3-三氟甲基-4-[(4-甲基哌嗪-1-基)甲基]苯胺 | 694499-26-8

• 物质功能分类: 原料药 - 抗肿瘤药 - 替尼类抗肿瘤药
• 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: 3-三氟甲基-4-[(4-甲基哌嗪-1-基)甲基]苯胺
• 中文别名: 4-[(4-甲基-1-哌嗪)甲基]-3-(三氟甲基)苯胺；4-(4-甲基哌嗪-1-甲基)-3-三氟甲基苯胺
• 英文名称: 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline
• 英文别名: 3-trifluoromethyl-4-((4-methylpiperazin-1-yl)methyl)-aniline；4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine；4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline；4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline
• CAS: 694499-26-8
• 化学式: C₁₃H₁₈F₃N₃
• mdl: MFCD09909924
• 分子量: 273.301
• InChiKey: ZMWAZMYBMAAMAW-UHFFFAOYSA-N

物化性质

• 沸点：
  329.1±42.0 °C(Predicted)
• 密度：
  1.227

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  32.5
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 海关编码：
  2933599090
• 危险性防范说明：
  P280,P305+P351+P338,P310
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  2-8°C

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: 4-(4-Methylpiperazinomethyl)-3-(trifluoromethyl)aniline
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: 4-(4-Methylpiperazinomethyl)-3-(trifluoromethyl)aniline
CAS number: 694499-26-8

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C13H18F3N3
Molecular weight: 273.3

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides, hydrogen fluoride.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

根据提供的信息，普纳替尼（Ponatinib）的合成路线可以总结如下：

1. 原料化合物6：

   • 从3-碘-4-甲基苯甲酸甲酯出发，通过钯催化偶联反应、水解生成3-乙炔基-4-甲基苯甲酸甲酯。

2. 中间体7：

   • 在氮杂环碳（NHC）的参与下，将化合物6与化合物3进行偶联反应，得到3-(咪唑［1，2-b］哒嗪-3-乙炔基)-4-甲基苯甲酸甲酯。

3. 最终产物普纳替尼：

   • 通过与4-((4-甲基哌嗪-1-基)亚甲基)-3-三氟甲基苯胺的缩合反应，生成目标化合物普纳替尼（Ponatinib）。

每个步骤的具体操作如下：

步骤详解 化合物6 的合成

• 原料: 3-碘-4-甲基苯甲酸甲酯 (4)
• 试剂: 碘化亚铜, 二(三苯基膦)二氯化钯, 乙酸乙酯, 三乙胺, 三甲基硅乙炔
• 溶剂: 乙醇
• 反应过程:
  • 在含有3-碘-4-甲基苯甲酸甲酯、碘化亚铜、二(三苯基膦)二氯化钯的乙酸乙酯溶液中加入三乙胺和三甲基硅乙炔，反应生成3-乙炔基-4-甲基苯甲酸甲酯。

化合物7 的合成

• 原料: 3-乙炔基-4-甲基苯甲酸甲酯 (6), 咪唑［1,2-b］哒嗪-3-乙炔基
• 试剂: 碘化亚铜, 二(三苯基膦)二氯化钯, N-甲基吡咯烷酮（NMP）
• 溶剂: 无水THF
• 反应过程:
  • 在含有3-乙炔基-4-甲基苯甲酸甲酯、化合物3的N-甲基吡咯烷酮溶液中加入碘化亚铜和二(三苯基膦)二氯化钯，生成3-(咪唑［1,2-b］哒嗪-3-乙炔基)-4-甲基苯甲酸甲酯。

普纳替尼的合成

• 原料: 4-((4-甲基哌嗪-1-基)亚甲基)-3-三氟甲基苯胺 (8), 化合物7
• 试剂: 叔丁醇钾, 四氢呋喃（THF）
• 溶剂: THF
• 反应过程:
  • 在含有4-((4-甲基哌嗪-1-基)亚甲基)-3-三氟甲基苯胺和化合物7的四氢呋喃溶液中，加入叔丁醇钾，在0℃下缓慢滴加反应物。室温下搅拌过夜后进行后续处理。

后处理

• 纯化: 反应完成后通过水萃取、干燥等操作提纯产物。
• 结晶: 最终产物普纳替尼需经过重结晶以进一步提高其纯度和产率。

此路线展示了从简单原料到复杂药物分子合成的过程，涉及多种官能团的引入与偶联。整个合成过程中需要严格控制反应条件（如温度、溶剂选择等）以确保目标化合物的高收率及良好的纯度。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  4-(4-甲基哌嗪-1-亚甲基)-3-三氟甲基-1-硝基苯	1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine	694499-24-6	C13H16F3N3O2	303.284
  [2-(三氟甲基)-4-氨基苯基](4-甲基-1-哌嗪基)甲酮	(4-amino-2-(trifluoromethyl)phenyl)(4-methylpiperazin-1-yl)methanone	853297-04-8	C13H16F3N3O	287.285
  ——	2,2,2-trifluoro-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-acetamide	709045-30-7	C15H17F6N3O	369.31
  5-氨基-2-甲基三氟甲苯	3-(trifluoromethyl)-4-methylaniline	65934-74-9	C8H8F3N	175.153
  4-氨基-2-(三氟甲基)苯甲醛	4-amino-2-(trifluoromethyl)benzaldehyde	876322-73-5	C8H6F3NO	189.137
  4-氨基-2-三氟甲基苯甲腈	4-amino-2-trifluoromethylbenzonitrile	654-70-6	C8H5F3N2	186.136

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	3-amino-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide	1581701-03-2	C20H23F3N4O	392.424
  ——	3-(4-bromophenyl)-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}propanamide	1613169-11-1	C22H25BrF3N3O	484.359
  ——	3-azido-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide	1408000-56-5	C20H21F3N6O	418.422
  ——	3-ethynyl-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide	957147-18-1	C23H24F3N3O	415.458
  3-碘-4-甲基-N-[4-[(4-甲基-1-哌嗪基)甲基]-3-(三氟甲基)苯基]苯甲酰胺	3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide	943320-50-1	C21H23F3IN3O	517.333
  ——	3-benzamido-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide	1581701-13-4	C28H29F3N4O2	510.559
  ——	3-azido-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide	1408000-29-2	C21H23F3N6O	432.448
  ——	3-azido-4-chloro-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide	1408000-58-7	C20H20ClF3N6O	452.867
  ——	3-azido-4-bromo-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide	1408000-59-8	C20H20BrF3N6O	497.318
  ——	N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isonicotinamide	1581701-11-2	C27H28F3N5O2	511.547

反应信息

• 作为反应物：
  描述：

  3-三氟甲基-4-[(4-甲基哌嗪-1-基)甲基]苯胺 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 potassium tert-butylate 、 三乙胺 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 23.0h， 生成 4-甲基-N-[4-[(4-甲基-1-哌嗪基)甲基]-3-(三氟甲基)苯基]-3-[2-(1H-吡唑并[3,4-b]吡啶-5-基)乙炔基]苯甲酰胺
  参考文献：
  名称：

  Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region–Abelson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Mutation-Induced Resistance against Imatinib

  摘要：

  Bcr-Abl(T315)I mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K-d values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC50 values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC50 values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.

  DOI：

  10.1021/jm301581y
• 作为产物：
  描述：

  4-氨基-2-三氟甲基苯甲腈 在 4-甲基苯磺酸吡啶 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 正己烷 、 乙酸乙酯 为溶剂， 反应 2.25h， 生成 3-三氟甲基-4-[(4-甲基哌嗪-1-基)甲基]苯胺
  参考文献：
  名称：

  Insights into the modular design of kinase inhibitors and application to Abl and Axl

  摘要：

  选择性分析和生物测试一个匹配的激酶抑制剂集合，导致鉴定出Abl（野生型和T315I）和Axl激酶的有效、选择性抑制剂。

  DOI：

  10.1039/d1md00296a

文献信息

• [EN] BCR-ABL TYROSINE-KINASE LIGANDS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME<br/>[FR] LIGANDS DE TYROSINE-KINASE BCR-ABL CAPABLES DE SE DIMÉRISER DANS UNE SOLUTION AQUEUSE, ET PROCÉDÉS D'UTILISATION DE CEUX-CI
  申请人：COFERON INC

  公开号：WO2015106292A1

  公开（公告）日：2015-07-16

  Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. invivo) to form a multimer (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding sites on a Bcr-Abl tyrosine kinase.

  本文描述了一种单体，当与水性介质中的另一个、两个、三个或更多其他单体接触时，能够形成生物学上有用的多聚体。在一个方面，这种单体可能能够在水性介质（例如体内）中与另一个单体结合以形成多聚体（例如二聚体）。考虑到的单体可能包括配体基团、连接元素和连接配体基团与连接元素的连接元素。在水性介质中，这些考虑到的单体可以通过每个连接元素结合在一起，因此可以同时调节一个或多个生物分子，例如，调节Bcr-Abl酪氨酸激酶上的两个或更多结合位点。
• [EN] IRE1 SMALL MOLECULE INHIBITORS<br/>[FR] INHIBITEURS DE PETITES MOLÉCULES IRE1
  申请人：QUENTIS THERAPEUTICS INC

  公开号：WO2018102751A1

  公开（公告）日：2018-06-07

  Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.

  本文提供了针对IRE1蛋白家族成员的小分子抑制剂。结合可以是直接的或间接的。此外，本文提供了使用IRE1小分子抑制剂用于治疗或改善受试者癌症的方法。此外，本文描述的IRE1小分子抑制剂用于治疗癌症，其中癌症是实体或血液系统的癌症。
• [EN] PHENOXY-PYRIDYL-PYRIMIDINE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS PHÉNOXY-PYRIDYL-PYRIMIDINE ET MÉTHODES D'UTILISATION ASSOCIÉES
  申请人：GENENTECH INC

  公开号：WO2020056089A1

  公开（公告）日：2020-03-19

  Described herein are phenoxy-pyridyl -pyrimidine compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula I structure or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

  本文描述了具有肌醇需要酶1（IRE1）调节活性或功能的苯氧基吡啶基嘧啶化合物，其具有Formula I结构或立体异构体、互变异构体或其药用可接受的盐，并具有所述的取代基和结构特征。还描述了包括Formula I化合物的药物组合物和药物，以及使用这种IRE1调节剂的方法，单独或与其他治疗剂联合使用，用于治疗通过雌激素受体介导或依赖的疾病或症状。
• Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance
  作者：Lu Wang、Qing Zhang、Gaoyuan Zhu、Zhimin Zhang、Yanle Zhi、Li Zhang、Tianxiao Mao、Xiang Zhou、Yadong Chen、Tao Lu、Weifang Tang

  DOI：10.1016/j.ejmech.2017.02.041

  日期：2017.4

  isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colon cells. The western

  同时靶向所有Raf同工型提供了增强的功效以及降低的抗药性的前景。本文描述了一系列具有强力泛肽抑制剂的具有DFG-out构象的嘧啶支架的发现和表征。其中，具有优异泛泛效能的I-41表现出对BRafWT表型黑素瘤和BRafV600E表型结肠细胞的抑制活性。Western blotting结果显示，人黑素瘤SK-Mel-2细胞系中Erk的抑制作用表明I-41抑制了SK-Mel-2细胞的增殖而没有Erk的反常激活，这支持I-41可能成为良好的候选化合物。克服黑素瘤对当前BRafV600E抑制剂疗法的耐药性。I-41在大鼠中也具有良好的药代动力学特征。合成，SAR，线索选择，
• Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT
  作者：Helena Kaitsiotou、Marina Keul、Julia Hardick、Thomas Mühlenberg、Julia Ketzer、Christiane Ehrt、Jasmin Krüll、Federico Medda、Oliver Koch、Fabrizio Giordanetto、Sebastian Bauer、Daniel Rauh

  DOI：10.1021/acs.jmedchem.7b00841

  日期：2017.11.9

  In modern cancer therapy, the use of small organic molecules against receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy. The association of cancer cells with dysregulated signaling pathways linked to RTKs represents a key element in targeted cancer therapies. The tyrosine kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK. KIT is targeted

  在现代癌症治疗中，已证明使用抗受体酪氨酸激酶（RTK）的有机小分子是一种有价值的策略。癌细胞与与RTK连锁的失调的信号通路的关联代表了靶向癌症治疗中的关键要素。酪氨酸激酶肥大/干细胞生长因子受体KIT是临床相关RTK的一个例子。KIT的目标是在胃肠道间质瘤（GIST）和慢性粒细胞性白血病（CML）中进行癌症治疗。但是，在催化域内获得性耐药突变降低了该策略的效力，并且是治疗失败的最常见原因。在这里，我们介绍了新型II型激酶抑制剂的结构化设计和合成，以克服KIT中的这些突变。