(1R,2R)-1-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-(difluoromethyl)cyclopropane-1-carboxylic acid | 1160633-68-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (1R,2R)-1-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-(difluoromethyl)cyclopropane-1-carboxylic acid
• CAS: 1160633-68-0
• 化学式: C₁₅H₂₃F₂NO₆
• 分子量: 351.348
• InChiKey: BXTCRVJEOPKERH-VXJOIVPMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  93.1
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  环丙磺酰胺 、 (1R,2R)-1-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-(difluoromethyl)cyclopropane-1-carboxylic acid 在 N,N'-羰基二咪唑 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 tert-butyl N-[(1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-(difluoromethyl)cyclopropyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
  参考文献：
  名称：

  [EN] FLUORINATED TRIPEPTIDE HCV SERINE PROTEASE INHIBITORS
  [FR] COMPOSÉS À BASE DE TRIPEPTIDES FLUORÉS INHIBANT LA SÉRINE PROTÉASE DU VHC

  摘要：

  公开号：

  WO2009076173A3
• 作为产物：
  描述：

  (1R,2R)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(difluoromethyl)cyclopropanecarboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 48.0h， 以100%的产率得到(1R,2R)-1-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-(difluoromethyl)cyclopropane-1-carboxylic acid
  参考文献：
  名称：

  [EN] FLUORINATED TRIPEPTIDE HCV SERINE PROTEASE INHIBITORS
  [FR] COMPOSÉS À BASE DE TRIPEPTIDES FLUORÉS INHIBANT LA SÉRINE PROTÉASE DU VHC

  摘要：

  公开号：

  WO2009076173A3

文献信息

• [EN] QUINOXALINE-CONTAINING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS<br/>[FR] COMPOSÉS CONTENANT DE LA QUINOXALINE EN TANT QU'INHIBITEURS DU VIRUS DE L'HÉPATITE C
  申请人：ENANTA PHARM INC

  公开号：WO2009064975A1

  公开（公告）日：2009-05-22

  The present invention discloses compounds of formula I and II or pharmaceutically acceptable salts, esters, or prodrugs thereof which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

  本发明公开了抑制丝氨酸蛋白酶活性的I和II公式化合物，或其药物可接受的盐、酯或前药，尤其是抑制丙型肝炎病毒（HCV）NS3-NS4A蛋白酶的活性。因此，本发明的化合物干扰丙型肝炎病毒的生命周期，并且也用作抗病毒剂。本发明进一步涉及包含前述化合物的药物组合物，用于给患有HCV感染的主体进行管理。本发明还涉及通过管理包含本发明化合物的药物组合物来治疗主体中的HCV感染的方法。
• Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis
  作者：Russell D. Cink、Kirill A. Lukin、Richard D. Bishop、Gang Zhao、Matthew J. Pelc、Timothy B. Towne、Bradley D. Gates、Matthew M. Ravn、David R. Hill、Chen Ding、Steven C. Cullen、Jianzhang Mei、M. Robert Leanna、Jeremy Henle、José G. Napolitano、Nandkishor K. Nere、Shuang Chen、Ahmad Sheikh、Jeffrey M. Kallemeyn

  DOI：10.1021/acs.oprd.9b00469

  日期：2020.2.21

  enabling synthesis was required to support the preclinical evaluation and subsequent Phase I clinical trials. The enabling route to glecaprevir was established through further development of the medicinal chemistry route. The key steps in the synthesis involved a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle and a challenging fluorination step to form a key amino acid. The enabling

  Glecaprevir被鉴定为有效的HCV NS3 / 4A蛋白酶抑制剂，需要进行有效的合成以支持临床前评估和随后的I期临床试验。通过进一步发展药物化学途径，确立了格列卡韦的赋能途径。合成中的关键步骤涉及闭环复分解（RCM）反应以形成18元大环，而挑战性的氟化步骤则是形成关键氨基酸。该成功途径已成功用于生产41千克格列卡韦韦，足以支持临床前评估和早期临床开发。
• CRYSTALLINE FORMS OF AN ANTIVIRAL COMPOUND
  申请人：Gilead Sciences, Inc.

  公开号：US20170267694A1

  公开（公告）日：2017-09-21

  Crystalline forms of the anti-HCV compound (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the crystalline forms.

  抗HCV化合物的晶体形式(1aR,5S,8S,9S,10R,22aR)-5-叔丁基-N-[(1R,2R)-2-(二氟甲基)-1-[(1-甲基环丙基)磺酰]氨基}环丙基]-9-乙基-18,18-二氟-14-甲氧基-3,6-二氧-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-十四环-8H-7,10-甲烷基环丙[18,19][1,10,3,6]二氧二氮杂环十九烷醯胺(化合物I)已在固态下制备和表征。此外，还提供了制造过程和使用晶体形式的方法。
• OXIMYL HCV SERINE PROTEASE INHIBITORS
  申请人：GAI YONGHUA

  公开号：US20090155210A1

  公开（公告）日：2009-06-18

  The present invention discloses compounds of formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
• HETEROARYL-CONTAINING TRIPEPTIDE HCV SERINE PROTEASE INHIBITORS
  申请人：GAI YONGHUA

  公开号：US20090202485A1

  公开（公告）日：2009-08-13

  The present invention relates to compounds of Formula I, or a pharmaceutically acceptable salt, ester, or prodrug, thereof: which inhibit serine protease activity, particularly the activity of hepatitis c virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis c virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.