Process for the preparation of aniline compounds from nitrobenzene and selective iodination of aniline compounds

Abstract

The application discloses a method for preparing aniline compounds by reducing nitrobenzene and selectively iodinating the aniline compounds, and belongs to the field of organic chemistry. a In the iodination reaction of the aniline compounds, ICl is selected as an iodinating reagent, and R a COOH is used as a reaction solvent, so that the iodination reaction of the aniline compounds has excellent selectivity, and 2-iodo-3-methyl-5-trifluoromethylaniline can be prepared in a high yield (more than 80% of liquid-phase yield). Meanwhile, in the method for preparing the aniline compounds by reducing nitrobenzene, hydrazine or hydrazine hydrate is used as a reducing agent, and a catalytic amount of Raney copper is used as a catalyst, so that a series of m-trifluoromethylaniline compounds can be prepared in a green, environment-friendly and efficient manner; wherein, the Raney copper only needs a catalytic amount, and still has catalytic activity after the reaction is completed, and can be recycled.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, specifically relating to methods for preparing aniline compounds by reducing nitrobenzene and selectively iodoaniline compounds. Background Technology

[0002] 3-Methyl-5-trifluoromethylaniline and 2-iodo-3-methyl-5-trifluoromethylaniline are both pharmaceutical intermediates with certain applications. For example, AbbVie (CN 107820494 A) reported that both 3-methyl-5-trifluoromethylaniline and 2-iodo-3-methyl-5-trifluoromethylaniline can be used to prepare a series of novel compounds for modulating the activity of Rorc and RORγt receptors.

[0003] Hainan Fansheng Biotechnology Co., Ltd. (CN 112079729 A) reported a method for preparing 3-methyl-5-trifluoromethylaniline from 1-methyl-3-nitro-5-trifluoromethylbenzene. The method uses metal elements such as iron powder or zinc powder at equivalent levels as reducing agents. On the one hand, this preparation method can only achieve a poor yield of 60%-70%, and on the other hand, it generates a large amount of metal oxide byproducts, which is not green and environmentally friendly.

[0004] While hydrazine hydrate is a relatively environmentally friendly reagent for reducing nitrobenzene to aniline, when nitrobenzene has a trifluoromethyl group at the meta position, a suitable reaction effect is often achieved using Ni-Co bimetallic nanoparticles as catalysts (see Catalysis Communication, 84 (2016), 25-29) or using a surfactant ionic liquid as a solvent and palladium nanoparticles as catalysts (see Catalysis Communication, 99 (2017), 57-60). However, both Ni-Co bimetallic nanoparticles and palladium nanoparticles are not widely commercialized and are difficult to apply in large-scale industrial reactions.

[0005] The preparation of 2-iodo-3-methyl-5-trifluoromethylaniline is even more challenging. Because the starting material 3-methyl-5-trifluoromethylaniline has three similar reaction sites, iodination reactions with such a substrate often lack selectivity, yielding various iodinated products at different positions, and even diiodo or triiodolated products. For example, AbbVie (CN107820494A) reported the preparation of 2-iodo-3-methyl-5-trifluoromethylaniline using benzyltrimethylamine dichloroiodate as the iodination reagent, with a yield of only 53%. Summary of the Invention

[0006] The present invention was made to solve the above-mentioned problems, and aims to provide a method for preparing aniline compounds by reducing nitrobenzene with high yield and a method for preparing iodoaniline compounds with high selectivity.

[0007] Option A:

[0008] This invention provides a method for selectively processing iodoaniline compounds, the reaction formula of which is as follows:

[0009]

[0010] In the formula, R b Selected from H or C1-C5 alkyl groups,

[0011] Includes the following steps:

[0012] At least in the presence of a solvent, the reaction of ICl (iodine chloride) with compound 5 yields compound 6.

[0013] Wherein, the solvent is R a COOH, R a Selected from H or C1-C5 alkyl groups.

[0014] In one embodiment of the present invention, the R b Specifically, methyl groups can be selected.

[0015] In one embodiment of the present invention, ICl is reacted with compound 5 in the presence of a solvent and a base reagent to obtain compound 6; wherein the base reagent is R. c COOX, R c Selected from H or C1-C5 alkyl groups, where X is K or Na.

[0016] In one embodiment of the present invention, the molar ratio of compound 5 to ICl is 1:(0.9-1.1).

[0017] In one embodiment of the present invention, the molar ratio of compound 5 to the base reagent is 1:(0-1.1). Further, the molar ratio of compound 5 to the base reagent is 1:(0.9-1.1).

[0018] In one embodiment of the present invention, the molar volume ratio of compound 5 to solvent is 1 mmol:(2-5) mL.

[0019] In one embodiment of the present invention, the method for selectively using iodoaniline compounds specifically includes:

[0020] Dispersions of compound 5 and ICl were prepared separately. The compound 5 dispersion and the ICl dispersion were mixed to form a mixture. An alkaline reagent was added to the mixture and the mixture was stirred to react.

[0021] In one embodiment of the present invention, the concentration of the dispersion of compound 5 is 0.5-0.6 mmol / mL.

[0022] In one embodiment of the present invention, the concentration of the ICl dispersion is 1.0-1.5 mmol / mL.

[0023] In one embodiment of the present invention, the volume ratio of the compound 5 dispersion and the ICl dispersion is 2:1.

[0024] In one embodiment of the present invention, after the reaction is completed, thiosulfate is added to quench the reaction, the solvent is removed, water and extractant are added, extraction is performed, the organic phase is collected, concentrated and dried to obtain compound 6.

[0025] In one embodiment of the present invention, the extractant is ethyl acetate, and the mass ratio of water to extractant is 1:(0.9-1.1).

[0026] In one embodiment of the present invention, compound 5 is prepared by the following method:

[0027]

[0028] Using hydrazine or hydrazine hydrate as a reducing agent and Raney copper as a catalyst, compound 4 is converted into compound 5.

[0029] Option B:

[0030] This invention provides a method for preparing aniline compounds by reducing nitrobenzene, the reaction formula of which is as follows:

[0031]

[0032] In the formula, R b Selected from H or C1-C5 alkyl groups,

[0033] Includes the following steps:

[0034] Using hydrazine or hydrazine hydrate as a reducing agent and Raney copper as a catalyst, compound 4 is converted into compound 5.

[0035] In one embodiment of the present invention, the R b It is a methyl group.

[0036] In one embodiment of the present invention, the method for preparing aniline compounds by reducing nitrobenzene includes:

[0037] Under inert gas protection, compound 4, the catalyst, and the reaction solvent are mixed, and then the reducing agent is added. After post-treatment, compound 5 is obtained.

[0038] In one embodiment of the present invention, the molar ratio of compound 4 to the reducing agent is 1:(1.8-2.2).

[0039] In one embodiment of the present invention, the mass ratio of compound 4 to the catalyst is 1:(0.08-0.2).

[0040] In one embodiment of the present invention, the reaction solvent is ethanol.

[0041] In one embodiment of the present invention, the molar volume ratio of compound 4 to the reaction solvent is 1 mmol:(2-5) mL.

[0042] The role and effect of invention

[0043] In the iodination reaction of aniline compounds involved in this invention, ICl is selected as the iodizing reagent, and R is used in conjunction with it. a Using COOH as a reaction solvent gives the iodination reaction of aniline compounds excellent selectivity, enabling the preparation of 2-iodo-3-methyl-5-trifluoromethylaniline in high yield (more than 80% liquid phase yield).

[0044] The method for preparing aniline compounds by reducing nitrobenzene according to this invention uses hydrazine or hydrazine hydrate as a reducing agent and Raney copper at a catalytically high level as a catalyst. During the reaction, hydrazine hydrate is oxidized to nitrogen and water, and the generated hydrazine anions can be stored by Raney copper, which then reduces the nitro group. This method can produce a series of m-trifluoromethylaniline compounds in a green, environmentally friendly, and efficient manner. Raney copper is only required at a catalytically high level and retains its catalytic activity even after the reaction is complete, making it recyclable. Attached Figure Description

[0045] Figure 1 This is the liquid phase spectrum of compound 5a obtained in Example 1 of the present invention, wherein the retention time of 6.058 min corresponds to compound 5a;

[0046] Figure 2 This is the liquid chromatography spectrum of the sample obtained in Comparative Example 1 of the present invention, wherein a retention time of 6.072 min corresponds to compound 5a, a retention time of 8.020 min corresponds to compound 4a, and a retention time of 11.326 min corresponds to compound 4a'; and

[0047] Figure 3 This is the liquid phase spectrum of the crude product obtained in Example 4 of the present invention, wherein the retention time of 8.409 min corresponds to compound 6a. Detailed Implementation

[0048] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments and accompanying drawings.

[0049] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.

[0050] In the following embodiments, the Raney copper is RTH-7110 type Raney copper produced by Dalian General Chemical Co., Ltd.

[0051] In the following examples, the Raney nickel is RTH-2110 type Raney nickel produced by Dalian General Chemical Co., Ltd.

[0052] In the following examples, NIS refers to N-iodosuccinimide.

[0053] In the following examples, IClPy refers to pyridine monoiodine chloride.

[0054] <Example 1>

[0055] A method for preparing 3-methyl-5-trifluoromethylaniline

[0056] This embodiment provides a method for preparing 3-methyl-5-trifluoromethylaniline, and the reaction formula is as follows:

[0057]

[0058] Includes the following steps:

[0059] 10 g of compound 4a (48.7 mmol, 1.0 eq), 1.0 g of Raney copper (10 wt%), and 100 mL of ethanol were added to a reaction vessel. The reaction system was heated to 70-75 °C, and under nitrogen protection, 5.0 g of hydrazine hydrate (100 mmol, 2.05 eq) was added dropwise. The reaction was maintained at 70-75 °C for 2 h. The mixture was filtered through diatomaceous earth to remove the solvent. Extraction was performed with 100 mL of ethyl acetate and 150 mL of water. The organic phase was collected, washed with n-heptane to remove the solvent, yielding 8.25 g of compound 5a, with a yield of 96.7% and an HPLC purity of 98.0% (HPLC chromatogram shown). Figure 1 (As shown).

[0060] Furthermore, the metal catalyst can be recovered after the reaction is complete, retaining its catalytic activity and thus being recyclable.

[0061] <Comparative Example 1>

[0062] A method for preparing 3-methyl-5-trifluoromethylaniline

[0063] This embodiment provides a method for preparing 3-methyl-5-trifluoromethylaniline, and the reaction formula is as follows:

[0064]

[0065] Includes the following steps:

[0066] 10 g of compound 4a (48.7 mmol, 1.0 eq), 1.0 g of Raney nickel (10 wt%), and 100 mL of ethanol were added to a reaction vessel. The reaction system was heated to 70-75 °C, and under nitrogen protection, 5.0 g of hydrazine hydrate (100 mmol, 2.05 eq) was added dropwise. The temperature was maintained at 70-75 °C for 2 h. Samples were taken and sent for HPLC analysis. Figure 2 This is the HPLC chromatogram for this embodiment. (As shown...) Figure 2 As shown, the reaction system contains 4.6% compound 5a, 59.1% compound 4a, and 35.6% compound 4a'.

[0067] It is evident that the preparation of 3-methyl-5-trifluoromethylaniline using nickel-based catalysts is very ineffective, with very low levels of the target product, mainly consisting of unreacted nitro compounds and nitrosyl byproducts.

[0068] <Example 2>

[0069] A method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline

[0070] This embodiment provides a method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline, the reaction formula of which is as follows:

[0071]

[0072] Includes the following steps:

[0073] Step 1: Dissolve 17.6g ICl (108.5mmol, 0.95eq) in 100mL acetic acid to obtain raw material solution A;

[0074] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of acetic acid to obtain raw material solution B;

[0075] Step 3: Control the temperature at 20℃-25℃, and add raw material solution B dropwise to raw material solution A while stirring. After the addition is complete, stir and react for 2 hours.

[0076] Step 4: Quench the reaction with 50g of saturated sodium thiosulfate aqueous solution, add 250g of water and 250g of ethyl acetate, extract, collect the organic phase, concentrate under reduced pressure, wash with n-heptane, and dry to obtain 27.5g of crude product. HPLC showed that in addition to compound 6a, the crude product contained an unknown impurity. The content of compound 6a (HPLC purity) was 85.2%, and the impurity content was 5.7%.

[0077] <Example 3>

[0078] A method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline

[0079] This embodiment provides a method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline, the reaction formula of which is as follows:

[0080]

[0081] Includes the following steps:

[0082] Step 1: Dissolve 17.6g ICl (108.5mmol, 0.95eq) in 100mL acetic acid to obtain raw material solution A;

[0083] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of acetic acid to obtain raw material solution B;

[0084] Step 3: Control the temperature at 20℃-25℃, and add raw material solution A dropwise to raw material solution B while stirring. After the addition is complete, stir and react for 2 hours.

[0085] Step 4: Quench the reaction with 50g of saturated sodium thiosulfate aqueous solution, add 250g of water and 250g of ethyl acetate, extract, collect the organic phase, concentrate under reduced pressure, wash with n-heptane, and dry to obtain 26.1g of crude product. HPLC showed that in addition to compound 6a, the crude product contained two unknown impurities. The content of compound 6a was 80.0%, and the sum of the contents of the two impurities was 11.9%.

[0086] <Example 4>

[0087] A method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline

[0088] This embodiment provides a method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline, the reaction formula of which is as follows:

[0089]

[0090] Includes the following steps:

[0091] Step 1: Dissolve 17.6g ICl (108.5mmol, 0.95eq) in 100mL acetic acid to obtain raw material solution A;

[0092] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of acetic acid to obtain raw material solution B;

[0093] Step 3: Control the temperature at 20℃-25℃. While stirring, add raw material solution A dropwise to raw material solution B. After the addition is complete, stir and react for 1 hour. Then add 8.9g sodium acetate (108.5mmol, 0.95eq) and continue stirring and reacting for another hour.

[0094] Step 3: Quench the reaction with 50g of saturated sodium thiosulfate aqueous solution, add 250g of water and 250g of ethyl acetate, extract, collect the organic phase, concentrate under reduced pressure, wash with n-heptane, and dry to obtain 29.6g of crude product. The HPLC chromatogram of the crude product is shown below. Figure 3 As shown, the HPLC purity of compound 6a is 97.3%.

[0095] <Example 5>

[0096] Screening of iodination reaction conditions

[0097] This embodiment, based on Examples 2-3, screened the solvents and iodizing reagents used in the preparation method of 2-iodo-3-methyl-5-trifluoromethylaniline. The screening method is as follows:

[0098] Step 1: Dissolve the iodine reagent in 100 mL of solvent to obtain raw material solution A;

[0099] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of solvent to obtain raw material solution B;

[0100] Step 3: Control the temperature at 20℃-25℃, and add raw material solution B dropwise to raw material solution A while stirring. After the addition is complete, stir the reaction for 2 hours, take a sample and send it to HPLC for detection to determine the liquid phase yield (HPLC purity) of the product (compound 6a).

[0101] The method for calculating liquid phase yield is as follows:

[0102] Liquid phase yield = (peak area of ​​the product peak) / (sum of the areas of all peaks except the solvent peak) × 100%

[0103] The screening results are shown in Table 1.

[0104] Table 1

[0105] Serial Number Iodizing reagent (equivalent) solvent Liquid phase yield 1 NIS(1.1eq) Acetic acid 62.1％ 2 NIS(1.1eq) ethanol 23.1％ 3 NIS(1.1eq) Acetonitrile 22.2％ 4 NIS(1.1eq) dichloromethane 12.3％ 5 NIS(1.1eq) Acetic acid / toluene (1:1, v / v) 67.1％ 6 ICl(1.1eq) ethanol 23.4％ 7 IClPy(1.0eq) methanol 45.4％ 8 IClPy(1.0eq) Acetic acid 48.6％ 9 IClPy(1.0eq) Trifluoroacetic acid 20.4％

[0106] As can be seen from the table above, in addition to the conditions in Examples 2-4, this application has also explored a large number of iodination conditions. However, since the iodination reactions in the table generate a variety of iodinated isomers and polyiodinated products, good selectivity has not been demonstrated. Therefore, the liquid phase yields of the target compounds are all below 70%.

[0107] The role and effect of the embodiments

[0108] According to the iodination reaction of the aniline compounds involved in this application, since ICl is selected as the iodizing reagent and CH3COOH is used as the reaction solvent, the iodination reaction of the aniline compounds in this application has excellent selectivity, thereby enabling the preparation of 2-iodo-3-methyl-5-trifluoromethylaniline in high yield.

[0109] Furthermore, this application also improves the yield of the target compound by adding sodium acetate to the reaction, thereby adjusting the reactivity of ICl and enhancing the selectivity of ICl.

[0110] According to the method for preparing aniline compounds by reducing nitrobenzene involved in this application, the applicant unexpectedly discovered that when hydrazine hydrate is used as a reducing agent, Raney copper as a catalyst has stronger reduction activity for substrates such as compound 4a compared with Raney nickel as a catalyst, thus enabling the green, environmentally friendly and efficient preparation of the target aniline compounds.

[0111] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.

Claims

1. A method for selectively processing iodoaniline compounds, characterized in that, The reaction formula is as follows: In the formula, R b Selected from C1-C5 alkyl groups, Includes the following steps: In the presence of a solvent and a base reagent, ICl reacts with compound 5 to give compound 6. Wherein, the solvent is R a COOH, R a The base reagent is methyl; c COOX, R c X is a methyl group, and K or Na is a methyl group.

2. The method for selectively processing iodoaniline compounds according to claim 1, characterized in that, Includes the following steps: Dispersions of compound 5 and ICl were prepared separately. The compound 5 dispersion and the ICl dispersion were mixed to form a mixture. An alkaline reagent was added to the mixture and the mixture was stirred to react.

3. The method for selectively processing iodoaniline compounds according to claim 1, characterized in that: in, The molar ratio of compound 5 to ICl is 1:(0.9-1.1); the molar ratio of compound 5 to the base reagent is 1:(0-1.1); and the molar volume ratio of compound 5 to the solvent is 1 mmol:(2-5) mL.

4. The method for selectively processing iodoaniline compounds according to any one of claims 1-3, characterized in that, in, The reaction formula for preparing compound 5 is as follows: The reaction steps include the following: Using hydrazine or hydrazine hydrate as a reducing agent and Raney copper as a catalyst, compound 4 is converted into compound 5.

5. A method for preparing aniline compounds by reducing nitrobenzene, characterized in that, The reaction formula is as follows: In the formula, R b Selected from C1-C5 alkyl groups, Includes the following steps: Using hydrazine or hydrazine hydrate as a reducing agent and Raney copper as a catalyst, compound 4 is converted into compound 5.

6. The method for preparing aniline compounds by reducing nitrobenzene according to claim 5, characterized in that: in, The R b It is a methyl group.

7. The method for preparing aniline compounds by reducing nitrobenzene according to claim 5, characterized in that, Includes the following steps: Under inert gas protection, compound 4, the catalyst, and the reaction solvent are mixed, and then the reducing agent is added. After post-treatment, compound 5 is obtained.

8. The method for preparing aniline compounds by reducing nitrobenzene according to claim 5, characterized in that: in, The molar ratio of compound 4 to the reducing agent is 1:(1.8-2.2).

9. The method for preparing aniline compounds by reducing nitrobenzene according to any one of claims 5-8, characterized in that: in, The mass ratio of compound 4 to the catalyst is 1:(0.08-0.2).

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