A method for synthesizing biphenylhydrazine ester

Abstract

This invention belongs to the field of compound synthesis technology, specifically relating to a method for synthesizing biphenylhydrazine, comprising the following steps: (1) mixing isopropyl chloroformate and hydroxylamine hydrochloride in solvent a, and reacting under certain temperature and alkaline conditions to obtain intermediate 1; (2) mixing intermediate 1 with a hydrocarbon sulfonyl halide in solvent b, and reacting under certain temperature and alkaline conditions to obtain intermediate 2; (3) mixing intermediate 2 with 3-amino-4-methoxybiphenyl in solvent c, and reacting under certain temperature and alkaline conditions to obtain biphenylhydrazine. This invention provides a novel method for synthesizing biphenylhydrazine. The synthesis of biphenylhydrazine in this application uses new raw materials and intermediates, which has the advantages of inexpensive raw materials, short synthesis route, mild reaction conditions, high yield, and ease of industrial production.

Description

Technical Field

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

[0002] Bifenazate, CAS No.: 149877-41-8, Molecular Formula: C 17 H 20 N₂O₃, with a molecular weight of 300.35, is a novel selective foliar acaricide. It is not systemic and is primarily used to control active spider mites, but it also has ovicidal activity against other mites, especially the two-spotted spider mite. It exhibits good control effects against agricultural mites such as the citrus red spider mite, rust mite, yellow spider mite, short-haired mite, hawthorn spider mite, carmine spider mite, and two-spotted spider mite. However, existing synthetic routes are either lengthy or costly, and involve hazardous reagents and processes; therefore, new synthetic routes need to be developed.

[0003] In the existing technology, it is roughly as follows:

[0004] Route 1:

[0005]

[0006] This route uses 4-hydroxybiphenyl as a raw material. The reaction process involves dangerous reactions such as nitration, diazotization, hydrogenation, and reduction. It also uses highly toxic dimethyl sulfate and flammable and explosive raw materials such as sodium hydrosulfite during the reduction process.

[0007] Route 2:

[0008]

[0009] This route uses 4-methoxyaniline as the starting material, which undergoes a diazotization reaction to obtain the 4-methoxyaniline diazonium salt. The 4-methoxyaniline diazonium salt is then decomposed to form an aryl radical, which is coupled with a certain amount of benzene to obtain 4-methoxybiphenyl. This radical is then halogenated with a halogenating agent to obtain 4-methoxy-3-halobiphenyl. Finally, a metal amine (such as sodium amide) is added for nucleophilic substitution to obtain 4-methoxy-3-aminobiphenyl, which is then diazotized, reduced, and finally condensed with isopropyl chloroformate to obtain biphenylhydrazine. Although nitration is avoided in this process, the coupling reaction follows a free radical mechanism, posing safety risks during scale-up production. Furthermore, the coupling process uses benzene, a strong carcinogen. Additionally, the yield is low during the substitution of bromine with an amino anion, and using palladium as a catalyst would be costly.

[0010] Route 3:

[0011]

[0012] This route uses 4-hydroxybiphenyl as a raw material, which is brominated, methylated, and then coupled with isopropyl hydrazine carbamate to obtain the product. If the noble metal palladium is used in the coupling process, the cost is high, and if other catalysts are used, the yield is low.

[0013] Route 4:

[0014]

[0015] This route uses 2-nitro-4-chloroanisole as a starting material, first reducing it with hydrogen, then reacting the substrate with magnesium powder under nitrogen protection using dry tetrahydrofuran as a solvent to obtain a Grignard reagent. This reagent is then coupled with a halobenzene under the catalysis of a catalyst, followed by diazotization, reduction, and condensation to obtain biphenylhydrazine ester. This route involves hydrogenation and Grignard reactions, requiring strict hydrophobic and nitrogen protection. The reaction conditions are harsh, and self-coupling byproducts are generated during the reaction, which are difficult to separate, resulting in low yields.

[0016] Therefore, this invention is proposed. Summary of the Invention

[0017] To address the problems existing in the prior art, the present invention provides a novel method for synthesizing biphenylhydrazine ester.

[0018] To achieve the above objectives, the present invention adopts the following technical solution:

[0019] A method for synthesizing biphenylhydrazine ester includes the following steps:

[0020] (1) Isopropyl chloroformate and hydroxylamine hydrochloride were mixed in solvent a and reacted under certain temperature and alkaline conditions to obtain intermediate 1.

[0021] (2) Intermediate 1 and hydrocarbon sulfonyl halide are mixed in solvent b and reacted under certain temperature and alkaline conditions to obtain intermediate 2;

[0022] (3) Intermediate 2 and 3-amino-4-methoxybiphenyl are mixed in solvent c and reacted under certain temperature and alkaline conditions to obtain biphenylhydrazine ester.

[0023] In step (1), solvent a is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, chloroform, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, and butyl acetate; in step (2), solvent b is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, chloroform, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, and butyl acetate; in step (3), solvent c is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, isopropanol, DMSO, DMF, N-methylpyrrolidone, 2-methyltetrahydrofuran, dichloromethane, chloroform, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, and butyl acetate.

[0024] The alkaline solution in the alkaline conditions of steps (1) to (3) is selected from one or more of triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0025] In step (1), the molar ratio of isopropyl chloroformate to hydroxylamine hydrochloride is 1:(1-3); the molar ratio of isopropyl chloroformate to alkaline solution is 1:(1-3.5); and the volume ratio of isopropyl chloroformate to solvent a is 1:(1-10).

[0026] The molar ratio of intermediate 1 to hydrocarbon sulfonyl halide is 1:(1-3); the molar ratio of intermediate 1 to alkaline solution is 1:(1-3.5); and the volume ratio of intermediate 1 to solvent b is 1:(1-10).

[0027] The molar ratio of intermediate 2 to 3-amino-4-methoxybiphenyl is 1:(1-3); the molar ratio of intermediate 2 to alkaline solution is 1:(1-3.5); and the volume ratio of intermediate 2 to solvent c is 1:(1-10).

[0028] The temperature in steps (1) to (3) is set between -10 and 160°C.

[0029] The reaction time in steps (1) to (3) is set to 2-24 hours.

[0030] The synthetic route for the biphenylhydrazine ester is as follows:

[0031]

[0032] Where X is selected from Cl, Br, I; R is an alkyl or aryl group and its derivatives.

[0033] The beneficial effects of this invention are as follows:

[0034] (1) This application provides a new method for synthesizing biphenylhydrazine. The biphenylhydrazine is synthesized using new raw materials and intermediates, which has the advantages of low raw material price, short synthesis route, mild reaction conditions, high yield and easy industrial production.

[0035] (2) Compared with the existing technical solutions, the raw materials are cheap and readily available, the reaction operation is simple, green and environmentally friendly, and can reduce safety hazards, reduce production energy consumption and the amount of waste, the reaction has good atom economy, low raw material cost, high product quality, and low industrialization cost, which is in line with the concept of green synthesis technology. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0037] In the description of the embodiments of this application, the technical terms "first" and "second" are used only to distinguish different objects and should not be construed as indicating or implying relative importance or implicitly indicating the number, specific order, or primary and secondary relationship of the indicated technical features.

[0038] The term "embodiment" in this document means that a particular feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of this application. The appearance of this phrase in various places in the specification does not necessarily refer to the same embodiment, nor is it a separate or alternative embodiment that is mutually exclusive with other embodiments.

[0039] In the embodiments of this application, the term "or / and" is only a description of the relationship between related objects, indicating that there can be three kinds of relationships. For example, A or / and B can represent three situations: A exists alone, A and B exist at the same time, and B exists alone.

[0040] Additionally, the character " / " in this article generally indicates that the objects before and after it are in an "or" relationship.

[0041] In this application embodiment, "multiple" means two or more (including two), similarly, "multiple groups" means two or more (including two groups), and "multiple layers" means two or more (including two layers), unless otherwise explicitly specified and limited.

[0042] In the embodiments of this application, "at least one" means one or more.

[0043] In the embodiments of this application, the technical terms "length," "width," "thickness," "upper," "lower," "front," "rear," "left," "right," "vertical," and "horizontal," etc., indicating the orientation or positional relationship, are based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing the embodiments of this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation or be constructed in a specific orientation, etc., and should not be construed as a limitation on the embodiments of this application. Those skilled in the art can understand the specific meaning of the above terms in the embodiments of this application according to the specific circumstances.

[0044] A method for synthesizing biphenylhydrazine ester includes the following steps:

[0045] (1) Isopropyl chloroformate and hydroxylamine hydrochloride were mixed in solvent a and reacted under certain temperature and alkaline conditions to obtain intermediate 1.

[0046] (2) Intermediate 1 and hydrocarbon sulfonyl halide are mixed in solvent b and reacted under certain temperature and alkaline conditions to obtain intermediate 2;

[0047] (3) Intermediate 2 and 3-amino-4-methoxybiphenyl are mixed in solvent c and reacted under certain temperature and alkaline conditions to obtain biphenylhydrazine ester.

[0048] In step (1), solvent a is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, chloroform, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, and butyl acetate; in step (2), solvent b is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, chloroform, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, and butyl acetate; in step (3), solvent c is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, isopropanol, DMSO, DMF, N-methylpyrrolidone, 2-methyltetrahydrofuran, dichloromethane, chloroform, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, and butyl acetate. In steps (1) to (3), the alkaline solution in the alkaline conditions is selected from one or more of the following: triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0049] In step (1), the molar ratio of isopropyl chloroformate to hydroxylamine hydrochloride is 1:(1-3); the molar ratio of isopropyl chloroformate to alkaline solution is 1:(1-3.5); and the volume ratio of isopropyl chloroformate to solvent a is 1:(1-10). The molar ratio of intermediate 1 to alkyl sulfonyl halide is 1:(1-3); the molar ratio of intermediate 1 to alkaline solution is 1:(1-3.5); and the volume ratio of intermediate 1 to solvent b is 1:(1-10). The molar ratio of intermediate 2 to 3-amino-4-methoxybiphenyl is 1:(1-3); the molar ratio of intermediate 2 to alkaline solution is 1:(1-3.5); and the volume ratio of intermediate 2 to solvent c is 1:(1-10). The temperatures in steps (1) to (3) are set between -10°C and 160°C. The reaction time in steps (1) to (3) is set to 2-24h.

[0050] The synthetic route for biphenylhydrazine in this application is as follows:

[0051]

[0052] Where X is selected from Cl, Br, I; R is an alkyl or aryl group and its derivatives.

[0053] Example

[0054] The specific experimental procedure for the synthesis of biphenylhydrazine esters consists of the following steps:

[0055] (1) Preparation of intermediate 1

[0056] In a clean 500ml three-necked flask, with stirring, the mixture was cooled to 0-5℃. 200ml of isopropyl ether, 13.9g of hydroxylamine hydrochloride, and 17.7g of sodium bicarbonate were added sequentially, followed by dropwise addition of 24.5g of isopropyl chloroformate. The temperature was controlled at 0-5℃. After the addition was complete, the mixture was kept at this temperature for 3 hours. Samples were taken for monitoring. After the reaction was complete, the mixture was filtered. The filter cake was washed with 10ml of isopropyl ether to obtain an isopropyl ether solution of intermediate 1, which was directly used in the next reaction step.

[0057] (2) Preparation of intermediate 2

[0058] In a clean 500ml three-necked flask, while stirring, add the isopropyl ether solution of intermediate 1 obtained in the previous step and cool to 0-5℃. Then add 17.7g of sodium bicarbonate, followed by the uniform addition of a hydrocarbon sulfonyl halide (such as p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, ethanesulfonyl chloride, etc.). Control the temperature at 0-5℃. After the addition is complete, keep the reaction at this temperature for 4 hours. Take a sample for monitoring. After the raw materials have reacted completely, raise the temperature to 20-25℃, add 100ml of water, stir for 10 minutes, allow to stand and separate the layers, remove the aqueous layer, and obtain the isopropyl ether solution of intermediate 2.

[0059] (3) Preparation of biphenylhydrazine

[0060] In a clean 500ml three-necked flask, with stirring, add the isopropyl ether solution of intermediate 2 obtained in the previous step and 100ml of DMF. Heat to 70℃, recover the isopropyl ether under normal pressure, and then heat to 75℃ until no distillate comes out. Cool the residual liquid in the flask to 10-15℃, then add 39.8g of 3-amino-4-methoxybiphenyl, followed by 30.4g of potassium carbonate in portions. After the addition is complete, heat to 75-80℃ and maintain the temperature for 5 hours. Take samples for monitoring. After the raw materials have reacted completely, control the temperature below 85℃, recover DMF under reduced pressure, and after no distillate comes out, replenish the vacuum with nitrogen. Cool to room temperature, then add 100ml of water to the reaction flask, cool to 5℃, filter until no droplets remain, dry the solid, and obtain 55.8g of biphenylhydrazine ester, with a yield of 93.0% and an external standard content of 98.2%.

[0061] This application discloses a synthetic method that uses isopropyl chloroformate and hydroxylamine hydrochloride as starting materials, reacts them under alkaline conditions and a certain temperature to generate intermediate 1, then intermediate 1 reacts with a hydrocarbon sulfonyl halide to generate intermediate 2, and finally intermediate 2 reacts with 3-amino-4-methoxybiphenyl to generate biphenylhydrazine ester. This method has advantages such as low raw material prices, short synthetic route, and mild reaction conditions, and solves the shortcomings of existing process technologies, such as expensive raw materials, unstable raw material sources, high reaction risk, high production costs, large equipment investment, high requirements for production equipment, and high production energy consumption.

[0062] Existing technical route one involves hazardous reactions such as nitration, hydrogenation, diazotization, and reduction, and uses flammable sodium hydrosulfite; the proposed technical solution successfully avoids hazardous reactions and reagents, and achieves high yield and low cost. Existing technical route two uses a free radical mechanism in the coupling reaction, posing safety risks during scale-up production. Furthermore, it uses benzene, a strong carcinogen, in the coupling process. Additionally, the reaction yield is low during the substitution of bromine by amino anions, and using palladium as a catalyst increases costs; the proposed technical solution successfully avoids hazardous reactions and carcinogenic reagents, and achieves high yield and low cost. Existing technical route three incurs high costs if palladium is used in the coupling process, and low yields if other catalysts are used; the proposed technical solution successfully avoids hazardous reactions and expensive reagents, and achieves high yield and low cost. Existing technical route four requires magnesium powder as a Grignard reagent and generates self-coupling byproducts, resulting in low yield; the proposed technical solution successfully avoids the Grignard reaction, achieving high yield and low cost.

[0063] In summary, the novel method for synthesizing biphenylhydrazine provided in this application features inexpensive raw materials, a short synthetic route, simple operation, high yield, and ease of industrial production. Compared with existing technologies, the method provides inexpensive and readily available raw materials, simple reaction operation, low safety risks, environmental friendliness, effective reduction of energy consumption and waste, good atom economy, low raw material cost, high yield, high product quality, and low industrialization cost, making it a practical and feasible industrial production method.

[0064] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the synthesis of bifemelastine, characterized in that, Comprising the following steps: (1) mixing isopropyl chloroformate and hydroxylamine hydrochloride in solvent a, and reacting under certain temperature and alkaline conditions to obtain intermediate 1; (2) mixing intermediate 1 and hydrocarbyl sulfonyl halide in solvent b, and reacting under certain temperature and alkaline conditions to obtain intermediate 2; (3) mixing intermediate 2 and 3-amino-4-methoxy biphenyl in solvent c, and reacting under certain temperature and alkaline conditions to obtain biphenyl hydrazine ester; wherein the intermediate 1 has the structural formula ; the intermediate 2 has the structural formula ; the hydrocarbyl sulfonyl halide has the structural formula X is selected from the group consisting of Cl, Br, I; and R is a hydrocarbyl group.

2. A process for the synthesis of flupyradifurone according to claim 1, characterized in that: The solvent a in step (1) is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, butyl acetate; the solvent b in step (2) is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, butyl acetate; the solvent c in step (3) is selected from one or more of acetonitrile, water, isopropyl ether, diethyl ether, methyl tert-butyl ether, isopropyl alcohol, DMSO, DMF, N-methyl pyrrolidone, 2-methyl tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, butyl acetate.

3. The process for synthesis of flupyradifurone as claimed in claim 1 wherein: The alkali liquid in the alkaline conditions of steps (1)-(3) is selected from one or more of triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide.

4. The process for synthesis of flupyradifurone as claimed in claim 1 wherein: The material molar ratio of isopropyl chloroformate to hydroxylamine hydrochloride in step (1) is 1:(1-3); the material molar ratio of isopropyl chloroformate to alkali liquid is 1:(1-3.5); the volume ratio of isopropyl chloroformate to solvent a is 1:(1-10).

5. The process for synthesis of flupyradifurone as claimed in claim 1 wherein: The material molar ratio of intermediate 1 to hydrocarbyl sulfonyl halide is 1:(1-3); the material molar ratio of intermediate 1 to alkali liquid is 1:(1-3.5); the volume ratio of intermediate 1 to solvent b is 1:(1-10).

6. The process for synthesis of flupyradifurone as claimed in claim 1 wherein: The material molar ratio of intermediate 2 to 3-amino-4-methoxy biphenyl is 1:(1-3); the material molar ratio of intermediate 2 to alkali liquid is 1:(1-3.5); the volume ratio of intermediate 2 to solvent c is 1:(1-10).

7. The process for synthesis of flupyradifurone as claimed in claim 1 wherein: The temperature in steps (1)-(3) is set to be between-10 and 160℃.

8. The process for synthesis of flupyradifurone as claimed in claim 1 wherein: The reaction time in steps (1)-(3) is set to be 2-24h.

9. The process for synthesis of flupyradifurone according to claim 1, wherein, The synthesis route of the biphenyl hydrazine ester is as follows: ， wherein X is selected from Cl, Br, I; R is a hydrocarbon group.

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