Improved preparation method of biphenylamide compounds

Abstract

The present invention relates to an improved preparation method of a biphenylamide compound, characterized in that the method uses N,N-dimethylbenzylamine as an acid-binding agent and is prepared by the following reaction.

Description

Technical Field

[0001] The present invention relates to an improved process for the preparation of biphenylamide compounds. Background Art

[0002] Biphenylamide compounds are important chemical raw materials. There are mainly the following methods for reacting aniline compounds with acyl chloride compounds to prepare biphenylamide compounds: (1) directly vacuuming without using an acid-binding agent. This method requires controlling the vacuum degree and reaction temperature, is difficult to operate, and is not conducive to production; (2) using an organic base as an acid-binding agent, such as pyridine or triethylamine.

[0003] In Chinese patent CN104220417B, 3-difluoromethyl-1-methyl-1-piperazole-4-yl chloride is used as a raw material to react with 2-(3,4,5-trifluorophenyl)aniline, toluene is used as a solvent, pyridine is used as an acid-binding agent, the reaction is carried out at 55°C, and the product is obtained by column chromatography with a yield of 92%. The pyridine used in this method has a very strong pungent fishy smell and is highly toxic, making it difficult to use in large-scale industrial production.

[0004] Non-patent document 1 records that triethylamine is used as an acid-binding agent and toluene is used as a solvent to react 2-(3,4,5-trifluorophenyl)aniline and 3-difluoromethyl-1-methyl-1H-pyrazole-4-yl chloride at 60° C. for 18 hours to obtain a product with a yield of 92.2%. The reaction time of this method is too long, which is not conducive to industrial production.

[0005] Non-patent document 1: Patrizio O, "Pd-Catalysed Suzuki–Miyauracross-couplingofaryl chlorides at low catalyst loadings in water for the synthesis of foundustrially important fungicides", Green Chemistry, 23, 2021: 8169-8180. Summary of the invention

[0006] The inventors of the present application found that when using pyridine as an acid-binding agent to prepare biphenylamide compounds, the generated pyridine hydrochloride was unstable, which affected the reaction yield; in addition, pyridine also had high toxicity and a pungent fishy odor.

[0007] When triethylamine is used as an acid-binding agent, a large amount of solid is precipitated during the reaction and adheres to the inner wall of the reaction bottle. In addition, when triethylamine evaporates and encounters acid gas to generate solid, it will block the nozzle for adding acid chloride. In addition, when the reaction liquid is extracted and separated after the reaction is completed, the organic phase and the aqueous phase have similar colors and are difficult to separate.

[0008] The applicant also tried to use inorganic base sodium carbonate as an acid-binding agent. Since the reaction is an anhydrous system, a large amount of inorganic salts generated are insoluble and affect the mixing of the raw materials, resulting in incomplete reaction; water generated by the reaction of sodium carbonate and hydrogen chloride gas will react with the acyl chloride, which is not conducive to the reaction.

[0009] In order to solve the above problems, the inventors of the present application conducted various attempts and found that using N,N-dimethylbenzylamine as an acid-binding agent for the above reaction can solve the above problems. Moreover, the recovery rate of using N,N-dimethylbenzylamine as an acid-binding agent is high and can be reused, which is more economical and environmentally friendly.

[0010] Specifically, the present invention relates to:

[0011] (1) An improved preparation method of a biphenylamide compound, wherein N,N-dimethylbenzylamine is used as an acid-binding agent and the compound is prepared by the following reaction:

[0012]

[0013] In the formula, R1 is C 1-10 Alkyl, C 6-20 Aryl, C 5-20 Heteroaryl, wherein the alkyl, aryl, heteroaryl are optionally substituted by 1 or more selected from C 1-6 Alkyl, halogen, halogenated C 1-6 The alkyl group is substituted; R1 is preferably C 5-20 Heteroaryl, more preferably pyrazolyl or pyridinyl;

[0014] R2 is F, Cl or Br, and R2 is located at the meta position or para position of the phenyl group. There may be one or more R2 groups, and the more than two R2 groups may be the same or different.

[0015] (2) The method according to the above (1), wherein the molar ratio of the aniline compound represented by formula (2) to the acid chloride compound represented by formula (3) is 1:(0.8 to 2), preferably 1:(1 to 1.2).

[0016] (3) The method according to (1) or (2) above, wherein the molar ratio of the acid-binding agent N,N-dimethylbenzylamine to the aniline compound represented by formula (2) is (1-3):1, preferably (1.5-2):1.

[0017] (4) The method according to any one of (1) to (3) above, wherein the solvent used is toluene or xylene, preferably xylene.

[0018] (5) The method according to any one of (1) to (4) above, wherein the reaction is carried out under anhydrous conditions.

[0019] (6) The method according to any one of (1) to (5) above, wherein the reaction is the following reaction:

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 These are photos of the reaction process and finished product of Flupyraclostrobin prepared in Example 1 of the present application.

[0022] Figure 2 This is a photo of the reaction process of fluopyrabendazim prepared in Comparative Example 1 of the present application.

[0023] Figure 3 The reaction process and finished product photos of Flupyraclostrobin prepared in Comparative Example 2 of the present application.

[0024] Figure 4 This is a photo of the reaction process of fluopyram prepared in Comparative Example 3 of the present application. DETAILED DESCRIPTION

[0025] In this application, unless otherwise specified, "%" refers to weight percentage.

[0026] In the present application, the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0027] One aspect of the present invention provides the following method for preparing a biphenylamide compound:

[0028]

[0029] In the formula,

[0030] R1 is C 1-10 Alkyl, C 6-20 Aryl, C 5-20 Heteroaryl, wherein the alkyl, aryl, heteroaryl are optionally substituted by 1 or more selected from C 1-6 Alkyl, halogen, halogenated C 1-6 Substitution of alkyl groups;

[0031] R2 is F, Cl or Br, and R2 is located at the meta position or para position of the phenyl group. There may be one or more R2 groups, and the more than two R2 groups may be the same or different.

[0032] More specifically, R1 can be C 5-20Heteroaryl may further be pyrazolyl or pyridyl, wherein pyrazolyl or pyridyl is optionally substituted by 1 or more selected from C 1-6 Alkyl, halogen, halogenated C 1-3 The alkyl group is substituted by a substituent; R2 can be F or Cl.

[0033] In the present invention, N,N-dimethylbenzylamine is used instead of commonly used pyridine, triethylamine, inorganic base, etc. as an acid binding agent, thereby solving the above-mentioned problems caused by these substances as acid binding agents.

[0034] In some specific embodiments, the molar ratio of the acid-binding agent N,N-dimethylbenzylamine to the aniline compound represented by formula (2) is (1-3):1, preferably (1.5-2):1.

[0035] In the method of the present invention, toluene or xylene is preferably used as the reaction solvent, and xylene is more preferably used as the reaction solvent. The reaction rate is accelerated by increasing the reaction temperature, and the reaction temperature is set between 60°C and 100°C, preferably between 70°C and 90°C.

[0036] In some specific embodiments, the molar ratio of the aniline compound represented by formula (2) to the acyl chloride compound represented by formula (3) is 1:(0.8-2), preferably 1:(1-1.2).

[0037] In some specific embodiments, the preparation method of the present invention is carried out in an anhydrous system.

[0038] In some specific embodiments, the biphenylamide compound of formula (1) is fluopicolide or boscalid.

[0039] In some specific embodiments, the improved preparation method of the present invention is used in the following reaction:

[0040]

[0041] In a more specific embodiment, the above reaction can be performed as follows but is not limited thereto: aniline, an acid binding agent, an acyl chloride and a solvent are added to a reaction bottle, the reaction temperature is controlled, and the reaction is carried out at a temperature-keeping temperature. After the reaction is completed, the reaction is washed with water twice for liquid separation, and the target product is obtained by cooling and crystallization.

[0042] In a more specific embodiment, after the above reaction is completed, the water washing and separation should be hot separation at a temperature of 90-95° C., and the pH of the system is controlled at 7-8 during separation.

[0043] In a more specific embodiment, a gradient cooling method is used during crystallization.

[0044] In a more specific embodiment, during the crystallization by cooling, the temperature is first lowered to 80-85°C, and then the temperature is further lowered to 20-25°C after the crystals are precipitated.

[0045] Example

[0046] The present invention is described in more detail below by way of examples, but the present invention is not limited to these specific implementation modes and examples, and any modifications and changes without departing from the gist of the present invention fall within the scope of the present invention.

[0047] In the following examples and comparative examples, the conditions for high performance liquid chromatography analysis are as follows: the instrument is an Agilent 1100LC liquid chromatograph, a UV detector, a chromatographic column is C18, 250 mm × 4.6 mm × 5.0 um, the mobile phase is acetonitrile: water (adjusted to pH = 3.7 to 4.1 with formic acid) = 80:20, the column temperature is 30 ° C, the flow rate is 1.0 mL / min, and the wavelength is 225 nm.

[0048] Example 1

[0049] Pure 2-(3,4,5-trifluorophenyl)aniline (46.6 g, 0.2 mol) and N,N-dimethylbenzylamine (48.7 g, 0.36 mol) were dissolved in 50 g of xylene, stirred, heated to 80°C, and 119.0 g of a xylene solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-yl chloride (solution concentration 39.24%, 0.24 mol) was added dropwise. After the addition, the temperature was controlled at 90-95°C. After the reaction was kept warm for 1 hour, a sample was taken for HPLC detection to confirm that the content of 2-(3,4,5-trifluorophenyl)aniline was less than 1%, and the reaction was completed.

[0050] Add 50.0g of water, heat to 90-95°C, stir for 0.5h, control pH = 7-8, separate the liquids, and remove the water layer; pour the organic phase back into the reaction bottle, heat to 90°C, then slowly add 50g of water, heat to 90-95°C, stir for 0.5h, separate the liquids, and remove the water layer.

[0051] The organic phase was slowly cooled to 85°C, stirred for 0.5h, and after precipitation, the temperature was further cooled to 20-25°C, stirred for 0.5h, and filtered. The organic phase was rinsed with 30g of xylene and dried at 85-90°C to obtain 76.3g of pure fluopyrabamide as a white solid with a content of 97.5% and a yield of 97.5%.

[0052] Comparative Example 1 Pyridine as Acid Binding Agent

[0053] Pure 2-(3,4,5-trifluorophenyl)aniline (46.6 g, 0.2 mol) and pyridine (28.5 g, 0.36 mol) were dissolved in 50 g of xylene, stirred, heated to 85°C, and 119.0 g of a xylene solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-yl chloride (solution concentration 39.24%, 0.24 mol) was added dropwise. After the addition, the temperature was controlled at 90-95°C. After the reaction was kept warm for 1 hour, a sample was taken for HPLC detection to confirm that the content of 2-(3,4,5-trifluorophenyl)aniline was less than 1%, and the reaction was completed.

[0054] Add 50.0g of water, heat to 90-95°C, stir for 0.5h, control pH = 7-8, separate the liquids, and remove the water layer; pour the organic phase back into the reaction bottle, heat to 90°C, then slowly add 50g of water, heat to 90-95°C, stir for 0.5h, separate the liquids, and remove the water layer.

[0055] The organic phase was slowly cooled to 85°C, stirred for 0.5h, and after precipitation, the temperature was further cooled to 20-25°C, stirred for 0.5h, and filtered. The organic phase was rinsed with 30g of xylene and dried at 85-90°C to obtain 68.2g of pure fluopyrabamide as a white solid with a content of 92% and a yield of 82.3%.

[0056] Comparative Example 2 Triethylamine as Acid Binding Agent

[0057] Pure 2-(3,4,5-trifluorophenyl)aniline (46.6 g, 0.2 mol) and triethylamine (36.4 g, 0.36 mol) were dissolved in 50 g of xylene, stirred, heated to 80°C, and 119.0 g of a xylene solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-yl chloride (solution concentration 39.24%, 0.24 mol) was added dropwise. After the addition, the temperature was controlled at 90-95°C. After the reaction was kept warm for 1 hour, a sample was taken for HPLC detection to confirm that the content of 2-(3,4,5-trifluorophenyl)aniline was less than 1%, and the reaction was completed.

[0058] Add 50.0g of water, heat to 90-95°C, stir for 0.5h, control pH = 7-8, separate the liquids, and remove the water layer; pour the organic phase back into the reaction bottle, heat to 90°C, then slowly add 50g of water, heat to 90-95°C, stir for 0.5h, separate the liquids, and remove the water layer.

[0059] The organic phase was slowly cooled to 85°C, stirred for 0.5h, and after precipitation, the temperature was further cooled to 20-25°C, stirred for 0.5h, and filtered. The organic phase was rinsed with 30g of xylene and dried at 85-90°C to obtain 62.7g of pure fluopyrabamide, which was yellow in appearance, had a content of 90.0%, and a yield of 74%.

[0060] Comparative Example 3 Inorganic alkali as acid binding agent

[0061] Add 10.6g sodium carbonate (0.1mol) to a xylene solution of 65.2g 2-(3,4,5-trifluorophenyl)aniline (solution concentration 35.76%, 0.1mol), stir, heat to 80℃, and drop 59.5g xylene solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-yl chloride (solution concentration 39.24%, 0.12mol). After the dropwise addition, control the temperature at 90-95℃ and keep the temperature for reaction. Take a sample for HPLC detection. When the reaction is carried out for 5h, the content of 2-(3,4,5-trifluorophenyl)aniline remains 6%, a large amount of inorganic salts are generated, and the reaction cannot continue.

[0062] Example 2: Recovery rate experiment of N,N-dimethylbenzylamine

[0063] Pure 2-(3,4,5-trifluorophenyl)aniline (46.6 g, 0.2 mol) and N,N-dimethylbenzylamine (48.7 g, 0.36 mol) were dissolved in 50 g of xylene, stirred, heated to 80°C, and 119.0 g of a xylene solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-yl chloride (solution concentration 39.24%, 0.24 mol) was added dropwise. After the addition, the temperature was controlled at 90-95°C. After the reaction was kept warm for 1 hour, a sample was taken for HPLC detection to confirm that the content of 2-(3,4,5-trifluorophenyl)aniline was less than 1%, and the reaction was completed.

[0064] After the reaction is completed, add 50.0g of water and stir for 0.5h. Use 30% sodium hydroxide solution to adjust the pH of the reaction solution to 12. The freed N,N-dimethylbenzylamine enters the organic phase. Separate the liquid and remove the water layer. Pour the organic phase back into the reaction bottle and heat it to 90°C. Then slowly add 50g of water, heat it to 90-95°C, stir for 0.5h, separate the liquid and remove the water layer.

[0065] The organic phase was slowly cooled to 85°C, stirred for 0.5h, and after precipitation, the temperature was further cooled to 20-25°C, stirred for 0.5h, and filtered. It was washed with 30g of xylene, dried at 85-90°C, and crystallized to obtain 75.4g of flupyraclostrobin solid with a content of 98.1%. 158.2g of mother liquor was obtained. The content of N,N-dimethylbenzylamine in the mother liquor was 20.3% by HPLC, and the recovery rate was 66%.

[0066] The mother liquor was applied to the next batch of reactions, and the amount of N,N-dimethylbenzylamine was reduced by 66%. The reaction was qualified, and the content of the obtained fluopyraclostrobin product was 97.7%.

Claims

1. An improved method for preparing a biphenylamide compound, characterized in that: The method uses N,N-dimethylbenzylamine as an acid-binding agent and is prepared by the following reaction: In the formula, R1 is C 1-10 Alkyl, C 6-20 Aryl, C 5-20 Heteroaryl, wherein the alkyl, aryl, heteroaryl are optionally substituted by 1 or more selected from C 1-6 Alkyl, halogen, halogenated C 1-6 The alkyl group is substituted; R1 is preferably C 5-20 Heteroaryl, more preferably pyrazolyl or pyridinyl; R2 is F, Cl or Br, and R2 is located at the meta position or para position of the phenyl group. There may be one or more R2 groups, and the more than two R2 groups may be the same or different.

2. The method according to claim 1, characterized in that: The molar ratio of the aniline compound represented by the formula (2) to the acid chloride compound represented by the formula (3) is 1:(0.8 to 2), preferably 1:(1 to 1.2).

3. The method according to claim 1 or 2, characterized in that: The molar ratio of the acid-binding agent N,N-dimethylbenzylamine to the aniline compound represented by formula (2) is (1 to 3):1, preferably (1.5 to 2):

1.

4. The method according to any one of claims 1 to 3, characterized in that The solvent used is toluene or xylene, preferably xylene.

5. The method according to any one of claims 1 to 4, characterized in that: The reaction is carried out under anhydrous conditions.

6. The method according to any one of claims 1 to 5, characterized in that The reaction is as follows:

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