Preparation method of pinoxaden

Abstract

The invention discloses a preparation method of pinoxaden, and belongs to the field of organic synthesis. The synthesis method comprises the following synthesis steps: (1) reacting dimethyl malonate with hydrazine hydrate under the action of alkali to generate pyrazolidine-3, 5-diketone; (2) carrying out cyclization on the pyrazolidine-3, 5-diketone and diethylene glycol dimethanesulfonate to generate dihydro-1H-pyrazolo [1, 2-d] [1, 4, 5] oxadiaze-7, 9 (2H, 8H)-diketone; (3) carrying out a coupling reaction on the dihydro-1H-pyrazolo [1, 2-d] [1, 4, 5] oxadiaze-7, 9 (2H, 8H)-diketone and 2, 6-diethyl-4-methyl bromobenzene, so as to obtain 8-(2, 6-diethyl-4-methyl phenyl)-tetrahydropyrazolo [1, 2-d] [1, 4, 5] oxadiaze-7, 9-diketone; and (4) carrying out a reaction on the 8-(2, 6-diethyl-4-methylphenyl)-tetrahydropyrazolo [1, 2-d] [1, 4, 5] oxadiaza-7, 9-diketone and pivaloyl chloride to generate the pinoxaden. The method disclosed by the invention is simple to operate, mild in reaction condition and suitable for industrial mass production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing pinoxaden. Background Art

[0002] Pinoxaden is a new type of phenylpyrazole herbicide developed by Syngenta Crop Protection Co., Ltd. in Switzerland. It is an acetyl-CoA carboxylase (ACC) inhibitor. Its mechanism of action is mainly to inhibit fatty acid synthesis, thereby hindering plant cell growth and division, destroying the lipid structure of the cell membrane, and ultimately leading to the death of weed plants. This variety has systemic conductivity and is mainly used as a post-emergence herbicide in cereal fields, suitable for grass weeds. It has a unique chemical structure and a different site of action from other acetyl-CoA carboxylase inhibitors, making it an important tool for controlling resistant weeds.

[0003] Literature research found that the traditional synthesis of pinoxaden mainly involves two key intermediates, namely intermediate 1: [1,4,5]-oxadiazaheptane dihydrobromide; intermediate 2: 2,6-diethyl-4-methylphenylmalonic acid derivative. Intermediate 1 and intermediate 2 react with triethylamine to generate intermediate 3, and intermediate 3 reacts with pivaloyl chloride under the action of 4-dimethylaminopyridine and triethylamine to obtain the target product pinoxaden. The traditional synthesis method has a long process, intermediate 1 adopts a protection / deprotection strategy, and the cost is high. The synthesis of intermediate 2 usually requires the use of highly toxic reagents, and there are problems of industrial waste. For example, patent WO9947525 reported that 2-(2,6-dibromo-4-methylphenyl)malonate diester was used as raw material, and pinoxadenine was obtained through metal-catalyzed coupling, metal-catalyzed hydrogenation reduction, amine transesterification cyclization and acylation reaction. The intermediate synthesis of this route requires the use of highly toxic tributyl vinyl stannane reagent, and there are many industrial wastes, which poses a safety hazard. The metal-catalyzed hydrogenation step has high requirements for equipment, so it is not suitable for industrial production.

[0004]

[0005] In addition, there are also reports that the intermediate dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9(2H, 8H)-dione is reacted with 2,6-diethyl-4-methylbromobenzene to generate intermediate three, and intermediate three is reacted with pivaloyl chloride under the action of triethylamine and 4-dimethylaminopyridine to obtain the target product pinoxaden. For example, patent CN108864144 reports a method for synthesizing pinoxaden using 2,6-diethyl-4-methylaniline and diethyl malonate as raw materials, sequentially through Sandmeyer reaction, metal-catalyzed coupling reaction, amine transesterification cyclization reaction and acylation reaction. The synthesis of the intermediate dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione in this method needs to be carried out at high temperature (180°C), which has high requirements on equipment, and the intermediate needs to be purified by column chromatography separation, which is not suitable for industrial production. Patent WO2019110613 also reported a similar method of synthesizing the intermediate dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione by condensation reaction of malonic acid derivatives and [1,4,5]-oxadiazaheptane, and then synthesizing pinoxadenine by metal-catalyzed coupling reaction and acylation reaction. This method also has the problem that the dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione intermediate is difficult to purify.

[0006] Summary of the invention

[0007] In view of the deficiencies of the prior art, the present invention provides a method for preparing pinoxaden. The method is simple to operate, the raw materials are cheap and readily available, the reaction conditions are mild, the equipment requirements are low, it is technically feasible, economically reasonable, and has a high cost-effectiveness, and is very suitable for industrial production.

[0008] The synthesis method of pinoxaden of the present invention comprises the following steps:

[0009] Step 1: using dimethyl malonate as a raw material, reacting with hydrazine hydrate under the action of a base to generate pyrazolidine-3,5-dione;

[0010] Step 2: Pyrazolidine-3,5-dione is cyclized with diethylene glycol dimethanesulfonate in the presence of triethylamine to generate dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9 (2H, 8H)-dione;

[0011] Step 3: Dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9 (2H, 8H)-dione and 2,6-diethyl-4-methylbromobenzene are subjected to coupling reaction in the presence of a catalyst and a base to obtain 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione;

[0012] Step 4: 8-(2,6-Diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione is reacted with pivaloyl chloride in the presence of 4-dimethylaminopyridine (DMAP) and a base to give pinoxaden.

[0013] The reaction route is as follows:

[0014]

[0015] Preferably, in step 1, the molar ratio of dimethyl malonate to base and hydrazine hydrate is 1:1.0-5.0:0.5-5.0. For example, 1:1.0:0.5, 1:1.5:1.0, 1:2.0:1.5, 1:2.5:2.0, 1:3.0:2.5, 1:3.5:3.0, 1:4.0:3.5, 1:4.5:4.0, 1:5.0:4.5 or 1:5.0:5.0.

[0016] Preferably, in step 1, the solvent is any one or a combination of at least two of commonly used alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, etc.

[0017] Preferably, the reaction in step 1 is carried out at an appropriate temperature, which is greater than or equal to room temperature and less than or equal to the boiling point of the reaction solvent, such as 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0018] Preferably, in step 1, the base is any one of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, or a combination of at least two thereof, and sodium methoxide and / or sodium ethoxide are further preferred.

[0019] Preferably, in step 2, the molar ratio of pyrazolidine-3,5-dione to triethylamine and diethylene glycol dimethanesulfonate is 1:0.5-5.0:0.5-5.0, for example 1:0.5:0.5, 1:1.5:1.5, 1:2.5:2.5, 1:3.5:3.5 or 1:5.0:5.0.

[0020] More preferably, the molar ratio of pyrazolidine-3,5-dione to triethylamine and diethylene glycol dimethanesulfonate is 1:1.0-1.5:1.0-5.0, for example 1:1.0:1.0, 1:1.1:1.5, 1:1.2:2.5, 1:1.3:3.0, 1:1.4:4.0 or 1:1.5:5.0.

[0021] More preferably, the molar ratio of pyrazolidine-3,5-dione to triethylamine and diethylene glycol dimethanesulfonate is 1:1.0-1.2:2.0-5.0, for example 1:1.0:2.0, 1:1.1:3.5 or 1:1.2:5.0.

[0022] Preferably, in step 2, the solvent is any one or a combination of at least two of commonly used aromatic solvents such as toluene, xylene or chlorobenzene.

[0023] Preferably, the reaction in step 2 is carried out at an appropriate temperature, which is greater than or equal to room temperature and less than or equal to the boiling point of the reaction solvent, such as 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0024] Preferably, in step 3, the molar ratio of dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9(2H, 8H)-dione to 2,6-diethyl-4-methylbromobenzene, the catalyst and the base is 1:1.0-1.5:0.01-0.05:1.0-5.0. For example, 1:1.0:0.01:1.0, 1:1.1:0.02:2.0, 1:1.2:0.03:3.0, 1:1.3:0.04:4.0, 1:1.4:0.05:5.0 or 1:1.5:0.05:5.0.

[0025] Preferably, in step 3, the solvent is any one of toluene, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or hexamethylphosphoric acid triamide, or a combination of at least two thereof.

[0026] Preferably, the reaction in step 3 is carried out at an appropriate temperature, which is greater than or equal to room temperature and less than or equal to the boiling point of the reaction solvent, such as 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0027] Preferably, in step 3, the catalyst is any one of a copper catalyst, a palladium catalyst, a palladium-copper alloy catalyst, a nickel catalyst, and a platinum catalyst, or a combination of at least two thereof, and a copper catalyst and / or a palladium catalyst are further preferred; the base is any one of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or sodium hydride, or a combination of at least two thereof, and sodium tert-butoxide and / or potassium tert-butoxide are further preferred.

[0028] Preferably, in step 4, the molar ratio of 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione to DMAP, base and pivaloyl chloride is 1: 0.01-0.1:0.5-2.0:1.0-1.5, for example 1:0.01:0.5:1.0, 1:0.02:0.8:1.1, 1:0.05:1.0:1.2, 1:0.07: 1.5:1.3, 1:0.09:1.8:1.4 or 1:0.1:2.0:1.5.

[0029] Preferably, in step 4, the solvent is any one of dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, and dioxane, or a combination of at least two thereof.

[0030] Preferably, the reaction in step 4 is carried out at an appropriate temperature, which is greater than or equal to 0°C and less than or equal to the boiling point of the reaction solvent, such as 0°C, 5°C, 10°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0031] Preferably, in step 4, the base is any one of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, or a combination of at least two thereof.

[0032] Further, each reaction step is specifically:

[0033] In step 1, the reaction conditions for generating pyrazolidine-3,5-dione by reacting dimethyl malonate with hydrazine hydrate under the action of a base are:

[0034] Dissolve dimethyl malonate in methanol or ethanol, add alkali at room temperature, slowly add hydrazine hydrate dropwise, raise the temperature of the system to reflux for reaction after the addition is complete, remove most of the solvent by distillation under reduced pressure, adjust the pH of the system to 2-3 with hydrochloric acid, precipitate a white solid, filter, and dry the solid to obtain the product, namely pyrazolidine-3,5-dione.

[0035] In step 2, pyrazolidine-3,5-dione is cyclized with diethylene glycol dimethanesulfonate under the action of triethylamine to generate dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9 (2H, 8H)-dione under the following reaction conditions:

[0036] Pyrazolidine-3,5-dione is dissolved in toluene, triethylamine and diethylene glycol dimethanesulfonate are added in sequence, the system is heated to reflux after the raw materials are added, and after the reaction is completed, the solvent is removed by distillation under reduced pressure, the pH of the system is adjusted to 11-12 with an aqueous sodium hydroxide solution, the aqueous phase is extracted with ethyl acetate, the aqueous phases are combined, and the pH of the aqueous phase is adjusted to 2-3 with hydrochloric acid, a white solid is precipitated, filtered, and the solid is dried to obtain the product, namely dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione.

[0037] In step 3, dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione and 2,6-diethyl-4-methylbromobenzene are subjected to a coupling reaction in the presence of a catalyst and a base to obtain 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiaza-7,9-dione, and the reaction conditions are:

[0038] Dissolve dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9 (2H, 8H)-dione in N,N-dimethylformamide, add 2,6-diethyl-4-methylbromobenzene, sodium tert-butoxide and palladium catalyst in sequence at room temperature, and heat the system to reflux under nitrogen protection. After the reaction is completed, cool the reaction solution to room temperature, filter out insoluble matter, adjust the pH of the filtrate to 2-3 with hydrochloric acid, and precipitate a white solid. Filter and dry the solid to obtain the product, i.e., 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione.

[0039] In step 4, 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione reacts with pivaloyl chloride in the presence of 4-dimethylaminopyridine and a base to produce pinoxaden under the following reaction conditions:

[0040] Dissolve 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione in tetrahydrofuran, add 4-dimethylaminopyridine and triethylamine at 0°C, slowly add pivaloyl chloride dropwise, and after the addition is complete, stir the system at room temperature. After the reaction is completed, distill under reduced pressure to remove most of the solvent, and a white solid precipitates. The solid is filtered and dried to obtain the product, namely pinoxaden.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] The method for synthesizing pinoxaden provided by the invention has simple reaction operation, mild reaction conditions, cheap and readily available raw materials, low requirements on equipment, and meets the needs of large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the NMR spectrum of dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione.

[0044] Figure 2 This is the NMR spectrum of 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione.

[0045] Figure 3 This is the NMR spectrum of pinoxaden. DETAILED DESCRIPTION

[0046] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0047] Example:

[0048] (1) Preparation of pyrazolidine-3,5-dione. The specific preparation method is as follows:

[0049]

[0050] Dissolve dimethyl malonate (10.00 g, 75.69 mmol, 1.0 eq) in 50 mL methanol, add sodium methoxide (12.27 g, 227.08 mmol, 3.0 eq) at room temperature, slowly drop hydrazine hydrate (18.95 g, 378.46 mmol, 5.0 eq), after the dropwise addition, heat the system to reflux (65 °C), and terminate the reaction when the reaction stops by TLC monitoring. Remove most of the solvent by vacuum distillation, adjust the pH of the system to 2-3 with hydrochloric acid, and a large amount of solid precipitates in the system. Filter by suction, dry the solid, and obtain a white solid product, pyrazolidine-3,5-dione (6.81 g, yield: 90%).

[0051] Dissolve dimethyl malonate (10.00 g, 75.69 mmol, 1.0 eq) in 50 mL of ethanol, add sodium methoxide (12.27 g, 227.08 mmol, 3.0 eq) at room temperature, slowly drop hydrazine hydrate (18.95 g, 378.46 mmol, 5.0 eq), after the dropwise addition, heat the system to reflux (78 °C), and terminate the reaction when the reaction is no longer progressing as monitored by TLC. Remove most of the solvent by vacuum distillation, adjust the pH of the system to 2-3 with hydrochloric acid, and a large amount of solid precipitates from the system. Filter by suction, and dry the solid to obtain a white solid product, pyrazolidine-3,5-dione (4.54 g, yield: 60%).

[0052] Dissolve dimethyl malonate (10.00 g, 75.69 mmol, 1.0 eq) in 50 mL methanol, add sodium ethoxide (15.45 g, 227.08 mmol, 3.0 eq) at room temperature, slowly drop hydrazine hydrate (18.95 g, 378.46 mmol, 5.0 eq), after the dropwise addition, heat the system to reflux (65 °C), and terminate the reaction when the reaction is no longer progressing as monitored by TLC. Remove most of the solvent by vacuum distillation, adjust the pH of the system to 2-3 with hydrochloric acid, and a large amount of solid precipitates from the system. Filter by suction, and dry the solid to obtain a white solid product, pyrazolidine-3,5-dione (5.07 g, yield: 67%).

[0053] Dissolve dimethyl malonate (10.00 g, 75.69 mmol, 1.0 eq) in 50 mL of ethanol, add sodium ethoxide (15.45 g, 227.08 mmol, 3.0 eq) at room temperature, slowly drop hydrazine hydrate (18.95 g, 378.46 mmol, 5.0 eq), after the dropwise addition, heat the system to reflux (65 °C), and terminate the reaction when the reaction stops by TLC monitoring. Remove most of the solvent by vacuum distillation, adjust the pH of the system to 2-3 with hydrochloric acid, and a large amount of solid precipitates in the system. Filter by suction, dry the solid, and obtain pyrazolidine-3,5-dione (5.45 g, yield: 72%) as a white solid product.

[0054] (2) Preparation of dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione, the specific preparation method is as follows:

[0055]

[0056] Dissolve oxazolidine-3,5-dione (6.06 g, 60.55 mmol, 1.0 eq) in 60 mL toluene, add triethylamine (18.38 g, 181.66 mmol, 3.0 eq) and diethylene glycol dimethanesulfonate (15.88 g, 60.55 mmol, 1.0 eq) at room temperature, and heat the system to 110 °C and reflux for 18 h. The reaction is terminated when the reaction no longer proceeds as monitored by TLC. The pH value of the system was adjusted to 11-12 with 1 M sodium hydroxide aqueous solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), the aqueous phases were combined, and the pH value of the aqueous phase was adjusted to 2-3 with 1 M hydrochloric acid. A white solid was precipitated, filtered, and the solid was dried to obtain the product, namely dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione (8.76 g, yield: 85%). 1 H NMR (400MHz, CDCl3) δ 4.11 ~ 3.92 (m, 4H), 3.91 ~ 3.75 (m, 4H), 3.25 (s, 2H).

[0057] Dissolve oxazolidine-3,5-dione (6.06 g, 60.55 mmol, 1.0 eq) in 60 mL toluene, add triethylamine (21.45 g, 211.94 mmol, 3.5 eq) and diethylene glycol dimethanesulfonate (15.88 g, 60.55 mmol, 1.0 eq) at room temperature, and heat the system to 110 °C and reflux for 18 h. The reaction is terminated when the reaction no longer proceeds as monitored by TLC. The pH value of the system was adjusted to 11-12 with 1 M sodium hydroxide aqueous solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), the aqueous phases were combined, and the pH value of the aqueous phase was adjusted to 2-3 with 1 M hydrochloric acid. A white solid was precipitated, filtered, and the solid was dried to obtain the product, namely dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione (8.24 g, yield: 80%). 1 H NMR (400MHz, CDCl3) δ 4.11 ~ 3.92 (m, 4H), 3.91 ~ 3.75 (m, 4H), 3.25 (s, 2H).

[0058] Dissolve oxazolidine-3,5-dione (6.06 g, 60.55 mmol, 1.0 eq) in 60 mL toluene, add triethylamine (30.64 g, 302.77 mmol, 5.0 eq) and diethylene glycol dimethanesulfonate (15.88 g, 60.55 mmol, 1.0 eq) at room temperature, and heat the system to 110 °C and reflux for 18 h. The reaction is terminated when the reaction no longer proceeds as monitored by TLC. The pH value of the system was adjusted to 11-12 with 1 M sodium hydroxide aqueous solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), the aqueous phases were combined, and the pH value of the aqueous phase was adjusted to 2-3 with 1 M hydrochloric acid. A white solid was precipitated, filtered, and the solid was dried to obtain the product, namely dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione (6.49 g, yield: 63%). 1 H NMR (400MHz, CDCl3) δ 4.11 ~ 3.92 (m, 4H), 3.91 ~ 3.75 (m, 4H), 3.25 (s, 2H).

[0059] (3) Preparation of 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiaza-7,9-dione, the specific preparation method is as follows:

[0060]

[0061] Dissolve dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione (8.76 g, 51.48 mmol, 1.0 eq) in 50 mL N,N-dimethylformamide, and add 2,6-diethyl-4-methylbromobenzene (17.54 g, 77.22 mmol, 1.5 eq), sodium tert-butoxide (17.32 g, 180.18 mmol, 3.5 eq) and bistriphenylphosphine palladium dichloride (364.99 mg, 0.52 mmol, 0.01 eq) in turn at room temperature. Under nitrogen protection, the system was heated to reflux (150 °C) for 3-5 min. h. After the reaction was completed, the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration, and the pH of the filtrate was adjusted to 2-3 with hydrochloric acid. A white solid precipitated, which was filtered and dried to obtain the product, namely 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (14.66 g, yield: 90%). 1 H NMR (400 MHz, CDCl3 ) δ 6.92 (d, J = 10.4 Hz, 2H), 4.70 (s, 1H), 4.36 ~ 4.20 (m, 2H), 4.18~ 3.84 (m, 4H), 3.83 ~ 3.66 (m, 2H), 2.69 (dd, J = 15.8, 7.9 Hz, 2H), 2.29(s, 3H), 2.28 ~ 2.21 (m, 2H), 1.25 (t, J = 7.7 Hz, 3H), 1.19 (t, J = 7.6 Hz, 3H).

[0062] Dissolve dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione (8.76 g, 51.48 mmol, 1.0 eq) in 50 mL N,N-dimethylformamide, and add 2,6-diethyl-4-methylbromobenzene (17.54 g, 77.22 mmol, 1.5 eq), sodium tert-butoxide (17.32 g, 180.18 mmol, 3.5 eq) and tetrakistriphenylphosphine palladium (600.89 mg, 0.52 mmol, 0.01 eq) in turn at room temperature. Under nitrogen protection, the system was heated to reflux (150 °C) for 3-5 min. h. After the reaction was completed, the reaction solution was cooled to room temperature and the insoluble matter was removed by filtration. The pH of the filtrate was adjusted to 2-3 with hydrochloric acid. A white solid precipitated and was filtered and dried to obtain the product, namely 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (13.36 g, yield: 82%). 1 H NMR (400 MHz, CDCl3 ) δ6.92 (d, J = 10.4 Hz, 2H), 4.70 (s, 1H), 4.36 ~ 4.20 (m, 2H), 4.18 ~ 3.84 (m,4H), 3.83 ~ 3.66 (m, 2H), 2.69 (dd, J = 15.8, 7.9 Hz, 2H), 2.29 (s, 3H), 2.28~ 2.21 (m, 2H), 1.25 (t, J = 7.7 Hz, 3H), 1.19 (t, J = 7.6 Hz, 3H).

[0063] Dissolve dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9 (2H, 8H)-dione (8.76 g, 51.48 mmol, 1.0 eq) in 50 mL N,N-dimethylformamide, and add 2,6-diethyl-4-methylbromobenzene (17.54 g, 77.22 mmol, 1.5 eq), potassium tert-butoxide (20.22 g, 180.18 mmol, 3.5 eq) and bistriphenylphosphine palladium dichloride (364.99 mg, 0.52 mmol, 0.01 eq) in turn at room temperature. Under nitrogen protection, the system was heated to reflux (150 °C) for 3-5 min. h. After the reaction was completed, the reaction solution was cooled to room temperature and the insoluble matter was removed by filtration. The pH of the filtrate was adjusted to 2-3 with hydrochloric acid. A white solid precipitated and was filtered and dried to obtain the product, namely 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (13.85 g, yield: 85%). 1 H NMR (400 MHz, CDCl3 ) δ 6.92 (d, J = 10.4 Hz, 2H), 4.70 (s, 1H), 4.36 ~ 4.20 (m, 2H), 4.18~ 3.84 (m, 4H), 3.83 ~ 3.66 (m, 2H), 2.69 (dd, J = 15.8, 7.9 Hz, 2H), 2.29(s, 3H), 2.28 ~ 2.21 (m, 2H), 1.25 (t, J = 7.7 Hz, 3H), 1.19 (t, J = 7.6 Hz, 3H).

[0064] (4) Preparation of pinoxaden, the specific preparation method is as follows:

[0065]

[0066] 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (14.66 g, 46.33 mmol, 1.0 eq) was dissolved in 50 mL tetrahydrofuran, 4-dimethylaminopyridine (339.63 mg, 2.78 mmol, 0.06 eq) and triethylamine (9.38 g, 92.67 mmol, 2.0 eq) were added at 0 °C, and pivaloyl chloride (7.26 g, 60.23 mmol, 1.3 eq) was slowly added dropwise. After the addition was completed, the system was stirred at room temperature. After the reaction was completed, most of the solvent was distilled off under reduced pressure, and a white solid precipitated. The solid was filtered and dried to obtain the product, which was pinoxaden (17.63 g, yield: 95%). 1 H NMR (400 MHz, CDCl3) δ 6.87 (s, 2H), 4.33 ~ 4.21 (m, 2H), 4.01 ~ 3.90 (m, 2H), 3.90 ~ 3.75 (m, 4H), 2.71 ~ 2.34 (m, 4H), 2.28 (s, 3H), 1.11 (t, J = 7.6 Hz, 6H), 1.02 (s, 9H).

[0067] 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (14.66 g, 46.33 mmol, 1.0 eq) was dissolved in 50 mL of dichloromethane, 4-dimethylaminopyridine (339.63 mg, 2.78 mmol, 0.06 eq) and triethylamine (9.38 g, 92.67 mmol, 2.0 eq) were added at 0 °C, and pivaloyl chloride (7.26 g, 60.23 mmol, 1.3 eq) was slowly added dropwise. After the addition was completed, the system was stirred at room temperature. After the reaction was completed, most of the solvent was distilled off under reduced pressure, and a white solid precipitated. The solid was filtered and dried to obtain the product, which was pinoxaden (15.78 g, yield: 85%). 1 H NMR (400 MHz, CDCl3) δ 6.87 (s, 2H), 4.33 ~ 4.21 (m, 2H), 4.01 ~ 3.90 (m, 2H), 3.90 ~ 3.75 (m, 4H), 2.71 ~ 2.34 (m, 4H), 2.28 (s, 3H), 1.11 (t, J = 7.6 Hz, 6H), 1.02 (s, 9H).

[0068] 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiaza-7,9-dione (14.66 g, 46.33 mmol, 1.0 eq) was dissolved in 50 mL of acetonitrile, 4-dimethylaminopyridine (339.63 mg, 2.78 mmol, 0.06 eq) and triethylamine (9.38 g, 92.67 mmol, 2.0 eq) were added at 0 °C, and pivaloyl chloride (7.26 g, 60.23 mmol, 1.3 eq) was slowly added dropwise. After the addition was completed, the system was stirred at room temperature. After the reaction was completed, most of the solvent was distilled off under reduced pressure, and a white solid precipitated. The solid was filtered and dried to obtain the product, which was pinoxaden (14.29 g, yield: 77%). 1 H NMR (400 MHz, CDCl3) δ 6.87 (s, 2H), 4.33 ~ 4.21 (m, 2H), 4.01 ~ 3.90 (m, 2H), 3.90 ~ 3.75 (m, 4H), 2.71 ~ 2.34 (m, 4H), 2.28 (s, 3H), 1.11 (t, J = 7.6 Hz, 6H), 1.02 (s, 9H).

[0069] The present invention illustrates the synthesis method of pinoxaden of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing pinoxaden, characterized in that The steps include: Step 1: using dimethyl malonate as a raw material, reacting with hydrazine hydrate under the action of a base to generate pyrazolidine-3,5-dione; Step 2: Pyrazolidine-3,5-dione is cyclized with diethylene glycol dimethanesulfonate in the presence of triethylamine to generate dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9 (2H, 8H)-dione; Step 3: Dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9 (2H, 8H)-dione and 2,6-diethyl-4-methylbromobenzene are subjected to coupling reaction in the presence of a catalyst and a base to obtain 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione; Step 4: 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione reacts with pivaloyl chloride in the presence of 4-dimethylaminopyridine and a base to generate pinoxaden; The reaction route is as follows: 。 2. The preparation method according to claim 1, characterized in that: In step 1, the molar ratio of dimethyl malonate to base and hydrazine hydrate is 1:1.0-5.0:0.5-5.

0.

3. The preparation method according to claim 1, characterized in that: In step 1, the base is any one of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, or a combination of at least two thereof.

4. The preparation method according to claim 1, characterized in that: In step 2, the molar ratio of pyrazolidine-3,5-dione to triethylamine and diethylene glycol dimethanesulfonate is 1:0.5-5.0:0.5-5.

0.

5. The preparation method according to claim 1, characterized in that: In step 3, the molar ratio of dihydro-1H-pyrazolo[1,2-d][1,4,5]oxadiaza-7,9(2H, 8H)-dione to 2,6-diethyl-4-methylbromobenzene, the catalyst and the base is 1:1.0-1.5:0.01-0.05:1.0-5.

0.

6. The preparation method according to claim 1, characterized in that: In step 3, the catalyst is any one of a copper catalyst, a palladium catalyst, a palladium-copper alloy catalyst, a nickel catalyst, and a platinum catalyst, or a combination of at least two thereof; the base is any one of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or sodium hydride, or a combination of at least two thereof.

7. The preparation method according to claim 1, characterized in that: In step 4, the molar ratio of 8-(2,6-diethyl-4-methylphenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione to DMAP, base and pivaloyl chloride is 1: 0.01-0.1: 0.5-2.0: 1.0-1.

5.

8. The preparation method according to claim 1, characterized in that: In step 4, the base is any one of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, or a combination of at least two thereof.

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