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)pivalohydrazide. Under nitrogen protection, using an aryl halide and pivalohydrazide as reaction raw materials, adding an alkali, a copper catalyst, a ligand, sodium iodide and a solvent, heating to 50-150 °C, and controlling the reaction time within 4-24 h; after the reaction is completed, cooling to room temperature, filtering through silica gel and diatomaceous earth to remove solids, washing the filter cake with ethyl acetate, concentrating the obtained organic phase in vacuo, and separating and purifying by column chromatography to obtain the target product. This method has cheap and easily prepared raw materials, a simple operation process, mild conditions, simple post-treatment, safety and high efficiency, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention 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 Art

[0002] N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide, CAS No.: 51167-18-1, molecular formula C 14 H 20 Cl2N2O2, molecular weight 319.23, and the structure is as follows:

[0003]

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

[0005]

[0006] The existing synthetic route starts from 2,4-dichloro-5-nitroisopropoxybenzene, and the target product is obtained through four steps: nitro reduction, diazotization, diazonium salt reduction, and acylation reaction. This route of production process has disadvantages such as long steps, complex operation, high energy consumption, and high safety risks. Therefore, how to optimize its production process is a key and difficult problem. Summary of the Invention

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

[0008] The preparation method of the organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide of the present invention is to use aryl halide and pivalohydrazide as reaction raw materials under nitrogen protection, add a base, a copper catalyst, a ligand, sodium iodide and a solvent, and then heat up to carry out an Ullmann coupling reaction to prepare N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide. The reaction route is as follows:

[0009]

[0010] The specific preparation steps are as follows:

[0011] Under nitrogen protection, using aryl halide and pivaloyl hydrazide as reaction raw materials, adding a base, a copper catalyst, a ligand, sodium iodide and a solvent, heating to 50 - 150 °C, and controlling the reaction time to 4 - 24 h; after the reaction is completed, cooling to room temperature, filtering through silica gel and diatomaceous earth to remove solids, washing the filter cake with ethyl acetate, and separating and purifying the obtained organic phase by column chromatography (petroleum ether:ethyl acetate = 3:1, volume ratio).

[0012] Among them:

[0013] The molar ratio of aryl halide to pivaloyl hydrazide is 1:(1.0 - 5.0).

[0014] The molar ratio of aryl halide to the base, copper catalyst, ligand, and sodium iodide is controlled to be 1:(1.0 - 5.0):(0.01 - 0.40):(0.01 - 0.40):(0 - 0.30).

[0015] After adding the solvent to the system, the concentration of aryl halide is controlled to be 0.2 - 2.0 mol / L.

[0016] The base is selected from one or a combination of more of potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert - butoxide, and potassium tert - butoxide.

[0017] The copper catalyst is selected from one or a combination of more of cuprous oxide, cuprous iodide, cuprous bromide, and cuprous chloride.

[0018] The ligand is selected from one or a combination of more of N,N - dimethylglycine, L - proline, 8 - hydroxyquinoline, N,N′ - dimethylethylenediamine, trans - 1,2 - cyclohexanediamine, 1,10 - phenanthroline, acetylacetone, N 1 ,N 2 -bis(2 - thiophenemethyl)oxamide, N 1 ,N 2 -bis(1 - naphthylmethyl)oxamide, N 1 ,N 2 -bis(1 - naphthyl)oxamide, N 1 ,N 2 -bis(2 - pyridyl)oxamide, N 1 ,N 2 -bis(4 - (dimethylamino)naphthyl)oxamide, N 1 ,N 2 -bis(4 - (trifluoromethyl)phenyl)oxamide, N′ 1 ,N′ 2 -dibenzoyl oxalyl hydrazide in one or a combination of more.

[0019] The solvent is selected from one or a combination of isopropanol, tert-butanol, ethylene glycol, ethylene glycol methyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, toluene, dimethyl sulfoxide.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] 1. The synthetic route involved in the present invention is short, and N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide can be obtained in only one step, while the existing process route requires 4 steps to obtain the target product. The present invention not only reduces the complexity of process operation but also reduces the cost.

[0022] 2. The conditions of the present invention are mild, avoiding the three high-risk processes of hydrogenation, diazotization, and stannous chloride reduction in the prior art route, and reducing the cost of safe production.

[0023] 3. Compared with the prior art route, the present invention omits the stannous chloride reduction process. This step of stannous chloride reduction requires a special ceramic reaction kettle due to high temperature, high pressure, and strong acid conditions. This equipment is produced and assembled in India, and its mechanical seal and stirring are produced in Germany. However, since no domestic enterprise currently produces this equipment, this key process is also restricted by foreign countries. The new route proposed by the present invention avoids this step of process, thus well solving this problem.

[0024] 4. The synthetic route involved in the present invention is short. Compared with the prior art route, it not only improves the atom economy but also reduces the energy consumption. Specific Embodiments

[0025] The present invention will be further described in detail below with specific embodiments, but the implementation manners of the present invention are not limited thereto.

[0026] Example 1:

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

[0028]

[0029] Under nitrogen protection, 0.2840 g (1 mmol) of 2,4-dichloro-5-bromoisopropoxybenzene, 0.2324 g (2 mmol) of pivalohydrazide, 0.2074 g (1.5 mmol) of potassium carbonate, 0.0144 g (0.1 mmol) of cuprous oxide, and 0.0485 g (0.2 mmol) of N 1 ,N 2-Bis(2-pyridyl)oxamide (1 mmol) and 1 mL of dimethyl sulfoxide were added. After the addition was complete, the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the solid was removed by filtration through silica gel and diatomaceous earth, and the filter cake was washed with 40 mL of ethyl acetate. The solution was then removed by rotary evaporation and purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1, v / v), with a yield of 47%. 1 1H 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 13C 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.

[0030] Example 2:

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

[0032]

[0033] The experimental procedure of this example was the same as that of Example 1, except that the solvent dimethyl sulfoxide was changed to isopropanol. The yield of this example was 7%.

[0034] Example 3:

[0035] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0036]

[0037] The experimental procedure of this example was the same as that of Example 1, except that the solvent dimethyl sulfoxide was changed to tert-butanol. The yield of this example was 5%.

[0038] Example 4:

[0039] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0040]

[0041] The experimental procedure of this example was the same as that of Example 1, except that the solvent dimethyl sulfoxide was changed to N,N-dimethylformamide. The yield of this example was 37%.

[0042] Example 5:

[0043] In this example, the synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide are as follows:

[0044]

[0045] The experimental steps of this example are the same as those of Example 1, except that the solvent dimethyl sulfoxide is changed to N,N-dimethylacetamide. The yield of this example is 33%.

[0046] Example 6:

[0047] In this example, the synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide are as follows:

[0048]

[0049] The experimental steps of this example are the same as those of Example 1, except that the solvent dimethyl sulfoxide is changed to toluene. The yield of this example is 15%.

[0050] From the result comparison of Examples 1 to 6, dimethyl sulfoxide is more favorable for this reaction.

[0051] Example 7:

[0052] In this example, the synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide are as follows:

[0053]

[0054] The experimental steps of this example are the same as those of Example 1, except that the temperature of 80 °C is changed to 100 °C. The yield of this example is 52%.

[0055] From the result comparison of Example 1 and Example 7, 100 °C is more favorable for this reaction.

[0056] Example 8:

[0057] In this example, the synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide are as follows:

[0058]

[0059] The experimental steps of this example are the same as those of Example 7, except that the ligand is changed from N 1 ,N 2 -bis(2-pyridyl)oxamide to N 1 ,N 2 -bis(1-naphthylmethyl)oxamide. The yield of this example is 3%.

[0060] Example 9:

[0061] In this example, the synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide are as follows:

[0062]

[0063] The experimental steps of this example are the same as those of Example 7, except that the ligand is changed from N 1 ,N 2 -bis(2-pyridyl)oxamide to N 1 ,N 2 -bis(4-(dimethylamino)naphthyl)oxamide. The yield of this example is 14%.

[0064] Example 10:

[0065] In this example, the synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide are as follows:

[0066]

[0067] The experimental steps of this example are the same as those of Example 7, except that the ligand is changed from N 1 ,N 2 -bis(2-pyridyl)oxamide to N 1 ,N 2 -bis(1-naphthyl)oxamide. The yield of this example is 58%.

[0068] From the comparison of the results of Examples 7 to 10, N 1 ,N 2 -bis(1-naphthyl)oxamide as a ligand is more favorable for this reaction.

[0069] Example 11:

[0070] In this example, the synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide are as follows:

[0071]

[0072] Under nitrogen protection, 0.2840 g (1 mmol) of 2,4-dichloro-5-bromoisopropoxybenzene, 0.2324 g (2 mmol) of pivalohydrazide, 0.2074 g (1.5 mmol) of potassium carbonate, 0.0144 g (0.1 mmol) of copper(I) oxide, and 0.0485 g (0.2 mmol) of N 1 ,N 2-Bis(2-pyridyl)oxamide, 0.0150 g (0.1 mmol) of sodium iodide, 1 ml of dimethyl sulfoxide. After adding the materials, the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the solid was filtered off by padding with silica gel and diatomaceous earth, and the filter cake was washed with 40 ml of ethyl acetate. Then the solution was removed by a rotary evaporator, and then purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1, volume ratio), with a yield of 61%.

[0073] From the comparison of the results of Examples 10 - 11, the addition of sodium iodide is more beneficial to this reaction.

[0074] The above are all coupling reactions of bromoaromatic rings. The following is about the coupling reaction of iodoaromatic rings.

[0075] Example 12:

[0076] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0077]

[0078] Under nitrogen protection, 0.3320 g (1 mmol) of 2,4-dichloro-5-iodoisopropoxybenzene, 0.4647 g (4 mmol) of pivalohydrazide, 0.2123 g (1 mmol) of potassium phosphate, 0.0144 g (0.1 mmol) of cuprous oxide, 0.0653 g (0.2 mmol) of N' 1 ,N' 2 -Dibenzoyl oxalohydrazide, 1 ml of dimethyl sulfoxide were added to a 15 ml reaction tube in sequence. After adding the materials, the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the solid was filtered off by padding with silica gel and diatomaceous earth, and the filter cake was washed with 40 ml of ethyl acetate. Then the solution was removed by a rotary evaporator, and then purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1, volume ratio), with a yield of 56%.

[0079] Example 13:

[0080] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0081]

[0082] The experimental steps of this example are the same as those of Example 12, only changing the catalyst cuprous oxide to cuprous chloride. The yield of this example is 43%.

[0083] Example 14:

[0084] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0085]

[0086] The experimental procedure of this example is the same as that of Example 12, except that cuprous oxide as the catalyst is changed to cuprous bromide. The yield of this example is 41%.

[0087] Example 15:

[0088] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0089]

[0090] The experimental procedure of this example is the same as that of Example 12, except that cuprous oxide as the catalyst is changed to cuprous iodide. The yield of this example is 48%.

[0091] Example 16:

[0092] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0093]

[0094] The experimental procedure of this example is the same as that of Example 12, except that potassium phosphate is changed to sodium carbonate. The yield of this example is 55%.

[0095] Example 17:

[0096] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0097]

[0098] The experimental procedure of this example is the same as that of Example 12, except that potassium phosphate is changed to potassium carbonate. The yield of this example is 68%.

[0099] Example 18:

[0100] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0101]

[0102] The experimental procedure of this example is the same as that of Example 12, except that potassium phosphate is changed to cesium carbonate. The yield of this example is 49%.

[0103] Example 19:

[0104] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0105]

[0106] The experimental steps of this example are the same as those of Example 12, except that potassium phosphate is changed to sodium tert-butoxide. The yield of this example is 38%.

[0107] Example 20:

[0108] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0109]

[0110] The experimental steps of this example are the same as those of Example 12, except that potassium phosphate is changed to potassium tert-butoxide. The yield of this example is 17%.

[0111] From the result comparison of Example 12 and Examples 16 - 20, potassium carbonate as the base is more favorable for this reaction.

[0112] Example 21:

[0113] The synthesis steps of N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide in this example are as follows:

[0114]

[0115] The experimental steps of this example are the same as those of Example 17, except that the ligand is changed from N' 1 ,N' 2 -dibenzoyl oxalohydrazide to N 1 ,N 2 -bis(2-pyridyl)oxalamide. The yield of this example is 73%.

[0116] The above are only general examples of the present invention, and do not impose any formal restrictions on the present invention. Any simple modifications and equivalent changes made to the above examples based on the technical essence of the present invention all fall within the protection scope of the present invention.

Claims

1. A preparation method of organic intermediate N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide, characterized in that: Under nitrogen protection, using aryl halide and pivalohydrazide as reaction raw materials, adding a base, a copper catalyst, a ligand, sodium iodide and a solvent, heating to 50-150 °C for an Ullmann coupling reaction, and controlling the reaction time within 4-24 h; after the reaction is completed, cooling to room temperature, filtering through silica gel and diatomaceous earth to remove solids, washing the filter cake with ethyl acetate, concentrating the obtained organic phase in vacuo and separating and purifying by column chromatography to obtain the target product N'-(2,4-dichloro-5-isopropoxyphenyl)pivalohydrazide; The reaction route is as follows: The base is selected from one or more combinations of potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide; The copper catalyst is selected from one or more combinations of cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride; The ligand is selected from one or more combinations of N,N-dimethylglycine, L-proline, 8-hydroxyquinoline, N,N'-dimethylethylenediamine, trans-1,2-cyclohexanediamine, 1,10-phenanthroline, acetylacetone, N 1 ,N 2 -bis(2-thienylmethyl)oxamide, N 1 ,N 2 -bis(1-naphthylmethyl)oxamide, N 1 ,N 2 -bis(1-naphthyl)oxamide, N 1 ,N 2 -bis(2-pyridyl)oxamide, N 1 ,N 2 -bis(4-(dimethylamino)naphthyl)oxamide, N 1 ,N 2 -bis(4-(trifluoromethyl)phenyl)oxamide, N' 1 ,N' 2 -dibenzoyl oxalyl hydrazide.

2. The preparation method according to claim 1, characterized in that: The molar ratio of aryl halide to pivalohydrazide is 1:(1.0-5.0).

3. The preparation method according to claim 1, characterized in that: The molar ratio of aryl halide to base, copper catalyst, ligand, sodium iodide is controlled to be 1:(1.0-5.0):(0.01-0.40):(0.01-0.40):(0-0.30).

4. The preparation method according to claim 1, characterized in that: After adding the solvent to the system, controlling the concentration of aryl halide to be 0.2-2.0 mol / L.

5. The preparation method according to claim 1, characterized in that: The solvent is selected from one or more combinations of isopropanol, tert-butanol, ethylene glycol, ethylene glycol methyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, toluene, dimethyl sulfoxide.

6. The preparation method according to claim 1, characterized in that: When separating by column chromatography, the eluent is petroleum ether:ethyl acetate = 3:1, by volume.

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