4-(3-溴苯基)四氢-2H-吡喃-4-甲酰胺 | 329025-26-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-(3-溴苯基)四氢-2H-吡喃-4-甲酰胺
• 英文名称: tetrahydro-4-(3-bromophenyl)-2H-pyran-4-carboxamide
• 英文别名: 4-(3-bromophenyl)-tetrahydro-2H-pyran-4-carboxamide；4-(3-Bromophenyl)tetrahydro-2H-pyran-4-carboxamide；4-(3-bromophenyl)oxane-4-carboxamide
• CAS: 329025-26-5
• 化学式: C₁₂H₁₄BrNO₂
• 分子量: 284.153
• InChiKey: ZBBPOKGRGPCSHF-UHFFFAOYSA-N

物化性质

• 沸点：
  456.6±45.0 °C(Predicted)
• 密度：
  1.459±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  52.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(3-溴苯基)四氢-2H-吡喃-4-甲酰胺 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium methylate 、 sodium t-butanolate 作用下， 以 2-甲基四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 4.0h， 生成 化合物 T16503
  参考文献：
  名称：

  Development an Efficient Route to the 5-Lipoxygenase Inhibitor PF-04191834

  摘要：

  A convergent six-step process for the synthesis of PF-04191834 (1), a potent and selective 5-lipoxygenase inhibitor, has been developed and used to deliver over 20 kg of API. The process uses the same bond-forming steps as the initial medicinal chemistry route, including the use of two consecutive Pd-catalyzed Ar-S couplings to form the key diaryl thioether linkage. The reaction conditions and downstream processing have been optimized to eliminate column chromatography and aqueous work-ups and to minimize disproportionation of 1, to ensure successful scale-up.

  DOI：

  10.1021/op200173g
• 作为产物：
  描述：

  3-溴氰苄 在 四丁基硫酸氢铵 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 异丙醇 为溶剂， 反应 8.0h， 生成 4-(3-溴苯基)四氢-2H-吡喃-4-甲酰胺
  参考文献：
  名称：

  开发用于四氢-4- [3- [4- [4-（2-甲基-1 H-咪唑-1-基）苯基]硫代]苯基-的碳-硫键形成的Migita反应新变体的开发2 H-吡喃-4-羧酰胺

  摘要：

  探索了使用改良的Migita反应条件形成钯催化的碳-硫键，并将其应用于前抗哮喘候选药物四氢-4- [3- [4-（2-甲基-1 H-咪唑-1-基] ）苯基]硫基]苯基-2 H-吡喃-4-羧酰胺（5）。该反应已发展为硫代芳基卤化物交叉偶联的一般方法，并且是用于合成关键中间体四氢-4- [3-（4-氟苯基）硫代]苯基-2 H-吡喃-4的具体实例。-羧酰胺（6）被大规模证明可提供5的II期临床供应。多步I相工艺和两步II相工艺的比较表明，与从普通原料（1）到API 5的键形成步骤相比，总的产量优势为40％。详细描述了改良的Migita反应中的配体效应。放大工艺的第二步说明了在不使用钯催化的情况下形成碳-氮键，这与第一反应形成了鲜明对比。两种反应均发展为有效的单容器直接分离工艺。

  DOI：

  10.1021/op800098a

文献信息

• [EN] BICYCLIC HETEROARYL AMINE COMPOUNDS AS PI3K INHIBITORS<br/>[FR] COMPOSÉS AMINE HÉTÉROARYLES BICYCLIQUES UTILISÉS COMME INHIBITEURS DE LA PI3K
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2016064957A1

  公开（公告）日：2016-04-28

  Disclosed are compounds of Formula (I) or a salt thereof; wherein: X is N or CH; Q1 is: (i) C1, Br, I, -CN, -CH3, or -CF3; (ii) a 5-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl; (iii) a 6?membered heteroaryl selected from pyridinyl, pyridazinyl, and pyrimidinyl; or (iv) a bicyclic heteroaryl selected from indolyl, pyrrolopyridinyl, pyrazolopyridinyl and benzo[d]oxazolyl; wherein each of said 5-membered, 6-membered, and bicyclic heteroaryl is substituted with zero to 1 Ra and zero to 1 Rb; and R1, R2, R3, R4, R5, R6, Ra, and Rb are defined herein. Also disclosed are methods of using such compounds as modulators of PI3K, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.

  公开了Formula (I)或其盐的化合物；其中：X为N或CH；Q1为：(i) C1、Br、I、-CN、-CH3或-CF3；(ii)从吡咯基、吡唑基、咪唑基、噁唑基、噻唑基、三唑基、噁二唑基和噻二唑基中选择的5-成员杂芳基；(iii)从吡啶基、吡啶嗪基和嘧啶基中选择的6-成员杂芳基；或(iv)从吲哚基、吡咯吡啶基、吡唑吡啶基和苯并[d]噁唑基中选择的双环杂芳基；其中所述的5-成员、6-成员和双环杂芳基中的每一个都被零至1个Ra和零至1个Rb取代；R1、R2、R3、R4、R5、R6、Ra和Rb在此处被定义。还公开了使用这些化合物作为PI3K调节剂的方法，以及包含这些化合物的药物组合物。这些化合物在治疗、预防或减缓炎症性和自身免疫性疾病方面是有用的。
• [EN] PYRAZOLE DERIVATIVES AS 5-LO INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLE COMME INHIBITEURS DE 5-LO
  申请人：PFIZER

  公开号：WO2009069044A1

  公开（公告）日：2009-06-04

  The invention relates to compounds of formula (I) processes for their preparation, their use as 5-lipoxygenase inhibitors and pharmaceutical compositions containing the same.

  该发明涉及式（I）化合物，其制备方法，其作为5-脂氧化酶抑制剂的用途以及含有该化合物的药物组合物。
• Process for making 5-lipoxygenase inhibitors having varied heterocyclic ring systems
  申请人：——

  公开号：US06344563B1

  公开（公告）日：2002-02-05

  process is described for preparing a compound of Formula (1.3.0): comprising: establishing a reaction mixture consisting of in an aprotic solvent; in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;—and optionally—in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst, especially a quaternary ammonium salt or a phosphonium salt—followed by—heating said reaction mixture under a nitrogen atmosphere; whereby there is produced a compound of Formula (1.3.0); and in a preferred embodiment the aprotic solvent is DMSO, the strong base in solid form is NaOH in powder or pellet form, and the phase transfer catalyst is tetra-n-butylammonium chloride (TBAC), which is used to prepare a preferred compound, useful as a 5-lipoxygenase inhibitor, of the formula: especially the substantially pure methanesulfonate salt thereof.

  描述了制备化合物Formula（1.3.0）的过程：包括：在无极性溶剂中建立反应混合物；在固体形式的强碱的存在下，所述强碱选自氢氧化钠（NaOH）和氢氧化钾（KOH）等组成的群体；—并且—在需要时，在氧化镉（Cs2CO3）的催化剂量或相转移催化剂，特别是季铵盐或磷铵盐的存在下—随后—在氮气氛下加热所述反应混合物；从而产生化合物Formula（1.3.0）；在一种优选实施例中，无极性溶剂为DMSO，固体形式的强碱为粉末或颗粒形式的NaOH，相转移催化剂为四正丁基铵盐（TBAC），用于制备一种优选化合物，其作为5-脂氧合酶抑制剂，具有特定的化学式：尤其是其相对纯的甲磺酸盐。
• Pyrazole Analogs
  申请人：Graneto Mathew J.

  公开号：US20080125474A1

  公开（公告）日：2008-05-29

  The invention relates to the compounds of formula (I): or a pharmaceutically acceptable salt and solvate thereof, wherein R 1 is F or H and to processes for the preparation of, intermediates used in the preparation of, compositions containing the uses of, such compounds. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular allergic and respiratory diseases, disorders and conditions

  该发明涉及以下化合物的公式(I)：或其药学上可接受的盐和溶剂化合物，其中R1为F或H，以及用于制备、用于制备的中间体、含有这些化合物的组合物的制备方法。根据本发明的化合物在许多疾病、紊乱和症状中具有用途，特别是过敏和呼吸系统疾病、紊乱和症状。
• Development of the Commercial Route for the Manufacture of a 5-Lipoxygenase Inhibitor PF-04191834
  作者：Brian Chekal、David Damon、Danny LaFrance、Kyle Leeman、Carlos Mojica、Andrew Palm、Michael St. Pierre、Janice Sieser、Karen Sutherland、Rajappa Vaidyanathan、John Van Alsten、Brian Vanderplas、Carrie Wager、Gerald Weisenburger、Gregory Withbroe、Shu Yu

  DOI：10.1021/op500412a

  日期：2015.12.18

  A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless, and readily available commodity chemical iso-octyl-3-mercaptopropionate as a sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethers via Migita coupling. A kinetic study revealed that; at high temperature, reductive elimination could be the rate-limiting step in the catalytic cycle, which opens pathways for the generation of undesired impurities. By proper control of the reaction conditions, the desired API was synthesized in >70% crude yield and in 55% isolated yield after vigorous purifications. This process was successfully demonstrated on a 20 kg scale.