化合物 T27204 | 214287-90-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 化合物 T27204
• 英文名称: DPC963
• 英文别名: (4s)-4-(Cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1h)-one；(4S)-4-(2-cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-1,3-dihydroquinazolin-2-one
• CAS: 214287-90-8
• 化学式: C₁₄H₉F₅N₂O
• 分子量: 316.23
• InChiKey: QCNJQJJFXFJVCX-ZDUSSCGKSA-N

物化性质

• 熔点：
  187 °C
• 沸点：
  340.3±42.0 °C(Predicted)
• 密度：
  1.54±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  41.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  化合物 T27204 在 lithium aluminium tetrahydride 、 邻二氯苯 作用下， 以 四氢呋喃 为溶剂， 生成 化合物 T27201
  参考文献：
  名称：

  Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1

  摘要：

  摘要：针对鉴定对K103N突变型人类免疫缺陷病毒（HIV）具有增强效力且保持一日一次剂量的药代动力学一致性的扩展谱非核苷类逆转录酶抑制剂的研究项目已经取得成果，发现了4-环丙炔基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 961和DPC 963，以及4-环丙烯基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 082和DPC 083用于临床开发。DPC 961、DPC 963、DPC 082和DPC 083均对野生型病毒、K103N和L100I单突变变种以及许多多种氨基酸替换的HIV-1突变体表现出低纳摩尔级别的效力。这种高度的效力与口服生物利用度高度结合，如在恒河猴和黑猩猩中展示的那样，并且具有可以导致显著药物自由水平的血浆血清蛋白结合。

  DOI：

  10.1128/aac.43.12.2893
• 作为产物：
  描述：

  邻氨基三氟甲基酮 在 4β-morpholinocaran-3α-ol 、 溶剂黄146 、 苯磺酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲苯 、 xylene 为溶剂， 反应 16.0h， 生成 化合物 T27204
  参考文献：
  名称：

  An Efficient Chiral Moderator Prepared from Inexpensive (+)-3-Carene:  Synthesis of the HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor DPC 963

  摘要：

  [GRAPHICS]The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

  DOI：

  10.1021/ol006321x

文献信息

• Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1
  作者：Jeffrey W. Corbett、Soo S. Ko、James D. Rodgers、Susan Jeffrey、Lee T. Bacheler、Ronald M. Klabe、Sharon Diamond、Chii-Ming Lai、Shelley R. Rabel、Jo Anne Saye、Stephen P. Adams、George L. Trainor、Paul S. Anderson、Susan K. Erickson-Viitanen

  DOI：10.1128/aac.43.12.2893

  日期：1999.12

  A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3,4-dihydro-2(1 H )quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3,4-dihydro-2(1 H )quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.

  摘要：针对鉴定对K103N突变型人类免疫缺陷病毒（HIV）具有增强效力且保持一日一次剂量的药代动力学一致性的扩展谱非核苷类逆转录酶抑制剂的研究项目已经取得成果，发现了4-环丙炔基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 961和DPC 963，以及4-环丙烯基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 082和DPC 083用于临床开发。DPC 961、DPC 963、DPC 082和DPC 083均对野生型病毒、K103N和L100I单突变变种以及许多多种氨基酸替换的HIV-1突变体表现出低纳摩尔级别的效力。这种高度的效力与口服生物利用度高度结合，如在恒河猴和黑猩猩中展示的那样，并且具有可以导致显著药物自由水平的血浆血清蛋白结合。
• Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors
  申请人：——

  公开号：US20010044540A1

  公开（公告）日：2001-11-22

  This invention relates generally to the asymmetric synthesis of quinazolin-2-ones that are useful as inhibitors of HIV reverse transcriptase. The synthesis is accomplished through the chiral ligand mediated addition of cyclopropylacetylide.

  这项发明通常涉及对喹唑啉-2-酮的不对称合成，这些化合物可用作HIV逆转录酶的抑制剂。合成是通过手性配体介导的环丙基乙炔加成实现的。
• J. Med. Chem. 2000, 43, 2019-2030
  作者：

  DOI：——

  日期：——
• Org. Lett. 2000, 2, 3119-3121
  作者：

  DOI：——

  日期：——
• NMR Spectroscopic Investigations of Mixed Aggregates Underlying Highly Enantioselective 1,2-Additions of Lithium Cyclopropylacetylide to Quinazolinones
  作者：Rodney L. Parsons,、Joseph M. Fortunak、Roberta L. Dorow、Gregory D. Harris、Goss S. Kauffman、William A. Nugent、Mark D. Winemiller、Timothy F. Briggs、Bosong Xiang、David B. Collum

  DOI：10.1021/ja0105616

  日期：2001.9.1

  The solution structures of mixed aggregates derived from lithium alkoxides and lithium acetylides were investigated as part of a program to develop practical syntheses of quinazolinone-based nonnucleoside reverse transcriptase inhibitors. Low-temperature Li-6, C-13, and N-15 NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide (RCCLi), a -(+)-carene-derived amino alkoxide (R*OLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (RCCLi)(3)(R*OLi) mixed tetramer, a C-2-symmetric and asymmetric (RCCLi)(2)(R*OLi)(2) mixed tetramer, and a C-3-symmetric (RCCLi)(R*OLi)(3) mixed tetramer. Analogous mixtures of RCCLi/R*OLi in Et2O and Me2NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C2-symmetric (RCCLi)2(R*OLi)2 mixed tetramer is formed in Et2O, whereas the asymmetric isomer is formed in Me2NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-RCCLi or LiHMDS-R*OLi mixed aggregates. LiHMDS-RCCLi mixtures form mixed aggregates in Me2NEt.