阅读说明：本技术 一种苯唑草酮中间体的制备方法 (Preparation method of topramezone intermediate ) 是由 曲仁渝 纪雷 阎志超 张浩婷 顾怡 于 2021-09-23 设计创作，主要内容包括：本发明涉及一种苯唑草酮中间体的制备方法。为了解决现有苯唑草酮中间体3-(4,5二氢异噁唑-3-基)-2-甲基-4-甲砜基苯甲酸合成路线不可避免使用活泼金属试剂以及毒性较大的一氧化碳等原料,存在一定的生产安全风险,且对反应设备要求较高,同时存在反应效率不高、后处理繁琐、产物纯度不高、成本高、对环境不友好等问题,本申请将3-(3-溴代-2-甲基-6-甲砜基苯基)-4,5-二氢异噁唑和二氧化碳在相转移催化剂存在的条件下于极性溶剂中经电催化羧化反应得到3-(4,5二氢异噁唑-3-基)-2-甲基-4-甲砜基苯甲酸。本发明的制备方法效率高、成本低、对环境友好并且可实现循环生产,适合工业化生产。(The invention relates to a preparation method of a topramezone intermediate. In order to solve the problems that the existing synthetic route of the topramezone intermediate 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoic acid can not avoid the use of active metal reagents, carbon monoxide with high toxicity and other raw materials, has certain production safety risk and high requirement on reaction equipment, meanwhile, the method has the problems of low reaction efficiency, complex post-treatment, low product purity, high cost, environmental friendliness and the like, and 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole and carbon dioxide are subjected to electrocatalytic carboxylation reaction in a polar solvent in the presence of a phase transfer catalyst to obtain the 3- (4, 5-dihydroisoxazole-3-yl) -2-methyl-4-methylsulfonylbenzoic acid. The preparation method has high efficiency and low cost, is environment-friendly, can realize circular production, and is suitable for industrial production.)

1. The preparation method of the topramezone intermediate is characterized in that the topramezone intermediate is obtained by electrocatalytic carboxylation reaction of a compound 1 and carbon dioxide in a polar solvent in the presence of a phase transfer catalyst, wherein the structural formula of the compound 1 is shown in the specification：The structural formula of the topramezone intermediate is as follows:

2. the method according to claim 1, wherein the polar solvent is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, butanol, water, and acetonitrile.

3. The method according to claim 1, wherein the material of the positive electrode and the negative electrode for electrocatalysis is one or more of copper, silver, magnesium, nickel and titanium.

4. The preparation method of claim 1, wherein the electrocatalysis is carried out at a current density of 1-6 mA/cm²。

5. The method of claim 1, wherein the electrocatalysis is a galvanostatic electrolysis.

6. The preparation method according to claim 1, wherein the phase transfer catalyst is one or more of tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, 18 crown 6, chain polyethylene glycol dialkyl ether and cyclodextrin.

7. The preparation method according to claim 1, wherein the concentration of the compound 1 in the polar solvent is 0.05 to 1 mol/L;

and/or the concentration of the phase transfer catalyst in the polar solvent is 0.05-1 mol/L.

8. The method of claim 1, wherein the temperature of the electrocatalytic carboxylation reaction is-10 ℃ to 40 ℃.

9. The method according to claim 1, wherein the pressure of the carbon dioxide introduced into the polar solvent is 0.1MPa to 2 MPa.

10. The process according to claim 1, further comprising a post-treatment step of removing the polar solvent from the reacted solution, adding ethyl acetate, filtering and drying to obtain a solid, i.e., the topramezone intermediate.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a topramezone intermediate.

Background

Topramezone, the common name in english; the first herbicides of the benzyl pyrazolone class, developed by basf under the trade name bracter, belong to the class of inhibitors of p-hydroxyphenylpyruvate dioxygenase (HPPD) and have the following structure:

the topramezone is a post-emergence corn field herbicide, has the advantages of wide herbicide controlling spectrum, high activity, strong miscibility, environmental friendliness, safety to corn and afterreap crops and the like, and is suitable for various corns: the conventional corn, sweet corn, waxy corn, cracked corn and the like have excellent selectivity on the corn, can prevent and kill main gramineous weeds and broad-leaved weeds on corn crops in the world, and comprise chenopodium quinoa, acalypha australis, black nightshade, crab grass, green bristlegrass, eleusine indica, cyperus rotundus, purslane, redroot pigweed, barnyard grass, abutilon, xanthium and the like, and have remarkable advantages in herbicidal activity and herbicidal spectrum compared with other similar corn field herbicides (such as mesotrione, isoxaflutole, tembotrione and the like). More particularly, topramezone has good control effect on weeds resistant to glyphosate, triazines, acetolactate synthase inhibitors and acetyl coenzyme A carboxylase inhibitors. Due to its excellent herbicidal properties and range, new standards are defined for corn field weeding. In addition, topramezone compounded medicaments comprise terbuthylazine, nicosulfuron, atrazine, mesotrione, clodinafop-propargyl, florasulam and the like, and the compounded products are also paid much attention and are developed by a plurality of enterprises. With the expiration of the patent (patent number: CN98802797.6) of topramezone in China in 2018, 1 month and 8 days, the registration and the new process development become new places for competition of various large agro-chemical enterprises.

According to statistics, the sale amount of topramezone in 2018 and 2019 exceeds 1 billion dollars, but the global market value composite growth rate in recent 6 years is only 0.3%, and the composite growth rate is 124.53% in the same period, so that the global demand space of topramezone serving as an ultra-efficient herbicide is opened, but the price and supply shortage of expensive raw medicines become the greatest constraint of market growth and present the difficulty of short supply and short demand. At present, China has not realized the large-scale production of topramezone in one enterprise.

It is not difficult to find from literature reports that topramezone can be synthesized from two ways, namely, a method which is mainly characterized in that 2, 3-dimethyl nitrobenzene reported by basf corporation in patent CN1300284A is used as a raw material to prepare a 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole intermediate, and then the intermediate is subjected to one-step carbonyl insertion reaction with pyrazolone to construct a target molecule. In the current production, the topramezone is industrially produced mainly by using a transition metal palladium-catalyzed interposing carbonyl reaction method, the production of the topramezone is greatly limited by the defects of high cost, large usage amount, difficult recovery, incapability of using mechanically and the like of a palladium catalyst in the process, and the reaction yield can only be maintained at a medium level, so that the whole process cost of the topramezone is high due to the factors.

The second method is mainly characterized in that a 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonyl benzoic acid fragment is preferentially constructed, topramezone is prepared through esterification and rearrangement reaction, and compared with a transition metal catalytic reaction, the method for preparing topramezone through benzoic acid has the advantages that although the steps are prolonged, the reaction efficiency is greatly improved, and the cost is greatly reduced. In summary, the construction of benzoic acid fragments in the strategy is particularly critical, japanese caokada patent CN1278259A reports that 2, 3-dimethyl-4-methylsulfonylbenzoic acid methyl ester is used as a raw material, and a target molecule is prepared through bromination, carbonylation, oximation, cyclization, hydrolysis, chlorination, esterification and rearrangement reactions. Patent CN 110183392a reports that a carboxylic acid product is generated from a bromide 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole intermediate under the action of carbon dioxide, and then conventional esterification and rearrangement reactions are used to prepare topramezone, which has a high yield, but inevitably uses an active metal reagent, so that there is a certain production safety risk and the requirement on reaction equipment is high.

Therefore, the development of an efficient and mild synthesis process of the topramezone key intermediate 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoic acid becomes a research hotspot at present, so that the reduction of the synthesis difficulty and the process cost of topramezone is realized. Under the condition of huge market demand, the reduction of the process cost of topramezone certainly brings huge economic and social benefits.

Disclosure of Invention

The invention aims to provide a novel preparation method of topramezone key intermediate 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4 methylsulfonylbenzoic acid, which has the advantages of mild reaction conditions, high yield and low cost and is suitable for large-scale industrial production.

In order to achieve the purpose, the invention adopts the technical scheme that:

the invention provides a preparation method of a topramezone intermediate, which comprises the following steps of carrying out electrocatalysis and carboxylation on a compound 1 and carbon dioxide in a polar solvent in the presence of a phase transfer catalyst to obtain the topramezone intermediate, wherein the structural formula of the compound 1 is as follows:the structural formula of the topramezone intermediate is as follows:

the name of the compound 1 is 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole.

The name of compound 2 (the topramezone intermediate) is 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoic acid.

According to the invention, the polar solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, butanol, water and acetonitrile.

Preferably, the polar solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide and N, N-dimethylacetamide.

According to the invention, the materials of the anode and the cathode used for electrocatalysis are respectively one or more of copper, silver, magnesium, nickel and titanium.

Preferably, the material of the positive electrode is magnesium.

Preferably, the material of the negative electrode is copper, nickel or silver.

According to the invention, the current density adopted by the electrocatalysis is 1-6 mA/cm²。

Preferably, the current density adopted by the electrocatalysis is 2-5 mA/cm²。

Further preferably, the current density adopted by the electrocatalysis is 3-5 mA/cm²。

According to the invention, the electrocatalysis is a galvanostatic electrolysis.

According to the invention, the phase transfer catalyst is one or more of tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, 18 crown 6, chain polyethylene glycol dialkyl ether and cyclodextrin.

According to the invention, the concentration of the compound 1 in the polar solvent is 0.05-1 mol/L.

Preferably, the concentration of the compound 1 in the polar solvent is 0.08-1 mol/L.

Further preferably, the concentration of the compound 1 in the polar solvent is 0.08-0.8 mol/L.

Still more preferably, the concentration of the compound 1 in the polar solvent is 0.08-0.5 mol/L.

According to the invention, the concentration of the phase transfer catalyst in the polar solvent is 0.5-1 mol/L.

Preferably, the concentration of the phase transfer catalyst in the polar solvent is 0.08-1 mol/L.

Further preferably, the concentration of the phase transfer catalyst in the polar solvent is 0.08-0.8 mol/L.

Still further preferably, the concentration of the phase transfer catalyst in the polar solvent is 0.08-0.5 mol/L.

Preferably, the molar ratio of the compound 1 to the phase transfer catalyst is 0.8-1.2: 1.

According to the invention, the temperature of the electrocatalysis and carboxylation reaction is-10 ℃ to 40 ℃.

Preferably, the temperature of the electrocatalysis and carboxylation reaction is-10-30 DEG C

Further preferably, the temperature of the electrocatalytic and carboxylation reaction is-10 ℃ to 20 ℃.

Still further preferably, the temperature of the electrocatalytic and carboxylation reaction is-5 ℃ to 20 ℃.

Even more preferably, the temperature of the electrocatalytic and carboxylation reaction is between 0 ℃ and 20 ℃.

According to the invention, the pressure of the carbon dioxide introduced into the polar solvent is 0.1 MPa-2 MPa.

Specifically, the preparation method comprises the following specific steps: in an electrochemical electrolytic cell with metal positive and negative electrodes in a device, a compound 1 and a phase transfer catalyst are dissolved in a polar solvent, after the pressure and the electrolysis temperature of carbon dioxide gas flow are set, electrocatalysis and carboxylation are carried out on the compound 1 and carbon dioxide through constant current, when the peak area of a raw material compound 1 in electrolyte is less than 1% through HPLC detection, the reaction is stopped, and a carboxylic acid compound 2, namely a topramezone key intermediate 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoic acid, is obtained.

The reaction equation of the invention is as follows:

according to the invention, the preparation method further comprises a post-treatment method, wherein the post-treatment method comprises the steps of removing the polar solvent from the reacted solution, adding ethyl acetate, filtering and drying to obtain a gray solid, namely the topramezone intermediate.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

the preparation method of the invention does not need to use transition metal, active metal reagent, carbon monoxide with larger toxicity and other raw materials, utilizes the metal electrode which can be recycled and is easy to prepare, realizes the green synthesis of the topramezone key intermediate 3- (4, 5-dihydroisoxazole-3-yl) -2-methyl-4-methylsulfonylbenzoic acid, not only reduces the high-risk reaction risk and the process cost, but also avoids the generation of waste solid metal, is environment-friendly, can repeatedly use the reaction solvent, avoids the generation of waste liquid, more importantly, greatly improves the reaction efficiency of preparing the key intermediate 3- (4, 5-dihydroisoxazole-3-yl) -2-methyl-4-methylsulfonylbenzoic acid by utilizing the electrolytic catalysis carboxylation reaction, has simple post-treatment process, the product has high purity, and is beneficial to the subsequent synthesis and purification of topramezone. Therefore, the preparation method has high efficiency and low cost, is environment-friendly, can realize circular production, and is suitable for industrial production.

Detailed Description

All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations where mutually exclusive features or steps are expressly stated. The invention will now be further described with reference to specific examples, but the invention should not be limited to these examples, but may be substituted by other equivalent or similarly purposed alternative features unless specifically stated. Unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features. Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.

The method for preparing the topramezone key intermediate 3- (4, 5-dihydroisoxazole-3-yl) -2-methyl-4-methylsulfonylbenzoic acid disclosed in the prior art has the disadvantages that active metal reagents, carbon monoxide with high toxicity and other raw materials cannot be used in a synthesis route of the topramezone key intermediate 3- (4, 5-dihydroisoxazole-3-yl) -2-methyl-4-methylsulfonylbenzoic acid, certain production safety risk exists, the requirement on reaction equipment is high, and the problems of low reaction efficiency, complex post-treatment, low product purity, high cost, environmental friendliness and the like exist.

In view of the deficiencies in the prior art, the inventors of the present invention have made extensive studies and extensive practices to provide technical solutions of the present invention. The technical solution, its implementation and principles, etc. will be further explained as follows.

The embodiment of the invention provides an electrolytic method for preparing 3- (4, 5-dihydroisoxazole-3-yl) -2-methyl-4-methylsulfonylbenzoic acid. Putting 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole and a phase transfer catalyst in a polar solvent and a carbon dioxide atmosphere, putting a positive electrode and a negative electrode made of a metal material in the polar solvent, and successfully preparing the 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoic acid through an electrolytic catalytic carboxylation reaction under the conditions of a certain current density and temperature.

And removing the polar solvent from the reacted solution, adding ethyl acetate, filtering and drying to obtain a gray solid, namely the purified topramezone intermediate.

According to the invention, the carboxylation reaction of the electrolytic catalysis compound 1 and carbon dioxide is used, so that active metal reagents, carbon monoxide with high toxicity and other raw materials are avoided, the reaction is milder, the post-treatment is simplified, the operation is more convenient, the environment is friendly, and the cost is low.

Furthermore, the purity and yield of the 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoic acid are improved by optimizing reaction conditions, a proper phase transfer catalyst is selected, a proper current, a proper reaction temperature and the like are selected, the yield and purity can reach more than 93 percent in a short reaction time, and the production cost is greatly reduced.

The present invention will be further described with reference to the following examples. However, the present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not mentioned are conventional conditions in the industry. The technical features of the embodiments of the present invention may be combined with each other as long as they do not conflict with each other.

In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.

In the following examples, the preparation of compound 1 is referred to patent CN1300284A, and the rest of the raw materials or reagents and the like are commercially available.

Example 1

In an electrolytic cell equipped with positive and negative electrode rings, magnesium was fixed as the positive electrode, silver was fixed as the negative electrode, 31.8 g of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole (compound 1) and 36.9 g of tetrabutylammonium iodide were dissolved in 500 ml of N, N-dimethylformamide, carbon dioxide gas was slowly introduced at normal pressure, and constant current (3.5 mA/cm) was carried out at 10 ℃ with the temperature maintained (3.5 mA/cm)²) Electrolyzing for 3h, and monitoring the peak area of the compound 1 in the electrolytic cell by HPLC<1 percent, stopping the reaction, decompressing and drying the solvent in the electrolyte, recovering the solvent for later use, adding 200 ml of ethyl acetate into the solid residue, violently stirring, filtering to remove the organic solvent to obtain a crude product, and drying to obtain an off-white solid, namely the compound 2(27.8g, the content of 94.6 percent, the yield of 93 percent).

¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),8.08(d,J＝8.4,1H),7.82(d,J＝8.4,1H),4.48(t,J＝10.0,2H),3.36(t,J＝10.0,2H),3.30(s,3H),2.42(s,3H).

Example 2

In an electrolytic cell equipped with positive and negative electrode rings, magnesium was fixed as the positive electrode, copper was fixed as the negative electrode, 31.8 g of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole (compound 1) and 36.9 g of tetrabutylammonium iodide were dissolved in 1 liter of N, N-dimethylformamide, carbon dioxide gas was slowly introduced at normal pressure, and constant current (5 mA/cm) was carried out at 10 ℃ with the temperature maintained²) Electrolyzing for 15h, stopping reaction, decompressing and drying the solvent in the electrolyte, recovering the solvent for later use, adding 200 ml of ethyl acetate into the solid residue, violently stirring, filtering out the organic solvent to obtain a crude product, and drying to obtain an off-white solid, namely the compound 2(19.1g, the content of 93 percent, the yield of 63 percent).

Example 3

In being equipped with positive and negative electricityIn an electrolytic cell of a polar ring, fixed magnesium is used as a positive electrode, nickel is used as a negative electrode, 31.8 g of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole (compound 1) and 36.9 g of tetrabutylammonium iodide are dissolved in 1L of N, N-dimethylformamide, carbon dioxide gas is slowly introduced at normal pressure, and constant current (4 mA/cm) is carried out at the temperature of 0 DEG C²) Electrolyzing for 20h, stopping reaction, removing the solvent in the electrolyte under reduced pressure, recovering the solvent for later use, adding 200 ml of ethyl acetate into the solid residue, stirring vigorously, filtering out the organic solvent to obtain a crude product, and drying to obtain an off-white solid, namely the compound 2(16.4g, the content is 90%, and the yield is 52%).

Example 4

In an electrolytic cell equipped with positive and negative electrode rings, magnesium is fixed as a positive electrode, silver is fixed as a negative electrode, 31.8 g of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole (compound 1) and 36.9 g of tetrabutylammonium iodide are dissolved in 500 ml of dimethyl sulfoxide, carbon dioxide gas is slowly introduced at normal pressure, the temperature is kept at 0 ℃, and constant current (4 mA/cm) is carried out at 0 DEG C²) Electrolyzing for 5h, and monitoring the peak area of the compound 1 in the electrolytic cell by HPLC<1 percent, stopping the reaction, decompressing and drying the solvent in the electrolyte, recovering the solvent for later use, adding 200 ml of ethyl acetate into the solid residue, violently stirring, filtering out the organic solvent to obtain a crude product, and drying to obtain a gray solid, namely the compound 2(28g, the content of 93 percent, the yield of 92 percent).

Example 5

In an electrolytic cell equipped with positive and negative electrode rings, magnesium is fixed as a positive electrode, silver is fixed as a negative electrode, 31.8 g of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole (compound 1) and 32.2 g of tetrabutylammonium bromide are dissolved in 500 ml of dimethyl sulfoxide, carbon dioxide gas is slowly introduced at normal pressure, the temperature is kept at 20 ℃ and constant current (3.5 mA/cm)²) Electrolyzing for 10h, and monitoring the peak area of the compound 1 in the electrolytic cell by HPLC<1 percent, stopping the reaction, decompressing and drying the solvent in the electrolyte, recovering the solvent for later use, adding 200 ml of ethyl acetate into the solid residue, violently stirring, filtering out the organic solvent to obtain a crude product, and drying to obtain a gray solid, namely the compound 2(27.3g, the content of 91 percent, the yield of 88 percent).

Example 6

In an electrolytic cell equipped with positive and negative electrode rings, magnesium is fixed as a positive electrode, silver is fixed as a negative electrode, 31.8 g of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole (compound 1) and 26.4 g of 18 crown 6 are dissolved in 500 ml of N, N-dimethylformamide, carbon dioxide gas is slowly introduced at normal pressure, and constant current (5 mA/cm) is carried out at 10 ℃ while maintaining the temperature²) Electrolyzing for 24h, stopping reaction, drying the solvent in the electrolyte under reduced pressure, recovering the solvent for later use, adding 200 ml of ethyl acetate into the solid residue, stirring vigorously, filtering out the organic solvent to obtain a crude product, and drying to obtain a gray solid, namely the compound 2(18.3g, the content of 85 percent, the yield of 55 percent).

Example 7

In an electrolytic cell equipped with positive and negative electrode rings, magnesium was fixed as the positive electrode, silver was fixed as the negative electrode, 31.8 g of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4, 5-dihydroisoxazole (compound 1) and 36.9 g of tetrabutylammonium iodide were dissolved in 500 ml of N, N-dimethylacetamide, carbon dioxide gas was slowly introduced at normal pressure, and constant current (3.5 mA/cm) was carried out at 20 ℃ with the temperature maintained (3.5 mA/cm)²) Electrolyzing for 8h, and monitoring the peak area of the compound 1 in the electrolytic cell by HPLC<1 percent, stopping the reaction, decompressing and drying the solvent in the electrolyte, recovering the solvent for later use, adding 200 ml of ethyl acetate into the solid residue, violently stirring, filtering out the organic solvent to obtain a crude product, and drying to obtain a gray solid, namely the compound 2(27.8g, the content is 95 percent, and the yield is 93.3 percent).

The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.