Synthesis method of substituted 2-nitrobiphenyl

Abstract

The invention relates to a synthetic method of substituted 2-nitrobiphenyl, and belongs to the technical field of organic synthesis.The method comprises the steps that under nitrogen protection, magnesium chips and substituted bromobenzene serve as raw materials to prepare a Grignard reagent; then, in the presence of a catalyst, carrying out coupling reaction on the Grignard reagent and o-nitrobenzene sulfonate; after the reaction is finished, post-treatment is performed to obtain substituted 2-nitrobiphenyl, and the substituted bromobenzene is parachlorobromobenzene or 3, 4, 5-trifluorobromobenzene. According to the method, substituted bromobenzene and o-nitrobenzene sulfonate are directly used as raw materials, the problems of multi-step operation and low yield of phenylboronic acid preparation in a traditional route are solved, meanwhile, precious metal is replaced with the cheap copper catalyst, the raw material cost and environmental protection pressure are remarkably reduced, and the method is short in reaction route, easy to operate, high in yield and suitable for industrial production. The method is suitable for industrial large-scale production.

Description

A method for synthesizing substituted 2-nitrobenzene Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing substituted 2-nitrobenzene. Background Technology

[0002] Substituted 2-nitrobiphenyls are important intermediates in fungicide products such as fluopyram and boscalid. Fluopyram and boscalid belong to the class of highly effective and low-toxicity succinate dehydrogenase inhibitors (SDHIs). They inhibit succinate dehydrogenase in complex II of the mitochondrial respiratory chain, thereby inhibiting spore germination, germ tube, and hyphal growth of target fungi, exhibiting broad-spectrum fungicidal effects. They are widely used in crops such as cereals, soybeans, cotton, fruits, and vegetables, and their application is constantly expanding, indicating a promising market outlook. The chemical structural formulas of fluopyram and its intermediates, and boscalid and its intermediates are as follows:

[0003]

[0004]

[0005] Currently, numerous patents and publications both domestically and internationally report methods for synthesizing substituted 2-nitrobenzenes. Among the existing synthetic methods, such as world patents WO2018035685 and WO2022243099, and Chinese patents CN109942433 and CN117088777, substituted phenylboronic acid and o-chloronitrobenzene are used as raw materials, and substituted 2-nitrobenzenes are obtained by coupling under various catalytic conditions. The synthetic routes are shown below. In these synthetic methods, substituted phenylboronic acid is usually prepared from substituted bromobenzene through Grignard reaction, borate ester addition, and hydrolysis. The yield is very low, and there is a lot of waste. In addition, the subsequent coupling reaction uses expensive precious metal catalysts, which makes the raw material cost of substituted 2-nitrobenzenes high.

[0006]

[0007] Therefore, the search for a clean, efficient, low-cost, and suitable alternative 2-nitrobenzene synthesis process for industrial-scale production is a key focus of research in this field. Summary of the Invention

[0008] This invention provides a method for synthesizing substituted 2-nitrobenzene, which solves the problems mentioned in the background art. The synthesis method is simpler and more efficient, and is suitable for industrial production.

[0009] The present invention solves the above-mentioned technical problems as follows: a method for synthesizing substituted 2-nitrobenzene, the method comprising the following steps:

[0010] Step 1: Under nitrogen protection, magnesium shavings and solvent are added to the reaction flask, and then substituted bromobenzene is added dropwise. The substituted bromobenzene is p-chlorobromobenzene or 3,4,5-trifluorobromobenzene. After the addition is completed, the reaction is kept at a constant temperature to prepare Grignard reagent for later use.

[0011] Step 2: Add o-nitrobenzenesulfonate, solvent, and catalyst to another reaction flask, and add the Grignard reagent mentioned above dropwise. After the addition is complete, keep the reaction at the temperature.

[0012] Step 3: After the reaction is complete, the product is neutralized with dilute hydrochloric acid and washed with water. The mixture is then separated and concentrated to obtain the substituted 2-nitrobenzene. The synthetic route is as follows.

[0013]

[0015] Based on the above technical solution, the present invention can be further improved as follows.

[0016] Furthermore, the sulfonate group T in the o-nitrobenzene sulfonate is selected from p-toluenesulfonyl (Ts). p-Toluenesulfonyl is a good leaving group, which can make nucleophilic substitution reaction easier to carry out and improve reaction efficiency and yield. At the same time, the raw materials of this group are readily available and have low cost. The sulfonate group T can also be selected from methanesulfonyl (Ms).

[0017] Furthermore, the catalyst is cuprous iodide, and its dosage is 0.1%-3% of the mass of bromobenzene. Cuprous iodide is an inexpensive copper catalyst, which avoids the use of precious metals (such as palladium) and greatly reduces costs. Within this dosage range, high catalytic activity can be guaranteed, while avoiding side reactions and waste caused by excessive catalyst, so that the reaction yield can be kept at a high level. The catalyst can also be cuprous bromide or cuprous chloride.

[0018] Furthermore, the molar ratio of the substituted bromobenzene, magnesium shavings, and o-nitrobenzene sulfonate is 1:1.0-1.5:1.0-1.5. A slight excess of magnesium shavings ensures complete conversion of the substituted bromobenzene into the Grignard reagent; a slight excess or equivalent amount of o-nitrobenzene sulfonate facilitates complete conversion of the Grignard reagent, improves product yield, avoids excessive waste of a certain raw material, and optimizes atom economy.

[0019] Furthermore, the coupling and heat preservation reaction described in Step 2 is carried out at a temperature of 50-60℃ for 5-6 hours. This temperature range is mild and easy to control industrially, ensuring both the reaction rate and conversion rate while avoiding side reactions at high temperatures (such as the decomposition of Grignard reagents or the reduction of nitro groups). Controlling the time to 5-6 hours allows the reaction to proceed fully while ensuring production efficiency, making it suitable for industrial production.

[0020] Furthermore, the solvent is a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, or toluene. These solvents can effectively dissolve Grignard reagents and o-nitrobenzene sulfonates, and are stable to Grignard reagents without undergoing side reactions. Among them, tetrahydrofuran and 2-methyltetrahydrofuran have good solubility for Grignard reagents, while toluene can increase the reaction temperature and is inexpensive. Using them in combination can adjust the solvent polarity and optimize the reaction effect.

[0021] The beneficial effects of this invention are: This invention provides a method for synthesizing substituted 2-nitrobenzene, which has the following advantages:

[0022] 1. This method uses substituted bromobenzene and o-nitrobenzene sulfonate directly as raw materials, avoiding the multi-step reaction to prepare phenylboronic acid from substituted bromobenzene with very low yield. It also avoids the use of precious metal catalysts. This synthesis method has a short reaction route, high raw material utilization, and greatly reduced raw material costs.

[0023] 2. This invention effectively solves many problems existing in the prior art. The prior art requires the substituted bromobenzene to be prepared into substituted phenylboronic acid through multiple steps. This process has a low yield and generates a large amount of waste. The subsequent coupling reaction must rely on expensive precious metal (such as palladium) catalysts, resulting in high overall production costs. This invention simplifies the operation steps through process route innovation, significantly reduces raw material costs and environmental pressure, and is more suitable for industrial-scale production.

[0024] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the preferred embodiments of the present invention are described in detail below. Specific embodiments of the present invention are given in detail in the following examples. Detailed Implementation

[0025] The principles and features of the present invention are described below. The examples given are for illustrative purposes only and are not intended to limit the scope of the invention. The invention is described more specifically by way of example in the following paragraphs. The advantages and features of the invention will become clearer from the following description.

[0026] Example 1: Step 1, under nitrogen protection, add 3.0g of magnesium shavings and 50g of tetrahydrofuran solvent to the reaction flask, and add 21.1g (0.1mol) of 3,4,5-trifluorobromobenzene dropwise to the above materials, control the temperature at 25-30℃, and after the dropwise addition is completed, keep the reaction at the temperature for 2h before use;

[0027] Step 2: In another reaction flask, add 32.2g of o-nitrophenyl p-toluenesulfonate, 0.2g of cuprous iodide catalyst, and 50g of tetrahydrofuran solvent. Add the Grignard reagent prepared in Step 1 dropwise to the above materials, control the temperature at 50-60℃, and after the addition is complete, keep the reaction at the temperature for 5-6 hours.

[0028] Step 3: After the reaction was completed, the mixture was neutralized with 10% dilute hydrochloric acid and washed with water. The phases were separated, and the organic phase was concentrated under reduced pressure to obtain 24.2 g of 3',4',5'-trifluoro-2-nitrobenzene, with a yield of 95.6%.

[0029] LC-MS(ESI-):(MH) - 252.

[0030] The reaction route is shown below:

[0031] .

[0032] Example 2: Step 1, under nitrogen protection, add 3.0g of magnesium shavings and 50g of tetrahydrofuran solvent to the reaction flask, and add 19.1g (0.1mol) of p-chlorobromobenzene dropwise to the above materials, control the temperature at 25-30℃, and after the dropwise addition is completed, keep the reaction at the temperature for 2 hours before use;

[0033] Step 2: In another reaction flask, add 32.2g of o-nitrophenyl p-toluenesulfonate, 0.2g of cuprous iodide catalyst, and 50g of tetrahydrofuran solvent. Add the Grignard reagent prepared in Step 1 dropwise to the above materials, control the temperature at 50-60℃, and after the addition is complete, keep the reaction at the temperature for 5-6 hours.

[0034] Step 3: After the reaction was completed, 10% dilute hydrochloric acid was added to neutralize the water and wash the mixture. The phases were separated, and the organic phase was concentrated under reduced pressure to obtain 22.1 g of 4'-chloro-2-nitrobenzene, with a yield of 94.5%.

[0035] LC-MS(ESI+):(M+H) + 234.

[0036] The reaction route is shown below:

[0037] .

[0038] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Those skilled in the art can readily implement the present invention based on the above description. However, any modifications, alterations, or variations made by those skilled in the art without departing from the scope of the present invention, using the disclosed technical content, are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, or variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. A method for synthesizing substituted 2-nitrobenzene, characterized in that, The synthesis method includes the following steps: Step 1, under nitrogen protection, magnesium shavings and solvent are added to a reaction flask, and then substituted bromobenzene is added dropwise. The substituted bromobenzene is either p-chlorobromobenzene or 3,4,5-trifluorobromobenzene. After the addition is complete, the reaction is maintained at a constant temperature to obtain a Grignard reagent for later use. Step 2, o-nitrobenzene sulfonate, solvent, and catalyst are added to another reaction flask, and the Grignard reagent obtained in Step 1 is added dropwise. After the addition is complete, the reaction is maintained at a constant temperature. Step 3, after the reaction is complete, the mixture is neutralized with dilute hydrochloric acid aqueous solution, washed with water, and concentrated by phase separation to obtain substituted 2-nitrobenzene. The synthetic route is as follows. 。 2. The method for synthesizing a substituted 2-nitrobenzene according to claim 1, characterized in that, The sulfonate group T in the o-nitrobenzene sulfonate is selected from p-toluenesulfonyl.

3. The method for synthesizing a substituted 2-nitrobenzene according to claim 1, characterized in that, The catalyst is cuprous iodide, and its amount is 0.1%-3% of the mass of the substituted bromobenzene.

4. The method for synthesizing a substituted 2-nitrobenzene according to claim 1, characterized in that, The molar ratio of the substituted bromobenzene, magnesium oxide, and o-nitrobenzene sulfonate is 1:1.0-1.5:1.0-1.

5.

5. The method for synthesizing a substituted 2-nitrobenzene according to claim 1, characterized in that, The temperature of the heat preservation reaction in Step 2 is 50-60℃, and the heat preservation time is 5-6 hours.

6. The method for synthesizing a substituted 2-nitrobenzene according to claim 1, characterized in that, The solvent is a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, or toluene.

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