(1R,2S)-2-methyl-4-oxocyclohexane-1-carboxylic acid | 53791-83-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,2S)-2-methyl-4-oxocyclohexane-1-carboxylic acid
• 英文别名: cis-2-Methyl-4-oxocyclohexane-1-carboxylic acid
• CAS: 53791-83-6
• 化学式: C₈H₁₂O₃
• 分子量: 156.181
• InChiKey: HUZUVHCSCARZQU-CAHLUQPWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (1R,2S)-2-methyl-4-oxocyclohexane-1-carboxylic acid 在 N-甲基吗啉 、 双(三甲基硅烷基)氨基钾 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， -78.0~80.0 ℃ 、101.33 kPa 条件下， 反应 4.0h， 生成 methyl (1R,3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylate
  参考文献：
  名称：

  Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

  摘要：

  Novel tricyclic analogues were designed, synthesized, and evaluated as ROR gamma t inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

  DOI：

  10.1021/acsmedchemlett.0c00063
• 作为产物：
  描述：

  ethyl 1R-(1α,2α)-(-)-2-methyl-4-oxo-cyclohexancarboxylate 以48%的产率得到
  参考文献：
  名称：

  ISODA SUMIRO, CHEM. AND PHARM. BULL., 1979, 27, NO 12, 3039-3048

  摘要：

  DOI：

文献信息

• Development of a Scalable Synthetic Route to BMS-986251. Part 1: Synthesis of the Cyclohexane Dicarboxylate Fragment
  作者：Sankar Kuppusamy、Aravind S. Gangu、Srinivas Kalidindi、Muthukrishnan Ponnusamy、Shankar Tendulkar、Alla Venu、Senthil Palani、Vedhachalam Nagappan、Arun Vinodini、Boguslaw Mudryk、Sanjeewa Rupasinghe、Candice L. Joe、John R. Coombs、William P. Gallagher、Nathaniel Kopp、Francisco Gonzalez-Bobes、Martin D. Eastgate、Rajappa Vaidyanathan

  DOI：10.1021/acs.oprd.1c00124

  日期：2021.7.16

  The cyclohexane dicarboxylate unit of BMS-986251 (1), a potent and efficacious RORγt inverse agonist, was synthesized starting from Hagemann’s ester in seven chemical transformations with five isolated intermediates. The synthesis involved an enzymatic kinetic resolution, a two-step telescoped enol tosylation followed by carboxylation using a benign CO surrogate for the installation of the second carboxylate

  BMS-986251 ( 1 )的环己烷二羧酸酯单元是一种有效的 RORγt 反向激动剂，它是从哈格曼酯开始，经过七次化学转化和五个分离的中间体合成的。该合成涉及酶动力学拆分、两步伸缩式烯醇甲苯磺酰化，然后使用良性 CO 替代物进行羧化以安装第二个羧酸酯官能团，以及 Crabtree 催化剂介导的非对映选择性烯烃氢化。该过程已成功证明可生产 3.6 kg 的化合物3。
• [EN] SUBSTITUTED INDAZOLE COMPOUNDS AS RORGAMMAT INHIBITORS AND USES THEREOF<br/>[FR] COMPOSÉS INDAZOLE SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE RORGAMMAT ET UTILISATIONS ASSOCIÉES
  申请人：MERCK SHARP & DOHME

  公开号：WO2017075182A1

  公开（公告）日：2017-05-04

  The present invention relates to compounds according to Formula (I) and pharmaceutically acceptable salts thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.

  本发明涉及式(I)化合物及其药用可接受的盐。此类化合物可用于治疗RORgammaT介导的疾病或状况。
• Enantioselective synthesis of the hexahydronaphthalene nucleus of (−)-compactin from ethyl (1R,2S)-2-methyl-4-oxocyclohexanecarboxylate and 2-(3-nitropropyl)-1,3-dioxolane as four carbon bifunctional annelating agent.
  作者：Achille Barco、Simonetta Benetti、Anna Bianchi、Alberto Casolari、Gian P Pollini、Romeo Romagnoli、Giampiero Spalluto、Vinicio Zanirato

  DOI：10.1016/s0040-4020(01)85667-2

  日期：1994.1

  An enantioselective approach to the synthesis of the hexahydronaphthalene nucleus of natural compactin is described. The key elements of the synthesis are as follows: (i) the preparation of the chiral starting material through enzymatic resolution of the readily available cis 2-methyl-4-oxocyclohexane carboxylic acid, (ii) conversion into the suitably protected (4S,5S)4-hydroxymethyl-5-methyl-2-cyclohexen-2-one

  描述了合成天然紧致蛋白的六氢萘核的对映选择性方法。合成的关键要素如下：（i）通过酶解易得的顺式制备手性原料2-甲基-4-氧代环己烷羧酸，（ii）通过区域选择性引入α，β-碳-碳转化为适当保护的（4S，5S）4-羟甲基-5-甲基-2-环己烯-2-酮Pd（II）催化的脱氢硅烷化作用形成双键，（iii）使用2-（3-硝基丙基）-1,3-二氧戊环作为四碳双官能化成环剂，将新的六元环构建到预先存在的碳骨架中（iv ）通过官能团处理将衍生的六氢萘酮加工成已经带到天然目标物的高级前体，包括在C-1处将硝基转化为氧化官能团，以及将烯丙醇脱水为所需的1,3-二烯部分。
• SYNTHETIC PROCESS
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20220048859A1

  公开（公告）日：2022-02-17

  The invention generally relates to a process for preparing compounds, including Compound of Formula (I), useful as key intermediates in the preparation of compounds having RORγt antagonist properties.

  本发明通常涉及一种制备化合物的方法，包括式（I）化合物，该化合物可用作制备具有RORγt拮抗剂特性的化合物的关键中间体。
• Asymmetric Synthesis of the Cyclohexyl Fragment in RORγt Inhibitor (BMS-986251) Enabled by a Dynamic Kinetic Resolution of Hageman’s Ester
  作者：William P. Gallagher、John R. Coombs、Carlos A. Guerrero、Boguslaw M. Mudryk、Kishta Katipally、Candice L. Joe、Sanjeewa Rupasinghe、Jason Zhu、Francisco González-Bobes

  DOI：10.1021/acs.oprd.1c00339

  日期：2022.3.18

  fragment 1 in BMS-986251 was synthesized starting from Hagemann’s ester 2 in 7 steps and 5 isolations. The route is highlighted by a dynamic kinetic resolution (DKR), a telescoped enol nonaflation followed by a palladium-catalyzed carbonylation, and a rhodium-catalyzed directed diastereoselective olefin hydrogenation. The optimized process was demonstrated on 1 kg scale, with an overall 51% yield and >99%

  BMS-986251 中的环己基片段1是从哈格曼酯2开始，分 7 步和 5 次分离合成的。该路线的亮点是动态动力学拆分 (DKR)、伸缩烯醇非膨胀然后钯催化的羰基化和铑催化的定向非对映选择性烯烃氢化。优化的工艺在 1 kg 规模上进行了演示，总产率为 51%，ee 和 dr>99%。