Preparation method of organic intermediate N '-(2, 4-dichloro-5-isopropoxyphenyl) pivaloyl hydrazine

Abstract

The invention discloses a preparation method of an organic intermediate N '-(2, 4-dichloro-5-isopropoxyphenyl) pivaloyl hydrazide, and belongs to the technical field of organic synthesis. The invention provides N '-(2, 4-dichloro-5-isopropoxy phenyl) pivaloyl hydrazine which is generated by taking aryl bromide and pivaloyl hydrazine as reaction raw materials under the protection of nitrogen, adding alkali, Cu2O, N1, N2-bis (1-naphthyl) oxamide, a related catalyst and a water / alcohol solvent, heating, and carrying out Ullmann coupling reaction. The method has the advantages of cheap raw materials, easy preparation, simple operation process, green and mild reaction conditions, simple post-treatment, safety and high efficiency, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing an organic intermediate N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloyl hydrazide. This study was funded by the Anhui Provincial Major Science and Technology Project (2022e03020005). Background Art

[0002] N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide, molecular formula C 14 H 20 Cl2N2O2, molecular weight 319.23, CAS number: 51167-18-1, structural formula is as follows:

[0003]

[0004] This product is an important synthetic precursor of the herbicide oxadiazon. Currently, the existing synthetic routes of this product are as follows:

[0005]

[0006] The above-mentioned synthetic route starts with 2-isopropoxy-1,5-dichloro-4-nitrobenzene as raw material, and undergoes four steps of nitro reduction, diazotization, diazonium salt reduction, and acylation reaction to obtain the target product. The production process of this route is limited by defects such as lengthy steps, complex operation, high energy consumption, and high safety risks. In addition, in the method reported in the CN 117466769 patent, 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 method used for post-treatment is column chromatography, which is not suitable for large-scale industrial production. Therefore, how to optimize the above-mentioned route into a green, cheap, safe, efficient and easy-to-handle production process is a key and difficult problem. Summary of the invention

[0007] In view of the above problems, the present invention provides a method for preparing an organic intermediate N′-(2,4-dichloro-5-isopropoxyphenyl) pivaloyl hydrazide. Compared with the previous synthetic route, this route has many advantages such as cheap raw materials and easy preparation, simple operation process, green and mild reaction conditions, simple post-treatment, safety and high efficiency.

[0008] The method for preparing the organic intermediate N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide of the present invention comprises the following steps:

[0009] Under nitrogen protection, aryl bromide and pivaloyl hydrazide were used as the reaction raw materials, and alkali, Cu2O, N 1 ,N 2-bis(1-naphthyl)oxalamide, catalyst and water / alcohol solvent, heating to produce N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloyl hydrazide by Ullmann coupling reaction. The reaction route is as follows:

[0010]

[0011] The specific steps include:

[0012] Under nitrogen protection, aryl bromide and pivaloyl hydrazide were used as the reaction raw materials, and alkali, Cu2O, N 1 ,N 2 -bis(1-naphthyl)oxalamide, catalyst and water / alcohol solvent, the reaction temperature is controlled at 50-120°C, and the reaction time is controlled at 4-24h. After the reaction is completed, it is cooled to room temperature, filtered, separated, concentrated and diluted with ethyl acetate, the organic phase is washed with water and then concentrated, then n-hexane is added to heat and pulp, and finally cooled to room temperature and the product is filtered out.

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

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

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

[0016] The alkali 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, tert-butanol, tert-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 hexadecyltrimethylammonium bromide.

[0019] Compared with the reports of the prior art routes, the water / alcohol type solvent used in the present invention has greener and more environmentally friendly conditions, safer and more efficient reactions, simpler post-treatment, and is more suitable for industrial large-scale production. DETAILED DESCRIPTION

[0020] The present invention is further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

[0021] Embodiment 1:

[0022] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0023]

[0024] Under nitrogen protection, 0.2840 g (1 mmol) 2,4-dichloro-1-bromo-5-isopropoxybenzene, 0.1394 g (1.2 mmol) pivaloyl hydrazide, 0.3184 g (1.5 mmol) potassium phosphate, 0.0144 g (0.1 mmol) cuprous oxide, 0.0681 g (0.2 mmol) N 1 ,N 2 -bis(1-naphthyl)oxalamide, 0.0370 g (0.1 mmol) TBAI, 1 mL H2O, and stirred at 90°C for 12 h. After the reaction, 10 mL ethyl acetate was added for extraction, and after concentration, 1,1,2,2-tetrachloroethane was added as an internal standard to calculate the NMR yield, which was 61%.

[0025] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=2.9Hz,1H),7.26(s,1H),6.42(s,1H),6.31(d,J=3.3Hz,1H),4.44–4.32(m,1H),1.33(d,J=6.1Hz,6H),1.27(s,9H). 13 C NMR (101MHz, CDCl3) δ178.27,153.24,143.79,130.33,116.14,111.67,101.97,72.70,38.35,27.42,22.06.

[0026] Embodiment 2:

[0027] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0028]

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

[0030] Embodiment 3:

[0031] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0032]

[0033] The experimental steps of this example are the same as those 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 to 3, the preferred base is potassium phosphate.

[0035] Embodiment 4:

[0036] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0037]

[0038] Under nitrogen protection, 0.2840 g (1 mmol) 2,4-dichloro-1-bromo-5-isopropoxybenzene, 0.1394 g (1.2 mmol) pivaloyl hydrazide, 0.3184 g (1.5 mmol) potassium phosphate, 0.0014 g (0.01 mmol) cuprous oxide, 0.0068 g (0.02 mmol) N 1 ,N 2 -bis(1-naphthyl)oxalamide, 0.0370 g (0.1 mmol) TBAI, 1 mL H2O, and stirred at 100°C for 16 h. After the reaction, 10 mL ethyl acetate was added for extraction, and after concentration, 1,1,2,2-tetrachloroethane was added as an internal standard to calculate the NMR yield, which was 64%.

[0039] Embodiment 5:

[0040] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0041]

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

[0043] Embodiment 6:

[0044] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0045]

[0046] The experimental steps of this example are the same as those of Example 4, except that the solvent 1 mL of H2O is changed to a mixed solvent of 0.9 mL of H2O and 0.1 mL of ethylene glycol. The yield of this example is 64%.

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

[0048] Embodiment 7:

[0049] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0050]

[0051] The experimental steps of this example are the same as those of Example 5, except that the solvents 0.9 mL H2O and 0.1 mL n-butanol are changed to 0.4 mL H2O and 0.6 mL n-butanol. The yield of this example is 81%.

[0052] Embodiment 8:

[0053] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0054]

[0055] The experimental steps of this example are the same as those of Example 5, except that the solvents 0.9 mL H2O and 0.1 mL n-butanol are changed to 0.1 mL H2O and 0.9 mL n-butanol. The yield of this example is 32%.

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

[0057] Embodiment 9:

[0058] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0059]

[0060] Under nitrogen protection, 2.8397 g (10 mmol) 2,4-dichloro-1-bromo-5-isopropoxybenzene, 1.3939 g (12 mmol) pivaloyl hydrazide, 3.1841 g (15 mmol) potassium phosphate, 0.0107 g (0.075 mmol) cuprous oxide, 0.0511 g (0.15 mmol) N 1 ,N 2-bis(1-naphthyl)oxalamide, 0.1499 g (1 mmol) NaI, 4 mL H2O and 6 mL n After the addition of BuOH, the mixture was stirred at 100°C for 24 hours. After the reaction was completed, 30 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 NMR yield, which was 81%.

[0061] Embodiment 10:

[0062] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0063]

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

[0065] Embodiment 11:

[0066] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment are as follows:

[0067]

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

[0069] By comparing the results of Examples 9 to 11, the preferred catalyst is NaI. Even in Example 7, TBAI can achieve a yield of 81%, but the post-treatment of NaI is simpler.

[0070] Embodiment 12:

[0071] The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this embodiment 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 changed to i The yield of PrOH in this example is 84%.

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

[0075] Embodiment 13:

[0076] This example is a 100-gram reaction. The synthesis steps of N′-(2,4-dichloro-5-isopropoxyphenyl)pivaloylhydrazide in this example are as follows:

[0077]

[0078] The feeding process of this embodiment is exactly the same as that of Example 12, except that the amount of each material is proportionally enlarged 40 times. The post-processing process is as follows: after the above reaction is completed, it is cooled to room temperature, and successively undergoes filtering, liquid separation and concentration processes, and then diluted with 200-600mL ethyl acetate, and the organic phase is washed with 400mL pure water. The solid obtained after concentration is added with 200-600mL normal hexane and heated for pulping, and finally cooled to room temperature, the product is filtered out and dried. 99.42g of product is obtained, and the isolated yield is 78%.

[0079] From the data of Example 13, the conditions still have a high separation yield in a 100-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 description is only a general embodiment of the present invention and does not limit the present invention in any form. Any simple modification or equivalent change made to the above embodiment according to the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for preparing an organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl)pivaloyl hydrazide, characterized in that: Under nitrogen protection, aryl bromide and pivaloyl hydrazide were used as the reaction raw materials, and alkali, Cu2O, N 1 ,N 2 -bis(1-naphthyl)oxalamide, a catalyst and a water / alcohol solvent, heating to produce an Ullmann coupling reaction to generate N'-(2,4-dichloro-5-isopropoxyphenyl)pivaloyl hydrazide; The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that The steps include: Under nitrogen protection, aryl bromide and pivaloyl hydrazide were used as the reaction raw materials, and alkali, Cu2O, N 1 ,N 2 -bis(1-naphthyl)oxalamide, catalyst and water / alcohol solvent, the reaction temperature is controlled at 50-120°C, and the reaction time is controlled at 4-24h. After the reaction is completed, it is cooled to room temperature, filtered, separated, concentrated and diluted with ethyl acetate, the organic phase is washed with water and then concentrated, then n-hexane is added to heat and pulp, and finally cooled to room temperature and the product is filtered out.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the aryl bromide to pivaloyl hydrazide is 1:(1.0-2.0).

4. The preparation method according to claim 3, characterized in that: Aryl bromide, base, Cu2O, N 1 ,N 2 -The molar ratio of bis(1-naphthyl)oxalamide and catalyst is controlled to be 1:(1.0~3.0):(0.005~0.2):(0.005~0.4):(0~0.30).

5. The preparation method according to claim 3, characterized in that: The concentration of the aryl bromide in the reaction system is controlled at 0.2-2.0 mol / L.

6. The preparation method according to claim 2, characterized in that: The alkali is selected from one or more combinations of sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

7. The preparation method according to claim 2, characterized in that: The volume ratio of water to alcohol in the water / alcohol solvent is controlled at 1:(0.1-9.0).

8. The preparation method according to claim 7, characterized in that: The alcohol is selected from one or more combinations of n-propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, glycerol, and cyclohexanol.

9. The preparation method according to claim 2, characterized in that: The catalyst is selected from one or more combinations of sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium chloride, and hexadecyltrimethylammonium bromide.

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