Preparation method of 3-fluoro-4-nitroaniline

Abstract

The invention provides a preparation method of 3-fluoro-4-nitroaniline, which comprises the following steps: # imgabs0 takes 2, 4-difluoronitrobenzene as an initial raw material, the 2, 4-difluoronitrobenzene and bis (t-butyloxycarboryl) amine react under an alkali condition to generate an intermediate state, and then the intermediate state is subjected to a deprotection reaction to generate the 3-fluoro-4-nitroaniline. The 3-fluoro-4-nitroaniline is synthesized from the 3-fluoro-4-nitroaniline and bis (t-butyloxycarboryl) amine under an alkali condition, the bis (t-butyloxycarboryl) amine is large in steric hindrance, high in selectivity and easy to treat, and the yield of the one-step method reaches up to 60%.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of 3-fluoro-4-nitroaniline. Background Art

[0002] 3-Fluoro-4-nitroaniline is a key pharmaceutical intermediate. Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3286 - 3295 discloses the following route for synthesizing 3-fluoro-4-nitroaniline compound I: ; In the above synthesis method, the yield of the product 3-fluoro-4-nitroaniline is only 2%, and 98% are isomers, which is not conducive to industrial scale-up production.

[0003] Journal of the Chemical Society. Perkin transactions I, 1988, p. 681- 690 discloses the following route for synthesizing 3-fluoro-4-nitroaniline compound I: ; In the above synthesis method, during the synthesis of 3-fluoro-4-nitroaniline, acetic anhydride is used for protection first and then nitration. Not only is the raw material cost high, involving dangerous chemical reactions such as nitration, but there are also isomers in nitration, which is not conducive to industrial scale-up production. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of 3-fluoro-4-nitroaniline to solve the technical problems raised in the above background art.

[0005] To achieve the above purpose, the present invention provides the following technical solutions: A preparation method of 3-fluoro-4-nitroaniline, comprising the following steps: ; Using 2,4-difluoronitrobenzene as the starting material, reacting with bis(tert-butoxycarbonyl)amine under alkaline conditions to form an intermediate state, and then generating 3-fluoro-4-nitroaniline through a deprotection reaction.

[0006] Preferably, the reaction solvent is at least one of N,N-dimethylformamide and tetrahydrofuran.

[0007] Preferably, the alkaline condition is sodium hydride.

[0008] Preferably, the content of sodium hydride is 60%.

[0009] Preferably, the molar ratio of 2,4-difluoronitrobenzene, bis(tert-butoxycarbonyl)amine, and sodium hydride is 1:(1.1 - 1.3):(1.1 - 1.3).

[0010] Preferably, the intermediate reaction conditions are: temperature is 30 - 50 °C, and the reaction time is 1 - 6 h.

[0011] Preferably, the deprotection reaction conditions of the intermediate are: temperature is 10 - 30 °C, and the reaction time is 1 - 3 h.

[0012] Compared with the prior art, the beneficial effects of the present invention are: The present invention uses 2,4-difluoronitrobenzene as the starting material, and synthesizes 3-fluoro-4-nitroaniline with bis(tert-butoxycarbonyl)amine under alkaline conditions. Bis(tert-butoxycarbonyl)amine not only has a large steric hindrance, high selectivity, and is easy to handle, but also the one-step yield is as high as 60%. Description of the Drawings

[0013] Figure 1 It is the 1H-NMR spectrum of 3-fluoro-4-nitroaniline obtained in Example 1; Figure 2 It is the GC spectrum of 3-fluoro-4-nitroaniline obtained in Example 1. Detailed Embodiments

[0014] The technical solutions of the present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to these embodiments. Example 1

[0015] A preparation method of 3-fluoro-4-nitroaniline, the preparation method comprising the following steps: (1) Synthesis of Compound I Add 800 ml of tetrahydrofuran, 159 g (1 mol) of 2,4-difluoronitrobenzene (Compound II), and 238.7 g (1.1 mol) of bis(tert-butoxycarbonyl)amine to the reaction flask, heat to 50 °C, and slowly add 44 g (1.1 mol) of 60% sodium hydride in multiple times. After adding, keep warm and stir for 3 h, and track the reaction by TLC until 2,4-difluoronitrobenzene reacts completely; cool down, quench with dilute hydrochloric acid, adjust the pH to 1 - 2, keep warm and stir at 30 °C for 1 h after adjustment, and track the reaction by TLC until the intermediate reaction is complete. Concentrate under reduced pressure to dryness, and slurry with water and toluene in sequence, then filter to obtain 93.6 g of Compound I, with a molar yield of 60%.

[0016] Among them, Figure 11H-NMR spectrum of 3-fluoro-4-nitroaniline compound I, 1H-NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 9.1 Hz, 1H, ArH), 6.95 (s, 2H, NH2), 6.48 – 6.29 (m, 2H, ArH) Figure 2 The gas chromatogram of 3-fluoro-4-nitroaniline compound I shows that the purity of 3-fluoro-4-nitroaniline compound I is greater than 98.4%. Example 2

[0017] A preparation method of 3-fluoro-4-nitroaniline, the preparation method comprising the following steps: (1) Synthesis of compound I Add 800 ml of N,N-dimethylformamide, 159 g (1 mol) of 2,4-difluoronitrobenzene, and 260.4 g (1.2 mol) of bis(tert-butoxycarbonyl)amine to a reaction flask, heat to 40 °C, and slowly add 48 g (1.2 mol) of 60% sodium hydride in multiple portions. After addition, keep warm and stir for 1 h. Monitor the reaction by TLC until 2,4-difluoronitrobenzene is completely reacted; cool down, quench with dilute hydrochloric acid, adjust the pH to 1 - 2, keep warm and stir at 20 °C for 2 h. Monitor the reaction by TLC until the intermediate state is completely reacted. Concentrate under reduced pressure to dryness, and slurry with water and toluene in sequence, then filter to obtain 84.2 g of compound I, molar yield: 54%. Example 3

[0018] A preparation method of 3-fluoro-4-nitroaniline, the preparation method comprising the following steps: (1) Synthesis of compound I Add 800 ml of tetrahydrofuran, 159 g (1 mol) of 2,4-difluoronitrobenzene, and 282.1 g (1.3 mol) of bis(tert-butoxycarbonyl)amine to a reaction flask, heat to 30 °C, and slowly add 52 g (1.3 mol) of 60% sodium hydride in multiple portions. After addition, keep warm and stir for 6 h. Monitor the reaction by TLC until 2,4-difluoronitrobenzene is completely reacted; cool down, quench with dilute hydrochloric acid, adjust the pH to 1 - 2, keep warm and stir at 10 °C for 3 h. Monitor the reaction by TLC until the intermediate state is completely reacted. Concentrate under reduced pressure to dryness, and slurry with water and toluene in sequence, then filter to obtain 65.5 g of compound I, molar yield: 42%.

[0019] Although the present invention has been illustrated and described with reference to specific embodiments, it will be apparent to those skilled in the art that many other changes and modifications can be made without departing from the spirit and scope of the invention. Therefore, all such changes and modifications that fall within the scope of the invention are intentionally included in the appended claims.

Claims

1. A preparation method of 3-fluoro-4-nitroaniline, characterized in that, It includes the following steps: ； Using 2,4-difluoronitrobenzene as the starting material, reacting with bis(tert-butoxycarbonyl)amine under basic conditions to form an intermediate state, and then undergoing a deprotection reaction to produce 3-fluoro-4-nitroaniline.

2. The method according to claim 1, characterized in that, The reaction solvent is at least one of N,N-dimethylformamide and tetrahydrofuran.

3. The method according to claim 1, wherein The basic conditions are sodium hydride.

4. The method according to claim 3, characterized in that The content of the sodium hydride is 60%.

5. The method according to claim 3, characterized in that, The molar ratio of the 2,4-difluoronitrobenzene, bis(tert-butoxycarbonyl)amine, and sodium hydride is 1:(1.1 - 1.3):(1.1 - 1.3).

6. The method according to claim 1, wherein The reaction conditions for the intermediate state are: the temperature is 30 - 50 °C, and the reaction time is 1 - 6 h.

7. The method according to claim 1, wherein The reaction conditions for the deprotection reaction of the intermediate state are: the temperature is 10 - 30 °C, and the reaction time is 1 - 3 h.

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