(3aS,9bS)-1-{(2R)-2-benzyl-3-[(2S)-oxiran-2-yl]propanoyl}-2,2-dimethyl-1,3a,4,9b-tetrahydro-2H-chromeno[4,3-d][1,3]oxazole | 342600-31-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (3aS,9bS)-1-{(2R)-2-benzyl-3-[(2S)-oxiran-2-yl]propanoyl}-2,2-dimethyl-1,3a,4,9b-tetrahydro-2H-chromeno[4,3-d][1,3]oxazole
• 英文别名: (2R)-1-[(3aS,9bS)-2,2-dimethyl-4,9b-dihydro-3aH-chromeno[4,3-d][1,3]oxazol-1-yl]-2-benzyl-3-[(2S)-oxiran-2-yl]propan-1-one
• CAS: 342600-31-1
• 化学式: C₂₄H₂₇NO₄
• 分子量: 393.483
• InChiKey: QIZUZYWFBFUHEY-OSZJIOELSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  51.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3aS,9bS)-1-{(2R)-2-benzyl-3-[(2S)-oxiran-2-yl]propanoyl}-2,2-dimethyl-1,3a,4,9b-tetrahydro-2H-chromeno[4,3-d][1,3]oxazole 在 盐酸 、 溶剂黄146 作用下， 以 醋酸异丙酯 、 N,N-二甲基甲酰胺-d7 为溶剂， 反应 116.0h， 生成 (2R,4S)-2-benzyl-5-[(5S)-2-[5-(5-chloropyridin-2-yl)-2-furyl]-4-oxo-3-(2,2,2-trifluoroethyl)-1,3,6-triazabicyclo[3.3.1]non-6-yl]-N-[(3S,4S)-3-hydroxy-3,4-dihydro-2H-chromen-4-yl]-4-hydroxypentanamide
  参考文献：
  名称：

  Total synthesis of a second generation HIV protease inhibitor

  摘要：

  An efficient stereoselective preparation of HIV protease inhibitor (+)-1 was synthesized on multi-kilogram scale in 16 steps without the use of chromatography. The key steps include the diastereoselective alkylation of acetal 3, a diastereoselective iodo-hydroxylation to generate epoxide 6, and a reductive amination in the final coupling step that averts a non-productive Cyclic aminal intermediate. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2003.09.023
• 作为产物：
  描述：

  cis-4-amino-3-chromanol 在 甲烷磺酸 、 sodium methylate 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 醋酸异丙酯 为溶剂， 反应 3.0h， 生成 (3aS,9bS)-1-{(2R)-2-benzyl-3-[(2S)-oxiran-2-yl]propanoyl}-2,2-dimethyl-1,3a,4,9b-tetrahydro-2H-chromeno[4,3-d][1,3]oxazole
  参考文献：
  名称：

  Total synthesis of a second generation HIV protease inhibitor

  摘要：

  An efficient stereoselective preparation of HIV protease inhibitor (+)-1 was synthesized on multi-kilogram scale in 16 steps without the use of chromatography. The key steps include the diastereoselective alkylation of acetal 3, a diastereoselective iodo-hydroxylation to generate epoxide 6, and a reductive amination in the final coupling step that averts a non-productive Cyclic aminal intermediate. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2003.09.023

文献信息

• Gamma-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides and uses thereof
  申请人：Merck & Co., Inc.

  公开号：US06642237B1

  公开（公告）日：2003-11-04

  &ggr;-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamide compounds are inhibitors of HIV protease and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HV 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. These compounds are effective against HIV viral mutants which are resistant to HIV protease inhibitors currently used for treating AIDS and HIV infection.

  -Hydroxy-2-(氟烷基氨基甲酰)-1-哌嗪戊二酰胺化合物是HIV蛋白酶的抑制剂，也是HIV复制的抑制剂。这些化合物在预防或治疗HV感染以及治疗艾滋病方面非常有用，无论是作为化合物、药学上可接受的盐、药物组成成分，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。这些化合物对目前用于治疗艾滋病和HIV感染的HIV蛋白酶抑制剂产生耐药性的HIV病毒突变体具有有效作用。
• Synthesis and activity of novel HIV protease inhibitors with improved potency against multiple PI-resistant viral strains
  作者：Joseph L. Duffy、Nancy J. Kevin、Brian A. Kirk、Kevin T. Chapman、William A. Schleif、David B. Olsen、Mark Stahlhut、Carrie A. Rutkowski、Lawrence C. Kuo、Lixia Jin、Jiunn H. Lin、Emilio A. Emini、James R. Tata

  DOI：10.1016/s0960-894x(02)00425-0

  日期：2002.9

  Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.

  用三氟乙基酰胺部分取代HIV蛋白酶抑制剂（PI）茚地那韦的类似物中的叔丁基甲酰胺取代基可赋予针对野生型（NL4-3）病毒和PI抗性HIV的更大效力。三氟乙基取代基在体内的清除速度也较慢（狗）。但是，这可能是由于更有效地抑制了至少两种P450亚型。
• Approaches to installing a N-gem-dimethylmethylene-2-oxazolyl group and application to the synthesis of a second generation HIV protease inhibitor
  作者：Norihiro Ikemoto、Ross A. Miller、Fred J. Fleitz、Jinchu Liu、Daniel E. Petrillo、Joseph F. Leone、Joseph Laquidara、Benjamin Marcune、Sandor Karady、Joseph D. Armstrong、Ralph P. Volante

  DOI：10.1016/j.tetlet.2005.01.103

  日期：2005.3

  Two syntheses of the title compound I were developed based on different approaches for installing the oxazole ring moiety. Formation and dehydration of ketoamide was initially used and scaled up to afford I on several kilogram scale, then oxazolyl anion/iminium coupling reaction was developed for a more convergent approach. (C) 2005 Elsevier Ltd. All rights reserved.
• The design, synthesis and evaluation of novel HIV-1 protease inhibitors with high potency against PI-resistant viral strains
  作者：Fengqi Zhang、Kevin T. Chapman、William A. Schleif、David B. Olsen、Mark Stahlhut、Carrie A. Rutkowski、Lawrence C. Kuo、Lixia Jin、Jiunn H. Lin、Emilio A. Emini、James R. Tata

  DOI：10.1016/s0960-894x(03)00474-8

  日期：2003.8

  Replacement of the pyridylmethyl moiety in indinavir with a pyridyl oxazole yielded HIV-1 protease inhibitors (PI) with greatly improved potency against PI-resistant HIV-1 strains. A meta-methoxy group on the pyridyl ring and a gem-dimethyl methyl linkage afforded compound 10 with notable in vitro antiviral activity against HIV-1 viral strains with reduced susceptibility to the clinically available PIs. Compound 10 also demonstrated favorable in vivo pharmacokinetics in animal models. (C) 2003 Elsevier Ltd. All rights reserved.
• Synthesis of novel HIV protease inhibitors (PI) with activity against PI-resistant virus
  作者：Subharekha Raghavan、Zhijian Lu、Teresa Beeson、Kevin T. Chapman、William A. Schleif、David B. Olsen、Mark Stahlhut、Carrie A. Rutkowski、Lori Gabryelski、Emilio Emini、James R. Tata

  DOI：10.1016/j.bmcl.2007.07.040

  日期：2007.10

  A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described. (C) 2007 Elsevier Ltd. All rights reserved.