A process for the preparation of a chlorantraniliprole intermediate, 4'-chloro-2-nitrobiphenyl

Abstract

The present application belongs to the field of organic chemistry, and particularly relates to a green preparation method of 4'-chloro-2-nitrobiphenyl. The present application uses o-chloronitrobenzene and 4-chlorophenylboronic acid as raw materials, and synthesizes high-purity 4'-chloro-2-nitrobiphenyl through a Suzuki-Miyaura cross-coupling reaction. The process uses a low-palladium catalyst system, di-tert-butylphenyl phosphine as a ligand, and sodium bicarbonate as a base, and the whole process uses water as a green reaction medium, without using toxic and harmful organic solvents. The cross-coupling reaction can be successfully completed under mild conditions, and the reaction has good selectivity and high conversion efficiency. Compared with the traditional synthesis process, the preparation method has multiple advantages: the overall reaction operation is simple and easy to implement, the procurement channel of the core raw material is smooth, the cost is controllable, the water-phase reaction system has little environmental pollution, the yield of the target product is excellent, the product purity is high, the quality is stable and controllable, the overall process safety is high, the repeatability is high, and the process completely has the feasibility and popularization value of industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pesticides and fungicides, and in particular to a method for preparing the intermediate 4′-chloro-2-nitrobenzene of cyazofamid. Background Technology

[0002] Cyclosulfuron-methyl is a novel nicotinamide fungicide developed by BASF, Germany. It was the first systemic nicotinamide fungicide developed by BASF and has been registered in over 50 countries, including Europe and the United States, for the control of 80 diseases on 100 crops. It is an inhibitor of succinate-coenzyme Q reductase in the mitochondrial respiratory chain. Its mechanism of action involves translocation through leaf penetration into the plant, inhibiting mitochondrial succinate dehydrogenase, hindering the tricarboxylic acid cycle, leading to amino acid and sugar deficiency, reduced energy, and interference with cell division and growth. It also exhibits neuroactive activity against diseases, providing both protective and curative effects. It inhibits the main stages of fungal growth and reproduction, including spore germination, bacterial tube elongation, appressorium formation, hyphal growth, and spore mother cell formation. It exhibits excellent resistance to rain washout and long-lasting effects. The fungicidal action is directly caused by the parent active substance and has no corresponding metabolic activity. It shows no cross-resistance with fungicides such as carbendazim and iprodione. Cyclocarb is a novel amide fungicide with broad-spectrum activity, effective against almost all types of fungal diseases. It can effectively control a variety of diseases caused by ascomycetes and deuteromycetes on fruits, vegetables and other crops. It is very effective against powdery mildew, gray mold, sclerotinia rot and various rot diseases, and is also effective against resistant fungi to other fungi. It is mainly used for the control of diseases in rapeseed, grapes, fruit trees, vegetables and field crops.

[0003] The main challenge facing agricultural pest control today is the increasingly severe problem of resistance. The main strategies for addressing this include two directions: first, developing novel active ingredients that do not exhibit cross-resistance with existing pesticides; and second, scientifically compounding existing pesticide varieties. However, the development of new ingredients not only requires huge investment and is time-consuming, but its progress also lags far behind the evolution of pesticide resistance in pests. Meanwhile, the long-term use of a single insecticide has significant drawbacks—frequent application not only accelerates the formation of pesticide resistance in pests but may also lead to excessive residues in agricultural products and environmental pollution. In contrast, the rational mixing of different active ingredients can both delay the development of resistance and reduce environmental risks, making it a more practical solution. An important intermediate in the synthesis of boscalid is 4′-chloro-2-nitrobenzene. With increasingly stringent environmental protection requirements and a growing market demand for 4′-chloro-2-nitrobenzene, it is necessary to develop new production processes for 4′-chloro-2-nitrobenzene to improve the economic and social benefits for enterprises. However, these processes generally suffer from technical deficiencies, as detailed below:

[0004] (1) Document W09733846A1 discloses a method for preparing 4′-chloro-2-nitrobenzene via a Suzuki coupling reaction. This reaction uses 2-chloronitrobenzene and 4-chlorophenylboronic acid as raw materials and is carried out under the synergistic effect of a palladium catalyst and a triphenylphosphine ligand. However, this method has several technical defects: First, the preparation process of the key raw material 4-chlorophenylboronic acid is complex, and self-coupling side reactions are prone to occur during the reaction to generate di-(4-chlorophenyl)boronic acid; second, the boronic acid compound has poor thermal stability and is prone to dehydration condensation to form 4-chlorophenylboronic anhydride; in addition, the organophosphine ligands used in the reaction system are difficult to effectively recover and recycle.

[0005]

[0006] (2) Sinochem Lantian Group Co., Ltd. (CN 105017025 B, 2018-06-12) disclosed a method for preparing 4′-chloro-2-nitrobenzene. This method employs a nickel catalytic system to facilitate the cross-coupling reaction between a magnesium granite reagent (p-chlorophenyl halide) and 2-nitrobenzene halopropionate in a suitable solvent. Compared to the traditional palladium-catalyzed Suzuki coupling route, this method offers advantages such as low catalyst cost, simple synthesis steps, and relatively ideal reaction selectivity and yield. However, this process still faces significant industrialization bottlenecks: the amount of solvent and catalyst used is relatively large, the reaction conditions are quite harsh, and the preparation of the granite reagent involves flammable and explosive risks, making it generally unfavorable for large-scale production.

[0007]

[0008] X 1 X 2 Independently selected from Cl, Br, I

[0009] (3) BASF Europe (CN102348675B, 2014-10-01) disclosed a method for preparing 4-chloro-2-nitrobiphenyl. This method uses 1-chloro-4-(6-nitrocyclohexyl-3-enyl)benzene as the starting material and methanol as the solvent. Under alkaline conditions, a bromination reaction is carried out to obtain 1-chloro-4-(6-bromo-6-nitrocyclohexyl-3-enyl)benzene or chlorinated 1-chloro-4-(6-chloro-6-nitrocyclohexyl-3-enyl)benzene. Subsequently, this intermediate undergoes an oxidative dehydrogenation reaction with potassium tert-butoxide and manganese dioxide in DMF solvent, ultimately generating the target product 4′-chloro-2-nitrobiphenyl. However, this synthetic route has significant drawbacks: the overall yield is low, the raw materials are diverse, the operation steps are lengthy, the post-processing is complex, the amount of waste generated is large, and industrial implementation is difficult.

[0010]

[0011] X = Br; Cl

[0012] (4) Literature CN104478726A discloses a method for synthesizing 4′-chloro-2-nitrobenzene. This method uses 2-chloronitrobenzene and substituted diphenylboronic acid as coupling substrates, and prepares the target product by a Suzuki coupling reaction catalyzed by palladium on carbon under tetrabutylammonium bromide phase transfer catalyst and alkaline conditions. However, this process still has obvious limitations to industrialization: the amount of palladium on carbon catalyst required is large, and the price of the key raw material, substituted diphenylboronic acid, is high, resulting in high overall production costs and making it difficult to meet the needs of large-scale industrial production.

[0013]

[0014] (5) The Suzuki coupling reaction is an important method for synthesizing 4′-chloro-2-nitrobenzene. In recent years, related research has mainly focused on two aspects: raw material screening and ligand optimization. Nantong Jiahe Chemical Co., Ltd. (CN 104478726 A, 2015-04-01) reported a Suzuki coupling reaction using 2-chloronitrobenzene and disubstituted phenylboronic acid as substrates and a Pd / C catalyst under phosphine-free ligand conditions. This strategy effectively suppressed side reactions in traditional methods and solved the problem of difficult organophosphine ligand recovery. Tianjin Junkai Chemical Technology Co., Ltd. (CN 105732392 A, 2016-07-06) developed a process using o-chloronitrobenzene and potassium p-chlorotrifluorophenylboronic acid as raw materials, with the reaction carried out in a weakly alkaline aqueous solution under the synergistic effect of a phase transfer catalyst and a cyclic palladium catalyst. This route has the characteristics of simple operation, readily available raw materials, environmental friendliness, high yield, and excellent product quality. Jingbo Agrochemical Technology Co., Ltd. (CN 109912425 A, 2019-06-21) significantly improved reaction efficiency and effectively controlled impurity generation by optimizing the reaction system and using bis(di-tert-butylphenylphosphine)palladium dichloride as a catalyst. Although the catalytic coupling route has advantages such as short synthesis steps, convenient operation, and relatively ideal yields, its industrial application still faces multiple challenges: the high price of precious metal catalysts and ligands, the high cost of the key raw material p-chlorophenylboronic acid, and the complex post-processing all contribute to high production costs, limiting large-scale promotion.

[0015]

[0016] Therefore, it is of great significance to develop a method for preparing 4′-chloro-2-nitrobenzene with high product yield, low raw material cost and minimal environmental pollution. Summary of the Invention

[0017] To address the shortcomings of existing technologies, such as low yield, high cost, and harsh reaction conditions, this invention provides a method for preparing the boscalid intermediate 4′-chloro-2-nitrobenzene. This method uses palladium acetate as a catalyst to carry out the Suzuki coupling reaction. The raw materials are readily available, the yield is high, and it has significant advantages such as a short reaction route, simple operation, high yield, and low cost, making it suitable for large-scale industrial production.

[0018] The specific plan is as follows:

[0019]

[0020] A method for preparing the boscalid intermediate 4′-chloro-2-nitrobenzene involves using 4-chlorophenylboronic acid (Formula 1) and o-chloronitrobenzene (Formula 2) in the presence of a transition metal catalyst, a phosphine ligand, and a base, mixed with a solvent, to carry out a Suzuki-Miyaura coupling reaction to synthesize 4′-chloro-2-nitrobenzene (Formula 3).

[0021] The method of this invention can achieve one-pot production, reducing reaction steps and thus improving product yield; the raw materials used in the synthesis method are obtained through diverse means and have high economic benefits.

[0022] Preferably, the reaction is carried out under the protection of inert nitrogen gas, which has a good protective effect.

[0023] Preferably, the synthesis takes place in the presence of a transition metal catalyst, a phosphine ligand, and a solvent.

[0024] Preferably, the transition metal catalyst is a palladium catalyst, and the base is sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, potassium carbonate, n-butyllithium, or sodium bicarbonate, preferably sodium bicarbonate; the phosphine ligand is 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl, di-tert-butylphenylphosphine, 1,1′-bis(diphenylphosphine)ferrocene, or chloro[2-(di-tert-butylphosphine)] The following are preferred: 2-(2-aminoethyl)phenyl)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, di(tri-tert-butylphosphine)palladium, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-11′-biphenyl, or 1,2-bis(diphenylphosphine)ethane, preferably di-tert-butylphenylphosphine.

[0025] Preferably, the palladium catalyst is palladium acetate, palladium trifluoroacetate, palladium chloride, palladium on carbon, tris(dibenzylacetone)dipalladium, or tetra(triphenylphosphine)palladium.

[0026] Preferably, the palladium catalyst is palladium acetate, which has high catalytic activity.

[0027] Preferably, the solvent is safe and environmentally friendly water.

[0028] Preferably, the molar ratio of 4-chlorophenylboronic acid (Formula 1), o-chloronitrobenzene (Formula 2), base, ligand, and catalyst in the reaction is: 1.0–1.5: 1.0–1.5: 1.0–2.0: 0.005%–0.010%: 0.0002%–0.008%.

[0029] The present invention uses di-tert-butylphenylphosphine as the reaction ligand. This design has the following outstanding advantages: (1) The ligand is inexpensive and available on the market, which effectively reduces production costs; (2) The ligand is safe and reliable and can replace traditional flammable organophosphine ligands; (3) The ligand will be deactivated after reacting with the palladium catalyst in aqueous solution and will not remain in the product, which effectively improves the purity of the product.

[0030] The present invention uses palladium acetate as a catalyst. This design has the following outstanding advantages: (1) The catalyst has good solubility in common organic solvents (such as acetone, methanol, acetonitrile, dichloromethane, chloroform, etc.), which facilitates the preparation of homogeneous catalytic solutions, ensures uniformity of the reaction system, and improves catalytic efficiency. (2) The catalyst has high catalytic activity, which can significantly reduce the activation energy of the reaction and improve the reaction rate and yield. Attached Figure Description

[0031] The attached figures show the proton and carbon NMR spectra of the products from each embodiment. The figure numbers correspond to the embodiment numbers. A is the proton NMR spectrum, and B is the carbon NMR spectrum. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The image shows the carbon NMR spectrum of the product obtained in Example 1. Specific Implementation

[0032] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bidex, Sigma-Aldrich, Acros, Innochem, Energy Chemical, TCI China, Alfa Aesar, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M.

[0033] Example 1

[0034] (1) 181.2 mg (1.15 mmol) of o-chloronitrobenzene, 85.0 mg (1.0 mmol) of sodium bicarbonate and 156.4 mg (1.0 mmol) of 4-chlorophenylboronic acid were added to a 10 mL microwave reaction tube. The microwave reaction tube was replaced with a nitrogen atmosphere. 10 μL of a mixed solvent of palladium acetate and di-tert-butylphenylphosphine (0.002 M dissolved in dichloromethane) (0.002 mol%) and 0.8 mL of water were added. The mixture was heated to 120 °C and refluxed for 24 hours. After cooling to room temperature, the mixture was filtered, washed with water until neutral, concentrated, and recrystallized from n-butanol to obtain 231.3 mg of 4'-chloro-2-nitrobenzene, with a yield of 99%. 1 H NMR (400MHz, CDCl3) δ7.85 (dd, J=8.1, 1.3Hz, 1H), 7.60 (td, J=7.6, 1.3Hz, 1H), 7.47 (td, J=7.8, 1.4Hz, 1H), 7.41-7.34 (m, 3H), 7.26-7.20 (m, 2H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ149.1, 136.1, 135.3, 134.5, 132.7, 132.0, 129.4, 129.0, 128.7, 124.4ppm.

Claims

1. A method for preparing the boscalid intermediate 4′-chloro-2-nitrobenzene, characterized in that: 4′-chloro-2-nitrobenzene (Formula 3) was synthesized by a Suzuki-Miyaura coupling reaction using 4-chlorophenylboronic acid (Formula 1) and o-chloronitrobenzene (Formula 2) in the presence of a transition metal catalyst, phosphine ligand, and base, mixed with a solvent.

2. The synthesis method according to claim 1, characterized in that, The transition metal catalyst is a palladium catalyst.

3. The synthesis method according to claim 1, characterized in that, The alkali is sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, potassium carbonate, n-butyllithium, or sodium bicarbonate.

4. The synthesis method according to claim 2, characterized in that, The palladium catalyst is palladium acetate, palladium trifluoroacetate, palladium chloride, palladium on carbon, tris(dibenzylacetone)dipalladium, or tetra(triphenylphosphine)palladium.

5. The synthesis method according to claim 1, characterized in that, The reaction was carried out under the protection of the inert gas nitrogen.

6. The synthesis method according to claim 1, characterized in that, The phosphine ligands mentioned are 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl, di-tert-butylphenylphosphine, 1,1′-bis(diphenylphosphine)ferrocene, chloro[2-(di-tert-butylphosphine)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, di(tri-tert-butylphosphine)palladium, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-11′-biphenyl, or 1,2-bis(diphenylphosphine)ethane.

7. The synthesis method according to claim 1, characterized in that, The solvent is water.

8. The synthesis method according to claim 1, characterized in that, The molar ratio of 4-chlorophenylboronic acid (Formula 1), o-chloronitrobenzene (Formula 2), base, ligand, and catalyst in the reaction is: 1.0–1.5: 1.0–1.5: 1.0–2.0: 0.005%–0.010%: 0.0002%–0.008%.

9. The synthesis method according to claim 1, characterized in that, The reaction temperature is 100℃~150℃.

10. The synthesis method according to claim 1, characterized in that, The reaction time is 15h to 30h.

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