阅读说明：本技术 一种2-溴-5-氟-4-硝基苯胺的合成方法及其中间体 (Synthetic method and intermediate of 2-bromo-5-fluoro-4-nitroaniline ) 是由 田广辉 吴建忠 李志强 杨春 丁飞飞 于 2018-06-22 设计创作，主要内容包括：本发明公开了一种2-溴-5-氟-4-硝基苯胺的合成方法及其中间体,2-溴-5-氟-4-硝基苯胺的合成包括使2-溴-5-氟苯胺与硝化试剂发生硝化反应生成2-溴-5-氟-4-硝基苯胺的步骤；或,包括：先使2-溴-5-氟苯胺与氨基保护试剂反应得到氨基被保护的2-溴-5-氟苯胺,然后使氨基被保护的2-溴-5-氟苯胺与硝化试剂发生硝化反应生成硝化产物即本发明的中间体,最后使硝化产物脱去氨基保护基得到2-溴-5-氟-4-硝基苯胺。本发明的合成方法,其反应收率高,产物纯度高,且原料易得。(The invention discloses a method for synthesizing 2-bromo-5-fluoro-4-nitroaniline and an intermediate thereof, wherein the synthesis of the 2-bromo-5-fluoro-4-nitroaniline comprises the step of carrying out nitration reaction on the 2-bromo-5-fluoroaniline and a nitration reagent to generate the 2-bromo-5-fluoro-4-nitroaniline; or, comprising: firstly, reacting 2-bromo-5-fluoroaniline with an amino protecting reagent to obtain amino-protected 2-bromo-5-fluoroaniline, then carrying out nitration reaction on the amino-protected 2-bromo-5-fluoroaniline and a nitration reagent to generate a nitration product, namely the intermediate of the invention, and finally removing the amino protecting group from the nitration product to obtain the 2-bromo-5-fluoro-4-nitroaniline. The synthesis method has the advantages of high reaction yield, high product purity and easily obtained raw materials.)

1. A synthetic method of 2-bromo-5-fluoro-4-nitroaniline is characterized by comprising the step of carrying out nitration reaction on 2-bromo-5-fluoroaniline and a nitration reagent to generate the 2-bromo-5-fluoro-4-nitroaniline.

2. The synthesis method of the 2-bromo-5-fluoro-4-nitroaniline (I) is characterized by adopting the following synthesis route:

wherein in formula III and formula IV, R is an amino protecting group, comprising:

(1) reacting 2-bromo-5-fluoroaniline (II) with an amino protecting reagent to produce compound III;

(2) carrying out nitration reaction on the compound III and a nitration reagent to generate a compound IV;

(3) removing the amino protecting group from the compound IV to obtain the 2-bromo-5-fluoro-4-nitroaniline (I).

3. The method for synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 1 or 2, characterized in that the nitration reaction is carried out at a temperature of-20 ℃ to 40 ℃.

4. The method for synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 1 or 2, characterized in that the nitration reaction is carried out in a solvent which is a combination of one or more selected from sulfuric acid, formic acid, acetic anhydride, dichloromethane, 1, 2-dichloroethane, chloroform, N-dimethylformamide and N, N-dimethylacetamide.

5. The method for synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 1 or 2, wherein the nitrating agent is nitric acid, a mixed acid of nitric acid and sulfuric acid, a mixture of nitric acid and acetic anhydride, a mixture of nitric acid and glacial acetic acid, potassium nitrate, sodium nitrate or calcium nitrate.

6. The process for the synthesis of 2-bromo-5-fluoro-4-nitroaniline according to claim 2, characterized in that the reaction of step (1) is carried out at a temperature of-20 ℃ to 30 ℃.

7. The process for the synthesis of 2-bromo-5-fluoro-4-nitroaniline according to claim 2, characterized in that the reaction of step (1) is carried out under basic conditions.

8. The method of synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 7 wherein the basic conditions are formed by adding one or more basic substances selected from triethylamine, diisopropylethylamine, pyridine, 3-methylpyridine, 4-dimethylaminopyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.

9. The method of synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 2 wherein the amino protecting group is formyl, acetyl, propionyl, isobutyryl, p-toluenesulfonyl, t-butoxycarbonyl, phthalimido, trityl, trichloroacetyl, trifluoroacetyl or benzyloxycarbonyl.

10. The method for synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 2 or 9, wherein in step (1), the amino protecting agent is a halide or an anhydride containing the amino protecting group.

11. The process for the synthesis of 2-bromo-5-fluoro-4-nitroaniline according to claim 2, characterized in that the reaction of step (3) is carried out under acidic or basic conditions at a temperature of-10 ℃ to 80 ℃ in a solvent.

12. The method for synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 11, wherein in step (3), the acidic condition is formed by adding one or more acids selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid; and/or the presence of a gas in the gas,

in the step (3), the alkaline condition is formed by adding one or more bases selected from cesium carbonate, sodium carbonate, potassium carbonate, hydrazine hydrate, ammonia water, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; and/or the presence of a gas in the gas,

in the step (3), the solvent is one or more selected from methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide and water.

13. The method of synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 1 or 2, characterized in that the method further comprises the step of reacting 2-bromo-5-fluoronitrobenzene with a nitro reducing agent at a temperature of-30 ℃ to 100 ℃ in a solvent to produce said 2-bromo-5-fluoroaniline.

14. The method for synthesizing 2-bromo-5-fluoro-4-nitroaniline according to claim 13, wherein in the step of preparing 2-bromo-5-fluoroaniline, the solvent is a combination of one or more selected from tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, 1, 2-dichloroethane, methanol, ethanol, N-propanol, isopropanol, N-dimethylformamide and N, N-dimethylacetamide; and/or the nitro reducing agent is stannous chloride and/or zinc chloride.

15. An intermediate for the preparation of 2-bromo-5-fluoro-4-nitroaniline, wherein the intermediate has the structure shown in formula iv below:

in the formula IV, R is an amino protecting group.

16. The intermediate for producing 2-bromo-5-fluoro-4-nitroaniline according to claim 15, wherein the amino protecting group is formyl, acetyl, propionyl, isobutyryl, p-toluenesulfonyl, tert-butoxycarbonyl, phthalimido, trityl, trichloroacetyl, trifluoroacetyl or benzyloxycarbonyl.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of 2-bromo-5-fluoro-4-nitroaniline and an intermediate thereof.

Background

Tezacaftor is useful for treating CFTR mediated diseases such as cystic fibrosis, having the chemical name (R) -1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) -N- (1- (2, 3-dihydroxypropyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide, and has the following structural formula:

the synthesis route of the 2-bromo-5-fluoro-4-nitroaniline serving as an important intermediate for synthesizing the Tezacaftor is as follows:

for example, chinese invention patent CN103038214B discloses a method for preparing cycloalkyl carboxamido-indole compounds, wherein the method for synthesizing 2-bromo-5-fluoro-4-nitroaniline is disclosed as follows:

in the method, 3-fluoro-4-nitroaniline is used as a raw material, N-bromosuccinimide is adopted in ethyl acetate for bromination reaction, but although the steps of the route are short, the starting material is expensive and is not easy to obtain in too large amount, the yield is only 50%, impurities brominated at other positions on a benzene ring in the obtained product can continuously participate in subsequent reaction, the purification and separation of a subsequent intermediate are difficult, and the method is not beneficial to industrial application.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects in the prior art and provide a novel method for synthesizing 2-bromo-5-fluoro-4-nitroaniline, which has high reaction yield and high product purity.

The invention also provides an intermediate for preparing the 2-bromo-5-fluoro-4-nitroaniline.

In order to solve the above technical problems, the present invention provides, on the one hand, a method for synthesizing 2-bromo-5-fluoro-4-nitroaniline, comprising the step of subjecting 2-bromo-5-fluoroaniline (II) and a nitrating agent to a nitration reaction to produce 2-bromo-5-fluoro-4-nitroaniline (I). The synthetic route of the method is shown as follows:

according to some preferred aspects of the invention, the nitration reaction is carried out at a temperature of-20 ℃ to 40 ℃. More preferably, the nitration reaction is carried out at a temperature of-10 ℃ to 10 ℃. According to a particular aspect of the invention, the nitration reaction is carried out at a temperature of between 0 ℃ and 5 ℃.

According to some specific and preferred aspects of the present invention, the nitration reaction is carried out in a solvent which is a combination of one or more selected from the group consisting of sulfuric acid, formic acid, acetic anhydride, dichloromethane, 1, 2-dichloroethane, chloroform, N-dimethylformamide and N, N-dimethylacetamide.

According to the present invention, the nitrating agent may be those commonly used in the art, without particular limitation, and specifically, the nitrating agent may be nitric acid (ordinary nitric acid or fuming nitric acid) or a mixture of nitric acid and an acid anhydride or other acids (e.g., sulfuric acid, phosphoric acid, perchloric acid, acetic anhydride, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.). The nitrating agent may also be a mixture of a nitrate salt (e.g., potassium nitrate, ammonium nitrate) with an anhydride or acid (e.g., sulfuric acid, acetic anhydride, etc.) or a mixture of a nitrate ester (e.g., methyl nitrate, butyl nitrate, etc.) with an anhydride or acid (e.g., trifluoroboric acid, etc.).

According to some specific and preferred embodiments of the present invention, the nitrating agent is nitric acid, a mixed acid of nitric acid and sulfuric acid, a mixture of nitric acid and acetic anhydride, a mixture of nitric acid and glacial acetic acid, or a nitrate salt.

According to some particular aspects of the invention, the nitrate may be potassium nitrate, sodium nitrate, calcium nitrate, or the like.

According to some preferred aspects of the invention, the molar ratio of the 2-bromo-5-fluoroaniline (II) charged to the nitrating agent is 1: 0.8 to 10. More preferably, the molar ratio of the 2-bromo-5-fluoroaniline (II) to the nitrating agent is 1: 1 to 3. Further preferably, the feeding molar ratio of the 2-bromo-5-fluoroaniline (II) to the nitrating agent is 1: 1.1 to 1.3.

The second aspect of the invention provides a synthetic method of 2-bromo-5-fluoro-4-nitroaniline (I), which adopts the following synthetic route:

wherein in formula III and formula IV, R is an amino protecting group, comprising:

(1) reacting 2-bromo-5-fluoroaniline (II) with an amino protecting reagent to produce compound III;

(2) carrying out nitration reaction on the compound III and a nitration reagent to generate a compound IV;

(3) removing the amino protecting group from the compound IV to obtain the 2-bromo-5-fluoro-4-nitroaniline (I).

According to some preferred aspects of the invention, the reaction of step (1) is carried out at a temperature of-20 ℃ to 30 ℃. More preferably, the reaction of step (1) is carried out at a temperature of-10 ℃ to 20 ℃. Further preferably, the reaction of step (1) is carried out at a temperature of-5 ℃ to 10 ℃. According to a particular aspect of the invention, the reaction of step (1) is carried out at a temperature of between 0 ℃ and 10 ℃.

According to some preferred aspects of the present invention, in step (1), the molar ratio of the 2-bromo-5-fluoroaniline (II) to the amino protecting agent charged is 1: 1 to 3. More preferably, in step (1), the molar ratio of the 2-bromo-5-fluoroaniline (II) to the amino protecting agent is 1: 1 to 1.5.

According to some preferred aspects of the invention, the reaction of step (1) is carried out under basic conditions. According to some specific and preferred aspects of the present invention, the basic conditions are formed by adding one or more basic substances of triethylamine, diisopropylethylamine, pyridine, 3-methylpyridine, 4-dimethylaminopyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

According to some preferred aspects of the present invention, in step (1), the molar ratio of the basic substance to the 2-bromo-5-fluoroaniline (II) is 1 to 10: 1. more preferably, in the step (1), the feeding molar ratio of the alkaline substance to the 2-bromo-5-fluoroaniline (II) is 1-5: 1. further preferably, in the step (1), the feeding molar ratio of the alkaline substance to the 2-bromo-5-fluoroaniline (II) is 1-3: 1.

according to some preferred aspects of the invention, the amino protecting group is formyl, acetyl, propionyl, isobutyryl, p-toluenesulfonyl, t-butoxycarbonyl, phthalimido, trityl, trichloroacetyl, trifluoroacetyl or benzyloxycarbonyl.

According to some specific and preferred aspects of the present invention, in step (1), the amino protecting agent is a halide or an anhydride containing the amino protecting group. Wherein the halide is preferably chloride or bromide.

Preferably, the amino protecting reagent is acetyl chloride, isobutyryl chloride, p-toluenesulfonyl chloride, trifluoroacetyl chloride, formyl chloride, di-tert-butyl dicarbonate (Boc anhydride), or the like.

According to some preferred aspects of the present invention, in the step (2), the nitration reaction is carried out at a temperature of-20 ℃ to 40 ℃. More preferably, in step (2), the nitration reaction is carried out at a temperature of-10 ℃ to 10 ℃. According to a particular aspect of the invention, in step (2), the nitration reaction is carried out at a temperature of between 0 ℃ and 5 ℃.

According to some preferred aspects of the present invention, in step (2), the molar ratio of the compound III to the nitrating agent is 1: 0.8 to 10. More preferably, in the step (2), the feeding molar ratio of the compound III to the nitrating agent is 1: 1 to 3. Further preferably, in the step (2), the feeding molar ratio of the compound III to the nitrating agent is 1: 1.1 to 1.3.

According to some specific and preferred aspects of the present invention, in step (2), the nitration reaction is carried out in a solvent which is a combination of one or more selected from the group consisting of sulfuric acid, formic acid, acetic anhydride, dichloromethane, 1, 2-dichloroethane, chloroform, N-dimethylformamide, N-dimethylacetamide.

According to the present invention, the nitrating agent in step (2) may be those commonly used in the art, without particular limitation, and specifically, the nitrating agent may be nitric acid (ordinary nitric acid or fuming nitric acid) or a mixture of nitric acid and an acid anhydride or other acid (e.g., sulfuric acid, phosphoric acid, perchloric acid, acetic anhydride trifluoroacetic anhydride, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.). The nitrating agent may also be a mixture of a nitrate salt (e.g., potassium nitrate, sodium nitrate, ammonium nitrate) and an anhydride or acid (e.g., sulfuric acid, acetic anhydride, etc.) or a mixture of a nitrate ester (e.g., methyl nitrate, butyl nitrate, etc.) and an anhydride or acid (e.g., trifluoroboric acid, etc.).

According to some specific and preferred embodiments of the present invention, the nitrating agent in step (2) is nitric acid, a mixed acid of nitric acid and sulfuric acid, a mixture of nitric acid and acetic anhydride, a mixture of nitric acid and glacial acetic acid, or a nitrate salt. Wherein the nitrate can be potassium nitrate, sodium nitrate or calcium nitrate.

According to some preferred aspects of the invention, the reaction of step (3) is carried out under acidic or basic conditions. According to some specific and preferred aspects of the present invention, the acidic conditions are formed by adding one or more acids selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid. According to some preferred aspects of the invention, in the step (3), the feeding molar ratio of the acidic substance to the compound IV is 0.5-10: 1. More preferably, in the step (3), the feeding molar ratio of the acidic substance to the compound IV is 0.8-5: 1. Further preferably, in the step (3), the feeding molar ratio of the acidic substance to the compound IV is 0.8-1.2: 1. According to some specific and preferred aspects of the present invention, the basic conditions are formed by adding one or more bases selected from sodium hydroxide, cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate. According to some preferred aspects of the invention, in the step (3), the feeding molar ratio of the basic substance to the compound IV is 1-10: 1. More preferably, in the step (3), the feeding molar ratio of the alkaline substance to the compound IV is 1-3: 1.

According to some preferred aspects of the invention, the reaction of step (3) is carried out at a temperature of-10 ℃ to 80 ℃. More preferably, the reaction of step (3) is carried out at a temperature of from 15 ℃ to 80 ℃. Further preferably, the reaction of step (3) is carried out at a temperature of 20 ℃ to 60 ℃.

According to some preferred aspects of the invention, the reaction of step (3) is carried out in a solvent. According to some specific and preferred aspects of the present invention, the solvent is a combination of one or more selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide and water.

According to some preferred aspects of the invention, the synthesis method further comprises the steps of: reacting 2-bromo-5-fluoronitrobenzene (V) with a nitro reducing agent in a solvent to produce said 2-bromo-5-fluoroaniline (II); the synthetic route is as follows:

according to some preferred aspects of the present invention, the solvent is a combination of one or more selected from the group consisting of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, 1, 2-dichloroethane, methanol, ethanol, N-propanol, isopropanol, N-dimethylformamide, and N, N-dimethylacetamide.

According to some preferred aspects of the invention, the nitro reducing agent is stannous chloride or zinc chloride. In the invention, stannous chloride or zinc chloride can enable the target product to have higher yield and purity compared with other nitro reducing agents.

According to some preferred aspects of the invention, the reaction to form 2-bromo-5-fluoroaniline (II) is carried out at a temperature of from-30 ℃ to 100 ℃. More preferably, the reaction to form 2-bromo-5-fluoroaniline (II) is carried out at a temperature of from-20 ℃ to 80 ℃. Further preferably, the reaction to produce 2-bromo-5-fluoroaniline (II) is carried out at a temperature of-20 ℃ to 50 ℃.

According to some preferred aspects of the invention, the molar dosing ratio of the 2-bromo-5-fluoronitrobenzene (V) to the nitro reducing agent is 1: 0.5 to 20. More preferably, the molar ratio of the 2-bromo-5-fluoronitrobenzene (V) to the nitro reducing agent is 1: 0.8 to 10. Further preferably, the feeding molar ratio of the 2-bromo-5-fluoronitrobenzene (V) to the nitro reducing agent is 1: 1 to 8.

The invention provides another technical scheme; an intermediate for the preparation of 2-bromo-5-fluoro-4-nitroaniline, said intermediate having the structure of formula iv:

in the formula IV, R is an amino protecting group.

According to some specific and preferred aspects of the invention, the amino protecting group is formyl, acetyl, propionyl, isobutyryl, p-toluenesulfonyl, tert-butoxycarbonyl, phthalimido, trityl, trichloroacetyl, trifluoroacetyl or benzyloxycarbonyl.

Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:

the preparation method has the advantages of remarkably higher yield, high purity of the obtained product, cheap and easily obtained raw materials, simple post-treatment and easy operation, and is suitable for industrial production.

Drawings

FIG. 1 is a nuclear magnetic spectrum of 2-bromo-5-fluoroacetanilide prepared in example 3-1;

FIG. 2 is a nuclear magnetic spectrum of 2-bromo-5-fluoro-4-nitroacetanilide prepared in example 3-1;

FIG. 3 is a nuclear magnetic spectrum of 2-bromo-5-fluoro-4-nitroaniline prepared in example 3-1.

Detailed Description

The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.

In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified. In the following, concentrated sulfuric acid refers to a 98% sulfuric acid aqueous solution by mass, concentrated nitric acid refers to a 65% nitric acid aqueous solution by mass, and concentrated hydrochloric acid refers to a 36.5% hydrogen chloride aqueous solution by mass.