3-hydroxy-7-fluoro-1(3H)-isobenzofuranone | 94930-46-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: 3-hydroxy-7-fluoro-1(3H)-isobenzofuranone
• 英文别名: 7-fluoro-3-hydroxyphthalide；7-fluoro-3-hydroxyisobenzofuran-1(3H)-one；7-fluoro-3-hydroxy-2-benzofuran-1(3H)-one；7-fluoro-3-hydroxy-3H-2-benzofuran-1-one
• CAS: 94930-46-8
• 化学式: C₈H₅FO₃
• 分子量: 168.124
• InChiKey: YZRBEOHYVNOOHA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-hydroxy-7-fluoro-1(3H)-isobenzofuranone 在 palladium on activated charcoal 盐酸 、 氢气 、 sodium acetate 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 96.0h， 生成 (+/-)-7-fluoro-1,3,4,10b-tetrahydropyrazino[2,1-a]isoindol-6(2H)-one
  参考文献：
  名称：

  Discovery of (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a Selective, Orally Active Agonist of the 5-HT_2C Receptor

  摘要：

  Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with > 300-fold functional selectivity over 5-HT2B and > 70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.

  DOI：

  10.1021/jm0612968
• 作为产物：
  描述：

  邻氟苯甲酸 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 水 、 palladium diacetate 作用下， 以 苯 为溶剂， 反应 37.0h， 生成 3-hydroxy-7-fluoro-1(3H)-isobenzofuranone
  参考文献：
  名称：

  手性双环咪唑催化的酰基动力学动力学拆分合成手性邻苯二甲酰基酯

  摘要：

  利用手性双环咪唑有机催化剂并采用连续注射工艺，已开发出另一种途径，可通过对映选择性酰化作用（3-99％ee）动态动力学拆分3-羟基邻苯二酚来有效合成手性邻苯二甲酸酯基前药。计算研究表明，一般的基础催化机理不同于广泛接受的亲核催化机理。关键过渡态的结构分析表明，催化剂与底物之间的CH-π相互作用而不是先前考虑的阳离子/π-π相互作用是引起观察到的立体控制的主要因素。

  DOI：

  10.1002/anie.202012445

文献信息

• Enantioselective Allylation of Oxocarbenium Ions Catalyzed by Bi(OAc)₃/Chiral Phosphoric Acid
  作者：Yu-Liang Pan、Han-Liang Zheng、Jie Wang、Chen Yang、Xin Li、Jin-Pei Cheng

  DOI：10.1021/acscatal.0c02585

  日期：2020.8.7

  Herein we disclose an asymmetric allylation of 3-hydroxyisobenzofuran-1(3H)-ones with boron allylation reagents to construct chiral phthalide derivatives. The simple Bi(OAc)3/chiral phosphoric acid catalytic system proves to be efficient in this method, delivering the desired chiral 3-allylisobenzofuran-1(3H)-ones in good yields (up to 99%) and high enantioselectivities (up to 99.5:0.5 e.r.) under mild

  邻苯二甲酸酯作为关键的核心骨架广泛存在于天然产物和生物活性分子中。本文中我们公开了3-羟基异苯并呋喃-1（3H）-与硼烯丙基化试剂的不对称烯丙基化，以构建手性邻苯二甲酸酯衍生物。简单的Bi（OAc）3 /手性磷酸催化体系在该方法中被证明是有效的，可提供所需的手性3-烯丙基苯并呋喃-1（3 H-在温和条件下收率高（高达99％）和高对映选择性（高达99.5：0.5 er）的化合物。产品的大规模反应和向具有潜在生物活性的各种支架的多样化转化使其更具吸引力。此外，通过控制反应，质谱，氘实验和DFT计算初步探讨了该机理。
• [EN] ISOINDOLINE DERIVATIVES COMPRISING PHENYL GROUPS AND THEIR USE IN THE TREATMENT OF PAIN DISORDERS<br/>[FR] DÉRIVÉS ISOINDOLINE COMPRENANT DES GROUPES PHÉNYLES ET LEUR UTILISATION DANS LE TRAITEMENT DE TROUBLES DE LA DOULEUR
  申请人：ASTRAZENECA AB

  公开号：WO2009145721A1

  公开（公告）日：2009-12-03

  Compounds of formula I are claimed, (I) wherein R1 is hydrogen, C1-3alkyl, Ci_3alkoxy, cyano, hydroxy or halo; and wherein said Ci^alkyl is optionally substituted by one or more substituents independently selected from hydroxy, Ci^alkoxy andfluoro; and said Ci^alkoxy is optionally substituted by one or morefluoro; m is 1 or 2; R2 and R3 is each and independently selected from hydrogen, Ci_4haloalkyl, Ci_4haloalkoxy, halo, Ci_4alkoxy, Ci_4alkyl and C3_7cycloalkyloxy; wherein said C3. γcycloalkyloxy is optionally substituted by one or morefluoro; and R2 and R3 may not both be hydrogen; D is C3_7cycloalkyl or C3_7heterocycloalkyl; and wherein said Cs-jcycloalkyl or Cs- γheterocycloalkyl may optionally be substituted by one or more X*; X4 is halo, Ci_3alkyl, Ci_3alkyl0Ci_3alkyl, Ci_3alkoxy, benzyl, Ci_4alkylsulfonyl, oxo, R4O(C=O), R5(C=O), or C5.6 heteroaryl; wherein said Cisalkyl, CisalkylOCisalkyl, Ci^alkoxy and C i^alkylsulfonyl is optionally substituted by one or more fluoro; R4 is Ci_4alkyl, Ci_4alkyl0Ci_4alkyl, C5_6cycloalkyl, or aryl; R5 is Ci_4alkyl, Ci_4fluoroalkyl or Cs_6 heteroaryl; Li is Ci_4alkylene or a bond; L2 is Ci_3alkylene; with the exception of the compound 2-(cyclohexylmethyl)-3-oxo-N-[2-(trifluoromethyl)benzyl]isoindoline-l-carboxamide; as well as a pharmaceutically acceptable salt, or isomer thereof, or a salt of said isomer. The compounds of the invention are useful in therapy such as pain therapy.

  公式I的化合物被要求，其中R1是氢，C1-3烷基，Ci_3烷氧基，氰基，羟基或卤素基；其中所述Ci^烷基可以选择性地被一个或多个取代基独立地选择自羟基，Ci^烷氧基和氟基；所述Ci^烷氧基可以选择性地被一个或多个氟基取代；m为1或2；R2和R3分别且独立地选择自氢，Ci_4卤代烷基，Ci_4卤代烷氧基，卤素，Ci_4烷氧基，Ci_4烷基和C3_7环烷氧基；其中所述C3. γ环烷氧基可以选择性地被一个或多个氟基取代；且R2和R3不能同时为氢；D为C3_7环烷基或C3_7杂环烷基；其中所述Cs-j环烷基或Cs-γ杂环烷基可以选择性地被一个或多个X*取代；X4为卤素，Ci_3烷基，Ci_3烷基0Ci_3烷基，Ci_3烷氧基，苄基，Ci_4烷基磺酰基，氧代，R4O(C=O)，R5(C=O)，或C5.6杂环烷基；其中所述Ci烷基，Ci烷基0Ci烷基，Ci^烷氧基和Ci^烷基磺酰基可以选择性地被一个或多个氟基取代；R4为Ci_4烷基，Ci_4烷基0Ci_4烷基，C5_6环烷基，或芳基；R5为Ci_4烷基，Ci_4氟烷基或Cs_6杂环烷基；Li为Ci_4烷基或键；L2为Ci_3烷基；除了化合物2-(环己基甲基)-3-氧代-N-[2-(三氟甲基)苄基]异吲哚啉-1-羧酰胺；以及其药学上可接受的盐，或其异构体的盐。本发明的化合物在治疗中如疼痛治疗中是有用的。
• [EN] ISOINDOLINE DERIVATIVES COMPRISING AN ADDITIONAL HETEROCYCLIC GROUP AND THEIR USE IN THE TREATMENT OF PAIN DISORDERS<br/>[FR] DÉRIVÉS ISOINDOLINE COMPRENANT UN GROUPE HÉTÉROCYCLIQUE SUPPLÉMENTAIRE ET LEUR UTILISATION DANS LE TRAITEMENT DE TROUBLES DE LA DOULEUR
  申请人：ASTRAZENECA AB

  公开号：WO2009145718A1

  公开（公告）日：2009-12-03

  Compounds of formula I are claimed, wherein R1is hydrogen, C1_3alkyl, C1_3alkoxy, cyano, hydroxy or halo; wherein C1-3alkyl may optionally be substituted by one or more substituents independently selected from hydroxy, C1-3alkoxy orfluoro; and wherein Ci^alkoxy may optionally be substituted by one or more fluoro; m is 1 or 2; R2 and R3 is each and independently selected from hydrogen, Ci_4haloalkyl, C1_4haloalkoxy, halo, C1_4alkoxy, C1_4alkyl and C3_7cycloalkyloxy; and wherein said C3_7cycloalkyloxy may optionally be substituted by one or more fluoro; and whereas both R2 and R3 can not be hydrogen; Het is selected from any one of pyridinyl, pyrazinyl, isoxazolyl, pyrazolyl, indolyl, triazolyl and pyrimidinyl, wherein each such heteroaryl may optionally be substituted by one or more X4; X4 is halo, C1-3alkyl, C1-3alkyl0C1-3alkyl, -CH(CH3)-O-C(CH3)3,C1_4alkoxy, cyano, or hydroxyl, or Ci_2hydroxyalkyl;; and wherein said C1-3alkyl, C 1-3alkylOC1-3alkyl, -CH(CH3)-O-C(CH3)3, or C1_4alkoxy may each optionally be substituted by one or more fluoro; L1 is C1_4alkylene, which may optionally be fluorinated or hydroxylated; and L2 is C1-3alkylene; with the exception of the compounds: 2-[1-(1,5-dimethyl-lH-pyrazol-4-yl)ethyl]-5,7-dimethoxy-3-oxo-N-[2-(trifluoromethyl)benzyl]isoindoline-1-carboxamide; N-(4-fluorobenzyl)-3-oxo-2-(-pyridin-4-yletyl)isoindoline-1-carboxamide and N-(2-chlorobenzyl)-2[2-(1H-indol-3-yl)-1-methyletyl]-3-oxoisoindoline-1-carboxamide; The invention further relates to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.

  公式I的化合物被要求，其中R1是氢，C1-3烷基，C1-3烷氧基，氰基，羟基或卤素；其中C1-3烷基可以选择性地被一个或多个取代基取代，这些取代基独立地选自羟基，C1-3烷氧基或氟基；而C1-3烷氧基可以选择性地被一个或多个氟基取代；m为1或2；R2和R3分别且独立地选自氢，C1-4卤代烷基，C1-4卤代烷氧基，卤素，C1-4烷氧基，C1-4烷基和C3-7环烷氧基；其中所述的C3-7环烷氧基可以选择性地被一个或多个氟基取代；而且R2和R3都不能是氢；Het选自吡啶基，吡嗪基，异噁唑基，吡唑基，吲哚基，三唑基和嘧啶基中的任何一种，其中每种这样的杂环烷基可以选择性地被一个或多个X4取代；X4是卤素，C1-3烷基，C1-3烷氧基C1-3烷基，-CH(CH3)-O-C(CH3)3，C1-4烷氧基，氰基，或羟基，或C1-2羟基烷基；而所述的C1-3烷基，C1-3烷氧基C1-3烷基，-CH(CH3)-O-C(CH3)3，或C1-4烷氧基可以选择性地被一个或多个氟基取代；L1是C1-4烷基，可以选择性地被氟化或羟基化；而L2是C1-3烷基；除了以下化合物：2-[1-(1,5-二甲基-1H-吡唑-4-基)乙基]-5,7-二甲氧基-3-氧代-N-[2-(三氟甲基)苯甲基]异吲哚啉-1-羧酰胺；N-(4-氟苯甲基)-3-氧代-2-(-吡啶-4-基乙基)异吲哚啉-1-羧酰胺和N-(2-氯苯甲基)-2[2-(1H-吲哚-3-基)-1-甲基乙基]-3-氧代异吲哚啉-1-羧酰胺；本发明还涉及含有所述化合物的药物组合物以及所述化合物在治疗中的使用。
• [EN] ISOINDOLINE DERIVATIVES COMPRISING A CYANO GROUP AND THEIR USE IN THE TREATMENT OF PAIN DISORDERS<br/>[FR] DÉRIVÉS D'ISO-INDOLINE COMPRENANT UN GROUPE CYANO ET LEUR UTILISATION DANS LE TRAITEMENT DE TROUBLES DE LA DOULEUR
  申请人：ASTRAZENECA AB

  公开号：WO2009145719A1

  公开（公告）日：2009-12-03

  Compounds of formula I are claimed, wherein R1 is hydrogen, C1_3alkyl, C1_3alkoxy, cyano, hydroxy or halo; and wherein said C1-3alkyl is optionally substituted by one or more substituents independently selected from hydroxy, C1_3alkoxy andfluoro; and said C1_3alkoxy is optionally substituted by one or more fluoro; m is 1, 2 or 3; R2 and R3 is each and independently selected from hydrogen, C1-4haloalkyl, C1-4haloalkoxy, halo, C1-4alkoxy, C1-4alkyl and C3_7Cycloalkyloxy; wherein said C3_7cycloalkyloxy is optionally substituted by one or more fluoro; and R2 and R3 may not both be hydrogen; L1 is C1-4alkylene, pentylene, or C3-6 cycloalkylene, wherein said C1-4alkylene, pentylene or C3-6 cycloalkylene may be optionally substituted by one or more X4; X4 is fluoro, C1_3alkyl, C3_7Cycloalkyl, C1_3alkylOCi_3alkyl, C1_3alkoxy, cyano, hydroxy, R4O(C=O)-, R4NR5(C=O)-, R4O(C=O)NR5-, R4NR5(C=O)NR5-, R4(C=O)O-, R4(C=O)NR5-, R4NR5(C=O)O-, R4NR5(C=O)NR5-, C5-6 heteroaryl(C=O), or C5-6 heteroaryl; R4 is C1-4 alkylOC1-4 alkyl, C5-6 cycloalkyl, aryl, or aryl-C1-2 alkyl; R5 is H or methyl; and wherein said C1-3 alkylOC1-3alkyl, C1-3alkoxy and C1-4alkylsulfonyl is optionally substituted by one or more fluoro; L2 is C1-3 alkylene, optionally substituted by one or more X4; as well as pharmaceutically acceptable salt, or isomer thereof, or a salt of said isomer. Compounds of the invention are useful in therapy, such as pain therapy.

  公式I的化合物被声明，其中R1是氢，C1_3烷基，C1_3烷氧基，氰基，羟基或卤素; 其中所述的C1-3烷基可以选择地被一个或多个独立选择自羟基，C1_3烷氧基和氟代基的取代基所取代; 所述的C1_3烷氧基可以选择地被一个或多个氟代基所取代; m为1、2或3; R2和R3分别且独立地选择自氢，C1-4卤代烷基，C1-4卤代烷氧基，卤素，C1-4烷氧基，C1-4烷基和C3_7环烷氧基; 其中所述的C3_7环烷氧基可以选择地被一个或多个氟代基所取代; R2和R3不能同时为氢; L1为C1-4烷基，戊烷基或C3-6环烷基，其中所述的C1-4烷基，戊烷基或C3-6环烷基可以选择地被一个或多个X4所取代; X4为氟代基，C1_3烷基，C3_7环烷基，C1_3烷基氧C1_3烷基，C1_3烷氧基，氰基，羟基，R4O(C=O)-，R4NR5(C=O)-，R4O(C=O)NR5-，R4NR5(C=O)NR5-，R4(C=O)O-，R4(C=O)NR5-，R4NR5(C=O)O-，R4NR5(C=O)NR5-，C5-6杂环芳基(C=O)，或C5-6杂环芳基; R4为C1-4烷氧基C1-4烷基，C5-6环烷基，芳基，或芳基-C1-2烷基; R5为H或甲基; 其中所述的C1-3烷氧基C1-3烷基，C1-3烷氧基和C1-4烷基磺酰基可以选择地被一个或多个氟代基所取代; L2为C1-3烷基，可以选择地被一个或多个X4所取代; 以及药学上可接受的盐，或其异构体，或所述异构体的盐。本发明的化合物在治疗中很有用，如疼痛治疗。
• NEW COMPOUNDS I/418
  申请人：Bjore Annika

  公开号：US20080015237A1

  公开（公告）日：2008-01-17

  There is provided compounds of formula I, wherein R 1 to R 7 have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

  提供了式I的化合物， 其中R1至R7在描述中给出了它们的含义，这些化合物在预防和治疗心律失常方面非常有用，特别是房性和室性心律失常。