6-chloro-4-cyclopropyl-1-(4-methoxybenzyl)-quinazolin-2(1H)-one | 150878-37-8

• 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: 6-chloro-4-cyclopropyl-1-(4-methoxybenzyl)-quinazolin-2(1H)-one
• 英文别名: 6-Chloro-4-cyclopropyl-1-(p-methoxybenzyl)quinazolin-2(1H)-one；6-chloro-4-cyclopropyl-1-[(4-methoxyphenyl)methyl]quinazolin-2-one
• CAS: 150878-37-8
• 化学式: C₁₉H₁₇ClN₂O₂
• 分子量: 340.809
• InChiKey: LDSJWPZEDCOUFF-UHFFFAOYSA-N

物化性质

• 沸点：
  523.1±60.0 °C(predicted)
• 密度：
  1.35±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  41.9
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-chloro-4-cyclopropyl-1-(4-methoxybenzyl)-quinazolin-2(1H)-one 在 正丁基锂 、 magnesium triflate 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 18.5h， 生成 6-chloro-3,4-dihydro-4-cyclopropyl-4-ethynyl-2(1H)-quinazolinone
  参考文献：
  名称：

  Synthesis of a Series of 4-(Arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

  摘要：

  As part of an ongoing effort to prepare novel non-nucleoside inhibitors of human immunodeficiency virus type-1 (HTV-1) reverse transcriptase (RT), a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones 4aa-1 has been prepared. Target compounds 4a-e were synthesized via addition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protected-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3-alkylation performed prior to deprotection. Alternatively, the target compounds 4f-1 were prepared by addition of 1-lithio-2-(trimethylsilyl)acetylene to 7, followed by deprotection and subsequent palladium-catalyzed coupling with various aryl halides, By incorporating an aryl group onto the end of the 4-acetylene functionality, the requirement for a metabolically labile 3-methyl group on the dihydroquinazolinone nucleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HTV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was' resolved via a four-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiomer and was selected as a candidate for further investigation.

  DOI：

  10.1021/jm00041a023
• 作为产物：
  描述：

  2-氨基-5-氯苯腈 在 lithium hexamethyldisilazane 作用下， 反应 13.0h， 生成 6-chloro-4-cyclopropyl-1-(4-methoxybenzyl)-quinazolin-2(1H)-one
  参考文献：
  名称：

  Synthesis of a Series of 4-(Arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

  摘要：

  As part of an ongoing effort to prepare novel non-nucleoside inhibitors of human immunodeficiency virus type-1 (HTV-1) reverse transcriptase (RT), a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones 4aa-1 has been prepared. Target compounds 4a-e were synthesized via addition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protected-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3-alkylation performed prior to deprotection. Alternatively, the target compounds 4f-1 were prepared by addition of 1-lithio-2-(trimethylsilyl)acetylene to 7, followed by deprotection and subsequent palladium-catalyzed coupling with various aryl halides, By incorporating an aryl group onto the end of the 4-acetylene functionality, the requirement for a metabolically labile 3-methyl group on the dihydroquinazolinone nucleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HTV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was' resolved via a four-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiomer and was selected as a candidate for further investigation.

  DOI：

  10.1021/jm00041a023

文献信息

• Chiral resolution process
  申请人：Merck & Co., Inc.

  公开号：US05457201A1

  公开（公告）日：1995-10-10

  A chiral resolution process is described for the purification of a substituted chiral quinazoline, by salt formation with a resolving agent, followed by crystallization.

  描述了一种手性分离过程，用于通过与一个分离剂形成盐，然后结晶来纯化取代手性喹啉。
• New quinazolines as inhibitors of HIV reverse transcriptase
  申请人：MERCK & CO. INC.

  公开号：EP0569083A1

  公开（公告）日：1993-11-10

  Compounds having a quinazolin-2-one nucleus with a substituted alkynyl or substituted alkenyl at the 4-position are described. These compounds are useful in the inhibition of HIV reverse transcriptase (including its resistant varieties), the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

  描述了在喹唑啉-2-酮核上具有取代炔基或取代烯基的化合物。这些化合物在抑制HIV逆转录酶（包括其耐药品种）、预防或治疗HIV感染以及治疗艾滋病方面具有用途，无论是作为化合物、药学上可接受的盐、药用组分成分，还是与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。还描述了治疗艾滋病的方法以及预防或治疗HIV感染的方法。
• Synthesis of a new generation reverse transcriptase inhibitor via the BCl3/GaCl3-induced condensation of anilines with nitriles (sugasawa reaction)
  作者：Ioannis N. Houpis、Audrey Molina、Alan W. Douglas、Lyndon Xavier、Joseph Lynch、R.P. Volante、P.J. Reider

  DOI：10.1016/0040-4039(94)85011-9

  日期：1994.9

  The synthesis of 1 was achieved in high overall yield through a mechanism-based improvement of the preparation of o-acyl anilines.

  通过基于机理的邻酰基苯胺制备方法的改进，以高总收率实现了1的合成。
• Quinazoline derivatives as inhibitors of HIV reverse transcriptase
  申请人：MERCK & CO. INC.

  公开号：EP0530994A1

  公开（公告）日：1993-03-10

  Compounds having a quinazolin-2-(thi)one nucleus are described. These compounds are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

  描述了具有喹唑啉-2-(硫)-1 核的化合物。这些化合物作为化合物、药学上可接受的盐、药物组合物成分，无论是否与其他抗病毒药物、免疫调节剂、抗生素或疫苗结合使用，均可用于抑制 HIV 逆转录酶、预防或治疗 HIV 感染和治疗 AIDS。还描述了治疗艾滋病的方法和预防或治疗艾滋病毒感染的方法。
• Lithium Alkoxides of Cinchona Alkaloids as Chiral Controllers for Enantioselective Acetylide Addition to Cyclic N-Acyl Ketimines
  作者：Mark A. Huffman、Nobuyoshi Yasuda、Ann E. DeCamp、Edward J. J. Grabowski

  DOI：10.1021/jo00111a016

  日期：1995.3

  Highly enantioselective acetylide addition to cyclic N-acyl ketimines 1 can be carried out using the lithium alkoxide of quinine as a stoichiometric chiral additive. Quinidine can be used to give the opposite enantiomer. Optimization of temperature is critical, with low or high temperatures reducing selectivity. Using the bulky 9-anthrylmethyl protecting group at a distal position on the imine, a 97% ee was achieved and applied to the asymmetric synthesis of HIV reverse transcriptase inhibitor 3.