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。

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 、