A method for synthesizing biphenylhydrazine ester

Abstract

This invention provides a method for synthesizing biphenylhydrazine, relating to the field of pesticide and intermediate synthesis technology. The method includes: (1) reacting 4-methoxybiphenyl with a brominating agent to obtain 3-bromo-4-methoxybiphenyl; (2) in the presence of a copper catalyst, a ligand, and a base, coupling the 3-bromo-4-methoxybiphenyl with methyl hydrazine formate to obtain methyl 3-(4-methoxybiphenyl-3-yl)hydrazine formate; and (3) subjecting the methyl 3-(4-methoxybiphenyl-3-yl)hydrazine formate to an isopropyl ester transesterification reaction to obtain the biphenylhydrazine. This invention avoids the use of high-risk reagents (such as nitrating agents) and expensive precious metal catalysts throughout the reaction process, is simple to operate, has a high overall yield, and good atom economy; the overall process is safe and efficient, suitable for industrial application.

Description

Technical Field

[0001] This invention relates to the field of pesticide and intermediate synthesis technology, specifically to a method for synthesizing biphenylhydrazine. Background Technology

[0002] Bifenazate (chemical name: isopropyl 3-(4-methoxybiphenyl-3-yl)hydrazinocarbamate) is a highly effective and selective acaricide that acts on GABA receptors in the central nervous system of mites. It exhibits excellent control efficacy against various agricultural mites at all growth stages and is safe for the environment and non-target organisms. With the continued growth in market demand, it is crucial to develop low-cost, safe, and environmentally friendly industrial synthesis routes.

[0003] The existing technologies for the synthesis of biphenylhydrazine esters mainly include the following routes: Nitration-reduction route: Using 4-hydroxybiphenyl as a raw material, the reaction proceeds through nitration, methylation, catalytic hydrogenation to reduce the nitro group, diazotization to reduce to hydrazine, and finally condensation with isopropyl chloroformate. This route is lengthy (5-6 steps) and involves highly hazardous nitration reactions, high-pressure hydrogenation, and the use of highly toxic dimethyl sulfate or stannous chloride, posing significant safety and environmental risks and exhibiting poor atom economy (CN117820174A, CN109988084B).

[0004] Noble metal coupling route: Direct coupling of 3-halo-4-methoxybiphenyl with isopropyl hydrazinoformate under palladium catalyst, or construction of a biphenyl skeleton via Suzuki coupling (e.g., CN115417797A). Although this route has fewer steps, it heavily relies on expensive palladium catalysts and / or unavailable boric acid reagents, resulting in high production costs and difficulty in industrialization.

[0005] Direct acylation route: The key intermediate 3-amino-4-methoxybiphenyl (or its hydrazine salt) is reacted directly with isopropyl chloroformate. The biggest drawback of this route is that isopropyl chloroformate is expensive, and the reaction is prone to over-acylation, generating more than 5% of diacylated impurities (isopropanol double-linked products), leading to difficult product purification and significant yield loss (CN115677540A). Other routes, such as those using Grignard reagents (CN117623947A Route 3), present operational hazards and numerous byproducts; while those using hazardous reagents such as boron trifluoride (US6093843) have stringent conditions, making them unsuitable for mass production.

[0006] Synthetic routes using 4-methoxybiphenyl as a key intermediate have attracted widespread attention because they can circumvent the dangerous nitration step required in the 4-hydroxybiphenyl route. A typical existing route (see CN115677540A) involves brominating 4-methoxybiphenyl and then coupling it with isopropyl hydrazinoformate in the presence of a palladium or copper catalyst to obtain the target product. However, this route has the following drawbacks: (1) High raw material costs: Isopropyl hydrazinocarbamate is expensive, which significantly increases production costs; (2) Product purity is difficult to control: Over-acylation or coupling is likely to occur during the reaction process, generating diacylated impurities (isopropanol double-linked impurities) that are difficult to separate, resulting in reduced product yield, difficulty in purification, and even affecting drug efficacy. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention discloses a method for synthesizing biphenylhydrazine esters. This method uses 4-methoxybiphenyl as a starting point, which can significantly reduce raw material costs and suppress the generation of key impurities, thus having significant industrial application value.

[0008] To achieve the above technical objectives, this invention proposes a method for synthesizing biphenylhydrazine ester, which includes the following steps: (1) 4-Methoxybiphenyl reacts with a brominating agent to give 3-bromo-4-methoxybiphenyl; (2) In the presence of a copper catalyst, a ligand and a base, the 3-bromo-4-methoxybiphenyl is coupled with methyl hydrazine formate to obtain methyl 3-(4-methoxybiphenyl-3-yl)hydrazine formate. (3) The methyl 3-(4-methoxybiphenyl-3-yl)hydrazine formate is subjected to transesterification reaction with isopropyl ester to obtain the biphenylhydrazine ester.

[0009] The process route of this invention is as follows: .

[0010] The above technical solution is a three-step route of synergistic bromination, copper-catalyzed coupling, and transesterification. The bromination reaction uses readily available and inexpensive 4-methoxybiphenyl for selective monobromination, reducing process costs. In the copper-catalyzed coupling, methyl hydrazinoate, which costs only a fraction of isopropyl hydrazinoate, is used as a raw material. CN coupling is performed in a relatively inexpensive copper catalytic system, successfully constructing the core framework of biphenylhydrazine ester in the presence of a ligand base, yielding the intermediate methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoate. This not only effectively reduces the process cost of the synthesis method of this invention, but also significantly reduces side reactions of copper-catalyzed coupling based on the reactivity and steric hindrance characteristics of the methyl ester group. The transesterification reaction uses isopropyl ester and the intermediate methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoate obtained in step (2) as raw materials, efficiently and specifically converting the methyl ester group into the target isopropyl ester group, ultimately yielding biphenylhydrazine ester.

[0011] The synthetic route described above does not involve two isopropyl ester donors, thus avoiding the main pathway for the formation of isopropanol double-attached impurities, significantly reducing their content (<0.2%). The HPLC purity of the biphenylhydrazine product can be stabilized above 99% without complex recrystallization or other purification steps. The overall synthetic method involves no high-risk reagents, is simple to operate, has a high overall yield, and exhibits outstanding atom economy.

[0012] Furthermore, the brominating reagent is selected from at least one of N-bromosuccinimide, dibromohydantoin, and bromine. It can utilize the electronic effects (methoxy activation) and steric effects (steric hindrance difference) of the substrate itself, combined with the mild bromination characteristics of the specific brominating reagent, to achieve highly selective monobromination without a catalyst.

[0013] Furthermore, the molar ratio of the brominating reagent to the 4-methoxybiphenyl is (1~1.3):1. Using a slight excess of the brominating reagent can improve reaction efficiency and product yield. In an optional example of the present invention, the molar ratio of the brominating reagent to the 4-methoxybiphenyl is (1.05~1.15):1.

[0014] Further, step (1) is carried out in the first organic solvent, with a reaction temperature ranging from 0°C to the reflux temperature of the first organic solvent, and a reaction time of 2-8 hours. It should be noted that in this invention, the solvent reflux temperature refers to the temperature at which the solvent reaches boiling point and condenses under reflux condensation conditions.

[0015] Furthermore, the first organic solvent is selected from at least one of acetonitrile, dichloromethane, chloroform, carbon tetrachloride, and ethyl acetate.

[0016] Furthermore, the mass ratio of the first organic solvent to the 4-methoxybiphenyl is (4~10):1. In an optional example of the present invention, the mass ratio of the first organic solvent to the 4-methoxybiphenyl is (5~8):1.

[0017] Preferably, step (1) is carried out under light-protected conditions to avoid photodegradation or side reactions of the photosensitive components.

[0018] Furthermore, step (1) also includes post-treatment of the material after the bromination reaction. The post-treatment includes ice-water quenching, solid-liquid separation, and drying. This post-treatment is simple, efficient, and highly operable. Specifically, adding ice water to the reaction solution quenches the reaction and promotes the precipitation of solids. The solid phase material is then obtained through solid-liquid separation (e.g., vacuum filtration, filtration, centrifugation), dried, and the 3-bromo-4-methoxybiphenyl is obtained. Optionally, the step also includes washing the solid phase material, which can be done with water until neutral (pH value does not change).

[0019] Further, in step (2), the molar ratio of methyl hydrazine formate to 3-bromo-4-methoxybiphenyl is (1.05~1.5):1, which is beneficial to improving the conversion rate of 3-bromo-4-methoxybiphenyl. In an optional example of the present invention, the molar ratio of methyl hydrazine formate to 3-bromo-4-methoxybiphenyl is (1.1~1.3):1.

[0020] Furthermore, the coupling reaction is carried out under an inert atmosphere at a temperature of 80°C to 130°C. It should be noted that in this invention, the inert atmosphere refers to a gaseous environment composed of gases that do not chemically interact with the reactants, such as a nitrogen atmosphere or an atmosphere formed by gases of Group 0 elements in the periodic table (such as argon). Optionally, the coupling reaction time is 10 to 15 hours, preferably 12 to 14 hours.

[0021] Furthermore, the coupling reaction is carried out in a second organic solvent, which is a polar aprotic solvent selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and 1,4-dioxane.

[0022] Furthermore, the mass ratio of the second organic solvent to the 3-bromo-4-methoxybiphenyl is (3~6):1. In an optional example of the present invention, the mass ratio of the second organic solvent to the 3-bromo-4-methoxybiphenyl is (4~5):1.

[0023] Furthermore, the copper catalyst is selected from at least one of cuprous halides, preferably at least one of cuprous iodide, cuprous bromide, and cuprous chloride, which can efficiently catalyze Ullmann-type coupling.

[0024] Furthermore, the amount of copper catalyst used is 1% to 15% of the molar amount of the 3-bromo-4-methoxybiphenyl.

[0025] Furthermore, the ligand is selected from at least one of 1,10-phenanthroline, 2,2'-bipyridine, N,N'-dimethylethylenediamine, L-proline, and 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl; optionally, the bidentate ligand can form a stable complex with copper ions, improving the solubility and stability of the catalyst, thereby enhancing the reaction efficiency; in addition, these optional ligands are relatively inexpensive and readily available, and in conjunction with the use of copper catalyst, further reduce the process cost.

[0026] Further, the amount of the ligand used is 10% to 30% of the molar amount of the 3-bromo-4-methoxybiphenyl. In an optional example of the present invention, the amount of the ligand used is 15% to 25% of the molar amount of the 3-bromo-4-methoxybiphenyl.

[0027] Furthermore, the alkali is selected from at least one of cesium carbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide, and potassium tert-butoxide, preferably at least one of cesium carbonate and potassium carbonate; the use of specific types of alkali can promote catalytic cycling, avoid unnecessary single-electron transfer processes by stabilizing catalytic intermediates, thereby suppressing side reactions and reducing the generation of dehalogenation impurities.

[0028] Furthermore, the amount of base used is 1.5 to 3 molar equivalents of the 3-bromo-4-methoxybiphenyl. A suitable amount of base can synergistically promote the reaction to proceed efficiently and selectively under mild conditions. In an optional example of the present invention, the amount of base used is 1.8 to 2.5 molar equivalents of the 3-bromo-4-methoxybiphenyl.

[0029] This invention utilizes a synergistic catalytic system comprising monovalent copper, ligands, and a base to catalyze coupling reactions. Combined with the process route of first coupling with methyl ester and then transesterification, this invention can enhance the high selectivity for CN bonds and effectively suppress side reactions such as dehalogenation.

[0030] Furthermore, step (2) also includes post-processing of the material after the coupling reaction; the post-processing operation includes ice-water quenching, solid-liquid separation, and drying. By adding ice water to the reacted material to quench the reaction and promote crystallization, and then by solid-liquid separation (such as vacuum filtration, filtration, centrifugation, etc.) and drying, the intermediate methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate is obtained. The overall post-processing operation is simple and efficient.

[0031] Further, the molar ratio of isopropanol to intermediate methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate is (2~10):1. The intermediate methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate, with its biphenylhydrazinoformate core skeleton, undergoes transesterification with excess isopropanol, which effectively promotes the forward reaction and increases the yield of the target product. In an optional example of the present invention, the molar ratio of isopropanol to intermediate methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate is (4~6):1.

[0032] Furthermore, the esterification reaction is carried out in a third organic solvent at a reflux temperature of the third organic solvent for a time of 4-15 hours.

[0033] Furthermore, the third organic solvent is selected from at least one of toluene, xylene, chlorobenzene, and benzene.

[0034] Furthermore, the transesterification reaction is carried out under the action of a catalyst, which is selected from at least one of tetraisopropyl titanate, tetrabutyl titanate, sodium methoxide, p-toluenesulfonic acid, and concentrated sulfuric acid.

[0035] Further, the amount of the transesterification catalyst is 0.5% to 10% of the molar amount of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate. In an optional example of the present invention, the amount of the transesterification catalyst is 5% to 10% of the molar amount of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate.

[0036] Furthermore, step (3) removes the methanol generated in the reaction by azeotropic distillation, thereby promoting the forward progress of the transesterification reaction. Specifically, step (3) can be carried out in a reaction system equipped with a water separator, which is used to remove the methanol generated in the reaction. It should be noted that the present invention does not limit the specific structure of the water separator; for example, a water separator including a water separator and a reflux condenser can be selected. Those skilled in the art can choose any device capable of distilling to remove methanol from the transesterification reaction system as needed.

[0037] Further, step (3) also includes: cooling and crystallizing the material after the transesterification reaction, performing solid-liquid separation, washing, and drying to obtain the biphenylhydrazine ester. The cooling and crystallization operation can be performed by cooling to 0-30°C for crystallization and then growing the crystals at 0-5°C for 1-3 hours; the solid-liquid separation operation can be performed by vacuum filtration, filtration, centrifugation, or other operations that can separate the solid phase material from the liquid phase material; the washing operation can be performed by washing the solid phase material with a fourth organic solvent, which can be at least one of toluene, xylene, chlorobenzene, and benzene. The present invention does not limit the specific conditions of the drying operation; it can be selected as needed under specific operating conditions.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention uses inexpensive and readily available 4-methoxybiphenyl as the starting material, and introduces the reaction site through selective monobromination; the copper-catalyzed coupling step uses methyl hydrazine formate, which is much cheaper than isopropyl hydrazine formate, as the coupling reagent, and with the relatively inexpensive copper catalytic system, the process cost is effectively controlled. In addition, in step (2) of the present invention, based on the reactivity and steric hindrance characteristics of the methyl ester group, efficient CN coupling is achieved under the synergistic effect of ligand / base, significantly reducing side reactions such as double coupling and dehalogenation, and constructing the biphenylhydrazine ester core skeleton with high selectivity to obtain the key intermediate methyl 3-(4-methoxybiphenyl-3-yl)hydrazine formate. In addition, the methyl ester group is specifically converted to the isopropyl ester group through transesterification reaction, and there is no diisopropyl ester group donor in the synthesis route from beginning to end, which fundamentally avoids the generation of "isopropanol double-attached impurities" (diacylated products) in the prior art, and the product HPLC purity can be ≥99% without complex recrystallization. The present invention avoids high-risk reagents (such as nitrating agents) and expensive precious metal catalysts throughout the reaction process. It is simple to operate, has a high overall yield, and good atom economy. The overall process is safe and efficient and suitable for industrial application. Attached Figure Description

[0039] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The liquid chromatogram of biphenylhydrazine ester prepared in Example 1 of the present invention is shown. Detailed Implementation

[0040] To facilitate understanding of the present invention, a more comprehensive description will be provided below, along with preferred embodiments. However, it should be understood that these embodiments are merely for more detailed explanation and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of protection of the invention.

[0041] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0042] Furthermore, it should be noted that although the various steps of the preparation method of the present invention are described in a specific order in the description of the present invention, these orders are not restrictive. Without departing from the basic principles of the present invention, those skilled in the art can perform the steps in different orders.

[0043] Furthermore, the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined with "first," "second," etc., may explicitly or implicitly include one or more of that feature. In the description of this invention, unless otherwise stated, "multiple" or "at least one" means two or more.

[0044] All numerical designations, such as temperature, time, and range, are approximate values. It should be understood that, while not always explicitly stated, all numerical designations are preceded by the term "approximately." It should also be understood that, while not always explicitly stated, the reagents described herein are merely examples, and their equivalents are known in the art.

[0045] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0046] Example 1

[0047] A method for synthesizing biphenylhydrazine ester, specifically: (1) Synthesis of 3-bromo-4-methoxybiphenyl 4-Methoxybiphenyl (36.8 g, 0.20 mol) and acetonitrile (250 mL) were added to a dry reaction flask and stirred to dissolve. N-bromosuccinimide (NBS, 39.1 g, 0.22 mol) was added in portions at room temperature. After the addition was complete, the mixture was stirred at 25 °C in the dark for 5 h. After the reaction was monitored by TLC until complete, the reaction solution was poured into 1 L of ice water and stirred to precipitate a solid. The solid was filtered, washed with water until neutral, and dried to give 52.1 g of a white solid with an HPLC purity of 98.8% and a yield of 98.0%.

[0048] (2) Synthesis of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate Under nitrogen protection, 3-bromo-4-methoxybiphenyl (25.4 g, 0.10 mol), methyl hydrazine formate (11.0 g, 0.12 mol), cuprous iodide (1.9 g, 0.01 mol, 10 mol%), 1,10-phenanthroline (3.6 g, 0.02 mol), anhydrous cesium carbonate (65.2 g, 0.20 mol), and anhydrous DMF (120 mL) were added sequentially to a dry reaction flask. The mixture was heated to 105 °C and stirred for 12 h. After cooling, the reaction solution was poured into 800 mL of ice water, stirred vigorously, filtered, washed with water, and dried. The resulting solid was slurried with ethanol (100 mL) for 1 h, filtered, and dried to obtain 26.5 g of an off-white solid with an HPLC purity of 98.1% and a yield of 92.7%.

[0049] (3) Synthesis of biphenylhydrazine Add the intermediate obtained in step (2) (28.6 g, 0.10 mol), isopropanol (24.0 g, 0.40 mol, 4.0 eq), tetraisopropyl titanate (2.8 g, 0.01 mol, 10 mol%), and toluene (150 mL) to a reactor equipped with a water separator and a reflux condenser. Heat under reflux for approximately 10 h until no more liquid separates from the water separator (azeotropically carrying out methanol). Cool the reaction mixture to room temperature; a large amount of solid precipitates. After cooling in an ice bath for 1 h, filter the mixture. Wash the filter cake with cold toluene and dry it under vacuum at 50 °C to obtain 29.8 g of a white crystalline solid, biphenylhydrazine, with an HPLC purity of 99.6% (see test results). Figure 1 The isopropanol double-linked impurity was not detected. The yield of this step was 99.3%. Based on 4-methoxybiphenyl, the overall yield of the three steps in this example was 90.2%.

[0050] Comparative Example 1 This comparative example uses a conventional method (directly using isopropyl hydrazinoformate), referring to the process and control conditions of Example 1, but replacing methyl hydrazinoformate with an equimolar amount of isopropyl hydrazinoformate in the reaction with 3-bromo-4-methoxybiphenyl.

[0051] HPLC analysis showed that the crude product obtained in this comparative example contained approximately 90% biphenylhydrazine, but also generated approximately 7% isopropanol double-linked impurities and other byproducts. After purification by column chromatography, a qualified product was obtained, but the yield was only 78%.

[0052] Example 2

[0053] Based on the synthesis method of biphenylhydrazine ester in Example 1, in this example, the solvent in step (1) is replaced with dichloromethane, and the reaction is carried out at 0°C. Specifically: In a dry reaction flask, 36.8 g (0.20 mol) of 4-methoxybiphenyl and 250 mL of dichloromethane were added and stirred to dissolve. N-bromosuccinimide (NBS, 39.1 g, 0.22 mol) was added in portions at 0 °C. After the addition was complete, the mixture was stirred at 0 °C in the dark for 6 h. After the reaction was monitored by TLC until complete, the reaction solution was poured into 1 L of ice water and stirred to precipitate a solid. The solid was filtered, washed with water until neutral, and dried to give 51.0 g of a white solid with an HPLC purity of 98.7% and a yield of 96.0%.

[0054] Example 3

[0055] Based on the synthesis method of biphenylhydrazine ester in Example 1, in this example, the ligand in step (2) is replaced with L-proline, and the reaction temperature is 90°C. Specifically: Under nitrogen protection, 3-bromo-4-methoxybiphenyl (25.4 g, 0.10 mol, from Example 2), methyl hydrazine formate (11.0 g, 0.12 mol), cuprous iodide (1.9 g, 0.01 mol), L-proline (2.3 g, 0.02 mol), anhydrous cesium carbonate (65.2 g, 0.20 mol), and anhydrous DMF (120 mL) were added sequentially to a dry reaction flask. The mixture was heated to 90 °C and stirred for 14 h. After cooling, the reaction solution was poured into 800 mL of ice water, stirred vigorously, filtered, washed with water, and dried. The resulting solid was slurried with ethanol (100 mL) for 1 h, filtered, and dried to obtain 25.7 g of an off-white solid with an HPLC purity of 98.4% and a yield of 92.7%.

[0056] Example 4

[0057] Based on the synthesis method of biphenylhydrazine ester in Example 1, in this example, the base in step (2) is replaced with potassium carbonate. Specifically: Under nitrogen protection, 3-bromo-4-methoxybiphenyl (25.4 g, 0.10 mol), methyl hydrazine formate (11.0 g, 0.12 mol), cuprous iodide (1.9 g, 0.01 mol), 1,10-phenanthroline (3.6 g, 0.02 mol), anhydrous potassium carbonate (27.6 g, 0.20 mol), and anhydrous DMF (120 mL) were added sequentially to a dry reaction flask. The mixture was heated to 105 °C and stirred for 12 h. After cooling, the reaction solution was poured into 800 mL of ice water, stirred vigorously, filtered, washed with water, and dried. The resulting solid was slurried with 100 mL of ethanol for 1 h, filtered, and dried to obtain 25.4 g of an off-white solid with an HPLC purity of 98.6% and a yield of 89.0%.

[0058] Example 5

[0059] Based on the synthesis method of biphenylhydrazine ester in Example 1, in this example, the catalyst in step (3) is replaced with p-toluenesulfonic acid (0.1 eq, 10 mol%). Specifically: An intermediate (28.6 g, 0.10 mol), isopropanol (24.0 g, 0.40 mol), p-toluenesulfonic acid (1.8 g, 0.01 mol, 10 mol%), and toluene (150 mL) were added to a reactor equipped with a water separator and a reflux condenser. The reaction mixture was heated under reflux for approximately 10 h until no more liquid separated from the water separator (azeotropically expelling methanol). The reaction mixture was cooled to room temperature, resulting in the precipitation of a large amount of solid. After cooling in an ice bath for 1 h, the mixture was filtered, the filter cake was washed with cold toluene, and dried under vacuum at 50 °C to obtain 27.6 g of a white crystalline solid, biphenylhydrazine, with an HPLC purity of 99.5% and an isopropanol di-terminated impurity content of 0.12%. The yield of this step was 92.0%. Based on 4-methoxybiphenyl, the overall yield of the three steps was 85.3%.

[0060] Example 6

[0061] Based on the synthesis method of biphenylhydrazine ester in Example 1, in this example, the solvent in step (3) is replaced with o-xylene. Specifically: The obtained intermediate (28.6 g, 0.10 mol), isopropanol (24.0 g, 0.40 mol), tetraisopropyl titanate (2.8 g, 0.01 mol), and o-xylene (150 mL) were added to a reactor equipped with a water separator and a reflux condenser. The reaction mixture was heated under reflux for approximately 11 h until no more liquid separated from the water separator (azeotropically expelling methanol). The reaction mixture was cooled to room temperature, and a large amount of solid precipitated. After cooling in an ice bath for 1 h, the mixture was filtered, and the filter cake was washed with cold o-xylene and dried under vacuum at 50 °C to give 29.1 g of a white crystalline solid, biphenylhydrazine, with an HPLC purity of 99.5% and an isopropanol di-terminated impurity content of 0.16%. The yield of this step was 97.0%. Based on 4-methoxybiphenyl, the overall yield of the three steps was 86.3%.

[0062] Example 7

[0063] Based on the synthesis method of biphenylhydrazine ester in Example 1, in this example, the amount of isopropanol in step (3) is adjusted to 5 equivalents, the amount of tetraisopropyl titanate catalyst is 0.5 mol%, and the reaction time is extended to 14 h. Specifically: The previously obtained intermediate (28.6 g, 0.10 mol), isopropanol (30.0 g, 0.50 mol), tetraisopropyl titanate (0.45 g, 0.005 mol, 0.5 mol%), and toluene (150 mL) were added to a reactor equipped with a water separator and a reflux condenser. The reaction mixture was heated under reflux for approximately 14 h until no more liquid separated from the water separator (azeotropically expelling methanol). The reaction mixture was cooled to room temperature, and a large amount of solid precipitated. After cooling in an ice bath for 1 h, the mixture was filtered, the filter cake was washed with cold toluene, and dried under vacuum at 50 °C to give 29.8 g of a white crystalline solid, biphenylhydrazine, with an HPLC purity of 99.3% and an isopropanol di-terminated impurity content of 0.13%. The yield of this step was 95.0%. The overall yield of the three steps, based on 4-methoxybiphenyl, was 88.1%.

[0064] Example 8

[0065] (1) Synthesis of 3-bromo-4-methoxybiphenyl 4-Methoxybiphenyl (36.8 g, 0.20 mol) and acetonitrile (250 mL) were added to a dry reaction flask and stirred to dissolve. Dibromohydantoin (57.2 g, 0.20 mol) was added in portions at room temperature. After the addition was complete, the mixture was stirred at 25 °C in the dark for 6 h. After the reaction was monitored by TLC until complete, the reaction solution was poured into 1 L of ice water and stirred to precipitate a solid. The solid was filtered, washed with water until neutral, and dried to give 51.5 g of a white solid with an HPLC purity of 98.2% and a yield of 97.0%.

[0066] (2) Synthesis of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate Under nitrogen protection, 3-bromo-4-methoxybiphenyl (25.4 g, 0.10 mol), methyl hydrazine formate (11.0 g, 0.12 mol), cuprous bromide (0.14 g, 0.001 mol, 1.0 mol%), 2,2'-bipyridine (3.1 g, 0.02 mol), anhydrous cesium carbonate (65.2 g, 0.20 mol), and anhydrous DMF (120 mL) were added sequentially to a dry reaction flask. The mixture was heated to 105 °C and stirred for 12 h. After cooling, the reaction was post-treated as in Example 1, and dried to obtain 26.0 g of a white solid with an HPLC purity of 98.0% and a yield of 90.9%.

[0067] (3) Synthesis of biphenylhydrazine Same as step (3) in Example 1. 28.8 g of biphenylhydrazine was obtained, with an HPLC purity of 99.3% and an isopropanol double-linked impurity content of 0.15%. The yield of this step was 96.0%. Based on 4-methoxybiphenyl, the overall yield of the three steps was 84.6%.

[0068] Example 9

[0069] (1) Synthesis of 3-bromo-4-methoxybiphenyl In a dry reaction flask, 36.8 g (0.20 mol) of 4-methoxybiphenyl and 250 mL of dichloromethane were added and stirred until dissolved. Under ice bath cooling, a 50 mL solution of elemental bromine (35.2 g, 0.22 mol, molar ratio 1.3:1) in dichloromethane was slowly added dropwise. After the addition was complete, the mixture was stirred at 25 °C in the dark for 4 h. After the reaction was complete as monitored by TLC, the reaction solution was poured into a saturated sodium bisulfite solution to quench excess bromine. The mixture was separated, the organic phase was washed, dried, and concentrated to give 53.0 g of a white solid with an HPLC purity of 97.5% and a yield of 95.0%.

[0070] (2) Synthesis of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate Under nitrogen protection, the following components were added sequentially to a dry reaction flask: 25.4 g (0.10 mol) of 3-bromo-4-methoxybiphenyl, methyl hydrazine (11.0 g (0.12 mol)), cuprous chloride (0.99 g (0.01 mol, 10 mol%), N,N'-dimethylethylenediamine (1.8 g (0.02 mol)), anhydrous potassium phosphate (42.4 g (0.20 mol)), and anhydrous NMP (120 mL). The mixture was heated to 120 °C and stirred for 12 h. After cooling, the reaction was post-treated as in Example 1, yielding 26.08 g of a white solid with an HPLC purity of 97.8% and a yield of 91.0%.

[0071] (3) Synthesis of biphenylhydrazine The above intermediate (28.6 g, 0.10 mol), isopropanol (36.0 g, 0.60 mol, 6.0 eq), tetrabutyl titanate (3.4 g, 0.01 mol, 10 mol%), and toluene (150 mL) were added to a reactor equipped with a water separator and a reflux condenser. The mixture was heated under reflux for approximately 15 h until no more liquid separated from the water separator. After cooling, the reaction was post-processed as in Example 1 to obtain 28.5 g of a white crystalline solid, biphenylhydrazine, with an HPLC purity of 98.8% and an isopropanol double-linked impurity content of 0.19%. The yield of this step was 95.0%. The overall yield of the three steps, based on 4-methoxybiphenyl, was 82.2%.

[0072] Example 10

[0073] (1) Synthesis of 3-bromo-4-methoxybiphenyl 4-Methoxybiphenyl (36.8 g, 0.20 mol) and acetonitrile (250 mL) were added to a dry reaction flask and stirred to dissolve. N-bromosuccinimide (NBS, 39.1 g, 0.22 mol) was added in portions at room temperature. After the addition was complete, the mixture was stirred at 25 °C in the dark for 5 h. After the reaction was monitored by TLC until complete, the reaction solution was poured into 1 L of ice water and stirred to precipitate a solid. The solid was filtered, washed with water until neutral, and dried to give 52.3 g of a white solid with an HPLC purity of 98.9% and a yield of 98.4%.

[0074] (2) Synthesis of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate Under nitrogen protection, 3-bromo-4-methoxybiphenyl (25.4 g, 0.10 mol), methyl hydrazine formate (11.0 g, 0.12 mol), cuprous iodide (0.95 g, 0.005 mol, 5 mol%), 1,10-phenanthroline (3.6 g, 0.02 mol), anhydrous cesium carbonate (65.2 g, 0.20 mol), and anhydrous DMF (120 mL) were added sequentially to a dry reaction flask. The mixture was heated to 105 °C and stirred for 12 h. After cooling, the reaction was post-treated as in Example 1, yielding 26.8 g of an off-white solid with an HPLC purity of 98.5% and a yield of 93.8%.

[0075] (3) Synthesis of biphenylhydrazine The above intermediate (28.6 g, 0.10 mol), isopropanol (36.0 g, 0.60 mol, 6.0 eq), sodium methoxide (0.54 g, 0.01 mol, 10 mol%), and toluene (150 mL) were added to a reactor equipped with a water separator and a reflux condenser. The reaction was heated under reflux for approximately 8 hours (the reaction was accelerated) until no more liquid separated from the water separator. After cooling, the reaction was post-processed as in Example 1 to obtain 29.5 g of a white crystalline solid, biphenylhydrazine, with an HPLC purity of 99.2% and an isopropanol double-linked impurity content of 0.14%. The yield of this step was 98.3%. Based on 4-methoxybiphenyl, the overall yield of the three steps was 88.7%.

[0076] Example 11

[0077] (1) Synthesis of 3-bromo-4-methoxybiphenyl In a dry reaction flask, 4-methoxybiphenyl (36.8 g, 0.20 mol) and acetonitrile (250 mL) were added and stirred to dissolve. At room temperature, N-bromosuccinimide (NBS, 37.4 g, 0.21 mol) was added in portions. After the addition was complete, the mixture was stirred at 25 °C in the dark for 5 h. After the reaction was monitored by TLC until complete, the reaction solution was poured into 1 L of ice water and stirred to precipitate a solid. The solid was filtered, the filter cake was washed with water until neutral, and dried to give 51.8 g of a white solid with an HPLC purity of 99.0% and a yield of 98.5%.

[0078] (2) Synthesis of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate Under nitrogen protection, 3-bromo-4-methoxybiphenyl (25.4 g, 0.10 mol), methyl hydrazine formate (11.0 g, 0.12 mol), cuprous iodide (1.52 g, 0.008 mol, 8 mol%), 1,10-phenanthroline (3.6 g, 0.02 mol), anhydrous cesium carbonate (65.2 g, 0.20 mol), and anhydrous DMF (120 mL) were added sequentially to a dry reaction flask. The mixture was heated to 105 °C and stirred for 12 h. After cooling, the reaction was treated as in Example 1, yielding 26.9 g of an off-white solid with an HPLC purity of 98.7% and a yield of 94.2%.

[0079] (3) Synthesis of biphenylhydrazine The above intermediate (28.6 g, 0.10 mol), isopropanol (60.0 g, 1.00 mol, 10.0 eq), concentrated sulfuric acid (0.1 g, 1 mol%), and toluene (150 mL) were added to a reactor equipped with a water separator and a reflux condenser. The mixture was heated under reflux for approximately 12 h until no more liquid separated from the water separator. After cooling, the reaction was post-processed as in Example 1 to obtain 28.9 g of a white crystalline solid, biphenylhydrazine, with an HPLC purity of 99.0% and an isopropanol dual-linked impurity content of 0.19%. The yield of this step was 96.3%. The overall yield of the three steps, based on 4-methoxybiphenyl, was 89.5%.

[0080] It should be noted that the above description is a further detailed explanation of the present invention in conjunction with specific embodiments, and it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, several simple improvements can be made without departing from the concept of the present invention, and all such improvements should be considered to fall within the scope of protection of the present invention.

Claims

1. A process for the synthesis of bifemelastine, characterized in that, Includes the following steps: (1) 4-Methoxybiphenyl reacts with a brominating agent to give 3-bromo-4-methoxybiphenyl; (2) In the presence of a copper catalyst, a ligand and a base, the 3-bromo-4-methoxybiphenyl is coupled with methyl hydrazine formate to obtain methyl 3-(4-methoxybiphenyl-3-yl)hydrazine formate. (3) The methyl 3-(4-methoxybiphenyl-3-yl)hydrazine formate is subjected to transesterification reaction with isopropyl ester to obtain the biphenylhydrazine ester.

2. The process for synthesis of bifenzuron according to claim 1, characterized in that, The brominating agent is selected from at least one of N-bromosuccinimide, dibromohydantoin, and bromine; And / or, the molar ratio of the brominated reagent to the 4-methoxybiphenyl is (1~1.3):1, preferably (1.05~1.15):

1.

3. The process for synthesis of bifenzuron as claimed in claim 1 wherein, The step (1) is carried out in the first organic solvent, the reaction temperature is from 0°C to the reflux temperature of the first organic solvent, and the reaction time is 2~8h; Preferably, the first organic solvent is selected from at least one of acetonitrile, dichloromethane, chloroform, carbon tetrachloride, and ethyl acetate; Preferably, the mass ratio of the first organic solvent to the 4-methoxybiphenyl is (4~10):1, more preferably (5~8):

1.

4. The process for synthesis of bifenzuron as claimed in claim 1 wherein, In step (2), the molar ratio of methyl hydrazine formate to 3-bromo-4-methoxybiphenyl is (1.05~1.5):1, preferably (1.1~1.3):1; And / or, the coupling reaction is carried out under an inert atmosphere and at a reaction temperature of 80°C to 130°C; And / or, the coupling reaction is carried out in a second organic solvent, the second organic solvent being selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and 1,4-dioxane; Preferably, the mass ratio of the second organic solvent to the 3-bromo-4-methoxybiphenyl is (3~6):1, more preferably (4~5):

1.

5. The method of synthesis of bifenzuron according to claim 1, wherein, The copper catalyst is selected from at least one of cuprous halides, preferably at least one of cuprous iodide, cuprous bromide, and cuprous chloride; And / or, the amount of the copper catalyst used is 1% to 15% of the molar amount of the 3-bromo-4-methoxybiphenyl.

6. The process for synthesis of bifenzuron as claimed in claim 1 wherein, The ligand is selected from at least one of 1,10-phenanthroline, 2,2'-bipyridine, N,N'-dimethylethylenediamine, L-proline, and 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl; And / or, the amount of the ligand used is 10% to 30% of the molar amount of the 3-bromo-4-methoxybiphenyl, preferably 15% to 25%.

7. The method of synthesis of bifenzuron according to claim 1, wherein, The alkali is selected from at least one of cesium carbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide, and potassium tert-butoxide; And / or, the amount of the base used is 1.5 to 3 molar equivalents of the 3-bromo-4-methoxybiphenyl, preferably 1.8 to 2.5 molar equivalents.

8. The method of synthesis of bifenzuron according to claim 1, wherein, The molar ratio of isopropanol to methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate is (2~10):1, preferably (4~6):1; And / or, the esterification reaction is carried out in a third organic solvent at a reflux temperature of the third organic solvent for a time of 4 to 15 hours. Preferably, the third organic solvent is selected from at least one of toluene, xylene, chlorobenzene, and benzene.

9. The method of synthesis of bifenzylhydrazine according to claim 1, wherein, The transesterification reaction is carried out in the presence of a catalyst, which is selected from at least one of tetraisopropyl titanate, tetrabutyl titanate, sodium methoxide, p-toluenesulfonic acid, and concentrated sulfuric acid. Preferably, the amount of the transesterification catalyst is 0.5% to 10% of the molar amount of methyl 3-(4-methoxybiphenyl-3-yl)hydrazinoformate, more preferably 5% to 10%.

10. The method for synthesizing biphenylhydrazine according to claim 1, characterized in that, In step (3), the methanol generated in the reaction is removed by azeotropic distillation.

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