One-pot synthesis method of 3’,4’,5’-trifluoro-2-nitro-biphenyl, an intermediate of fluxapyroxad

Abstract

The present invention relates to a one-pot synthesis method of the fluxapyroxad intermediate 3',4',5'-trifluoro-2-nitrobiphenyl, belonging to the technical field of organic synthesis. The method process includes the following steps: Step 1: Under nitrogen protection, add magnesium chips, a catalyst and a solvent to a reaction flask, and then dropwise add a mixed solution of 3,4,5-trifluorobromobenzene, o-chloronitrobenzene and borate ester. After the dropping is completed, keep the reaction under heat preservation; Step 2: After the reaction is completed, acidify and wash with 10% dilute hydrochloric acid, and after phase separation, the obtained organic phase is concentrated under reduced pressure to obtain 3',4',5'-trifluoro-2-nitrobiphenyl. In the present invention, compared with the traditional synthesis method of the fluxapyroxad intermediate, the synthesis method of the present fluxapyroxad intermediate does not need to prepare 3,4,5-trifluorophenylboronic acid first, but directly uses 3,4,5-trifluorobromobenzene and o-chloronitrobenzene as raw materials. The "one-pot" synthesis method has a short reaction route, high raw material utilization rate, and can greatly reduce the raw material cost.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a one-pot synthesis method of 3',4',5'-trifluoro-2-nitrobiphenyl, an intermediate of fluxapyroxad. Background Art

[0002] Fluxapyroxad is a succinate dehydrogenase inhibitor (SDHI) fungicide developed by BASF. It is a highly efficient and low-toxic fungicide that inhibits succinate dehydrogenase in complex II of the mitochondrial respiratory chain, thereby inhibiting spore germination, germ tube and hyphal growth of target fungi. It has a broad spectrum of fungicidal effects and is widely used in crops such as cereals, soybeans, cotton, fruits and vegetables. Its application crops are constantly expanding, and the market development prospect is good. The chemical structural formulas of fluxapyroxad and its intermediates are as follows.

[0003]

[0004] Currently, many patents and literatures at home and abroad have reported the synthesis methods of 3',4',5'-trifluoro-2-nitrobiphenyl, an intermediate of fluxapyroxad. In the existing synthesis methods, as in World Patents WO2018035685, WO2022243099, and Chinese Patents CN109942433, CN117088777, etc., 3,4,5-trifluorophenylboronic acid and o-chloronitrobenzene are used as raw materials and coupled under various catalyst conditions to obtain 3',4',5'-trifluoro-2-nitrobiphenyl. The synthesis route is shown in the following figure.

[0005]

[0006] In these synthesis methods, 3,4,5-trifluorophenylboronic acid is usually prepared from 3,4,5-trifluorobromobenzene through Grignard reaction, boric acid ester addition and hydrolysis to obtain 3,4,5-trifluorophenylboronic acid. Its preparation yield is very low and there are many three wastes. Due to the high price of the raw material 3,4,5-trifluorobromobenzene, the raw material cost of 3,4,5-trifluorophenylboronic acid is high, resulting in a high raw material cost of the intermediate 3',4',5'-trifluoro-2-nitrobiphenyl.

[0007] Therefore, seeking a clean, efficient, low-cost and suitable industrial-scale production synthesis process of 3',4',5'-trifluoro-2-nitrobiphenyl, an intermediate of fluxapyroxad, is the focus of research in this field. Summary of the Invention

[0008] The present invention provides a one-pot synthesis method of 3′,4′,5′-trifluoro-2-nitrobiphenyl, an intermediate of fluxapyroxad, which solves the problems raised in the above-mentioned background art, can further improve the yield and raw material utilization rate, has a lower raw material cost and a simple process, the overall reaction conditions are mild, and it has high industrial application value.

[0009] The solution of the present invention to the above technical problems is as follows:

[0010] A one-pot synthesis method of 3′,4′,5′-trifluoro-2-nitrobiphenyl, an intermediate of fluxapyroxad, is characterized in that the synthesis method comprises the following steps:

[0011] Step1: Under the protection of nitrogen, add magnesium chips, a catalyst and a solvent into a reaction flask. The catalyst is tetrakis(triphenylphosphine)palladium, and the solvent is tetrahydrofuran or 2-methyltetrahydrofuran. Then, dropwise add a mixed solution of 3,4,5-trifluorobromobenzene, o-chloronitrobenzene and borate ester. The molar ratio of 3,4,5-trifluorobromobenzene, o-chloronitrobenzene, magnesium chips and borate ester is 1:1.0-1.5:1.0-1.5:1.0-1.5. After the dropping is completed, keep the reaction at a constant temperature. The constant temperature is 40-50 °C, and the constant temperature time is 4-5 hours;

[0012] Step2: After the reaction is completed, add 10% dilute hydrochloric acid for acidification and washing with water. After phase separation, the obtained organic phase is concentrated under reduced pressure to obtain 3′,4′,5′-trifluoro-2-nitrobiphenyl. The synthesis process route is as follows:

[0013]

[0014] On the basis of the above technical solutions, the present invention can also be improved as follows.

[0015] Further, the dosage of the catalyst tetrakis(triphenylphosphine)palladium is 0.1%-5% of the mass of 3,4,5-trifluorobromobenzene.

[0016] Further, the solvent can also be a mixed solvent composed of one or more solvents among tetrahydrofuran, 2-methyltetrahydrofuran and toluene.

[0017] The beneficial effects of the present invention are as follows: The present invention provides a one-pot synthesis method of 3′,4′,5′-trifluoro-2-nitrobiphenyl, an intermediate of fluxapyroxad, which has the following advantages:

[0018] 1. Compared with the traditional synthesis method of fluxapyroxad intermediate, the synthesis method of this fluxapyroxad intermediate does not require the prior preparation of 3,4,5-trifluorophenylboronic acid. Instead, it directly uses 3,4,5-trifluorobromobenzene and o-chloronitrobenzene as raw materials, avoiding the synthesis steps of preparing 3,4,5-trifluorophenylboronic acid from 3,4,5-trifluorobromobenzene through multiple steps. This "one-pot" synthesis method has a short reaction route, high raw material utilization rate, and can greatly reduce the raw material cost.

[0019] 2. Compared with the traditional synthesis method, this "one-pot" synthesis method has a smooth reaction process and simple reaction conditions. It has a higher yield compared with the traditional synthesis method, is environmentally friendly and suitable for industrial scale-up production.

[0020] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the content of the specification, the following provides a detailed description of the preferred embodiments of the present invention. The specific implementation manners of the present invention are given in detail by the following embodiments. Specific Embodiments

[0021] The principles and features of the present invention are described below. The examples given are only for explaining the present invention and are not used to limit the scope of the present invention. The present invention is described more specifically by way of example in the following paragraphs. The advantages and features of the present invention will be clearer according to the following description and claims.

[0022] Example 1:

[0023] Step1: Under nitrogen protection, add 3.6 g of magnesium chips, 21 mg of tetrakis(triphenylphosphine)palladium and 50 g of solvent tetrahydrofuran to the reaction flask. Slowly add the mixed solution of 21.1 g (0.1 mol) of 3,4,5-trifluorobromobenzene, 18.9 g of o-chloronitrobenzene and 15.6 g of trimethyl borate in tetrahydrofuran (50 g) to the above materials, control the temperature at 40 - 50 °C, and keep the reaction for 4 - 5 h after the addition is completed;

[0024] Step2: After the reaction is completed, acidify and wash with 10% dilute hydrochloric acid. After phase separation, the obtained organic phase is concentrated under reduced pressure to obtain 24.4 g of 3’,4’,5’-trifluoro-2-nitrobiphenyl, with a yield of 96.4%.

[0025] In the LC-MS detection in the negative ion mode, the ion (m / z 252) after the molecule loses a proton was detected.

[0026] Example 2:

[0027] Step1: Under nitrogen protection, add 3.6 g of magnesium chips, 21 mg of tetrakis(triphenylphosphine)palladium, and 50 g of the solvent 2-methyltetrahydrofuran into the reaction flask. Slowly add a mixed solution of 21.1 g (0.1 mol) of 3,4,5-trifluorobromobenzene, 18.9 g of o-chloronitrobenzene, and 15.6 g of trimethyl borate in 2-methyltetrahydrofuran (50 g) dropwise to the above materials, control the temperature at 40 - 50 °C, and keep the reaction for 4 - 5 h after the addition is completed.

[0028] Step2: After the reaction is completed, acidify and wash with 10% dilute hydrochloric acid. After phase separation, the obtained organic phase is concentrated under reduced pressure to obtain 24.2 g of 3’,4’,5’-trifluoro-2-nitrobiphenyl, with a yield of 95.6%.

[0029] In the LC-MS detection in the negative ion mode, an ion (m / z 252) after the molecule loses a proton was detected.

[0030] As described above, it is only the preferred embodiment of the present invention and does not impose any form of limitation on the present invention; any ordinary technician in the industry can smoothly implement the present invention according to the above description; however, any equivalent changes such as slight modifications, decorations, and evolutions made by those skilled in the art within the scope of the technical solution of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications, and evolutions made to the above embodiments based on the substantial technology of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. One-pot synthesis method of fluxapyroxad intermediate 3’,4’,5’-trifluoro-2-nitrobiphenyl, characterized in that, The synthesis method comprises the following steps: Step 1: Under nitrogen protection, add magnesium chips, a catalyst and a solvent into a reaction flask. The catalyst is tetrakis(triphenylphosphine)palladium, and the solvent is a mixed solvent composed of one or more solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, and toluene. Then, dropwise add a mixed solution of 3,4,5-trifluorobromobenzene, o-chloronitrobenzene, and borate ester. The molar ratio of 3,4,5-trifluorobromobenzene, o-chloronitrobenzene, magnesium chips, and borate ester is 1:1.0 - 1.5:1.0 - 1.5:1.0 - 1.

5. After the dropwise addition, keep the reaction under heat preservation. The heat preservation temperature is 40 - 50 °C, and the heat preservation time is 4 - 5 hours. Step 2: After the reaction is completed, acidify and wash with 10% dilute hydrochloric acid. After phase separation, the obtained organic phase is concentrated under reduced pressure to obtain 3’,4’,5’-trifluoro-2-nitrobiphenyl. The synthetic process route is as follows: 。 2. The one-pot synthesis method of the fluxapyroxad intermediate 3’,4’,5’-trifluoro-2-nitrobiphenyl according to claim 1, characterized in that, The dosage of the catalyst tetrakis(triphenylphosphine)palladium is 0.1% - 5% of the mass of 3,4,5-trifluorobromobenzene.

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