A method for synthesizing 4-methoxy-2-methyldiphenylamine

Abstract

The application belongs to the technical field of fine chemical industry, and particularly relates to a synthesis method of 4-methoxy-2-methylaniline, which comprises the following steps: (1) synthesis: 4-methoxy-2-methylaniline, chlorobenzene, a catalyst, an acid binding agent and an imidazole-based catalyst are sequentially added into a reaction kettle, and after stirring until the system is uniformly dispersed, heat preservation is carried out for reaction, after the reaction is completed, the system is cooled to room temperature, and after post-treatment, an oily substance is obtained; (2) recrystallization: a mixed solvent of ethanol and water is added into the oily substance obtained in step (1), the system is heated to reflux and heat preserved for 0.5 h, then the cooling speed and stirring speed are controlled for crystallization, when the temperature of the system is reduced to 10 DEG C, the system is aged for a period of time, and then filtration and washing are carried out to obtain 4-methoxy-2-methylaniline. The product obtained by the method has a yield of 97.2% and a purity of more than 99%, has the advantages of less waste, high economic benefit, high atomic economy and the like, and is easy to implement in industrialization.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical process technology, specifically relating to a method for synthesizing 4-methoxy-2-methyldiphenylamine. Background Technology

[0002] Fluorescein dyes are currently the most widely used dyes in the world, accounting for two-thirds of the production of thermosensitive and pressure-sensitive dyes. As third-generation thermosensitive and pressure-sensitive dyes, they possess advantages such as high color density, high sensitivity, and good stability. Furthermore, they can produce black on their own, solving the problem of previously requiring color mixing to prepare black dyes. In particular, the thermosensitive dye ODB-2 (2-phenylamino-3-methyl-6-dibutylaminofluorane), as a typical fluorane compound, has seen its demand rise to 10,000 tons per year since its market launch, and it is widely used in thermosensitive and pressure-sensitive paper and other fields.

[0003] Currently, the main synthesis method for ODB-2 dye involves using DPA (4-methoxy-2-methyldiphenylamine) and BBA (2-[4-(dibutylamino)-2-hydroxybenzoyl]benzoic acid) as raw materials, followed by three steps: concentrated sulfuric acid catalytic condensation, water washing and curing, and base-catalyzed cyclization to obtain the target product. DPA, as a key intermediate in ODB-2 synthesis, has four main synthetic methods:

[0004] (1) Coupling-decarboxylation method: Patents (CN119751280 A, CN113004158 A, CN110467538 A, CN106946720 A, JP62226950 A) reported that the target product was obtained by two-step reaction of MMA (4-methoxy-2-methyldiphenylamine) and 2-chlorobenzoic acid as raw materials through coupling and high-temperature decarboxylation (>180°C). The yield of this method is up to 84%. It is necessary to introduce electron-withdrawing carboxyl groups in advance to improve the reaction efficiency. At the same time, the decarboxylation reaction requires high temperature, which further increases the energy consumption.

[0005] .

[0006] (2) Direct coupling method: ① Da-Liang Zhu et al. (Organic Chemistry Frontiers (2023), 10(14), 3612-3618) reported the room-temperature coupling of iodobenzene and 4-methoxy-2-methylaniline using nickel bromide in combination with bipyridine ligands to prepare 4-methoxy-2-methyldiphenylamine, with a yield of only 71%, and the ligands and iodobenzene are expensive; ② Sun Yat-sen University reported a heterogeneous catalytic coupling system of bromobenzene and 4-methoxy-2-methylaniline (Synthesis (2018), 50(19), 3911-3920, CN108218730) A) This method uses polystyrene grafted hydrazide compounds as a support and cuprous iodide as a catalyst to obtain 4-methoxy-2-methyldiphenylamine in 93% yield. The synthesis of the catalyst ligand PSL requires five steps: Ullmann coupling, mixed acid nitration, iron powder reduction, condensation, and re-reduction. It has disadvantages such as complex synthesis steps, many dangerous reactions, low efficiency, high preparation cost, and complex ligands, which are not conducive to industrial implementation. Scholz, Ulrich et al. catalyzed the coupling of bromobenzene and 4-methoxy-2-methylaniline with tris(dibenzylideneacetone)dipalladium and BINAP ligand in the presence of cesium carbonate (Tetrahedron (2005), 61(26), 6379-6385), with a yield of 95%. However, the catalyst is expensive and the cost of the acid-binding agent is high, resulting in low practical application value. ③ Using a catalyst composed of palladium source and phosphine ligand or nitrogen heterocyclic carbene ligand, 4-methoxy-2-methyldiphenylamine is prepared by coupling reaction of chlorobenzene and 4-methoxy-2-methyldiphenylamine. Although the yield of this method is relatively high (Journal of Catalysis (2021), 402, 238-243, Tetrahedron (2005), 61(26), 6379-6385, WO2021056466 A1, CN112574042 A), the catalyst in this method is expensive and the ligand is complex, which is not conducive to cost control and large-scale production.

[0007] .

[0008] (3) Phenol method: This method (CN110642725 A, CN104817458 A, CN102675129 A, RanliaoGongye (2002), 39(3), 30-31, 27.) uses palladium / platinum as catalysts and cyclohexanone as an auxiliary agent to prepare the target product at high temperature (200°C), which has high energy consumption.

[0009] .

[0010] (4) Cyclohexanone method: This method (Youji Huaxue (2005), 25(5), 561-566, Kongop Hwahak (1999), 10(2), 293-298, JP05117214 A) uses cyclohexanone to react with 4-methoxy-2-methylaniline to form an imine structure, and then obtains the target product through palladium-catalyzed dehydrogenation aromatization at high temperature. The yield is 90%, but it also has the disadvantage of expensive catalyst.

[0011] .

[0012] In summary, current methods for synthesizing 4-methoxy-2-methyldiphenylamine still face challenges such as high costs and energy consumption associated with precious metal catalysis, making it difficult to achieve both high yield and low cost. Furthermore, practical experience shows that the water content generated in coupling-decarboxylation and direct coupling methods can negatively impact the rate of catalytic coupling reactions. Therefore, developing a synthetic method for 4-methoxy-2-methyldiphenylamine that offers mild reaction conditions, high economic efficiency, and ease of industrialization is crucial. Summary of the Invention

[0013] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing 4-methoxy-2-methyldiphenylamine. This invention is based on the Ullmann coupling reaction, using chlorobenzene and 4-methoxy-2-methylaniline in the presence of a catalyst and an imidazole co-catalyst to prepare the target product, achieving a yield of 97.2%. Compared with existing methods, this method offers high economic efficiency, mild reaction conditions, significant competitive advantages, and ease of large-scale application.

[0014] To achieve the above objectives, the present invention adopts the following technical solution:

[0015] A method for synthesizing 4-methoxy-2-methyldiphenylamine includes the following steps:

[0016] (1) Synthesis: 4-methoxy-2-methylaniline, chlorobenzene, catalyst, acid-binding agent and imidazole co-catalyst are added to the reaction vessel in sequence. After stirring until the system is evenly dispersed, the reaction is carried out at 100-120 °C. After the reaction is completed, the temperature is lowered to room temperature and the oil is obtained after post-treatment.

[0017] The catalyst is a mixture of copper acetylacetonate and iron acetylacetonate in a molar ratio of 1:(0.95-1.05); the imidazole co-catalyst is one of 1,3-dimethylimidazolium chloride, 1-ethyl-3-methylimidazolium chloride, 1-methyl-3-propylimidazolium chloride, and (1-butyl-3-methylimidazolium chloride).

[0018] The amount of chlorobenzene is 3-6 times the amount of 4-methoxy-2-methylaniline, the mass of the catalyst is 0.01-0.06 times the mass of 4-methoxy-2-methylaniline, and the mass of the imidazole co-catalyst is 0.005-0.02 times the mass of 4-methoxy-2-methylaniline.

[0019] (2) Recrystallization: Add a mixture of ethanol and water to the oily substance obtained in step (1), heat to reflux and keep warm for 0.5 h, then control the cooling rate and stirring rate to crystallize. When the system temperature drops to 10 °C, after a period of crystal growth, filter and wash to obtain 4-methoxy-2-methyldiphenylamine.

[0020] Preferably, the acid-binding agent in step (1) is one of calcium oxide and magnesium oxide. The amount of the acid-binding agent in step (1) is 1-2 times the amount of 4-methoxy-2-methylaniline.

[0021] Preferably, the reaction time in step (1) is 6-12 h.

[0022] Preferably, the post-treatment in step (1) is as follows: ethyl acetate is added to the reaction solution, stirred, and then filtered. The filtrate is then distilled under reduced pressure to recover ethyl acetate and chlorobenzene, yielding an oily substance. The mass of the ethyl acetate is 3-5 times the mass of 4-methoxy-2-methylaniline.

[0023] Preferably, in step (2), the volume ratio of ethanol to water in the mixed solvent is (5-10):1, and the mass-volume ratio of 4-methoxy-2-methylaniline to the mixed solvent is 1g:(2-5)mL.

[0024] Preferably, in step (2), the cooling rate is controlled at 0.1-1 °C / min, and the stirring speed is controlled at 50-100 rpm. The crystal growth time in step (2) is 1-3 h.

[0025] Preferably, the washing in step (2) is a rinse with cold ethanol, and the temperature of the cold ethanol is controlled at 0-5℃.

[0026] Beneficial effects of the present invention

[0027] Compared with existing methods for preparing 4-methoxy-2-methyldiphenylamine, the present invention has at least the following advantages:

[0028] (1) This invention establishes a highly efficient copper-iron synergistic catalytic system to catalyze the direct coupling of chlorobenzene and 4-methoxy-2-methylaniline to prepare the target product 4-methoxy-2-methyldiphenylamine without the participation of precious metals and complex ligands.

[0029] (2) The present invention achieves the precise preparation of the target product through two steps of efficient synthesis and recrystallization, avoiding the high temperature reaction conditions of existing methods (coupling-decarboxylation, phenol and cyclohexanone), with low energy consumption and simple operation.

[0030] (3) The dual-function mechanism of chlorobenzene (acting as both a reactant and a solvent) in this invention avoids the problem of solvent separation and recovery that exists in traditional methods. Compared with bromobenzene, the synthesis cost of PDA using chlorobenzene as a raw material is lower and the competitive advantage is stronger.

[0031] (4) The acid-binding agents of the present invention are calcium oxide and magnesium oxide, which are hygroscopic (chemically dehydrated). The water in the coupling reaction can be consumed in situ, thereby overcoming the side reactions such as hydrolysis impurities caused by water in the catalytic system. More importantly, compared with the acid-binding agents such as potassium carbonate and potassium phosphate used in existing methods, calcium oxide and magnesium oxide have higher atom economy and can be removed by simple filtration in the post-treatment process.

[0032] In summary, compared with existing methods for synthesizing 4-methoxy-2-methyldiphenylamine, the method of this invention can achieve a product yield of up to 97.2% and a purity of over 99%. It has advantages such as less waste, higher economic efficiency, and higher atom economy, giving it a significant competitive advantage and making it easy to implement industrially. Attached Figure Description

[0033] Figure 1 The image shows the high-performance liquid chromatogram of 4-methoxy-2-methyldiphenylamine obtained in Example 4.

[0034] Figure 2 The image shows the 1H NMR spectrum of 4-methoxy-2-methyldiphenylamine obtained in Example 4. Detailed Implementation

[0035] The present invention provides the following specific embodiments to further describe the technical solution of the present invention; however, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0036] All raw materials used in this invention are commercially available products.

[0037] Example 1

[0038] A method for synthesizing 4-methoxy-2-methyldiphenylamine includes the following steps:

[0039] (1) Synthesis: At room temperature, 137.18 g (1 mol) of 4-methoxy-2-methylaniline, 450.24 g (4 mol) of chlorobenzene, 0.79 g of iron acetylacetone and 0.58 g of copper acetylacetone, 95.34 g (1.7 mol) of calcium oxide and 1.37 g of 1-ethyl-3-methylimidazole chloride were added to the reaction vessel in sequence. After stirring until the system was evenly dispersed, the reaction was carried out at 100℃ for 12 h. After the reaction was completed, the temperature was lowered to room temperature, 493.85 g of ethyl acetate was added to the reaction system, stirred and filtered. The filtrate was distilled under reduced pressure to recover ethyl acetate and chlorobenzene, and an oily substance was obtained.

[0040] (2) Recrystallization: Add a mixed solvent of 457.27 mL ethanol and 91.45 mL water to the oily substance obtained in step (1), heat to reflux and keep warm for 0.5 h, then control the cooling rate (0.4 °C / min) and stirring speed (50 rpm) to crystallize. When the system temperature drops to 10 °C, crystallize for 1 h and then filter. Wash with cold ethanol to obtain 206.23 g of 4-methoxy-2-methyldiphenylamine (yield 96.7%, purity 99.01%).

[0041] Example 2

[0042] A method for synthesizing 4-methoxy-2-methyldiphenylamine includes the following steps:

[0043] (1) Synthesis: At room temperature, 137.18 g (1 mol) of 4-methoxy-2-methylaniline, 337.68 g (3 mol) of chlorobenzene, 3.54 g of iron acetylacetone and 2.63 g of copper acetylacetone, 80.6 g (2 mol) of magnesium oxide and 0.69 g of 1-butyl-3-methylimidazolium chloride were added to the reaction vessel in sequence. After stirring until the system was evenly dispersed, the reaction was carried out at 108 °C for 8 h. After the reaction was completed, the temperature was lowered to room temperature, 411.54 g of ethyl acetate was added to the reaction system, stirred and filtered. The filtrate was distilled under reduced pressure to recover ethyl acetate and chlorobenzene, and an oily substance was obtained.

[0044] (2) Recrystallization: Add a mixed solvent of 356.67 mL ethanol and 54.87 mL water to the oily substance obtained in step (1), heat to reflux and keep warm for 0.5 h, then control the cooling rate (1 °C / min) and stirring speed (85 rpm) to crystallize. When the system temperature drops to 10 °C, crystallize for 3 h and then filter. Wash with cold ethanol to obtain 206.87 g of 4-methoxy-2-methyldiphenylamine (yield 97%, purity 99.007%).

[0045] Example 3

[0046] A method for synthesizing 4-methoxy-2-methyldiphenylamine includes the following steps:

[0047] (1) Synthesis: At room temperature, 137.18 g (1 mol) of 4-methoxy-2-methylaniline, 13.72 g (5 mol) of chlorobenzene, 1.97 g of iron acetylacetone and 1.46 g of copper acetylacetone, 56.08 g (1 mol) of calcium oxide and 2.74 g of 1,3-dimethylimidazole chloride were added to the reaction vessel in sequence. After stirring until the system was evenly dispersed, the reaction was carried out at 113℃ for 10 h. After the reaction was completed, the temperature was lowered to room temperature, 617.31 g of ethyl acetate was added to the reaction system, stirred and filtered. The filtrate was distilled under reduced pressure to recover ethyl acetate and chlorobenzene, and an oily substance was obtained.

[0048] (2) Recrystallization: Add a mixed solvent of 609.69 mL ethanol and 76.21 mL water to the oily substance obtained in step (1), heat to reflux and keep warm for 0.5 h, then control the cooling rate (0.1°C / min) and stirring speed (65 rpm) to crystallize. When the system temperature drops to 10 °C, crystallize for 2 h and then filter. Wash with cold ethanol to obtain 206.66 g of 4-methoxy-2-methyldiphenylamine (yield 96.9%, purity 99.011%).

[0049] Example 4

[0050] A method for synthesizing 4-methoxy-2-methyldiphenylamine includes the following steps:

[0051] (1) Synthesis: At room temperature, 137.18 g (1 mol) of 4-methoxy-2-methylaniline, 675.36 g (6 mol) of chlorobenzene, 4.73 g of iron acetylacetone and 3.5 g of copper acetylacetone, 52.39 g (1.3 mol) of magnesium oxide and 2.06 g of 1-methyl-3-propylimidazolium chloride were added to the reaction vessel in sequence. After stirring until the system was evenly dispersed, the reaction was carried out at 120℃ for 6 h. After the reaction was completed, the temperature was lowered to room temperature, 685.9 g of ethyl acetate was added to the reaction system, stirred and filtered. The filtrate was distilled under reduced pressure to recover ethyl acetate and chlorobenzene, and an oily substance was obtained.

[0052] (2) Recrystallization: Add a mixed solvent of 249.42 mL ethanol and 24.94 mL water to the oily substance obtained in step (1), heat to reflux and keep warm for 0.5 h, then control the cooling rate (0.7 °C / min) and stirring speed (100 rpm) to crystallize. When the system temperature drops to 10 °C, crystallize for 2 h and then filter. Wash with cold ethanol to obtain 207.3 g of 4-methoxy-2-methyldiphenylamine (yield 97.2%, purity 99.015%).

[0053] Figure 1At a retention time of 8.276 min, it is 4-methoxy-2-methyldiphenylamine.

[0054] Figure 2 middle, 1 H NMR (400 MHz, Chloroform-d) δ 7.38 – 7.17 (m, 3H), 7.04 –6.66 (m, 5H), 5.29 (s, 1H), 3.90 (s, 3H), 2.33 (s, 3H).

[0055] Example 5

[0056] Unlike Example 2, the catalyst used was a mixture of copper acetylacetonate in the same molar amount as in Example 2 and cuprous iodide in the same molar amount as in Iron acetylacetonate in Example 2, yielding 179.79 g of 4-methoxy-2-methyldiphenylamine (yield 84.3%, purity 98.97%).

[0057] Comparative Example 1

[0058] Unlike Example 1, no imidazole co-catalyst was added, and 193.22 g of 4-methoxy-2-methyldiphenylamine (yield 90.6%, purity 98.95%) was obtained.

Claims

1. A method for synthesizing 4-methoxy-2-methyldiphenylamine, characterized in that, Includes the following steps: (1) Synthesis: 4-methoxy-2-methylaniline, chlorobenzene, catalyst, acid-binding agent, and imidazole co-catalyst are added to the reaction vessel in sequence. After stirring until the system is evenly dispersed, the reaction is carried out at 100-120 °C. After the reaction is completed, the temperature is lowered to room temperature, and an oily substance is obtained after post-treatment. The acid-binding agent is one of calcium oxide and magnesium oxide. The catalyst is a mixture of copper acetylacetonate and iron acetylacetonate in a molar ratio of 1:(0.95-1.05); the imidazole co-catalyst is one of 1,3-dimethylimidazolium chloride, 1-ethyl-3-methylimidazolium chloride, 1-methyl-3-propylimidazolium chloride, and (1-butyl-3-methylimidazolium chloride). The amount of chlorobenzene is 3-6 times the amount of 4-methoxy-2-methylaniline; the mass of the catalyst is 0.01-0.06 times the mass of 4-methoxy-2-methylaniline; and the mass of the imidazole co-catalyst is 0.005-0.02 times the mass of 4-methoxy-2-methylaniline. (2) Recrystallization: Add a mixture of ethanol and water to the oily substance obtained in step (1), heat to reflux and keep warm for 0.5 h, then control the cooling rate and stirring rate to crystallize. When the system temperature drops to 10 °C, after a period of crystal growth, filter and wash to obtain 4-methoxy-2-methyldiphenylamine.

2. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 1, characterized in that, The amount of the acid-binding agent in step (1) is 1-2 times the amount of 4-methoxy-2-methylaniline.

3. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 1, characterized in that, The reaction time in step (1) is 6-12 h.

4. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 1, characterized in that, The post-processing in step (1) is as follows: Ethyl acetate is added to the reaction solution, stirred, and then filtered. The filtrate is then distilled under reduced pressure to recover ethyl acetate and chlorobenzene, yielding an oily substance.

5. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 4, characterized in that, The mass of ethyl acetate added is 3-5 times the mass of 4-methoxy-2-methylaniline.

6. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 1, characterized in that, In step (2), the volume ratio of ethanol to water in the mixed solvent is (5-10):

1.

7. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 1, characterized in that, In step (2), the mass-to-volume ratio of 4-methoxy-2-methylaniline to the mixed solvent is 1 g: (2-5) mL.

8. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 1, characterized in that, In step (2), the cooling rate is controlled at 0.1-1 °C / min, and the stirring speed is controlled at 50-100 rpm.

9. The method for synthesizing 4-methoxy-2-methyldiphenylamine according to claim 1, characterized in that, The crystal growth time in step (2) is 1-3 hours.

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