(2R,3aR,11aS,12aR,14aR,Z)-2-((2-(4-异丙基吡啶-2-基)-7-甲氧基-8-甲基喹啉-4-基)氧基)-5-甲基-4,14-二氧代-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-十四氢环戊[c]环丙并[g][1,6]二氮杂环四氢萘-12a(1H)-羧酸 | 923604-58-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 中文名称: (2R,3aR,11aS,12aR,14aR,Z)-2-((2-(4-异丙基吡啶-2-基)-7-甲氧基-8-甲基喹啉-4-基)氧基)-5-甲基-4,14-二氧代-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-十四氢环戊[c]环丙并[g][1,6]二氮杂环四氢萘-12a(1H)-羧酸
• 中文别名: (2R,3AR,11AS,12AR,14AR,Z)-2-(2-(4-异丙基噻唑-2-基)-7-甲氧基-8-甲基-4-喹啉氧基)-5-甲基-4,14-二氧-1,2,3,3A,4,5,6,7,8,9,11A,12,12A,13,14,14A-16氢环戊烷并[C]环丙基并[G][1,6]双氮杂十四烷-12A-羧酸
• 英文名称: (2R,3aR,10Z,11aS,12aR,14aR)-2-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid
• 英文别名: 17-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^4,6]octadec-7-ene-4-carboxylic acid；Cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid, 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, (2R,3aR,10Z,11aS,12aR,14aR)-；(1R,4R,6S,7Z,15R,17R)-17-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid
• CAS: 923604-58-4
• 化学式: C₃₅H₄₂N₄O₆S
• 分子量: 646.808
• InChiKey: XQOBFRSIHBMNMC-PLGQPLIWSA-N

物化性质

• 密度：
  1.251±0.06 g/cm3(Predicted)
• LogP：
  4.1 at 20℃ and pH7.1

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  46
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  159
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R,3aR,11aS,12aR,14aR,Z)-2-((2-(4-异丙基吡啶-2-基)-7-甲氧基-8-甲基喹啉-4-基)氧基)-5-甲基-4,14-二氧代-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-十四氢环戊[c]环丙并[g][1,6]二氮杂环四氢萘-12a(1H)-羧酸 在 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 (1R,3S,4Z,12R,14R,16R)-14-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-10-methyl-18-oxa-10,20-diazatetracyclo[15.2.1.01,3.012,16]icosa-4,17(20)-diene-11,19-dione
  参考文献：
  名称：

  WO2007/14926

  摘要：

  公开号：
• 作为产物：
  描述：

  (1R,4R,5R)-3-氧代-2-氧杂双环[2.2.1]庚烷-5-羧酸 在 4-二甲氨基吡啶 、 甲烷磺酸 、 lithium hydroxide monohydrate 、 [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II) 、 偶氮二甲酸二异丙酯 、 硫酸 、 2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 异丙醇 、 丙酮 、 甲苯 为溶剂， 反应 192.0h， 生成 (2R,3aR,11aS,12aR,14aR,Z)-2-((2-(4-异丙基吡啶-2-基)-7-甲氧基-8-甲基喹啉-4-基)氧基)-5-甲基-4,14-二氧代-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-十四氢环戊[c]环丙并[g][1,6]二氮杂环四氢萘-12a(1H)-羧酸
  参考文献：
  名称：

  Ring-Closing Metathesis on Commercial Scale: Synthesis of HCV Protease Inhibitor Simeprevir

  摘要：

  The key macrocyclization step in the synthesis of simeprevir, a hepatitis C virus (HCV) antiviral drug, was studied. N-Boc substitution on the diene precursor changes the site of insertion of the metathesis catalyst and, consequently, the kinetic model of the ring closing metathesis (RCM), enabling a further increase in the macrocyclization efficiency under simulated high dilution (SHD) conditions. NMR of the inserted species of both first and second generation RCM catalysts are reported and discussed.

  DOI：

  10.1021/acs.joc.8b03124

文献信息

• [EN] PROCESSES AND INTERMEDIATES FOR PREPARING A MACROCYCLIC PROTEASE INHIBITOR OF HCV<br/>[FR] PROCÉDÉS ET INTERMÉDIAIRES POUR PRÉPARER UN INHIBITEUR MACROCYCLIQUE DE PROTÉASE DU VHC
  申请人：ORTHO MCNEIL JANSSEN PHARM

  公开号：WO2010072742A1

  公开（公告）日：2010-07-01

  The present invention relates to the cinchonidine salt useful in the preparation of intermediates for preparing a macrocyclic HCV inhibitor, as well as processes involving this salt.

  本发明涉及可用于制备大环HCV抑制剂中间体的奎宁啶盐，以及涉及该盐的制备过程。
• [EN] POLYMORPHIC FORMS OF A MACROCYCLIC INHIBITOR OF HCV<br/>[FR] FORMES POLYMORPHES D'UN INHIBITEUR MACROCYCLIQUE DE HCV
  申请人：TIBOTEC PHARM LTD

  公开号：WO2008092954A2

  公开（公告）日：2008-08-07

  (EN) Provided are crystalline forms of the compound of formula (I), which is a macrocyclic inhibitor of HCV, processes for the preparation thereof, and pharmaceutical compositions comprising these crystalline forms.(FR) L'invention porte sur des formes cristallines du composé de formule (I) qui est un inhibiteur macrocyclique de HCV, sur des procédés de préparation de celles-ci et sur des compositions pharmaceutiques les comportant.

  提供了公式(I)化合物的晶体形式，该化合物是HCV的大环抑制剂，提供了其制备方法，以及包含这些晶体形式的药物组合物。
• POLYMORPHIC FORMS OF A MACROCYCLIC INHIBITOR OF HCV
  申请人：Stokbroekx Sigrid Carl Maria

  公开号：US20100029715A1

  公开（公告）日：2010-02-04

  Provided are crystalline forms of the compound of formula (I), which is a macrocyclic inhibitor of HCV, processes for the preparation thereof, and pharmaceutical compositions comprising these crystalline forms.

  提供了公式（I）化合物的晶体形式，该化合物是HCV的大环抑制剂，其制备过程以及包含这些晶体形式的制药组合物。
• Macrocyclic inhibitors of hepatitis c virus
  申请人：Simmen Kenneth Alan

  公开号：US20090281140A1

  公开（公告）日：2009-11-12

  Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is —OR 7 , —NH—SO 2 R 8 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkyl; R 4 is aryl or Het; n is 3, 4, 5, or 6; R 5 is halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, phenyl, or Het; R 6 is C 1-6 alkoxy, or dimethylamino; R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

  公式（I）及其N-氧化物，盐和立体异构体的HCV复制抑制剂，其中每个虚线表示一个可选的双键; X是N，CH，其中X带有双键时是C; R1是-OR7，-NH-SO2R8; R2是氢，当X为C或CH时，R2也可以是C1-6烷基; R3是氢，C1-6烷基，C1-6烷氧基C1-6烷基，C3-7环烷基; R4是芳基或杂环基; n为3、4、5或6; R5是卤素，C1-6烷基，羟基，C1-6烷氧基，苯基或杂环基; R6是C1-6烷氧基或二甲基氨基; R7是氢; 芳基; 杂环基; C3-7环烷基，可选地用C1-6烷基取代; 或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代; R8是芳基; 杂环基; C3-7环烷基，可选地用C1-6烷基取代; 或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代; 芳基是苯基，可选地用一个、两个或三个取代基取代; 杂环基是一个含有1-4个氮、氧和硫杂原子的5或6元饱和、部分不饱和或完全不饱和的杂环环，可选地用一个、两个或三个取代基取代; 包含化合物（I）的药物组合物和制备化合物（I）的过程也提供。还提供了公式（I）的HCV抑制剂与利托那韦的生物利用度组合。
• Macrocyclic Inhibitors Of Hepatitis C Virus
  申请人：Simmen Kenneth Alan

  公开号：US20110295012A1

  公开（公告）日：2011-12-01

  Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is —OR 7 or —NH—SO 2 R 8 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl; R 4 is aryl or Het; n is 3, 4, 5, or 6; R 5 is halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, phenyl, or Het; R 6 is C 1-6 alkoxy or dimethylamino; R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

  公式（I）的HCV复制抑制剂及其N-氧化物，盐和立体异构体，其中每个虚线表示可选的双键；X为N，CH，其中X带有双键时为C；R1为—OR7或—NH—SO2R8；R2为氢，其中X为C或CH时，R2也可以是C1-6烷基；R3为氢，C1-6烷基，C1-6烷氧基C1-6烷基或C3-7环烷基；R4为芳基或杂环基；n为3、4、5或6；R5为卤素，C1-6烷基，羟基，C1-6烷氧基，苯基或杂环基；R6为C1-6烷氧基或二甲基氨基；R7为氢，芳基，杂环基，C3-7环烷基，可选地用C1-6烷基取代；或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代；R8为芳基，杂环基，C3-7环烷基，可选地用C1-6烷基取代；或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代；芳基为苯基，可选地用一个、两个或三个取代基取代；杂环基为含有1到4个氮、氧和硫杂原子的5或6成员饱和、部分不饱和或完全不饱和的杂环环，可选地用一个、两个或三个取代基取代；包含化合物（I）的药物组合物和制备化合物（I）的方法。还提供了公式（I）的HCV抑制剂与利托那韦的生物利用度组合。