阅读说明：本技术 一种氟代苯胺的制备方法 (Preparation method of fluoroaniline ) 是由 刘辉 杨东 何立 杨建华 于 2021-10-20 设计创作，主要内容包括：本发明涉及化学合成领域,具体涉及氟代苯胺的制备方法,其包括如下步骤：S1、氟代苯(式Ⅰ)与对甲苯磺酰叠氮进行取代反应,以提供氟代苯基叠氮(式Ⅱ),S2、将氟代苯基叠氮进行还原反应,以制备氟代苯胺(式Ⅲ)。其中,n为0～4的整数,R选自F、Cl、三氟甲基、C1～C8的烷基、非氟取代的芳基；当n为2～4时,R的选择可相同或不同,且F的邻位至少有一个氢未被R取代。本发明的合成工艺从氟代苯(式Ⅰ)出发,经过两步反应,以较高的收率制备得到氟代苯胺(式Ⅲ)。另外发明所提供的氟代苯胺的制备方法所制备的氟代苯胺(式Ⅲ)具有无异构、三废少、易纯化、步骤短等优点,具有良好的产业化前景。(The invention relates to the field of chemical synthesis, in particular to a preparation method of fluoroaniline, which comprises the following steps: s1, carrying out a substitution reaction of fluorobenzene (formula I) and p-toluenesulfonyl azide to provide fluorophenyl azide (formula II), and S2, carrying out a reduction reaction of the fluorophenyl azide to prepare fluoroaniline (formula III). Wherein n is an integer of 0-4, R is selected from F, Cl, trifluoromethyl, C1-C8 alkyl and non-fluorine substituted aryl; when n is 2-4, R can be selected same or different, and at least one hydrogen in the ortho position of F is not substituted by R. The synthesis process of the invention starts from fluorobenzene (formula I), and prepares fluoroaniline (formula III) with higher yield through two-step reaction. In addition, the fluoroaniline (formula III) prepared by the preparation method of the fluoroaniline has the advantages of no isomerization, less three wastes, easy purification, short steps and the like, and has good propertiesAnd (4) the industrialization prospect.)

1. A preparation method of fluoroaniline comprises the following steps:

s1, carrying out a substitution reaction of fluorobenzene (formula I) and p-toluenesulfonyl azide to provide fluorophenyl azide (formula II);

s2, the fluoro-phenyl azide is subjected to reduction reaction to prepare the fluoro-aniline (formula III).

The chemical reaction process of the S1 step and the S2 step is as follows:

wherein n is an integer of 0-4, R is selected from F, Cl, trifluoromethyl, C1-C8 alkyl and non-fluorine substituted aryl; when n is 2-4, R can be selected same or different, and at least one hydrogen in the ortho position of F is not substituted by R.

2. The process for the preparation of fluoroanilines according to claim 1, characterised in that it comprises one or more of the following technical characteristics:

a: in step S1, after reacting fluorobenzene (formula I) with strong alkaline lithium, carrying out substitution reaction with p-toluenesulfonyl azide;

b: in the step S1, a crude product of the fluorophenyl azide (formula II) is obtained through a post-treatment process of the substitution reaction;

c: in step S1, the substitution reaction is performed under organic solvent conditions;

d: in step S1, the molar ratio of fluorobenzene (formula i) to p-toluenesulfonylazide is 1: 1-3;

e: in step S1, the reaction temperature of the substitution reaction is-90 to-40 ℃;

f: in step S2, the reduction reaction is a hydrogenation reduction reaction, and is performed in the presence of a reducing agent and a catalyst;

g: in step S2, the reduction reaction is performed under organic solvent conditions;

h: in the step S2, the temperature of the reduction reaction is 10-80 ℃;

i: in step S2, the reduction reaction is carried out under normal pressure or pressurization, and the pressure is 1-15 bar under the pressurization condition;

j: in step S2, the reduction reaction is followed by a post-treatment process to obtain fluoroaniline (formula III).

3. The process for the preparation of fluoroanilines according to claim 2, wherein said A comprises one or more of the following technical characteristics:

a1: the strong-alkaline lithium is selected from one or more of butyl lithium, tert-butyl lithium, sec-butyl lithium or lithium diisopropylamide;

a2: the molar ratio of fluorobenzene (formula I) to strongly basic lithium is 1: 1-3;

a3: the fluorobenzene (formula I) is selected from o-fluorotrifluorotoluene, m-fluorotrifluorotoluene, p-fluorotrifluorotoluene, o-fluoromethylbenzene or o-fluoroethylbenzene.

4. The process for producing fluoroaniline according to claim 3 wherein in A3, the fluorobenzene (formula I) is o-fluorotrifluorotoluene;

the chemical reaction process is as follows:

5. the process for the preparation of fluoroanilines according to claim 4, characterized in that it comprises at least one of the following technical characteristics:

a31: the strongly basic lithium is selected from butyl lithium and/or tert-butyl lithium;

a32: the molar ratio of the o-fluorotrifluorotoluene to the strongly basic lithium is 1: 1-3;

a33: the molar ratio of o-fluorotrifluorotoluene to tosylazide is 1: 1 to 3.

6. The method for preparing fluoroaniline according to claim 2 wherein in B, the post-treatment process comprises: quenching reaction, organic solvent extraction and organic phase concentration to obtain crude product of fluoro-phenyl azide (formula II).

7. The method for producing fluoroaniline according to claim 2 wherein the organic solvent in C is one or more selected from the group consisting of an ether solvent, an alkane solvent and an aromatic solvent.

8. The method for preparing fluoroaniline according to claim 2 wherein said F further comprises one of the following technical features:

f1: the molar ratio of the fluorophenylazide (formula II) to the reducing agent is 1: 1-5;

f2: the molar ratio of the catalyst to the fluoro-phenyl azide (formula II) is 0.001-0.1: 1;

f3: the catalyst is selected from one or more of palladium carbon catalyst, ruthenium carbon catalyst, rhodium carbon catalyst, platinum carbon catalyst, nickel-based catalyst and the like;

f4: the reducing agent is selected from hydrogen and/or hydrazine hydrate.

9. The method for producing fluoroaniline according to claim 2 wherein the organic solvent in G is one or a combination of two or more selected from the group consisting of ester solvents, carbonate solvents, alcohol solvents, aromatic hydrocarbons and ether solvents.

10. The process for producing fluoroaniline according to claim 8, wherein in F3, the post-treatment process comprises solid-liquid separation, organic phase concentration and purification;

wherein the purification is carried out by steam distillation to obtain the fluoroaniline (formula III).

Technical Field

The invention relates to the field of organic chemistry, in particular to a preparation method of fluoroaniline.

Background

Pramipexole (Proxalutamide) is a new-generation Androgen Receptor (AR) antagonist, shows a good therapeutic effect against metastatic castration-resistant prostate cancer and metastatic breast cancer, and is currently undergoing three-phase clinical research. After the new crown occurs, the treatment field is expanded to the new crown, the effect of reducing the death risk of severe patients with the new crown is found to be remarkable, and the three-phase clinical research is also carried out at present.

The 2-fluoro-3-trifluoromethylaniline is an important precursor compound for synthesizing the prochloraz, and the synthesis method of the p-2-fluoro-3-trifluoromethylaniline is shown as the following synthesis route method I and method II, and can be obtained by taking o-fluoro benzotrifluoride or o-chloro benzotrifluoride as a raw material and carrying out nitration reduction or nitration fluorination reduction. The compound can also be obtained by taking o-fluorobenzoic acid as a raw material, nitrifying, converting the o-fluorobenzoic acid and carboxyl tetrafluoride into trifluoromethyl, and finally reducing.

The method comprises the following steps:

however, the above-mentioned first, second and third methods require a nitration process with a high safety risk, and the nitration reaction has a large number of isomers of halogen para-nitration, and even under most conditions, the para-nitration product is mainly used and the three routes respectively generate isomersThe yield of the expected product is greatly reduced, and the isomer is similar to the target product in structure and similar in property and is not easy to separate and remove, so that the content of the target product is not high, and the product is troublesome to purify. The conversion of carboxyl to trifluoromethyl requires the use of the more toxic sulfur tetrafluoride.

Therefore, a method for synthesizing 2-fluoro-3-trifluoromethylaniline by using a simple process route is urgently needed in the field, which can reduce the generation of isomers and the occurrence of side reactions, reduce the difficulty in purifying the product and obtain a high-purity target product.

Disclosure of Invention

In view of the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide a method for preparing fluoroaniline, which solves the problems of the prior art.

To achieve the above and other related objects, the present invention provides a method for preparing fluoroaniline, comprising:

s1, carrying out a substitution reaction of fluorobenzene (formula I) and p-toluenesulfonyl azide to provide fluorophenyl azide (formula II);

s2, the fluoro-phenyl azide is subjected to reduction reaction to prepare the fluoro-aniline (formula III).

The chemical reaction process of the S1 step and the S2 step is as follows:

wherein n is an integer of 0-4, R is selected from F, Cl, trifluoromethyl, C1-C8 alkyl and non-fluorine substituted aryl; when n is 2-4, R can be selected same or different, and at least one hydrogen in the ortho position of F is not substituted by R.

In some embodiments of the invention, the preparation method comprises one or more of the following technical features:

a: in step S1, after reacting fluorobenzene (formula I) with strong alkaline lithium, carrying out substitution reaction with p-toluenesulfonyl azide;

b: in the step S1, a crude product of the fluorophenyl azide (formula II) is obtained through a post-treatment process of the substitution reaction;

c: in step S1, the substitution reaction is performed under organic solvent conditions;

d: in step S1, the molar ratio of fluorobenzene (formula i) to p-toluenesulfonylazide is 1: 1-3, preferably 1: 1 to 1.2;

e: in step S1, the reaction temperature of the substitution reaction is-90 to-40 ℃, and the preferable reaction temperature is-80 to-60 ℃;

f: in step S2, the reduction reaction is a hydrogenation reduction reaction, and is performed in the presence of a reducing agent and a catalyst;

g: in step S2, the reduction reaction is performed under organic solvent conditions;

h: in the step S2, the temperature of the reduction reaction is 10-80 ℃;

i: in step S2, the reduction reaction is performed under normal pressure or pressurized condition, wherein the pressure is 1 to 15bar, preferably 3 to 5 bar;

j: in step S2, the reduction reaction is followed by a post-treatment process to obtain fluoroaniline (formula III).

In some embodiments of the present invention, the a includes one or more of the following technical features:

a1: the strong-alkaline lithium is selected from one or more of butyl lithium, tert-butyl lithium, sec-butyl lithium or lithium diisopropylamide;

a2: the molar ratio of fluorobenzene (formula I) to strongly basic lithium is 1: 1-3, preferably 1: 1 to 1.2;

a3: the fluorobenzene (formula I) is selected from o-fluorotrifluorotoluene, m-fluorotrifluorotoluene, p-fluorotrifluorotoluene, o-fluoromethylbenzene or o-fluoroethylbenzene.

In some embodiments of the invention, the fluorobenzene (formula i) in a3 is ortho-fluorobenzotrifluoride;

the chemical reaction process is as follows:

in some embodiments of the invention, one or more of the following technical features are included:

a31: the strongly basic lithium is selected from butyl lithium and/or tert-butyl lithium;

a32: the molar ratio of the o-fluorotrifluorotoluene to the strongly basic lithium is 1: 1-3, preferably 1: 1 to 1.2;

a33: the molar ratio of o-fluorotrifluorotoluene to tosylazide is 1: 1-3, preferably 1: 1 to 1.2.

In some embodiments of the present invention, in B, the post-treatment process comprises: quenching reaction, organic solvent extraction and organic phase concentration to obtain crude product of fluoro-phenyl azide (formula II), and directly carrying out subsequent reaction.

In some embodiments of the present invention, in C, the organic solvent is selected from one or more of an ether solvent, an alkane solvent and an aromatic hydrocarbon solvent, and preferably, the organic solvent is tetrahydrofuran and/or toluene.

In some embodiments of the present invention, the F further includes one of the following technical features:

f1: the molar ratio of the fluorophenylazide (formula II) to the reducing agent is 1: 1-5, preferably 1: 1-3, preferably 1: 1-2, more preferably 1: 1 to 1.3;

f2: the molar ratio of the catalyst to the fluoro-phenyl azide (formula II) is 0.001-0.1: 1, preferably 0.001 to 0.05: 1, preferably 0.001 to 0.01: 1, 0.001-0.005: 1;

f3: the catalyst is selected from one or more of palladium carbon catalyst, ruthenium carbon catalyst, rhodium carbon catalyst, platinum carbon catalyst, nickel-based catalyst and the like;

f4: the reducing agent is selected from hydrogen and/or hydrazine hydrate;

in some embodiments of the invention, in step S2, the catalyst is raney nickel and/or palladium on carbon; the reaction solvent is methanol.

In some embodiments of the present invention, in the G, the organic solvent is selected from one or more of an ester solvent, a carbonate solvent, an alcohol solvent, an aromatic hydrocarbon or an ether solvent, and the like.

In some embodiments of the invention, in the F3, the post-treatment process comprises solid-liquid separation, organic phase concentration and purification; wherein the purification is carried out by steam distillation to obtain the fluoroaniline (formula III).

The preparation method of fluoroaniline provided by the invention starts from fluorobenzene (formula I), and prepares fluoroaniline (formula III) through two-step reaction with higher yield. In addition, the fluoroaniline (formula III) prepared by the preparation method of the fluoroaniline has the advantages of no isomerization, high yield, less three wastes, easy purification, short steps and the like, and has good industrialization prospect.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention clearer, the following detailed description of the present invention is provided with examples, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification.

The present inventors have made extensive studies and have provided a novel method for producing fluoroaniline, which has the characteristics of high yield, few steps, low cost, and the like, and is a method for producing fluoroaniline that is more suitable for industrial scale-up production.

The following is an example of 2-fluoro-3-trifluoromethylaniline, and the remaining fluoroaniline (formula III) describes the same compounds and methods as those described for the preparation of 2-fluoro-3-trifluoromethylaniline.

A preparation method of 2-fluoro-3-trifluoromethylaniline comprises the following steps:

s1, carrying out substitution reaction on o-fluoro benzotrifluoride and p-toluenesulfonyl azide to provide 2-fluoro-3-trifluoromethylphenyl azide;

s2, carrying out reduction reaction on the 2-fluoro-3-trifluoromethylphenyl azide to prepare the 2-fluoro-3-trifluoromethylaniline.

In step S1, the o-fluorobenzotrifluoride is substituted with p-toluenesulfonyl azide. O-fluorobenzotrifluoride is first reacted with strong alkali lithium and then with p-toluenesulfonyl azide (TosN) without separation₃) Substitution reactions were carried out to prepare 2-fluoro-3-trifluoromethylphenyl azide, the reaction equation being as follows:

in the above substitution reaction, the reaction is usually carried out in the presence of a solvent, which is usually a good solvent for the reaction system, and one skilled in the art can select an appropriate kind and amount of the solvent for the above substitution reaction. For example, an organic solvent may be used as the solvent used in the substitution reaction. For example, it may be specifically selected from one or a combination of plural kinds of ether solvents, alkane solvents, aromatic solvents, and the like. For another example, the solvent used in the substitution reaction may be selected from one or a combination of more of diethyl ether, propyl ether, isopropyl ether, methyl t-butyl ether, tetrahydrofuran, methyl cyclopentyl ether, methyl cyclohexyl ether, hexane, cyclohexane, heptane, benzene, toluene, xylene, trimethylbenzene, ethylbenzene, cumene, and the like. In the present invention, the solvent used in the substitution reaction is preferably one or a combination of more of tetrahydrofuran, methyltetrahydrofuran, toluene, hexane, cyclohexane, and the like. In the substitution reaction, the solvent used may be 1 to 10 times, 1 to 2 times, 2 to 4 times, 4 to 6 times, 6 to 8 times, or 8 to 10 times, preferably 2 to 6 times, the mass of the o-fluorobenzotrifluoride.

In the above substitution reaction, the reaction may be generally carried out at a relatively low temperature to prevent the reaction from being excessively violent. For example, the reaction temperature of the substitution reaction may be from-90 to-80 deg.C, -80 to-70 deg.C, -70 to-60 deg.C, -60 to-50 deg.C, or-50 to-40 deg.C, and preferably from-80 to-50 deg.C. The reaction time of the substitution reaction can be adjusted by the person skilled in the art according to the progress of the reaction, and methods for monitoring the progress of the reaction are known to the person skilled in the art. For example, the progress of the substitution reaction can be judged by an analytical method such as chromatography or nuclear magnetic resonance. Generally, the end point of the reaction can also be determined by TLC with substantial disappearance of the starting substrate. The reaction time of the substitution reaction may be 1 to 24 hours, 1 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, or 12 to 24 hours.

In the substitution reaction, the reaction is usually carried out under a gas blanket. Suitable gas protecting methods for providing the reaction system are known to those skilled in the art. The gas shield may be provided, for example, by nitrogen, inert gas, or the like. For another example, the inert gas may be one or a combination of helium, neon, argon, krypton, xenon, and the like.

In the substitution reaction, strong alkaline lithium can be selected in the hydrogen extraction reaction, the strong alkaline lithium is generally stored in an organic solution in the market, and the organic solution with the mass fraction of 10-80% of the strong alkaline lithium can be selected according to the preparation requirement. For example, a solution of butyl lithium, a solution of t-butyl lithium, a solution of sec-butyl lithium, lithium diisopropylamide, and the like. Specifically, the solvent may be one or a combination of more selected from butyl lithium hexane solution, butyl lithium cyclohexane solution, tert-butyl lithium hexane solution, tert-butyl lithium cyclohexane solution, sec-butyl lithium hexane solution, sec-butyl lithium cyclohexane solution, lithium diisopropylamide hexane solution, lithium diisopropylamide cyclohexane solution, lithium diisopropylamide toluene solution, lithium diisopropylamide tetrahydrofuran solution, and the like. Preferably, the solvent may be selected from one or more of butyl lithium hexane solution, butyl lithium cyclohexane solution, lithium diisopropylamide tetrahydrofuran solution, etc. Butyl lithium is generally used in substantially equal amounts or in excess relative to ortho-fluorobenzotrifluoride to ensure adequate reaction of the reaction substrate. For example, the molar ratio of ortho-fluorotrifluorotoluene to butyllithium may be 1: 1-2 and 1: 1-1.2, 1: 1.2-1.3, 1: 1.3-1.5, 1: 1.5-1.6, 1: 1.6-1.8, or 1: 1.8-2, preferably 1: 1 to 1.2.

In the substitution reaction, the azide-base reaction can generally select a solution of p-toluenesulfonyl azide, and generally is an organic solution of the toluenesulfonyl azide with the mass fraction of 10-80%. Specifically, the compound may be selected from a toluene solution of p-toluenesulfonyl azide and a tetrahydrofuran solution of p-toluenesulfonyl azide. The tosylazide is usually used in an amount substantially equal to or in excess relative to the amount of ortho-fluorotrifluorotoluene, so that sufficient reaction of the reaction substrate can be ensured. For example, the ortho-fluorobenzotrifluoride and tosylazide may be 1: 1-2 and 1: 1-1.2, 1: 1.2-1.3, 1: 1.3-1.5, 1: 1.5-1.6, 1: 1.6-1.8, or 1: 1.8-2, preferably 1: 1 to 1.2.

In the above substitution reaction, the person skilled in the art can select a suitable method for working up the product of the substitution reaction. For example, the post-treatment of the substitution reaction may include: quenching, extracting and concentrating. In a specific embodiment of the invention, after the reaction is finished, the reaction system can be quenched by water, extracted, washed and concentrated with a solvent, so that a crude product of the 2-fluoro-3-trifluoromethylphenyl azide can be prepared and used for the next reaction without further purification.

The invention provides a preparation method of 2-fluoro-3-trifluoromethylaniline, which comprises a step S2, wherein 2-fluoro-3-trifluoromethylphenyl azide is subjected to a reduction reaction, and the reduction reaction specifically comprises the following steps: the 2-fluoro-3-trifluoromethylphenyl azide is hydrogenated and reduced to prepare the 2-fluoro-3-trifluoromethylaniline, and the reaction equation is as follows:

in the above reduction reaction, the reaction is usually carried out in the presence of a catalyst, and a person skilled in the art can select an appropriate kind and amount of the catalyst for the hydrogenation reduction. For example, the catalyst may be selected from one or a combination of more of palladium carbon based catalysts, ruthenium carbon based catalysts, rhodium carbon based catalysts, platinum carbon based catalysts, nickel based catalysts, and the like. In one embodiment of the present invention, the catalyst may be a combination of one or more of palladium on carbon, raney nickel, and the like. The amount of catalyst used is generally catalytic, for example, the ratio of the mass of catalyst to the mass of 2-fluoro-3-trifluoromethylphenyl azide may be from 0.1 to 0.05: 1. 0.05-0.01: 1. 0.01 to 0.005: 1. or 0.005 to 0.001: 1, preferably 0.05 to 0.005: 1.

in the above reduction reaction, the reaction is usually carried out in the presence of a solvent, which is usually a good solvent for the reaction system, and a person skilled in the art can select an appropriate kind and amount of the solvent for the reduction reaction. For example, the solvent used in the reduction reaction may be selected from organic solvents, specifically, one or a combination of more of ester solvents, carbonate solvents, alcohol solvents, aromatic hydrocarbons, ether solvents, and the like. In one embodiment of the present invention, the solvent used in the reduction reaction may be selected from one or more of ethyl acetate, dimethyl carbonate, methanol, ethanol, toluene, tetrahydrofuran, methyl tetrahydrofuran, and the like. Preferably, it may be selected from one or a combination of more of methanol, ethanol, toluene, tetrahydrofuran, and the like. For another example, in the reduction reaction, the mass of the solvent used may be 1 to 10 times, 1 to 2 times, 2 to 4 times, 4 to 6 times, 6 to 8 times, or 8 to 10 times, preferably 2 to 6 times, the mass of the 2-fluoro-3-trifluoromethylphenyl azide.

In the above reduction reaction, the reaction may be carried out generally under a temperature condition from room temperature to the boiling point of the solvent to ensure that the reaction proceeds sufficiently in the forward direction. For example, the reaction temperature of the reduction reaction may be 10 to 80 ℃, 10 to 20 ℃, 20 to 30 ℃, 30 to 40 ℃, 40 to 50 ℃, 50 to 60 ℃, 60 to 70 ℃, or 70 to 80 ℃, preferably 20 to 50 ℃. The above reduction reaction is usually carried out under normal pressure or under pressure.

In the above reduction reaction, the reaction is usually carried out under the condition of a reducing agent, and a person skilled in the art can select an appropriate kind and amount of the reducing agent for the hydrogenation reduction. For example, the reducing agent may be selected from hydrogen or hydrazine hydrate. In one embodiment of the invention, the reducing agent may be hydrogen gas, hydrazine hydrate, and combinations of one or more thereof. The reducing agent is generally used in substantially equal amounts or in excess to ensure adequate reaction of the reaction substrates, e.g., the molar ratio of 2-fluoro-3-trifluoromethylphenyl azide to reducing agent may be 1: 1-5, 1: 1-2 and 1: 2-3, 1: 3-4, 1: 4 to 5, preferably 1: 1 to 1.3.

If the reduction reaction uses hydrogen as a reducing agent, the reaction can be carried out under a certain pressure to ensure the smooth progress of hydrogenation reduction. For example, the reaction pressure may be 1 to 3bar, 3 to 5bar, 5 to 7bar, 7 to 10bar, or 10 to 15bar, and preferably 3 to 5 bar. The reaction time of the reduction reaction can be adjusted according to the progress of the reaction by those skilled in the art, and methods for monitoring the progress of the reaction are known to those skilled in the art. For example, the progress of the reduction reaction can be judged by an analysis method such as chromatography or nuclear magnetic resonance. Generally, the end point of the reaction can also be determined by TLC with substantial disappearance of the starting substrate. For another example, the reaction time of the reduction reaction may be 1 to 24 hours, 1 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, or 12 to 24 hours.

The person skilled in the art can select suitable methods for working up the product of the reduction reaction. For example, the post-treatment of the reduction reaction may include: solid-liquid separation, desolventizing and purification. In a specific embodiment of the invention, after the reaction is finished, the product can be filtered, and the liquid phase can be concentrated and further subjected to steam distillation and purification to prepare the 2-fluoro-3-trifluoromethylaniline.

The preparation method of the 2-fluoro-3-trifluoromethylaniline provided by the invention starts from o-fluoro-benzotrifluoride, and prepares the 2-fluoro-3-trifluoromethylaniline with higher yield through two-step reaction. The preparation method of the 2-fluoro-3-trifluoromethylaniline provided by the invention has the advantages of no isomerization, high yield, less three wastes, easy purification, short steps and the like, and has good industrialization prospect.

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.

Example 1: synthesis of 2-fluoro-3-trifluoromethylphenyl azide

In a 2L dry reaction flask, 350g of tetrahydrofuran and 70g of o-fluorotrifluorotoluene are sequentially added, and the temperature is reduced to-70 ℃ under the protection of nitrogen. 306g of 10% butyl lithium hexane solution is dripped into the cooled system, and the mixture is stirred and reacted for 1 hour under the condition of heat preservation after dripping. Then 176.7g of a 50% toluene solution of p-toluenesulfonylazide was added dropwise thereto, and the reaction was stirred for 1 hour with keeping the temperature. The cooling bath is removed, and the temperature is naturally returned to the room temperature. 350g of water is dropped into the reaction system at room temperature to quench and react, layers are separated, the water phase is extracted by 100g of toluene, and the combined organic phase is washed by 200g of water once. The organic phase is decompressed and concentrated, 84.5g of residue is the crude product of the product 2-fluoro-3-trifluoromethylphenyl azide, the purity is 98.7 percent and the external standard yield is 93.6 percent through liquid chromatography detection, and the nuclear magnetic data is as follows:

¹H NMR(400MHz,CDCl₃):δ＝7.19-7.28(m,2H),7.33-7.37(m,1H).¹³C NMR (100MHz,CDCl₃):δ＝119.89,122.20,122.67,124.60,124.61,129.57,152.01.

example 2: synthesis of 2-fluoro-3-trifluoromethylphenyl azide

400g of tetrahydrofuran and 100g of o-fluorotrifluorotoluene are sequentially added into a 2L dry reaction bottle, and the temperature is reduced to-70 ℃ under the protection of nitrogen. 215g of 20% butyl lithium hexane solution is dropped into the cooled system, and the mixture is stirred and reacted for 1 hour under the condition of heat preservation after dropping. 252g of 50% p-toluenesulfonylazide solution in tetrahydrofuran was then added dropwise, and the reaction was stirred for 1 hour with constant temperature after the addition of the solution. The cooling bath is removed, and the temperature is naturally returned to the room temperature. 400g of water is dropped into the reaction system at room temperature to quench the reaction, the layers are separated, the water phase is extracted by 200g of toluene, and the combined organic phase is washed by 200g of water once. The organic phase is decompressed and concentrated, 125.7g of residue is the crude product of the product 2-fluoro-3-trifluoromethylphenyl azide, the purity is 98.1 percent, the external standard yield is 94.8 percent, and the nuclear magnetic data proves that the product is the 2-fluoro-3-trifluoromethylphenyl azide.

Example 3: synthesis of 2-fluoro-3-trifluoromethylaniline

84.5g (81.9 g of pure product measured by actual external standard) of crude 2-fluoro-3-trifluoromethylphenyl azide, 250g of methanol and 1.7g of Raney nickel are put into a 500mL autoclave. The reaction kettle is firstly replaced by nitrogen for three times and then replaced by hydrogen for three times. The reaction was carried out at 30 ℃ for 6 hours under a pressure of 4 bar. The catalyst was filtered off, the solvent was distilled off under reduced pressure and the residue was purified by steam distillation. 70.1g of product is obtained, the purity is 99.9% by liquid chromatography detection, and the nuclear magnetic data are as follows:

¹H NMR(400MHz,CDCl₃):δ＝3.86(b,2H),6.89-6.93(m,2H),6.95-6.99(m,1H). ¹³C NMR(100MHz,CDCl₃):δ＝115.36,118.36,120.37,122.95,124.17,135.63,148.32.

example 4: synthesis of 2-fluoro-3-trifluoromethylaniline

125.7g of crude 2-fluoro-3-trifluoromethylphenyl azide (containing 118.5g of pure product by actual external standard), 375g of methanol and 0.6g of 5% palladium-carbon are put into a 500mL reaction bottle. 72.3g of 40% aqueous hydrazine hydrate solution are added dropwise at 25 ℃ at room temperature. Stirring was continued at room temperature for 4 hours after dropping. Filtering, distilling the filtrate under reduced pressure to remove the solvent, and distilling and purifying the residue by steam. 100.9g of the product was obtained with a purity of 99.7%, which was confirmed by nuclear magnetic data to be 2-fluoro-3-trifluoromethylaniline.

In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.

The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.