2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-3-(5-fluoropyridin-3-yl)-4-oxo-4-((S)-5-oxopyrrolidin-2-yl)butanamide | 2331111-68-1

• 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: 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-3-(5-fluoropyridin-3-yl)-4-oxo-4-((S)-5-oxopyrrolidin-2-yl)butanamide
• 英文别名: (S)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide；(2S)-N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide；(2S)-N-[1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
• CAS: 2331111-68-1
• 化学式: C₂₂H₂₀ClF₃N₄O₃
• 分子量: 480.874
• InChiKey: LGDHZYFZGKAORP-KKFHFHRHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  91.4
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-3-(5-fluoropyridin-3-yl)-4-oxo-4-((S)-5-oxopyrrolidin-2-yl)butanamide 在 1,5,7-三氮杂双环[4.4.0]癸-5-烯 作用下， 以 乙醇 、 正庚烷 为溶剂， 反应 21.0h， 以65%的产率得到(S)-N-((S)-1-(2-chlorophenyl)-2- ((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
  参考文献：
  名称：

  [EN] A METHOD FOR PREPARING IVOSIDENIB AND AN INTERMEDIATE THEREOF
  [FR] PROCÉDÉ DE PRÉPARATION D'IVOSIDENIB ET D'UN INTERMÉDIAIRE DE CELUI-CI

  摘要：

  本申请涉及一种制备化合物IIa的基本和对映异构体纯结晶乙醇溶剂化物的方法及其用于合成伊伏尼布的使用方法。

  公开号：

  WO2021026436A1
• 作为产物：
  描述：

  2-氯苯甲醛 以 正庚烷 、 2,2,2-三氟乙醇 为溶剂， 生成 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-3-(5-fluoropyridin-3-yl)-4-oxo-4-((S)-5-oxopyrrolidin-2-yl)butanamide
  参考文献：
  名称：

  [EN] SOLID STATE FORMS OF IVOSIDENIB
  [FR] FORMES À L'ÉTAT SOLIDE D'IVOSIDÉNIB

  摘要：

  Ivosidenib的固态形式、其制备方法、其药物组合物和用途均已披露。

  公开号：

  WO2019104318A1

文献信息

• [EN] AN IMPROVED PROCESS OF PREPARATION OF IVOSIDENIB<br/>[FR] PROCÉDÉ AMÉLIORÉ DE PRÉPARATION D'IVOSIDENIB
  申请人：ALEMBIC PHARMACEUTICALS LTD

  公开号：WO2021028791A1

  公开（公告）日：2021-02-18

  The present invention relates to an improved process of preparation of Ivosidenib a compound of Formula (I). More particularly, present invention provides process of preparation of intermediates. Also provide process of preparation of amorphous form of Ivosidenib. Further, present invention provides process of preparation of chirally pure Ivosidenib a compound of Formula (I).

  本发明涉及一种改进的伊伏西替尼（Ivosidenib）制备过程，该化合物的化学式为（I）。更具体地，本发明提供了中间体的制备过程。同时提供了伊伏西替尼的非晶形态的制备过程。此外，本发明提供了手性纯度的伊伏西替尼的制备过程，该化合物的化学式为（I）。
• [EN] IMPROVED PROCESS FOR THE PREPARATION OF (2S)-N-{(1S)-1-(2-CHLOROPHENYL)-2-[(3,3-DIFLUOROCYCLOBUTYL)-AMINO]-2-OXOETHYL}-1-(4-CYANOPYRIDIN-2-YL)-N-(5-FLUOROPYRIDIN-3-YL)-5-OXOPYRROLIDINE-2-CARBOXAMIDE<br/>[FR] PROCÉDÉ AMÉLIORÉ DE PRÉPARATION DE (2S)-N-{(1S)-1-(2-CHLOROPHÉNYL)-2-[(3,3-DIFLUOROCYCLOBUTYL)-AMINO]-2-OXOÉTHYL}-1-(4-CYANOPYRIDIN-2-YL)-N-(5-FLUOROPYRIDIN-3-YL)-5-OXOPYRROLIDINE-2-CARBOXAMIDE
  申请人：MSN LABORATORIES PRIVATE LTD R&D CENTER

  公开号：WO2021079380A1

  公开（公告）日：2021-04-29

  The present invention relates to improved process for the preparation of (2S)-N-(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide and its pharmaceutically acceptable salts represented by the following structural formula. Formula-1 The present invention relates to novel intermediates useful in the preparation of Ivosidenib of formula-1 and novel process for the preparation of (2S)-N-(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2­oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. The present invention also relates to solid state forms of (2S)-N-(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2­ oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide.

  本发明涉及改进的制备过程，用于制备(2S)-N-(1S)-1-(2-氯苯基)-2-[(3,3-二氟环丁基)-氨基]-2-氧乙基}-1-(4-氰吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧吡咯啉-2-羧酰胺及其在以下结构式中表示的药用盐。 结构式-1 本发明涉及在制备结构式-1的Ivosidenib中有用的新中间体以及用于制备(2S)-N-(1S)-1-(2-氯苯基)-2-[(3,3-二氟环丁基)-氨基]-2-氧乙基}-1-(4-氰吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧吡咯啉-2-羧酰胺的新方法。 本发明还涉及(2S)-N-(1S)-1-(2-氯苯基)-2-[(3,3-二氟环丁基)-氨基]-2-氧乙基}-1-(4-氰吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧吡咯啉-2-羧酰胺的固态形式。
• [EN] PROCESS FOR THE PREPARATION OF AN INTERMEDIATE PRODUCT OF IVOSIDENIB<br/>[FR] PROCÉDÉ DE PRÉPARATION D'UN PRODUIT INTERMÉDIAIRE D'IVOSIDÉNIB
  申请人：SANDOZ AG

  公开号：WO2020127887A1

  公开（公告）日：2020-06-25

  The application relates to a process for preparing (3,3-difluorocyclobutyl)isonitrile of formula (2) comprising the steps of mixing N-(3,3-difluorocyclobutyl)formamide with an aprotic solvent and reacting the N-(3,3-difluorocyclobutyl)formamide with propylphosphonic acid anhydride in the presence of a tertiary amine base. The intermediate of formula (2) is used for the preparation of ivosidenib of formula (4).

  本发明涉及一种制备式（2）的（3,3-二氟环丁基）异腈的方法，包括将N-(3,3-二氟环丁基)甲酰胺与无水的溶剂混合，并在三级胺碱的存在下与丙基膦酸酐反应。式（2）的中间体用于制备式（4）的伊沃西替尼。
• Solid state forms of Ivosidenib
  申请人：ASSIA CHEMICAL INDUSTRIES LTD.

  公开号：US11066390B2

  公开（公告）日：2021-07-20

  Solid state forms of Ivosidenib, processes for preparation thereof, pharmaceutical compositions thereof, and uses thereof are disclosed.

  本研究公开了伊沃西地尼的固态形式、制备工艺、药物组合物及其用途。
• Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers
  作者：Janeta Popovici-Muller、René M. Lemieux、Erin Artin、Jeffrey O. Saunders、Francesco G. Salituro、Jeremy Travins、Giovanni Cianchetta、Zhenwei Cai、Ding Zhou、Dawei Cui、Ping Chen、Kimberly Straley、Erica Tobin、Fang Wang、Muriel D. David、Virginie Penard-Lacronique、Cyril Quivoron、Véronique Saada、Stéphane de Botton、Stefan Gross、Lenny Dang、Hua Yang、Luke Utley、Yue Chen、Hyeryun Kim、Shengfang Jin、Zhiwei Gu、Gui Yao、Zhiyong Luo、Xiaobing Lv、Cheng Fang、Liping Yan、Andrew Olaharski、Lee Silverman、Scott Biller、Shin-San M. Su、Katharine Yen

  DOI：10.1021/acsmedchemlett.7b00421

  日期：2018.4.12

  Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of D-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired Mutant cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.