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Method for preparing 3-ethynyl-4-fluoroaniline

A fluoroaniline and ethynyl technology, which is applied in the field of preparation of 3-ethynyl-4-fluoroaniline, can solve the problems of large amount of catalyst used, cumbersome and difficult post-processing, unsuitable for mass preparation, etc., and achieves simplified reaction process and post-processing. The effect of treatment process, less amount of reaction solvent, and improved yield

Active Publication Date: 2013-01-30
上海毕得医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method involves expensive reagents and complex reaction conditions, and uses a large amount of catalyst, and the post-treatment is cumbersome and difficult, and the yield is extremely low, so it is not suitable for mass production

Method used

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  • Method for preparing 3-ethynyl-4-fluoroaniline
  • Method for preparing 3-ethynyl-4-fluoroaniline
  • Method for preparing 3-ethynyl-4-fluoroaniline

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Example 1: Synthesis of ((2-fluoro-5-nitrobenzene)acetylene)trimethylsilane

[0024] Add 3-bromo-4-fluoronitrobenzene (44g, 0.20mol) to 500ml of triethylamine, under the protection of argon, add cuprous iodide (5g, 0.02mol), tetrakistriphenylphosphorus palladium (5g , 0.004mol), and then dropwise add trimethylsilyl acetylene (29.4g, 0.30mol), 40 ~ 50 ℃ overnight. Filter, spin off the triethylamine, add 1.5L of petroleum ether, filter with a pad of silica gel, and spin dry to obtain 45 g (brown liquid) of the product (yield 95%). The NMR spectrum of the product is as figure 1 Shown: 1H-NMR (CDCl3-d6) δ8.0-8.5 (m, 2H, aromatic), 7.22 (t, 1H, J=8.2 Hz aromatic H6), 0.3 (s, 9H, SiCH3). It was confirmed that the product was ((2-fluoro-5-nitrophenyl)acetylene)trimethylsilane.

Embodiment 2

[0025] Example 2: Synthesis of 4-fluoro-3((trimethylsilane)acetylene)aniline

[0026] The product obtained in Example 1 (45g, 0.19mol) was dissolved in 500ml methanol, 300ml (12N) hydrochloric acid, iron powder (53g, 0.95mol) was heated to reflux for 2 hours, TLC detected, the reaction was completed, the methanol was spun off, and carbonic acid was used. Adjust the pH to alkaline with sodium hydrogen, wash the filter cake with EA (2L), add 800 ml of water to the filtrate, separate, dry and spin dry to obtain 34.2 g (yellow liquid) product, with a yield of 87%. The NMR spectrum of the product is as figure 2 Shown: 1H-NMR (400MHz, CDCl3) δ 8.39 (dd, J = 6.0, 2.9 Hz, 1H), 8.26-8.11 (m, 1H), 7.24 (t, J = 8.5 Hz, 1H), 0.31 ( s, 9H).. The product was confirmed to be 4-fluoro-3((trimethylsilane)acetylene)aniline.

Embodiment 3

[0027] Example 3: Synthesis of 3-ethynyl-4-fluoroaniline

[0028] The compound (34.2g, 0.16mol) obtained in Example 2 was dissolved in 300ml methanol, potassium hydroxide (8.9g, 0.16mol) was added, stirred at room temperature for 4h, 1.5L ethyl acetate was added, and backwashed with saturated brine 2 It was dried and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 19.6 g of (brown powder) product with a yield of 88%. The NMR spectrum of the product is as image 3 Shown as: 1H-NMR (CDCl3-d6) δ6.2-7.0 (m, 3H, aromatic), 3.6 (brs, 2H, NH2), 3.25 (s, 1H, HC≡C). The product was confirmed to be 3-ethynyl-4-fluoroaniline.

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Abstract

The invention provides a method for preparing 3-ethynyl-4-fluoroaniline by using 3-bromo-4-fluoronitrobenzene as a raw material. By using tetra-triphenylphosphine palladium as a catalyst, the method is simple, mild in reaction, easy to control, readily available in raw materials and reagents, low in cost and few in three wastes. Moreover, the 3-ethynyl-4-fluoroaniline obtained by the method is high in yield, easy to purify and high in purity.

Description

Technical field [0001] The invention relates to a preparation method of 3-ethynyl-4-fluoroaniline as an important intermediate compound of anti-tumor therapeutic drugs. Background technique [0002] According to statistics from relevant parties, there are approximately 7 million cancer deaths worldwide each year, of which 24% occur in China. Since the beginning of the 21st century, the emergence of tumor-targeted chemotherapeutics has brought new directions for tumor chemotherapy. As biologically targeted anti-cancer drugs, the mechanism of action of tumor-targeted chemotherapeutics is different from traditional chemotherapy. Tumor-targeted chemotherapeutics target tumor cells to inhibit their growth and proliferation. Generally, the target of tumor-targeted chemotherapeutics is the human epidermal growth factor receptor (EGFR), which is used to transmit the "growth signal" of tumors and plays a key role in the formation and growth of various tumors. Tumor-targeted chemotherapeu...

Claims

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Application Information

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IPC IPC(8): C07C211/52C07C209/68
Inventor 郦荣浩黄冬瑞康治军毛永浩
Owner 上海毕得医药科技股份有限公司
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