-fluorophenyl)methyl]amino]carbonyl]-1,6-dihydro-1-methyl-2-[1-methyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-5-pyrimidinyl ester 在 N-甲基吗啉 、 羟基乙酸 、 5%-palladium/activated carbon 、 氢气 、 potassium hydroxide 作用下， 以 甲醇 、 水 、 乙酸乙酯 、 乙腈 为溶剂， -10.0~20.0 ℃ 、34.47 kPa 条件下， 反应 0.75h， 生成 雷特格韦
  参考文献：
  名称：

  开发HIV整合酶抑制剂Raltegravir钾的第二代高效生产路线

  摘要：

  通过氨基mid肟DMAD加合物6的热重排，开发了合成raltegravir钾1的生产路线，以构建关键的，高度官能化的羟基嘧啶酮核心7。利用该路线1，以九个线性化学步骤制备，总产率为22％。随后开发了第二代合成方法，解决了最初合成方法中的关键化学，生产率和环境影响问题。新合成的亮点包括高度选择性的甲基化，高3-4倍的生产率以及所产生的有机废物和含水废物减少了65％。有效的第二代生产路线提供了拉格韦韦钾1 总产量的35％。

  DOI：

  10.1021/op100257r
• 作为产物：
  描述：

  methyl 2-(2(((benzyloxy)carbonyl)amino)propan-2-yl)-5,6-dihydroxy-1,6-dihydropyrimidine-4-carboxylate 在 4-二甲氨基吡啶 、 三乙胺 、 lithium tert-butoxide 作用下， 以 乙醇 、 二甲基亚砜 、 乙酸乙酯 为溶剂， 反应 4.25h， 生成 Propanoic acid, 2,2-dimethyl-, 4-[[[(4-fluorophenyl)methyl]amino]carbonyl]-1,6-dihydro-1-methyl-2-[1-methyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-5-pyrimidinyl ester
  参考文献：
  名称：

  开发HIV整合酶抑制剂Raltegravir钾的第二代高效生产路线

  摘要：

  通过氨基mid肟DMAD加合物6的热重排，开发了合成raltegravir钾1的生产路线，以构建关键的，高度官能化的羟基嘧啶酮核心7。利用该路线1，以九个线性化学步骤制备，总产率为22％。随后开发了第二代合成方法，解决了最初合成方法中的关键化学，生产率和环境影响问题。新合成的亮点包括高度选择性的甲基化，高3-4倍的生产率以及所产生的有机废物和含水废物减少了65％。有效的第二代生产路线提供了拉格韦韦钾1 总产量的35％。

  DOI：

  10.1021/op100257r

文献信息

• [EN] PROCESS FOR PREPARING N-SUBSTITUTED HYDROXYPYRIMIDINONE CARBOXAMIDES<br/>[FR] PROCÉDÉ DE PRÉPARATION D'HYDROXYPYRIMIDINONE CARBOXAMIDES N-SUBSTITUÉS
  申请人：MERCK & CO INC

  公开号：WO2009088729A1

  公开（公告）日：2009-07-16

  Processes for preparing certain N-arylalkyl-1-(alkyl or aralkyl)-2-acylaminoalkyl- 5-hydroxy -6-oxo-1,6-dihydropyrimidine-4-carboxamides are disclosed. In one embodiment, the process comprises acylating the free amine in the corresponding N-arylalkyl-1-(alkyl or aralkyl)- 2-aminoalkyl-5-ester protected hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide and then deprotecting the 5-hydroxy by base hydrolysis. The hydroxypyrimidinone carboxamide products of the process are HTV integrase inhibitors which are useful for treating HTV infection, treating AIDS, or delaying the onset or progression of AIDS. Certain esterified N-arylalkyl hydroxypyrimidinone carboxamides that can be employed as process intermediates are also disclosed.

  揭示了制备某些N-芳基烷基-1-(烷基或芳基烷基)-2-酰胺基烷基-5-羟基-6-氧代-1,6-二氢嘧啶-4-羧酰胺的方法。在一种实施例中，该方法包括在相应的N-芳基烷基-1-(烷基或芳基烷基)-2-氨基烷基-5-酯保护羟基-6-氧代-1,6-二氢嘧啶-4-羧酰胺中酰化游离胺基，然后通过碱水解去除5-羟基。该过程的羟基嘧啶酮羧酰胺产物是HTV整合酶抑制剂，可用于治疗HTV感染、治疗艾滋病或延缓艾滋病的发作或进展。还揭示了可用作过程中间体的某些酯化N-芳基烷基羟基嘧啶酮羧酰胺。
• AN IMPROVED PROCESS FOR THE PREPARATION OF RALTEGRAVIR
  申请人：Budidet Shankar Reddy

  公开号：US20170334838A1

  公开（公告）日：2017-11-23

  The present invention provides a process for the preparation of crystalline anhydrous compound of Formula (X), Further, the present invention relates to the use of compound of Formula (X) preparation of Raltegravir (I) or its pharmaceutically acceptable salt thereof.

  本发明提供了一种制备公式（X）的结晶无水化合物的过程。此外，本发明还涉及使用公式（X）的化合物制备Raltegravir（I）或其药学上可接受的盐。
• PROCESS FOR PREPARING N-SUBSTITUTED HYDROXYPYRIMIDINONE CARBOXAMIDES
  申请人：Humphrey Guy R.

  公开号：US20100280244A1

  公开（公告）日：2010-11-04

  Processes for preparing certain N-arylalkyl-1-(alkyl or aralkyl)-2-acylaminoalkyl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides are disclosed. In one embodiment, the process comprises acylating the free amine in the corresponding N-arylalkyl-1-(alkyl or aralkyl)-2-aminoalkyl-5-ester protected hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide and then deprotecting the 5-hydroxy by base hydrolysis. The hydroxypyrimidinone carboxamide products of the process are HTV integrase inhibitors which are useful for treating HTV infection, treating AIDS, or delaying the onset or progression of AIDS. Certain esterified N-arylalkyl hydroxypyrimidinone carboxamides that can be employed as process intermediates are also disclosed.

  本发明揭示了制备某些N-芳基烷基-1-(烷基或芳基烷基)-2-酰基氨基烷基-5-羟基-6-氧代-1,6-二氢嘧啶-4-羧酰胺的工艺。在一种实施方式中，该工艺包括酰化相应的N-芳基烷基-1-(烷基或芳基烷基)-2-氨基烷基-5-酯保护羟基-6-氧代-1,6-二氢嘧啶-4-羧酰胺中的游离胺，然后通过碱水解去保护5-羟基。该工艺的羟基嘧啶酮羧酰胺产物是HTV整合酶抑制剂，可用于治疗HTV感染、治疗艾滋病或延缓艾滋病的发作或进展。还揭示了可用作工艺中间体的某些酯化的N-芳基烷基羟基嘧啶酮羧酰胺。
• Process for the preparation of raltegravir
  申请人：Budidet Shankar Reddy

  公开号：US10259778B2

  公开（公告）日：2019-04-16

  The present invention provides a process for the preparation of crystalline anhydrous compound of Formula (X), Further, the present invention relates to the use of compound of Formula (X) preparation of Raltegravir (I) or its pharmaceutically acceptable salt thereof.

  本发明提供了一种制备结晶无水式（X）化合物的工艺，此外，本发明还涉及使用式（X）化合物制备雷特格韦（I）或其药学上可接受的盐。
• Identification, Synthesis, and Strategy For Minimization of Potential Impurities Observed In Raltegravir Potassium Drug Substance
  作者：Gulabrao D. Patil、Siddheshwar W. Kshirsagar、Shivnath B. Shinde、Pankaj S. Patil、Mangesh S. Deshpande、Ashok T. Chaudhari、Swapnil P. Sonawane、Golak C. Maikap、Mukund K. Gurjar

  DOI：10.1021/op300077m

  日期：2012.8.17

  Multiple sources of anticipated degradation and process impurities of raltegravir potassium drug substance observed during the laboratory optimization and later during its bulk synthesis are described in this article. The impurities were monitored by UPLC, and their structures are tentatively assigned on the basis of fragmentation patterns in LC-MS and NMR spectroscopy. Most of the impurities are synthesized, and their assigned constitutions were confirmed by co-injection in UPLC. In addition to the formation, synthesis, and characterization, strategy for minimizing these impurities to the level accepted by ICH is also described. We feel that our study will be helpful to the generic industry for obtaining chemically pure raltegravir potassium.