Process for the preparation of the organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide

Abstract

This invention discloses a method for preparing the organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl)pentanoyl hydrazide, belonging to the field of organic synthesis technology. This invention provides a method for preparing the intermediate under nitrogen protection, using aryl bromide and pentanoyl hydrazide as reactants, and adding alkali, Cu₂O, and N₂. 1 N 2 N'-(2,4-dichloro-5-isopropoxyphenyl)pentanoylhydrazine is generated by a Ullmann coupling reaction involving bis(1-naphthyl)oxalamide, a relevant catalyst, and a water / alcohol solvent, followed by heating. This method utilizes inexpensive and readily available raw materials, has a simple operation process, operates under mild and environmentally friendly conditions, requires minimal post-processing, and is safe and efficient, making it suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide. BACKGROUND

[0002] N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide has a molecular formula of C 14 H 20 Cl2N2O2, a molecular weight of 319.23, a CAS number of 51167-18-1, and a structural formula as follows:

[0003]

[0004] The product is an important synthetic precursor of the herbicide oxadiazon. At present, the existing synthetic route of the product is as follows:

[0005]

[0006] The above synthetic route starts from 2-isopropoxy-1,5-dichloro-4-nitrobenzene as a raw material, and the target product is obtained through four steps of nitro reduction, diazotization, reduction of diazonium salt and acylation reaction. The production process of this route is limited by defects such as long steps, complex operation, high energy consumption, high safety risk and the like. In addition, in the method reported in the patent CN 117466769, the yield of aryl bromide as a substrate is low, the yield of aryl iodide as a substrate is improved, but the cost of iodide is generally too high, and the post-treatment method used is column chromatography, which is not suitable for industrial large-scale production. Therefore, how to optimize the above route into a green, cheap, safe and efficient production process with simple treatment is a key problem. SUMMARY

[0007] In view of the above problems, the application provides a preparation method of an organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide. Compared with the previous synthetic route, the route has many advantages such as cheap and easy-to-prepare raw materials, simple operation process, green and mild reaction conditions, simple post-treatment, safety and efficiency and the like.

[0008] The preparation method of the organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide provided by the application comprises the following steps:

[0009] Under the protection of nitrogen, aryl bromide and pivalohydrazide are used as reaction raw materials, a base, Cu2O, N 1 ,N 2- Bis(1-naphthyl)oxalamide, catalyst and water / alcohol solvent, the Ullmann coupling reaction occurs at elevated temperature to generate N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide. The reaction scheme is shown below:

[0010]

[0011] The specific steps include:

[0012] Under nitrogen protection, aryl bromide and pivalohydrazide are used as raw materials, a base, Cu2O, N 1 ,N 2 - Bis(1-naphthyl)oxalamide, catalyst and water / alcohol solvent, the reaction temperature is controlled at 50-120℃, and the reaction time is controlled at 4-24h. After the reaction is completed, it is cooled to room temperature, filtered, separated, concentrated, then diluted with ethyl acetate, washed with water, then concentrated, then heated with n-hexane to pulp, finally cooled to room temperature and filtered to obtain the product.

[0013] During the preparation process, the molar ratio of aryl bromide and pivalohydrazide is 1:(1.0-2.0).

[0014] During the preparation process, the molar ratio of aryl bromide, base, Cu2O, N 1 ,N 2 - The molar ratio of bis(1-naphthyl)oxalamide, catalyst is controlled at 1:(1.0-3.0):(0.005-0.2):(0.005-0.4):(0-0.30).

[0015] The concentration of aryl bromide in the reaction system is controlled at 0.2-2.0 mol / L.

[0016] The base is selected from one or more combinations of sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

[0017] The alcohol in the water / alcohol solvent is selected from one or more combinations of n-propanol, isopropanol, n-butanol, t-butanol, t-amyl alcohol, ethylene glycol, glycerol, and cyclohexanol, wherein the volume ratio of water to alcohol is controlled at 1:(0.1-9.0).

[0018] The catalyst is selected from one or more combinations of sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium chloride, and cetyltrimethylammonium bromide.

[0019] Compared with the reported prior art route, the water / alcohol type solvent used in the present application is more environmentally friendly, the reaction is safer and more efficient, the post-treatment is more simple, and it is more suitable for industrial large-scale production. DETAILED DESCRIPTION

[0020] The application will be further described in detail below with reference to examples, but the embodiments of the application are not limited thereto.

[0021] Example 1

[0022] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example are as follows:

[0023]

[0024] Under nitrogen protection, 0.2840 g (1 mmol) of 2,4-dichloro-1-bromo-5- isopropoxybenzene, 0.1394 g (1.2 mmol) of pivalohydrazide, 0.3184 g (1.5 mmol) of potassium phosphate, 0.0144 g (0.1 mmol) of cuprous oxide, 0.0681 g (0.2 mmol) of N 1 ,N 2 bis (1-naphthyl) oxalic amide, 0.0370 g (0.1 mmol) of TBAI, 1 mL of H2O were sequentially added into a 15 mL reaction tube, and after the addition was completed, it was placed in a 90°C water bath for stirring for 12 h. After the reaction was completed, 10 mL of ethyl acetate was added for extraction, and after concentration, 1,1,2,2-tetrachloroethane was added as an internal standard to calculate the yield by nuclear magnetic resonance, which was 61%.

[0025] 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 2.9 Hz, 1H), 7.26 (s, 1H), 6.42 (s, 1H), 6.31 (d, J = 3.3 Hz, 1H), 4.44-4.32 (m, 1H), 1.33 (d, J = 6.1 Hz, 6H), 1.27 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 178.27, 153.24, 143.79, 130.33, 116.14, 111.67, 101.97, 72.70, 38.35, 27.42, 22.06.

[0026] Example 2

[0027] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example are as follows:

[0028]

[0029] The experimental steps of this example are the same as those of Example 1, except that the potassium phosphate base is replaced by sodium hydroxide. The yield of this example is 44%.

[0030] Example 3

[0031] The synthesis of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0032]

[0033] The experimental procedure of this example is the same as that of Example 1, except that potassium phosphate is replaced by potassium hydroxide. The yield of this example is 50%.

[0034] From the comparison of the data of Examples 1-3, it is preferred that the base is potassium phosphate.

[0035] Example 4:

[0036] The synthesis of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0037]

[0038] Under nitrogen protection, 0.2840 g (1 mmol) of 2,4-dichloro-1-bromo-5- isopropoxybenzene, 0.1394 g (1.2 mmol) of pivalohydrazide, 0.3184 g (1.5 mmol) of potassium phosphate, 0.0014 g (0.01 mmol) of cuprous oxide, 0.0068 g (0.02 mmol) of N,N'-dimesityl-4-formylphenylhydroxylamine, 0.0370 g (0.1 mmol) of TBAI, 1 mL of H2O were sequentially added into a 15 mL reaction tube, and after the addition was completed, it was placed in a 100°C water bath for stirring for 16 h. After the reaction was completed, 10 mL of ethyl acetate was added for extraction, and after concentration, 1,1,2,2-tetrachloroethane was added as an internal standard for calculation of the yield by nuclear magnetic resonance, which was 64%. 1 ,N 2 - bis (1-naphthyl) oxalic acid amide, 0.0370 g (0.1 mmol) of TBAI, 1 mL of H2O, and after the addition was completed, it was placed in a 100°C water bath for stirring for 16 h. After the reaction was completed, 10 mL of ethyl acetate was added for extraction, and after concentration, 1,1,2,2-tetrachloroethane was added as an internal standard for calculation of the yield by nuclear magnetic resonance, which was 64%.

[0039] Example 5:

[0040] The synthesis of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0041]

[0042] The experimental procedure of this example is the same as that of Example 4, except that 1 mL of H2O is replaced by a mixed solvent of 0.9 mL of H2O and 0.1 mL of n-butanol. The yield of this example is 69%.

[0043] Example 6:

[0044] The synthesis of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0045]

[0046] The experimental procedure of this example is the same as that of Example 4, except that the solvent 1 mL H2O is replaced by a mixture of 0.9 mL H2O and 0.1 mL ethylene glycol. The yield of this example is 64%.

[0047] From the comparison of the data of Examples 4-6, the preferred solvent is a mixture of water / n-butanol.

[0048] Example 7:

[0049] The synthetic procedure of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0050]

[0051] The experimental procedure of this example is the same as that of Example 5, except that the solvent 0.9 mL H2O and 0.1 mL n-butanol is replaced by 0.4 mL H2O and 0.6 mL n-butanol. The yield of this example is 81%.

[0052] Example 8:

[0053] The synthetic procedure of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0054]

[0055] The experimental procedure of this example is the same as that of Example 5, except that the solvent 0.9 mL H2O and 0.1 mL n-butanol is replaced by 0.1 mL H2O and 0.9 mL n-butanol. The yield of this example is 32%.

[0056] From the comparison of the data of Examples 5, 7 and 8, the preferred volume ratio of water and alcohol is 4:6.

[0057] Example 9:

[0058] The synthetic procedure of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0059]

[0060] Into a 100 ml reaction flask, 2.8397 g (10 mmol) of 2,4-dichloro-1-bromo-5- isopropoxybenzene, 1.3939 g (12 mmol) of pivalohydrazide, 3.1841 g (15 mmol) of potassium phosphate, 0.0107 g (0.075 mmol) of cuprous oxide, 0.0511 g (0.15 mmol) of N,N'-dimethylglycine, 0.1000 g (0.75 mmol) of copper powder and 0.1000 g (0.75 mmol) of copper(I) oxide were sequentially added under nitrogen protection. 1 ,N 2- bis(1-naphthyl)oxamide, 0.1499 g (1 mmol) of NaI, 4 mL of H2O and 6 mL of n BuOH, after the addition was completed, it was stirred at 100°C for 24 h. After the reaction was completed, 30 mL of ethyl acetate was added for extraction, and after being concentrated, 1,1,2,2-tetrachloroethane was added as an internal standard to calculate the yield by NMR, which was 81%.

[0061] Example 10:

[0062] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example are as follows:

[0063]

[0064] The experimental steps of this example are the same as those of Example 9, except that the related catalyst NaI is replaced by TBAB. The yield of this example is 69%.

[0065] Example 11:

[0066] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example are as follows:

[0067]

[0068] The experimental steps of this example are the same as those of Example 9, except that the related catalyst NaI is replaced by TEBA. The yield of this example is 69%.

[0069] From the comparison of the results of Examples 9-11, the preferred related catalyst is NaI. Even in Example 7, TBAI can achieve a yield of 81%, but the post-treatment of NaI is more simple.

[0070] Example 12:

[0071] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl) pivalohydrazide in this example are as follows:

[0072]

[0073] The experimental steps of this example are the same as those of Example 9, except that the solvent n BuOH is replaced by i PrOH. The yield of this example is 84%.

[0074] From the comparison of the data of Examples 9 and 12, it is further preferred that the solvent be a mixed solvent of water and isopropanol.

[0075] Example 13:

[0076] This example is a hundred gram reaction, the synthesis of N'-(2,4-dichloro-5- isopropoxyphenyl) pivalohydrazide in this example is as follows:

[0077]

[0078] The feeding process of this example is exactly the same as example 12, only the amount of each material is enlarged 40 times. The post-treatment process is as follows: after the reaction, cool to room temperature, then go through the process of filtration, separation and concentration, then dilute with 200-600 mL ethyl acetate, wash the organic phase with 400 mL pure water, concentrate the solid, then add 200-600 mL n-hexane to heat and beat, finally cool to room temperature, filter the product and dry. 99.42 g product is obtained, the separation yield is 78%.

[0079] From the data of example 13, this condition still has a high separation yield in a hundred gram reaction, and the separation method is simple. This example further proves the feasibility of this method in large-scale production, and has the prospect of industrial production.

[0080] The above is only a general example of the present application, and does not limit the present application in any form. Any simple modification or equivalent change made to the above example according to the technical essence of the present application falls within the scope of protection of the present application.

Claims

1. A method for preparing the organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl)pentanoylhydrazine, characterized in that: Under nitrogen protection, 1 mmol of 2,4-dichloro-1-bromo-5-isopropoxybenzene, 1.2 mmol of pentanoyl hydrazine, 1.5 mmol of potassium phosphate, 0.01 mmol of cuprous oxide, and 0.02 mmol of N2 were added sequentially to the reaction tube. 1 N 2 A mixture of bis(1-naphthyl)oxalamide, 0.1 mmol TBAI, 0.4 mL H2O and 0.6 mL n-butanol was added and stirred at 100 °C for 16 h. After the reaction was completed, 10 mL ethyl acetate was added for extraction, and the product was concentrated to obtain the target product. The synthesis route is shown below: 。 2. A method for preparing the organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl)pentanoylhydrazine, characterized in that: Under nitrogen protection, 10 mmol of 2,4-dichloro-1-bromo-5-isopropoxybenzene, 12 mmol of pentanoyl hydrazine, 15 mmol of potassium phosphate, 0.075 mmol of cuprous oxide, and 0.15 mmol of N2 were added sequentially to the reaction flask. 1 N 2 -bis(1-naphthyl)oxalamide, 1 mmol NaI, 4 mL H2O and 6 mL n After adding BuOH, the mixture was stirred at 100 °C for 24 h. After the reaction was completed, 30 mL of ethyl acetate was added for extraction, and the product was concentrated to obtain the target product. The synthesis route is shown below: 。 3. A method for preparing the organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl)pentanoylhydrazine, characterized in that: Under nitrogen protection, 10 mmol of 2,4-dichloro-1-bromo-5-isopropoxybenzene, 12 mmol of pentanoyl hydrazine, 15 mmol of potassium phosphate, 0.075 mmol of cuprous oxide, and 0.15 mmol of N2 were added sequentially to the reaction flask. 1 N 2 -bis(1-naphthyl)oxalamide, 1 mmol NaI, 4 mL H2O and 6 mL i After adding PrOH, the mixture was stirred at 100 °C for 24 h. After the reaction was completed, 30 mL of ethyl acetate was added for extraction, and the product was concentrated to obtain the target product. The synthesis route is shown below: 。

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