阅读说明：本技术 一种4-氟取代芳基胺类化合物及其合成方法 (4-fluorine substituted aryl amine compound and synthetic method thereof ) 是由 刘文娟 刘智慧 崔志鹏 崔晓雷 田瑞芳 于 2021-06-23 设计创作，主要内容包括：本发明公开了一种4-氟取代芳基胺类化合物的合成方法,包括以下步骤：1)以酰基保护的苯基羟胺为底物,在极性溶剂中,以磺酰氟为氟源,在碱性条件下生成4-氟取代苯胺类化合物；2)在稀酸性条件下或者Pd催化氢化进行脱保护基团,得到所述4-氟取代芳基胺类化合物。本发明合成的4-氟取代的苯胺类化合物,由于氟原子引入极大程度上增加其亲脂性,因此能广泛用于含氟药物、农药以及染料中间体的制备；同时,本发明采用的原料均为工业化产品,价廉易得,具有市售；通过本发明制得的4-氟芳基苯胺收率高,能够以大于90％的收率得到纯度≥99％的产物；本发明操作简单,成本低廉的工艺十分适用于工业化,能够广泛推广使用。(The invention discloses a synthesis method of a 4-fluorine substituted aryl amine compound, which comprises the following steps: 1) using acyl protected phenylhydroxylamine as a substrate, and using sulfonyl fluoride as a fluorine source in a polar solvent to generate a 4-fluorine substituted aniline compound under an alkaline condition; 2) carrying out deprotection under dilute acid condition or Pd catalytic hydrogenation to obtain the 4-fluorine substituted aryl amine compound. The 4-fluorine substituted aniline compound synthesized by the invention can be widely used for preparing fluorine-containing medicaments, pesticides and dye intermediates because the introduction of fluorine atoms greatly increases the lipophilicity; meanwhile, the raw materials adopted by the invention are all industrial products, are low in price and easy to obtain, and are commercially available; the 4-fluoroarylaniline prepared by the method has high yield, and can obtain a product with the purity of more than or equal to 99% in the yield of more than 90%; the method is simple to operate, the process with low cost is very suitable for industrialization, and the method can be widely popularized and used.)

1. A synthetic method of a 4-fluorine substituted aryl amine compound is characterized by comprising the following steps:

1) using acyl protected phenylhydroxylamine as a substrate, and using sulfonyl fluoride as a fluorine source in a polar solvent to generate a 4-fluorine substituted aniline compound under an alkaline condition;

2) carrying out deprotection group under dilute acidic condition or Pd catalytic hydrogenation to obtain the 4-fluorine substituted aryl amine compound;

the reaction equation is as follows:

R¹selected from C1-C6 alkyl or C1-C10 alkoxy;

R²selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, halogen, amino, C1-C6 alkyl substituted amino, C1-C6 alkyl substituted mercapto, C1-C6 alkyl substituted sulfoxide or C1-C6 alkyl substituted sulfone.

2. The method of synthesis of claim 1, wherein R is¹＝-CH₃、 R²＝H、-CH₃、CH₃O-、CF₃、F、Cl、Br、I、NH₂、CH₃N、CH₃S-、CH₃SO-or CH₃SO₂-。

3. The synthesis method according to claim 1, wherein the step 1) further comprises a post-treatment step after the reaction is completed, the post-treatment step comprising: washing and vacuum rectification; meanwhile, the step 1) is specifically as follows: adding the compound (I), alkali and a polar solvent into a stirring reaction bottle, introducing sulfuryl fluoride, sealing the system, slowly heating to room temperature, continuing stirring, adding saturated saline solution for washing after the reaction is finished, concentrating the organic phase under reduced pressure to evaporate dichloromethane, and rectifying the crude product under reduced pressure to obtain white solid N-acetyl 4-fluoroaniline.

4. The method of synthesis according to claim 3, wherein the base is chosen from KF, CsF, K₂CO₃、Cs₂CO₃Triethylamine, pyridine or DBU; the polar solvent is selected from dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, toluene, xylene, N-dimethylformamide or N, N-dimethylacetamide.

5. The synthesis process according to claim 4, characterized in that the polar solvent is chosen from dichloromethane or 1, 2-dichloroethane.

6. The synthesis method according to claim 5, wherein the reaction temperature of the compound (I), the base and the polar solvent is-20 to 50 ℃.

7. The synthesis method according to claim 5, wherein the reaction temperature of the compound (I), the base and the polar solvent is 0 to 25 ℃.

8. The synthesis method according to any one of claims 1 to 7, wherein step 2) is specifically: adding the compound (II) into acid, heating and refluxing, adding NaOH to adjust the pH value to be alkaline after TLC detection reaction, adding dichloromethane for extraction, washing an organic phase with saturated saline solution, drying, carrying out reduced pressure distillation to recover a solvent, and carrying out reduced pressure distillation on a crude product to obtain the 4-fluorine substituted aryl amine compound.

9. The method of synthesis according to claim 8, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and the acid concentration is 2.0-5.0 mol/L.

10. A 4-fluoro substituted arylamine compound synthesized by the method of any one of claims 1 to 9, wherein the compound has a general structural formula shown in formula (III):

Technical Field

The invention belongs to the technical field of fine chemical engineering, relates to the technical field of organic synthesis, and particularly relates to a 4-fluorine substituted arylamine compound and a synthesis method thereof.

Background

As fluorine is the element with the largest electronegativity, the fluorine atom leads the fluorine-containing organic compound to have unique physical property, chemical property and physiological activity, and the fluorine-containing organic compound has the characteristics of chemical stability, surface activity, excellent temperature resistance and the like. Therefore, fluorine-containing compounds have been extensively and intensively studied and applied in many advanced technologies and major industrial projects and industries such as medicine and pesticide.

Para-fluorine substituted aryl aniline widely exists in a plurality of drug and pesticide molecules, and can be converted to synthesize other fluorine-containing aryl compounds, and the synthesis method is also the focus of attention.

The compound 4-fluoro substituted anilines have been prepared so far by the following methods:

route Scheme 1:

scheme 1(J.chem.Soc., chem.Commun.,1992,921-922) utilizes acyl protected phenylhydroxylamine as a substrate, methylene chloride as a solvent, and DAST (Cas: 38078-09-0) as a fluorinating agent at 0 ℃ to give a product that is para-fluorinated to amino groups. The fluoridation reagent used by the method is DAST which is expensive (about 3000 yuan/500 g), has poor thermal stability and is easy to explode, and is not beneficial to industrial production amplification.

Route Scheme 2:

scheme 2 the fluorination of aromatic rings directly from acyl protected anilines under different fluorinating agent conditions. The document Green chem.2017,19,3344 uses Selectfluor as fluorinating agent, the product being a mixture of ortho and para (R ═ Me, 58% for para and 20% for ortho); chem.1984,49,806-₃COOF as fluorinating reagent, but the products are mainly ortho-position products, para-position products are only very small amount of products (R ═ Me, para-position products 7%, ortho-position products 50%), document j. org. chem.2013,78,728 reports using high valent iodine as oxidizing agent, pyridine hydrogen fluoride as fluorinating reagent, obtaining para-position fluorinated products in moderate yield, with other oxidation by-products due to the oxidizing property of high valent iodine. The document J.org.chem.1985,50, 4576-containing 4582 uses CF₃OF is a fluorinating agent, and because OF its high activity, this reaction gives a mixture OF ortho-, para-, and difluoros-trifluoro-substituted products, which are difficult to separate. Therefore, the industrial production of the method is inhibited by problems such as poor regioselectivity for the fluorination of acylanilides, expensive reagents, difficulty in separation and purification, and the like.

Route Scheme 3:

the literature Nature 2015,524,208-211 reports the fluorination using aryl bromides, AgF and KF as fluorine sources under palladium catalysis, which is not suitable for scale-up production due to the use of air and water sensitive catalytic systems and the expensive reagents.

Disclosure of Invention

The present invention is directed to 4-fluoro substituted arylamine compounds and methods for synthesizing the same, which solve one or more of the problems set forth above in the prior art.

On one hand, the synthesis method of the 4-fluorine substituted aryl amine compound provided by the invention comprises the following steps:

1) using acyl protected phenylhydroxylamine as a substrate, and using sulfonyl fluoride as a fluorine source in a polar solvent to generate a 4-fluorine substituted aniline compound under an alkaline condition;

2) carrying out deprotection group under dilute acidic condition or Pd catalytic hydrogenation to obtain the 4-fluorine substituted aryl amine compound;

the reaction equation is as follows:

R¹selected from C1-C6 alkyl or C1-C10 alkoxy;

R²selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, halogen, amino, C1-C6 alkyl substituted amino, C1-C6 alkyl substituted mercapto, C1-C6 alkyl substituted sulfoxide or C1-C6 alkyl substituted sulfone.

In certain embodiments, R¹＝-CH₃、R²＝H、-CH₃、CH₃O-、CF₃、F、Cl、Br、I、NH₂、CH₃N、CH₃S-、CH₃SO-or CH₃SO₂-。

In certain embodiments, step 1) further comprises a post-treatment step after completion of the reaction, the post-treatment step comprising: washing and vacuum rectification; meanwhile, the step 1) is specifically as follows: adding the compound (I), alkali and a polar solvent into a stirring reaction bottle, introducing sulfuryl fluoride, sealing the system, slowly heating to room temperature, continuing stirring, adding saturated saline solution for washing after the reaction is finished, concentrating the organic phase under reduced pressure to evaporate dichloromethane, and rectifying the crude product under reduced pressure to obtain white solid N-acetyl 4-fluoroaniline.

In certain embodiments, the molar ratio of compound (I) to sulfonyl fluoride is 1: (1.5-3).

In certain embodiments, the molar ratio of compound (I) to base is 1: (0.1-1.0).

In certain embodiments, the base is selected from KF, CsF, K₂CO₃、Cs₂CO₃Triethylamine, pyridine or DBU; the polar solvent is selected from dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, toluene, xylene, N-dimethylformamide or N, N-dimethylacetamide.

In certain embodiments, the polar solvent is selected from dichloromethane or 1, 2-dichloroethane.

In certain embodiments, the reaction temperature of compound (I), base, and polar solvent is-20 to 50 ℃.

In certain embodiments, the reaction temperature of compound (I), base, and polar solvent is from 0 to 25 ℃.

In certain embodiments, step 2) is specifically: adding the compound (II) into acid, heating and refluxing, adding NaOH to adjust the pH value to be alkaline after TLC detection reaction, adding dichloromethane for extraction, washing an organic phase with saturated saline solution, drying, carrying out reduced pressure distillation to recover a solvent, and carrying out reduced pressure distillation on a crude product to obtain the 4-fluorine substituted aryl amine compound.

In certain embodiments, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and the acid concentration is 2.0 to 5.0 mol/L.

On the other hand, the invention provides a 4-fluorine substituted arylamine compound, which has a structural general formula shown in formula (III):

the synthesis method comprises the following steps:

1) using acyl protected phenylhydroxylamine as a substrate, and using sulfonyl fluoride as a fluorine source in a polar solvent to generate a 4-fluorine substituted aniline compound under an alkaline condition;

2) carrying out deprotection group under dilute acidic condition or Pd catalytic hydrogenation to obtain the 4-fluorine substituted aryl amine compound;

the reaction equation is as follows:

R¹selected from C1-C6 alkyl or C1-C10 alkoxy;

R²selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, halogen, amino, C1-C6 alkyl substituted amino, C1-C6 alkyl substituted mercapto, C1-C6 alkyl substituted sulfoxide or C1-C6 alkyl substituted sulfone.

Has the advantages that: the 4-fluorine substituted aniline compound synthesized by the invention can be widely used for preparing fluorine-containing medicaments, pesticides and dye intermediates because the introduction of fluorine atoms greatly increases the lipophilicity; meanwhile, the raw materials adopted by the invention are all industrial products, are low in price and easy to obtain, and are commercially available; the 4-fluoroarylaniline prepared by the method has high yield, and can obtain a product with the purity of more than or equal to 99% in the yield of more than 90%; the method is simple to operate, the process with low cost is very suitable for industrialization, and the method can be widely popularized and used.

Detailed Description

The present invention will be described in further detail below with reference to embodiments.

The synthetic route of the scheme is as follows:

example 1

Sequentially adding N-acetylphenylhydroxylamine (151g,1.0mol), KF (29g,0.5mol) and dichloromethane (1.0L) into a stirred 2L reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (202g, 2mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12 hours, adding saturated saline (500mL) after the reaction is finished, concentrating the organic phase under reduced pressure to evaporate dichloromethane (recycling), rectifying the crude product under reduced pressure to obtain white solid N-acetyl-4-fluoroaniline (142g), adding the N-acetyl-4-fluoroaniline into 2mol/L hydrochloric acid (500mL), heating for reflux reaction for 12 hours, adding NaOH (5mol/L) to adjust the pH value to alkalinity (8-10) after the TLC detection reaction is finished, adding an organic solvent dichloromethane (500mL) for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered by distillation under reduced pressure, and the crude product was distilled under reduced pressure to give a pure 4-fluoroaniline as a pale yellow liquid (101g, yield 91%, purity 99.3%).

1H NMR(400MHz,CDCl₃)：δ＝6.86(t,J＝8.7Hz,2H),6.64-6.60(m,2H),3.51(br-s,2H)。13C NMR(100MHz,CDCl₃):δ＝158.1,155.0,142.2,116.3。

Example 2

Sequentially adding N-pivaloyl phenylhydroxylamine (19.3g,0.1mol), KF (2.9g,0.05mol) and dichloromethane (200mL) into a stirred 500mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (20g, 0.2mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12h, adding saturated saline (50mL) after the reaction is finished, washing, concentrating the organic phase under reduced pressure to evaporate dichloromethane, carrying out reduced pressure rectification on the crude product to obtain N-pivaloyl 4-fluoroaniline (18.5g), adding the N-pivaloyl 4-fluoroaniline into 2mol/L hydrochloric acid (100mL), heating for reflux reaction for 12h, adding NaOH (5mol/L) to adjust the pH value to be alkaline (8-10) after the TLC detection reaction is finished, adding an organic solvent dichloromethane (100mL) for extraction, washing the organic phase with saturated saline, the mixture was dried over anhydrous sodium sulfate, the solvent was recovered by distillation under the reduced pressure, and the crude product was distilled under the reduced pressure to give a pure 4-fluoroaniline as a pale yellow liquid (10.3g, yield 92.7%).

Example 3

Sequentially adding N-Boc-phenylhydroxylamine (2.09g,0.01mol) and KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfuryl fluoride (2g, 0.02mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12h, adding saturated saline (25mL) after the reaction is finished, washing, concentrating the organic phase under reduced pressure to evaporate dichloromethane, distilling the crude product under reduced pressure to obtain N-Boc-4-fluoroaniline (2.05g), adding the N-Boc-4-fluoroaniline into 2mol/L hydrochloric acid (100mL), reacting for 2h at room temperature, adding NaOH (5mol/L) to adjust the pH to be alkaline (8-10) after the TLC detection reaction is finished, adding an organic solvent dichloromethane (100mL) for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, distilling under reduced pressure to recover solvent, and performing column chromatography on the crude product to obtain pure 4-fluoroaniline as pale yellow liquid (1.05g, yield 94.6%).

Example 4

Adding N-Cbz-phenylhydroxylamine (24.3g,0.1mol), KF (2.9g,0.05mol) and dichloromethane (150mL) into a stirred 50mL reaction bottle in sequence, cooling to 0 ℃, introducing sulfuryl fluoride (20.2g, 0.2mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12H, adding saturated saline (200mL) after the reaction is finished, washing by organic phase under reduced pressure, concentrating and evaporating dichloromethane to obtain N-Cbz-4-fluoroaniline (22.0g), adding N-Cbz-4-fluoroaniline into methanol (200mL), adding Pd/C (1g), introducing H2, reacting for 12H at room temperature, filtering Pd/C (recycling) after TLC detection reaction is finished, carrying out organic phase vacuum distillation to recover the solvent, carrying out column chromatography to obtain a pure 4-fluoroaniline as a light yellow liquid (10.2 g), yield 91.9%).

Example 5

Sequentially adding N-acetyl-2-methylphenylhydroxylamine (1.65g,0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12 hours, adding saturated saline (10mL) after the reaction is finished, washing, concentrating organic phase under reduced pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-methyl-4-fluoroaniline (1.56g), adding N-acetyl-2-methyl-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12 hours, adding NaOH (5mol/L) to adjust the pH to be alkaline (8-10) after TLC detection reaction is finished, adding organic solvent dichloromethane (20mL) for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, desolventizing under reduced pressure, and performing column chromatography on the crude product to obtain pure 2-methyl-4-fluoroaniline as yellow liquid (1.15g, yield 92%).

1H NMR(CDCl₃)：δ＝6.77(dd,J＝9.5,3.0Hz,1H),6.70(td,J＝9.0,3.0Hz,1H),6.56(dd,J＝8.5,5.0Hz,1H),4.65(s,2H),2.03(s,3H)。

Example 6

Sequentially adding N-acetyl-2-methoxyphenyl hydroxylamine (1.81g,0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12 hours, adding saturated saline (20mL) after the reaction is finished, washing, concentrating organic phase under reduced pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-methoxy-4-fluoroaniline (1.70g), adding the N-acetyl-2-methoxy-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12 hours, adding NaOH (5mol/L) to adjust the pH to be alkaline (8-10) after TLC detection reaction is finished, adding organic solvent dichloromethane (20mL) for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, desolventizing under reduced pressure, and performing column chromatography on the crude product to obtain the pure product 2-methoxy-4-fluoroaniline as yellow liquid (1.30g, yield 92.2%).

1H NMR(CDCl₃)：δ＝6.45-6.64(m,3H),3.82(s,3H)3.51(br,2H)。

Example 7

Sequentially adding N-acetyl-2-trifluoromethyl phenylhydroxylamine (2.19g,0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12 hours, adding saturated saline (20mL) after the reaction is finished, washing, concentrating organic phase under reduced pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-trifluoromethyl-4-fluoroaniline (2.1g), adding N-acetyl-2-trifluoromethyl-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12 hours, adding NaOH (5mol/L) to adjust the pH to alkalinity (8-10) after TLC detection reaction is finished, adding organic solvent dichloromethane (20mL) for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, desolventizing under reduced pressure, and performing column chromatography on the crude product to obtain the pure 2-trifluoromethyl-4-fluoroaniline as a yellow liquid (1.63g, yield 91.1%).

1H NMR(CDCl3)：δ＝6.45-6.64(m,3H),3.82(s,3H)3.51(br,2H)。

Example 8

Sequentially adding N-acetyl-2-bromophenylhydroxylamine (2.30g, 0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12 hours, adding saturated saline (20mL) after the reaction is finished, washing, concentrating organic phase under reduced pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-bromo-4-fluoroaniline (2.23g), adding N-acetyl-2-bromo-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12 hours, adding NaOH (5mol/L) to adjust the pH value to be alkaline (8-10) after TLC detection reaction is finished, adding organic solvent dichloromethane (50mL) for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, desolventized under reduced pressure, and the crude product was subjected to column chromatography to give pure 2-bromo-4-fluoroaniline as a red liquid (1.73g, yield 91.0%).

1H NMR(400MHz,CDCl₃)：δ＝7.17(dd,J＝8.1,2.8Hz,1H),6.86(ddd,J＝8.8,8.0,2.8Hz,1H),6.71(dd,J＝8.8,5.0Hz,1H),3.90(s,2H)。

Example 9

Sequentially adding N-acetyl-2-aminophenylhydroxylamine (1.66g, 0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12 hours, adding saturated saline (20mL) after the reaction is finished, washing, concentrating organic phase under reduced pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-amino-4-fluoroaniline (1.62g), adding N-acetyl-2-amino-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12 hours, adding NaOH (5mol/L) to adjust the pH to be alkaline (8-10) after TLC detection reaction is finished, adding organic solvent dichloromethane (50mL) for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, desolventizing under reduced pressure, and performing column chromatography on the crude product to obtain pure 2-amino-4-fluoroaniline as red liquid (1.15g, yield 92.2%).

1H NMR(CDCl3)：δ＝6.20-6.54(m,3H),3.40(br,4H)。

Example 10

Sequentially adding N-acetyl-2-methylthiophenylhydroxylamine (1.97g, 0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12 hours, adding saturated saline (20mL) after the reaction is finished, washing, concentrating organic phase under reduced pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-methylthio-4-fluoroaniline (1.90g), adding N-acetyl-2-methylthio-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12 hours, adding NaOH (5mol/L) after TLC detection reaction is finished, adjusting the pH to be alkaline (8-10), the resulting mixture was extracted with dichloromethane (50mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, desolventized under reduced pressure, and subjected to column chromatography to give 2-methylsulfanyl-4-fluoroaniline as a red liquid (1.42g, yield 91.2%).

1H NMR(400MHz,CDCl₃)：δ＝6.75(t,J＝8.1Hz,1H),6.64(s,1H),6.51(d,J＝8.1Hz,1H),3.90(br,2H),2.51(s,3H)。

Example 11

Sequentially adding N-acetyl-2-methylsulfonylphenylhydroxylamine (2.13g, 0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12h, adding saturated saline (20mL) after the reaction is finished, washing, concentrating under organic phase pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-methylsulfonyl-4-fluoroaniline (2.10g), adding N-acetyl-2-methylsulfonyl-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12h, adding NaOH (5mol/L) to adjust the pH value to be alkaline (8-10) after TLC detection reaction is finished, adding organic solvent dichloromethane (50mL) for extraction, washing an organic phase with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, performing desolventization under reduced pressure, and performing column chromatography on a crude product to obtain a pure product of the 2-methylsulfonyl-4-fluoroaniline as a red liquid (1.57g, yield 90.8%).

1H NMR(400MHz,CDCl₃)：δ＝7.36(s,1H),6.99(t,J＝8.0Hz,1H),6.83(d,J＝8.1Hz,1H),3.90(br,2H),2.64(s,3H)。

Example 12

Sequentially adding N-acetyl-2-methylsulfonylphenylhydroxylamine (2.29g, 0.010mol), KF (0.29g,0.005mol) and dichloromethane (20mL) into a stirred 50mL reaction bottle, cooling to 0 ℃, introducing sulfonyl fluoride (2.04g, 0.020mol), sealing the system, slowly heating to room temperature, stirring for reaction for 12h, adding saturated saline (20mL) after the reaction is finished, washing, concentrating organic phase under reduced pressure to evaporate dichloromethane to obtain white solid N-acetyl-2-methylsulfonyl-4-fluoroaniline (2.25g), adding N-acetyl-2-methylsulfonyl-4-fluoroaniline into 2mol/L hydrochloric acid (20mL), heating for reflux reaction for 12h, adding NaOH (5mol/L) to adjust the pH value to be alkaline (8-10) after TLC detection reaction is finished, adding organic solvent dichloromethane (50mL) for extraction, washing an organic phase with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, performing desolventizing under reduced pressure, and performing column chromatography on a crude product to obtain a pure product of the 2-methylsulfonyl-4-fluoroaniline as a red liquid (1.74g, the yield is 92.1%).

1H NMR(400MHz,CDCl₃)：δ＝7.64(s,1H),6.99(t,J＝8.0Hz,1H),6.89(d,J＝8.1Hz,1H),4.20(br,2H),3.32(s,3H)。

In summary, the following steps: the 4-fluorine substituted aniline compound synthesized by the invention can be widely used for preparing fluorine-containing medicaments, pesticides and dye intermediates because the introduction of fluorine atoms greatly increases the lipophilicity; meanwhile, the raw materials adopted by the invention are all industrial products, are low in price and easy to obtain, and are commercially available; the 4-fluoroarylaniline prepared by the method has high yield, and can obtain a product with the purity of more than or equal to 99% in the yield of more than 90%; the method is simple to operate, the process with low cost is very suitable for industrialization, and the method can be widely popularized and used.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these should be considered as within the scope of the present invention.