WO2023015629A1 - Method for preparing phloroglucinol from 2,4,6-triaminotoluene - Google Patents

Abstract

Provided is a method for preparing phloroglucinol from 2,4,6-triaminotoluene. The method comprises: using 2,4,6-triaminotoluene and a hydrochloride thereof as raw materials to carry out hydrolysis-isomerization reaction of trienamine to obtain 2,4,6-trihydroxytoluene; and then carrying out oxidative demethylation reaction on 2,4,6-trihydroxytoluene to obtain a target product phloroglucinol. In the method, a cheap and readily-available acid is used as a reagent in the conversion from 2,4,6-triaminotoluene and the hydrochloride thereof to 2,4,6-trihydroxytoluene, hydrolysis-isomerization of trienamine is achieved at 77-90%, and demethylation reaction of 2,4,6-trihydroxytoluene is achieved at a yield of 71-97% to obtain the target product phloroglucinol. In summary, the method innovates a synthetic route of phloroglucinol in a simple, efficient, safe and mild path, and lays a solid foundation for achieving low-cost and large-scale preparation of phloroglucinol.

Description

A method for preparing phloroglucinol by 2,4,6-triaminotoluene

This application claims the priority of the Chinese patent application submitted to the China Patent Office on August 13, 2021, with the application number 2021109324595 and the title of the invention "A method for preparing phloroglucinol from 2,4,6-triaminotoluene". rights, the entire contents of which are incorporated in this application by reference.

technical field

The invention relates to the fields of chemical industry and materials, and mainly relates to a method for preparing phloroglucinol from 2,4,6-triaminotoluene.

Background technique

Phloroglucinol (Phloroglucinol, trade name: Spafon) is an important antispasmodic drug, which is widely used in the treatment of diseases caused by smooth muscle spasm. At the same time, as a chemical raw material and synthetic intermediate, it plays an important role in fields such as medicine, organic porous materials, and insensitive explosives. Especially in the field of medicine, phloroglucinol and its derivatives (such as flavonoids) have the potential to be used in the development of various pharmaceutical products, such as anti-AIDS drugs and anti-tumor drugs. Due to the C3 symmetrical trihydroxyl functionality of phloroglucinol, it can be derivatized to prepare a large number of compounds and advanced materials with application value. However, although phloroglucinol is widely distributed in nature, and phloroglucinol and its derivatives can be found in plants, microorganisms, etc., it is not easy to directly isolate phloroglucinol from these natural resources. Therefore, it is of great value for the artificial synthesis of phloroglucinol and the application research in advanced materials.

At present, phloroglucinol is mainly prepared by oxidation of 1,3,5-triisopropylbenzene, hydrolysis of 1,3,5-trihalobenzene, and biosynthesis. However, there are certain problems in these synthetic approaches, which make the production cost of phloroglucinol remain high, and it is urgent to develop low-cost synthetic methods. Therefore, for the synthesis of phloroglucinol, a simple, efficient, safe, mild and low-cost synthetic method is urgently needed in this area.

Contents of the invention

In order to solve the above problems, the present invention provides a method for preparing phloroglucinol from 2,4,6-triaminotoluene, so as to achieve the purpose of simple, efficient, safe and low-cost synthesis of phloroglucinol. The specific content is as follows:

Step 1: Using 2,4,6-triaminotoluene represented by structural formula III and its hydrochloride as raw materials, carry out the hydrolysis-isomerization reaction of enamine in an acidic system to obtain 2,4-triaminotoluene represented by structural formula II ,6-trihydroxytoluene;

Step 2: Using 2,4,6-trihydroxytoluene shown in structural formula II as a raw material, carry out oxidative demethylation reaction to prepare the target product phloroglucinol shown in structural formula I;

Optionally, in the step 1, the acid selected in the acidic system includes at least one of sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid.

Optionally, when the acidic system is an acidic system composed of sulfuric acid and ammonium chloride solution, the sulfuric acid is dilute sulfuric acid diluted to 5% to 60% by mass fraction, and the sulfuric acid and the 2,4,6 - The mass ratio of triaminotoluene and its hydrochloride is 20:1 to 4:1, and the mass ratio of the ammonium chloride to the 2,4,6-triaminotoluene and its hydrochloride is 1:5 to 1 : 10, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 90～120 ℃, the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, the hydrolysis-isomerization reaction of the enamine The reaction time of the reaction is 2 to 12 hours;

When the acidic system is an acidic system composed of a phosphoric acid solution, the phosphoric acid solution is a phosphoric acid solution diluted to 5-60% mass fraction, and the phosphoric acid solution and the 2,4,6-triaminotoluene and its salts The mass ratio of acid salt is 20:1-4:1, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 60-180°C, the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, The reaction time of the hydrolysis-isomerization reaction of the enamine is 24～72h;

When the acidic system is an acidic system composed of methanesulfonic acid and ammonium chloride solution, the methanesulfonic acid is methanesulfonic acid diluted to 5% to 60% by mass fraction, and the methanesulfonic acid and the 2, The mass ratio of 4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1, and the mass ratio of the ammonium chloride to the 2,4,6-triaminotoluene and its hydrochloride is 1: 5～1:10, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 60～180°C, the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, the hydrolysis-isomerization reaction of the enamine- The reaction time of isomerization reaction is 4～14h;

When the acidic system is an acidic system composed of p-toluenesulfonic acid and ammonium chloride solution, the p-toluenesulfonic acid is p-toluenesulfonic acid diluted to 5% to 60% mass fraction, and the p-toluenesulfonic acid and The mass ratio of the 2,4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1, and the mass ratio of the ammonium chloride to the 2,4,6-triaminotoluene and its hydrochloride is The ratio is 1:5-1:10, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 60-180° C., the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, and the enamine The reaction time of the hydrolysis-isomerization reaction of the amine is 2-12 hours.

Optionally, in the step 2, the oxidative demethylation reaction includes:

Under the action of an oxidizing agent, the CH oxidation reaction is first carried out to obtain an oxidation reaction system containing 2,4,6-trihydroxybenzoic acid shown in structural formula IV;

Then, the oxidation reaction system is heated to 60-180° C. to carry out in-situ decarboxylation reaction for 2-6 hours, and the target product phloroglucinol shown in structural formula I is prepared.

Optionally, in the step 2, the oxidizing agent is any one of potassium permanganate, lead dioxide, and potassium dichromate. Optionally, when the oxidizing agent is potassium permanganate, the oxidation system of the CH oxidation reaction is an oxidation system of potassium permanganate and magnesium sulfate aqueous solution;

Wherein, the mass ratio of the potassium permanganate to the 2,4,6-trihydroxytoluene is 2:1～10:1; the mass ratio of the magnesium sulfate to the 2,4,6-trihydroxytoluene The ratio is 1:2-2:1; the reaction temperature of the oxidation reaction is 60-100° C., the reaction time of the oxidation reaction is 1-4 hours, and the reaction solvent of the oxidation reaction is water.

Optionally, when the oxidizing agent is lead dioxide, the oxidation system of the CH oxidation reaction is an aqueous system of lead dioxide and potassium hydroxide;

Wherein, the mass ratio of the lead dioxide to the 2,4,6-trihydroxytoluene is 4:1 to 8:1; the mass ratio of the potassium hydroxide to the 2,4,6-trihydroxytoluene The ratio is 4:1～6:1; the reaction temperature of the oxidation reaction is 90～150°C, the reaction pressure of the oxidation reaction is 0.4～1.2MPa, the reaction time of the oxidation reaction is 0.5～3h, the The reaction solvent for the oxidation reaction is water.

Optionally, when the oxidizing agent is potassium dichromate, an in-situ oxidation reaction is carried out in the reaction system obtained after the completion of the hydrolysis-isomerization reaction through an electrochemical electrode reaction, and the oxidation reaction of the CH oxidation reaction The system is an oxidant system composed of potassium dichromate and dilute sulfuric acid solution;

Wherein, the mass ratio of the potassium dichromate to the 2,4,6-trihydroxytoluene is 3:1-10:1; the dilute sulfuric acid solution is a sulfuric acid solution diluted to 5-60% mass fraction, The mass ratio of the dilute sulfuric acid solution to the 2,4,6-trihydroxytoluene is 20:1-5:1; the reaction temperature of the oxidation reaction is 30-100°C, and the reaction time of the oxidation reaction is 1-8h, the reaction solvent of the oxidation reaction is water.

Optionally, after the in-situ decarboxylation reaction, the method further includes: performing a second post-treatment on the decarboxylation reaction system obtained after the in-situ decarboxylation reaction, to obtain the target product phloroglucinol shown in structural formula I;

Wherein, when the oxidizing agent is potassium permanganate, the second post-treatment is: adjusting the decarboxylation reaction system to alkaline, then filtering, acidifying the filtrate, concentrating the acidified filtrate and re- Crystallization; wherein, the acid used in the acidification is concentrated hydrochloric acid, the volume ratio of the concentrated hydrochloric acid to the filtrate is 1:20 to 1:5, and the temperature of the frozen crystallization is -1 to 4°C;

When the oxidizing agent is lead dioxide, the second post-treatment method is: carry out vacuum filtration to the decarboxylation reaction system, then pass through deleading filtration, acidify the filtrate after deleading, concentrate and acidify the filtrate The concentrated solution is recrystallized; wherein, the acid used in the acidification is concentrated hydrochloric acid, the volume ratio of the concentrated hydrochloric acid to the filtrate is 1:20 to 1:5, and the temperature of the frozen crystallization is -1 to 4°C;

When the oxidizing agent is potassium coincidence acid, the second post-processing method is: filter the reaction stock solution after the oxidation reaction under reduced pressure, wash the filter residue with deionized water, collect the filtrate and concentrate, and then re-concentrate the concentrated solution. crystallization.

Optionally, the recrystallization of the concentrated solution includes: freezing and crystallizing the concentrated solution; or extracting the concentrated solution with ethyl acetate, concentrating the extract and then performing recrystallization.

The invention provides a method for preparing phloroglucinol from 2,4,6-triaminotoluene. The method comprises: using 2,4,6-triaminotoluene and its hydrochloride as raw materials to obtain 2,4,6-trihydroxytoluene through enamine hydrolysis-isomerization reaction; Trihydroxytoluene is used as a raw material, and the target product phloroglucinol is obtained by oxidative demethylation reaction under the action of an oxidizing agent (that is, the intermediate 2,4,6-trihydroxybenzoic acid is obtained through the CH oxidation of benzyl, and the intermediate is directly 2,4,6-trihydroxybenzoic acid was decarboxylated in situ to obtain the target product phloroglucinol). Compared with the prior art, the present invention at least also includes the following advantages:

1. The synthetic route provided by the present invention uses 2,4,6-triaminotoluene and its hydrochloride as raw materials, and introduces hydroxyl functional groups through the hydrolysis-isomerization reaction of trienylamines. On the one hand, it can accurately replace the target site , to reduce the formation of by-products under high temperature conditions, on the other hand, it can enhance the oxidation resistance of raw materials, and it is easier to improve the stability of product intermediates in the production process.

2. The present invention successfully prepares phloroglucinol by oxidative demethylation reaction. Firstly, the benzyl group is subjected to CH oxidation with a selective oxidation reagent, and the obtained oxidized product is decarboxylated in situ to directly obtain the target product. The synthesis process of the oxidative demethylation reaction has the advantages of simple operation and low cost, and is conducive to promoting large-scale preparation.

3. All the routes of the present invention are safe and controllable, and the intermediates are all non-explosive compounds, which is conducive to improving the safety of the synthesis process.

4. In the synthesis method provided by the present invention, there are few by-products produced in the reaction process, and the solvent catalyst can be recycled, which reduces environmental pollution and waste of resources.

In summary, the method provided by the invention uses 2,4,6-triaminotoluene and its hydrochloride as starting materials to prepare 2,4,6-trihydroxytoluene, and then passes 2,4,6-trihydroxytoluene The target product phloroglucinol was prepared by the demethylation reaction of toluene, which realized a simple, efficient, safe and mild synthetic route, and laid a solid foundation for the large-scale preparation of phloroglucinol.

Description of drawings

Fig. 1 shows the method flowchart of a kind of phloroglucinol synthetic method of the embodiment of the present invention;

Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the 2,4,6-trihydroxytoluene prepared in the embodiment 1 of the present invention;

Fig. 3 is the carbon nuclear magnetic resonance spectrogram of 2,4,6-trihydroxytoluene prepared in Example 1 of the present invention;

Fig. 4 is the infrared spectrogram of 2,4,6-trihydroxytoluene prepared in Example 1 of the present invention;

Fig. 5 is the high-resolution mass spectrum of 2,4,6-trihydroxytoluene prepared in Example 1 of the present invention;

Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of the 2,4,6-trihydroxybenzoic acid prepared in Example 1 of the present invention;

Fig. 7 is the carbon nuclear magnetic resonance spectrogram of 2,4,6-trihydroxybenzoic acid prepared in Example 1 of the present invention;

Figure 8 is an infrared spectrogram of 2,4,6-trihydroxybenzoic acid prepared in Example 1 of the present invention;

Fig. 9 is the high-resolution mass spectrum of 2,4,6-trihydroxybenzoic acid prepared in Example 1 of the present invention;

Fig. 10 is the proton nuclear magnetic resonance spectrogram of the phloroglucinol prepared in Example 1 of the present invention;

Fig. 11 is the carbon nuclear magnetic resonance spectrogram of the phloroglucinol prepared in Example 1 of the present invention;

Fig. 12 is the infrared spectrogram of the phloroglucinol prepared in Example 1 of the present invention;

Fig. 13 is a high-resolution mass spectrum of phloroglucinol prepared in Example 1 of the present invention.

Detailed ways

The following examples are provided in order to further understand the present invention better, are not limited to the best implementation mode, and do not limit the content and protection scope of the present invention, anyone under the inspiration of the present invention or use the present invention Any product identical or similar to the present invention obtained by combining features of other prior art falls within the protection scope of the present invention.

If no specific experimental steps or conditions are indicated in the examples, it can be carried out according to the operation or conditions of conventional experimental steps described in the prior art in this field. The reagents used and other instruments whose manufacturers are not indicated are all commercially available conventional reagent products.

The embodiment of the present invention provides a safe synthesis method of phloroglucinol shown in structural formula I, as shown in Fig. 1, the synthesis method comprises:

Step 1 (S1): Using 2,4,6-triaminotoluene represented by structural formula III and its hydrochloride as raw materials, carry out hydrolysis-isomerization reaction of enamine in an acidic system to obtain 2,4,6-triaminotoluene represented by structural formula II 2,4,6-Trihydroxytoluene.

During specific implementation, 2,4,6-triaminotoluene and its hydrochloride shown in structural formula III are used as raw materials, heated to reflux under acidic conditions, and the hydrolysis-isomerization reaction of enamine is carried out, and separation is carried out after the reaction is completed. Purification treatment (ie, the first post-treatment) to obtain 2,4,6-trihydroxytoluene represented by structural formula II.

Using 2,4,6-triaminotoluene and its hydrochloride as raw materials, the hydroxyl functional group is introduced through the hydrolysis-isomerization reaction of enamine. On the one hand, it can accurately replace the target site and reduce its by-products under high temperature conditions. On the other hand, it can enhance the oxidation resistance of raw materials, and it is easier to improve the stability of product intermediates in the production process.

Step 2 (S2): Using 2,4,6-trihydroxytoluene represented by structural formula II as a raw material, carry out oxidative demethylation reaction to obtain the target product phloroglucinol represented by structural formula I. That is, under the action of an oxidizing agent, the CH oxidation reaction is first carried out to obtain an oxidation reaction system containing 2,4,6-trihydroxybenzoic acid represented by structural formula IV, and then the oxidation reaction system is heated to 60-180°C for 2- The in-situ decarboxylation reaction of 6h prepared the target product phloroglucinol shown in structural formula I.

During specific implementation, CH oxidation reaction is carried out using 2,4,6-trihydroxytoluene represented by structural formula II as a raw material to obtain 2,4,6-trihydroxybenzoic acid represented by structural formula IV. In this implementation step, the benzyl group is selectively oxidized by a selective oxidizing agent, and basically no other side reactions occur, and the obtained oxidation products are all carboxylic acid intermediates shown in the structural formula IV. The target product phloroglucinol represented by the structural formula I can be obtained by subjecting the 2,4,6-trihydroxybenzoic acid represented by the structural formula IV to an in-situ decarboxylation reaction at 60-180° C. for 2-6 hours.

All the routes in the examples of the present invention are safe and controllable, and the intermediates are all non-explosive compounds, which is conducive to improving the safety of the synthesis process. Moreover, the synthesis method provided in this example has few by-products produced during the reaction, and the solvent and catalyst can be recycled, which reduces environmental pollution and waste of resources.

When implementing this embodiment, optionally, in step 1, the acid used in the acidic system includes at least one of sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid. That is, during specific implementation, the acid may be one of sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid, or a mixture of several types, which is not limited in this embodiment.

In the specific implementation of this embodiment, optionally, when the acidic system is an acidic system composed of sulfuric acid and ammonium chloride solution, the sulfuric acid is dilute sulfuric acid diluted to 5% to 60% by mass fraction, and sulfuric acid is the same as that shown in structural formula III The mass ratio of 2,4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1, and the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride shown in structural formula III 1:5～1:10, the reaction temperature of the hydrolysis-isomerization reaction of enamine is 90～120℃, the reaction solvent of the hydrolysis-isomerization reaction of enamine is water, the hydrolysis-isomerization reaction of enamine The reaction time of the reaction is 2 to 12 hours;

When the acidic system is an acidic system composed of a phosphoric acid solution, the phosphoric acid solution is a phosphoric acid solution with a mass fraction of 5 to 60%, and the mass ratio of the phosphoric acid solution to 2,4,6-triaminotoluene and its hydrochloride shown in structural formula III is 20:1～4:1, the reaction temperature of enamine hydrolysis-isomerization reaction is 180～250℃, the reaction solvent of enamine hydrolysis-isomerization reaction is water, the enamine hydrolysis-isomerization reaction The reaction time is 24～72h;

When the acidic system is an acidic system composed of methanesulfonic acid and ammonium chloride solution, methanesulfonic acid is methanesulfonic acid diluted to 5% to 60% mass fraction, and methanesulfonic acid and 2,4,6 shown in structural formula III -The mass ratio of triaminotoluene and its hydrochloride is 20:1～4:1, and the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride shown in structural formula III is 1:5～ 1:10, the reaction temperature of the hydrolysis-isomerization reaction of enamine is 60～180℃, the reaction solvent of the hydrolysis-isomerization reaction of enamine is water, and the reaction time of the hydrolysis-isomerization reaction of enamine is 4～14h;

When the acidic system is an acidic system composed of p-toluenesulfonic acid and ammonium chloride solution, p-toluenesulfonic acid is p-toluenesulfonic acid diluted to 5% to 60% mass fraction, p-toluenesulfonic acid and 2 shown in structural formula III , the mass ratio of 4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1, and the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride shown in structural formula III is 1:5～1:10, the reaction temperature of enamine hydrolysis-isomerization reaction is 60～180℃, the reaction solvent of enamine hydrolysis-isomerization reaction is water, the enamine hydrolysis-isomerization reaction The reaction time is 2 ~ 12h.

When implementing this embodiment, optionally, in step 2, the oxidizing agent is any one of potassium permanganate, lead dioxide, and potassium dichromate.

In the specific implementation of this embodiment, optionally, when the oxidizing agent is potassium permanganate or lead dioxide, in step 1, it is necessary to extract the product of 2,4,6-trihydroxytoluene shown in structural formula II . Therefore, after the hydrolysis-isomerization reaction of enamine is completed, the method provided in this embodiment further includes: obtaining 2,4,6-trihydroxytoluene represented by the structural formula II through the first post-treatment.

Wherein, the above-mentioned first post-treatment includes: adding an inorganic base to adjust to a solution of pH 2-5, after filtering, washing the filter residue several times to collect the filtrate, and concentrating crystallization; the inorganic base is sodium hydroxide, sodium carbonate, sodium bicarbonate at least one of .

During specific implementation, the first post-treatment can be: after the hydrolysis-isomerization reaction of enamine ends, the pH value of the filtrate of the system after the hydrolysis-isomerization reaction of enamine is adjusted to pH with an inorganic base 2-5, then filter the adjusted filtrate, wash the filter residue several times after filtration to collect the filtrate, and concentrate and crystallize the filtrate, the obtained crystal is 2,4,6-trihydroxytoluene shown in the structural formula II.

In the specific implementation of this embodiment, optionally, when the oxidizing agent is potassium permanganate, the oxidation system of the CH oxidation reaction is the oxidation system of potassium permanganate and magnesium sulfate aqueous solution;

Wherein, the mass ratio of potassium permanganate and 2,4,6-trihydroxytoluene shown in structural formula II is 2:1～10:1; magnesium sulfate and 2,4,6-trihydroxytoluene shown in structural formula II The mass ratio of the oxidation reaction is 1:2-2:1; the reaction temperature of the oxidation reaction is 60-100°C, the reaction time of the oxidation reaction is 1-4h, and the reaction solvent of the oxidation reaction is water.

In the specific implementation of this embodiment, optionally, when the oxidizing agent is lead dioxide, the oxidation system of the CH oxidation reaction is the aqueous system of lead dioxide and potassium hydroxide;

Wherein, the mass ratio of lead dioxide and 2,4,6-trihydroxytoluene shown in structural formula II is 4:1～8:1; potassium hydroxide and 2,4,6-trihydroxytoluene shown in structural formula II The mass ratio of the oxidation reaction is 4:1-6:1; the reaction temperature of the oxidation reaction is 100-200°C, the reaction time of the oxidation reaction is 0.5-3h, and the reaction solvent of the oxidation reaction is water.

In the specific implementation of this embodiment, optionally, when the oxidizing agent is potassium dichromate, there is no need to separate the 2,4,6-trihydroxytoluene shown in the structural formula II, and the electrochemical electrode reaction is performed in the hydrolysis-iso In-situ oxidation reaction is carried out in the reaction system obtained after the structuralization reaction is completed, and the oxidation system of the CH oxidation reaction is an oxidant system composed of potassium dichromate and dilute sulfuric acid solution;

Among them, the mass ratio of potassium dichromate to 2,4,6-trihydroxytoluene is 3:1 to 1:10; the dilute sulfuric acid solution is a sulfuric acid solution diluted to 5 to 60% by mass fraction, and the dilute sulfuric acid solution is mixed with 2, The mass ratio of 4,6-trihydroxytoluene is 20:1-5:1; the reaction temperature of the oxidation reaction is 30-100°C, the reaction time of the oxidation reaction is 1-8h, and the reaction solvent of the oxidation reaction is water.

In the specific implementation of this embodiment, optionally, after the in-situ decarboxylation reaction, the method provided in this embodiment further includes: performing a second post-treatment on the decarboxylation reaction system obtained after the in-situ decarboxylation reaction to obtain the structural formula I The target product phloroglucinol.

In the specific implementation of this embodiment, optionally, when the oxidizing agent is potassium permanganate, the second post-treatment method is: adjusting the decarboxylation reaction system to alkaline, then filtering, acidifying the filtrate, concentrating the acidified filtrate and Recrystallize the concentrated solution; wherein, the acid used for the acidification is concentrated hydrochloric acid, the volume ratio of the concentrated hydrochloric acid to the filtrate is 1:20-1:5, and the freezing crystallization temperature is -1-4°C.

In the specific implementation of this embodiment, optionally, when the oxidant is lead dioxide, the second post-treatment method is: carry out vacuum filtration on the decarboxylation reaction system, and then pass through lead removal filtration, acidify the filtrate after lead removal, concentrate Acidify the filtrate and recrystallize the concentrate; wherein, the acid used for acidification is concentrated hydrochloric acid, the volume ratio of concentrated hydrochloric acid to the filtrate is 1:20-1:5, and the temperature for freezing and crystallization is -1-4°C.

In the specific implementation of this embodiment, optionally, when the oxidizing agent is potassium coincidence acid, the second post-treatment method is: filter the reaction stock solution after the oxidation reaction under reduced pressure, wash the filter residue with deionized water, collect the filtrate and concentrate, The concentrate was then recrystallized.

In specific implementation, the above-mentioned "recrystallization of the concentrated solution" can be performed as follows: freezing and crystallizing the concentrated solution; or extracting the concentrated solution with ethyl acetate, concentrating the extract and then recrystallizing it.

It should be noted that the value ranges of the above-mentioned substances and parameters are only preferred solutions of the present invention, and the present invention does not limit the values, and any value ranges applicable to the present invention are feasible.

In order to enable those skilled in the art to better understand the present invention, the synthesis method of phloroglucinol represented by the structural formula I provided by the present invention is illustrated below through a plurality of specific examples.

Example 1

Step 1: Preparation of 2,4,6-trihydroxytoluene.

2,4,6-Triaminotoluene hydrochloride (100mmol, 24.65g) was dissolved in 130g of 5% dilute sulfuric acid (6.5g sulfuric acid, 123.5g deionized water), and NH ₄ Cl (45mmol, 2.4g) and heated to reflux at 105°C for 4h. After finishing the reaction, cool to room temperature, gradually add solid sodium hydroxide to the solution to adjust the pH of the solution to weakly acidic pH=5, and filter under reduced pressure. Wash the filter residue three times with deionized water (3×200mL), collect all the filtrate, concentrate the crystals by rotary evaporation, the temperature of the rotary evaporation is 50°C, and the pressure is 100mbar, and the solid product 2,4,6-trihydroxytoluene II (12.6 g, yield 90%).

Referring to Fig. 2, Fig. 3, Fig. 4 and Fig. 5, the proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and infrared spectrum of the product 2,4,6-trihydroxytoluene II of step 1 of embodiment 1 of the present invention are shown graphs and high-resolution mass spectra. It should be noted that, in order to detect the first intermediate product 2,4,6-trihydroxytoluene II generated in step 1 of this example, the reaction can be temporarily interrupted according to the reaction progress, and the reaction system can be processed to obtain pure The first intermediate product 2,4,6-trihydroxytoluene II is detected, and the formation of the first intermediate product 2,4,6-trihydroxytoluene II is determined according to various spectra detected.

Proton NMR spectrum ¹ H-NMR (400MHz, DMSO-D6) δ (ppm): 8.81 (s, 2H), 8.68 (s, 1H), 5.77 (s, 2H), 1.80 (s, 3H).

C NMR spectrum ¹³ C-NMR (101MHz, DMSO-D6) δ (ppm): 156.92, 155.98, 101.17, 94.46, 8.50.

Infrared spectrum FT-IR (ATR, cm ^-1 ): 3240cm ^-1 , 1599cm ^-1 , 1518cm ^-1 , 1469cm ^-1 , 1278cm ^-1 , 1139cm ^-1 , 1074cm ^-1 , 1003cm ^-1 , 814cm ^-1 .

High resolution mass spectrum HR-MS (ESI): 139.040084[MH] ^- (C ₇ H ₇ O ₃ , required 139.040068).

Step 2: the preparation of phloroglucinol

Dissolve 2,4,6-trihydroxytoluene (14g, 100mmol) and magnesium sulfate (20g) in water (300ml), heat up to 60°C and stir, and gradually add potassium permanganate solid to the mixed solution Powder (30g, 200mmol), keep stirring until the purple color disappears in the solution, the raw material conversion process is monitored by TLC chromatography column, after 4 hours of reaction, the temperature is raised to 150°C, and refluxed for 4 hours to achieve the purpose of oxidative demethylation.

Add NaOH (10g, 0.25mmol) solid in the solution and adjust the solution to alkaline, filter out the MnO in the reaction solution _solid , collect the filtrate, add concentrated hydrochloric acid to adjust the pH of the solution to acidity, put it in a refrigerator for 6 hours, Phloroglucinol (11.6 g, 97%) was obtained after filtration.

Referring to Fig. 6, Fig. 7, Fig. 8 and Fig. 9, it shows the proton nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of the oxidation intermediate product 2,4,6-trihydroxybenzoic acid in step 2 of embodiment 1 of the present invention , infrared spectra and high-resolution mass spectra. Since the intermediate product does not exist stably for a long time, it was only isolated and characterized in this example 1 for its relevant characterization spectra.

Proton NMR spectrum: ¹ H-NMR (400MHz, DMSO-D6) δ (ppm): 10.21, 6.54, 5.81.

Carbon NMR spectrum: ¹³ C-NMR (101MHz, DMSO-D6) δ (ppm): 172.66, 164.28, 162.98, 95.17, 94.04.

Infrared Spectrum FT-IR(ATR,cm ^-1 ): 3576cm ^-1 , 3470cm ^-1 , 3120cm -1 , 2617cm ^{-1 ,} 1614cm ^-1 , 1465cm ^-1 , 1378cm ^-1 , 1255cm ^-1 , 1164cm ^-1 , 1066cm ^-1 , 1014cm ^-1 , 834cm ^-1 , 822cm ^-1 , 723cm ^-1 , 694cm ^-1 .

High resolution mass spectrum HR-MS (ESI): 169.014206[MH] ^- (C ₇ H ₅ O ₃ , required 169.014247).

Referring to Fig. 10, Fig. 11, Fig. 12 and Fig. 13, the proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum and high-resolution mass spectrum of the product phloroglucinol I of step 2 of embodiment 1 of the present invention are shown picture.

Proton NMR spectrum: ¹ H-NMR (400MHz, DMSO-D6) δ (ppm): 8.95, 5.67.

Carbon NMR spectrum: ¹³ C-NMR (101MHz, DMSO-D6) δ (ppm): 159.38, 94.55.

Infrared spectrum: 3208cm ^-1 , 1621cm ^-1 , 1504cm -1 , 1415cm ^-1 , 1331cm ^-1 , 1298cm ^-1 , 1153cm ^-1 , 1006cm ^-1 , 997cm ^-1 , 813cm ^-1 , 799cm ^-1 , ^{666cm -1 1} , 579cm ^-1 , 518cm ^-1 .

High resolution mass spectrum: HR-MS (ESI): 125.024444[MH]-(C ₆ H ₅ O ₃ ,required 125.024418).

Example 2

The implementation content of step 1 of this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 1, the difference is that the mass ratio of sulfuric acid to 2,4,6-triaminotoluene and its hydrochloride is 20:1, ammonium chloride The mass ratio of 2,4,6-triaminotoluene and its hydrochloride is 1:5, the reaction temperature is 90°C, the reaction time is 2h, the inorganic base used is sodium carbonate, and the final 2,4,6- The yield of trishydroxytoluene II was 86%.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 1, the difference is that the mass ratio of potassium permanganate to 2,4,6-trihydroxytoluene is 2:1; magnesium sulfate and 2 , the mass ratio of 4,6-trihydroxytoluene was 1:2; the reaction temperature of the oxidation reaction was 60° C., the reaction time of the oxidation reaction was 1 h, and the yield of phloroglucinol finally obtained was 91%.

Example 3

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 1, the difference is that sulfuric acid is dilute sulfuric acid diluted to 20% by mass fraction, sulfuric acid and 2,4,6-triaminotoluene and its salts The mass ratio of acid salt is 10:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:7, the reaction temperature is 100°C, and the reaction time is 6h. The inorganic base used is Sodium bicarbonate, the yield of the finally obtained 2,4,6-trihydroxytoluene II was 88%.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 1, the difference is that the mass ratio of potassium permanganate to 2,4,6-trihydroxytoluene is 6:1; magnesium sulfate and 2 , the mass ratio of 4,6-trihydroxytoluene was 1:1.5; the reaction temperature of the oxidation reaction was 80° C., the reaction time of the oxidation reaction was 2 hours, and the yield of the finally obtained phloroglucinol was 94%.

Example 4

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 1, the difference is that sulfuric acid is dilute sulfuric acid diluted to 40% by mass fraction, sulfuric acid and 2,4,6-triaminotoluene and its salts The mass ratio of acid salt is 15:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:9, the reaction temperature is 110°C, and the reaction time is 10h. The final 2, The yield of 4,6-trihydroxytoluene II was 91%.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 1, the difference is that the mass ratio of potassium permanganate to 2,4,6-trihydroxytoluene is 10:1; magnesium sulfate and 2 , the mass ratio of 4,6-trihydroxytoluene is 2:1; the reaction temperature of the oxidation reaction is 100°C, the reaction time of the oxidation reaction is 4h, and the yield of the finally obtained phloroglucinol is 95%.

Example 5

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 1, the difference is that sulfuric acid is dilute sulfuric acid diluted to 60% by mass fraction, sulfuric acid and 2,4,6-triaminotoluene and its salts The mass ratio of acid salt is 4:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:10, the reaction temperature is 120°C, and the reaction time is 12h. The final 2, The yield of 4,6-trihydroxytoluene II was 94%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 1, and will not be repeated in this embodiment.

In the above-mentioned Examples 2-5, the obtained 2,4,6-trihydroxytoluene II has a hydrogen nuclear magnetic resonance spectrum, a carbon nuclear magnetic resonance spectrum, an infrared spectrum, and a high-resolution mass spectrum, which are respectively compared with those shown in Fig. 2, Fig. 3, Fig. 4, Fig. 5 are identical, no longer repeatedly provide in embodiment 2～5; The proton nuclear magnetic resonance spectrogram, carbon nuclear magnetic resonance spectrogram, infrared spectrogram, high-resolution mass spectrogram of the obtained phloroglucinol are respectively compared with Fig. 10, Fig. 11, Fig. 12, and Fig. 13 are the same, and are not repeated in Embodiments 2-5.

Example 6

Step 1: Preparation of 2,4,6-trihydroxytoluene.

2,4,6-triaminotoluene hydrochloride (100mmol, 24.65g) was dissolved in 150g mass fraction of 10% phosphoric acid solution (17.6g, 85wt% phosphoric acid solution, 132.4g deionized water), heated to 130 ℃ reflux 24h. After finishing the reaction, cool to room temperature, gradually add solid sodium hydroxide to the solution to adjust the pH of the solution to weakly acidic pH=4, and filter under reduced pressure. Wash the filter residue three times with deionized water (3×200mL), collect all the filtrate, concentrate the crystals by rotary evaporation, the temperature of the rotary evaporation is 50°C, and the pressure is 100mbar, and the solid product 2,4,6-trihydroxytoluene II (12.6 g, yield 90%).

The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the 2,4,6-trihydroxytoluene II obtained in this implementation step are respectively consistent with Fig. 2, Fig. 3, Fig. 4, Fig. 5 The same will not be repeated in this embodiment.

Step 2: the preparation of phloroglucinol

Dissolve 2,4,6-trihydroxytoluene (14g, 100mmol) and lead dioxide (56g, 234mmol) in 200mL deionized water, add solid potassium hydroxide (70g, 1.25mol), heat to 135°C and reflux for 3 hours , The raw material conversion process is monitored by a TLC chromatographic column. After the raw material conversion is complete, the temperature is raised to 150° C. and refluxed for 6 hours to achieve the purpose of oxidative demethylation.

Add NaOH (10g, 0.25mmol) solid to the solution to adjust the solution to alkalinity, filter the insoluble solids, collect the filtrate, add concentrated hydrochloric acid to adjust the pH of the solution to acidity, put it in a freezer for 6 hours, and obtain m-benzenetri Phenol (11.3 g, 90% yield).

The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the phloroglucinol I obtained in this implementation step are respectively the same as Fig. 10, Fig. 11, Fig. 12, and Fig. 13. In this implementation Examples will not be repeated.

Example 7

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 6, the difference is that the phosphoric acid solution is a phosphoric acid solution diluted to 5% mass fraction, and the phosphoric acid solution is mixed with 2,4,6-triaminotoluene and The mass ratio of the hydrochloride is 20:1, the reaction temperature of the enamine hydrolysis-isomerization reaction is 60°C, the reaction time of the enamine hydrolysis-isomerization reaction is 24h, and the finally obtained 2,4,6 - The yield of trihydroxytoluene II is 89%.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 6, the difference is that the mass ratio of lead dioxide to 2,4,6-trihydroxytoluene is 4:1; potassium hydroxide and 2 , the mass ratio of 4,6-trihydroxytoluene is 4:1; the reaction temperature of the oxidation reaction is 90°C, the reaction pressure of the oxidation reaction is 0.4MPa, and the reaction time of the oxidation reaction is 0.5h, and the finally obtained phloroglucinol The yield was 91%.

Example 8

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 6, the difference is that the phosphoric acid solution is a phosphoric acid solution diluted to 20% by mass fraction, and the phosphoric acid solution is mixed with 2,4,6-triaminotoluene and The mass ratio of the hydrochloride salt is 15:1, the reaction temperature of the enamine hydrolysis-isomerization reaction is 100°C, the reaction time of the enamine hydrolysis-isomerization reaction is 36h, and the finally obtained 2,4,6 - The yield of trihydroxytoluene II is 91%.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 6, the difference is that the mass ratio of lead dioxide to 2,4,6-trihydroxytoluene is 6:1; potassium hydroxide and 2 , the mass ratio of 4,6-trihydroxytoluene is 5:1; the reaction temperature of the oxidation reaction is 120°C, the reaction pressure of the oxidation reaction is 0.8MPa, and the reaction time of the oxidation reaction is 1.5h, and the finally obtained phloroglucinol The yield was 93%.

Example 9

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 6, the difference is that the phosphoric acid solution is a phosphoric acid solution diluted to 40% by mass, and the phosphoric acid solution is mixed with 2,4,6-triaminotoluene and The mass ratio of the hydrochloride is 10:1, the reaction temperature of the enamine hydrolysis-isomerization reaction is 140°C, the reaction time of the enamine hydrolysis-isomerization reaction is 48h, and the finally obtained 2,4,6 - The yield of trihydroxytoluene II is 92%.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 6, the difference is that the mass ratio of lead dioxide to 2,4,6-trihydroxytoluene is 8:1; potassium hydroxide and 2 , the mass ratio of 4,6-trihydroxytoluene is 6:1; the reaction temperature of the oxidation reaction is 150°C, the reaction pressure of the oxidation reaction is 1.2MPa, the reaction time of the oxidation reaction is 3h, and the final obtained phloroglucinol The yield was 93%.

Example 10

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 6, the difference is that the phosphoric acid solution is a phosphoric acid solution diluted to 60% by mass, and the phosphoric acid solution is mixed with 2,4,6-triaminotoluene and The mass ratio of its hydrochloride is 4:1, the reaction temperature of the hydrolysis-isomerization reaction of enamine is 180°C, the reaction solvent of the hydrolysis-isomerization reaction of enamine is water, and the hydrolysis-isomerization reaction of enamine The reaction time of the reaction was 72 hours, and the yield of the finally obtained 2,4,6-trihydroxytoluene II was 92%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment.

In the above-mentioned Examples 7-10, the hydrogen nuclear magnetic resonance spectrum, the carbon nuclear magnetic resonance spectrum, the infrared spectrum, and the high-resolution mass spectrum of the obtained 2,4,6-trihydroxytoluene II are respectively compared with Fig. 2, Fig. 3, Fig. 4, Fig. 5 are identical, no longer repeatedly provide in embodiment 7～10; The proton nuclear magnetic resonance spectrogram, carbon nuclear magnetic resonance spectrogram, infrared spectrogram, high-resolution mass spectrogram of the obtained phloroglucinol are respectively compared with Fig. 10, Fig. 11, Fig. 12, and Fig. 13 are the same, and are not repeated in Embodiments 7-10.

Example 11

Step 1: Preparation of 2,4,6-trihydroxytoluene.

2,4,6-Triaminotoluene hydrochloride (100 mmol, 24.65 g) was dissolved in 200 g of 5% methanesulfonic acid solution (10 g methanesulfonic acid, 190 g deionized water), and NH ₄ Cl ( 50mmol, 2.6g), heated to 90°C and refluxed for 10h. After finishing the reaction, cool to room temperature, gradually add solid sodium hydroxide to the solution to adjust the pH of the solution to weakly acidic pH=4, and filter under reduced pressure. Wash the filter residue three times with deionized water (3 × 200mL), collect all the filtrate, and concentrate the crystals by rotary evaporation. The temperature of the rotary evaporation is 50 °C and the pressure is 100 mbar. The solid product 2,4,6-trihydroxytoluene II (12.3 g, yield 88%).

The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the 2,4,6-trihydroxytoluene II obtained in this implementation step are respectively consistent with Fig. 2, Fig. 3, Fig. 4, Fig. 5 The same will not be repeated in this embodiment.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment. The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the phloroglucinol I obtained in this implementation step are respectively the same as Fig. 10, Fig. 11, Fig. 12, and Fig. 13. In this implementation Examples will not be repeated.

The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the phloroglucinol I obtained in this implementation step are respectively the same as Fig. 10, Fig. 11, Fig. 12, and Fig. 13. In this implementation Examples will not be repeated.

Example 12

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 11, the difference is that methanesulfonic acid is methanesulfonic acid diluted to 5% mass fraction, methanesulfonic acid and 2,4,6-tris The mass ratio of aminotoluene and its hydrochloride is 20:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:5, the reaction of hydrolysis-isomerization reaction of enamine The temperature is 60° C., the reaction time of the enamine hydrolysis-isomerization reaction is 4 h, and the yield of the final 2,4,6-trihydroxytoluene II is 87%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment.

Example 13

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 11, the difference is that methanesulfonic acid is methanesulfonic acid diluted to 20% mass fraction, methanesulfonic acid and 2,4,6-tris The mass ratio of aminotoluene and its hydrochloride is 15:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:7, the reaction of hydrolysis-isomerization reaction of enamine The temperature was 100° C., the reaction time of the enamine hydrolysis-isomerization reaction was 8 h, and the yield of the finally obtained 2,4,6-trihydroxytoluene II was 88%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment.

Example 14

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 11, the difference is that methanesulfonic acid is methanesulfonic acid diluted to 40% mass fraction, methanesulfonic acid and 2,4,6-tris The mass ratio of aminotoluene and its hydrochloride is 10:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:9, the reaction of hydrolysis-isomerization reaction of enamine The temperature is 140° C., the reaction time of the enamine hydrolysis-isomerization reaction is 10 h, the reaction solvent of the oxidation reaction is chloroform, and the yield of the final 2,4,6-trihydroxytoluene II is 90%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment.

Example 15

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 11, the difference is that methanesulfonic acid is methanesulfonic acid diluted to 60% mass fraction, methanesulfonic acid and 2,4,6-tris The mass ratio of aminotoluene and its hydrochloride is 4:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:10, the reaction of hydrolysis-isomerization reaction of enamine The temperature is 180° C., the reaction time of the enamine hydrolysis-isomerization reaction is 14 h, and the yield of the finally obtained 2,4,6-trihydroxytoluene II is 91%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment. In the above-mentioned Examples 12 to 15, the hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the obtained 2,4,6-trihydroxytoluene II are respectively compared with those in Fig. 2, Fig. 3, Fig. 4, Fig. 5 are identical, no longer repeatedly provide in embodiment 12～15; The proton nuclear magnetic resonance spectrogram, carbon nuclear magnetic resonance spectrogram, infrared spectrogram, high-resolution mass spectrogram of the obtained phloroglucinol are respectively compared with Figure 10, Figure 11, Figure 12, and Figure 13 are the same, and will not be repeated in Embodiments 12-15.

Example 16

Step 1: Preparation of 2,4,6-trihydroxytoluene.

2,4,6-Triaminotoluene hydrochloride (100mmol, 24.65g) was dissolved in 150g of 10% p-toluenesulfonic acid solution (15g methanesulfonic acid, 145g deionized water), heated to 70°C Reflux 4h. After finishing the reaction, cool to room temperature, gradually add solid sodium hydroxide to the solution to adjust the pH of the solution to weakly acidic pH=5, and filter under reduced pressure. Wash the filter residue three times with deionized water (3×200mL), collect all the filtrate, concentrate the crystals by rotary evaporation, the temperature of the rotary evaporation is 50°C, and the pressure is 100mbar, and the solid product 2,4,6-trihydroxytoluene II (11.9 g, yield 85%).

The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the 2,4,6-trihydroxytoluene II obtained in this implementation step are respectively consistent with Fig. 2, Fig. 3, Fig. 4, Fig. 5 The same will not be repeated in this embodiment.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment. The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the phloroglucinol I obtained in this implementation step are respectively the same as Fig. 10, Fig. 11, Fig. 12, and Fig. 13. In this implementation Examples will not be repeated.

Example 17

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 16, the difference is that p-toluenesulfonic acid is p-toluenesulfonic acid diluted to 5% mass fraction, p-toluenesulfonic acid and 2,4, The mass ratio of 6-triaminotoluene and its hydrochloride is 20:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:5, and the hydrolysis-isomerization of enamine The reaction temperature of the reaction is 60° C., the reaction time of the enamine hydrolysis-isomerization reaction is 2 h, and the yield of the finally obtained 2,4,6-trihydroxytoluene II is 84%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment.

Example 18

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 16, the difference is that p-toluenesulfonic acid is p-toluenesulfonic acid diluted to 20% mass fraction, p-toluenesulfonic acid and 2,4, The mass ratio of 6-triaminotoluene and its hydrochloride is 15:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:7, the hydrolysis-isomerization of enamine The reaction temperature of the reaction is 100° C., the reaction time of the enamine hydrolysis-isomerization reaction is 4 hours, and the yield of the finally obtained 2,4,6-trihydroxytoluene II is 88%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment.

Example 19

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 16, the difference is that p-toluenesulfonic acid is p-toluenesulfonic acid diluted to 40% mass fraction, p-toluenesulfonic acid and 2,4, The mass ratio of 6-triaminotoluene and its hydrochloride is 10:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:9, the hydrolysis-isomerization of enamine The reaction temperature of the reaction is 140° C., the reaction time of the enamine hydrolysis-isomerization reaction is 8 hours, and the yield of the finally obtained 2,4,6-trihydroxytoluene II is 90%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment.

Example 20

The implementation content of step 1 in this embodiment is similar to the implementation content of step 1 in the above-mentioned embodiment 16, the difference is that p-toluenesulfonic acid is p-toluenesulfonic acid diluted to 60% mass fraction, p-toluenesulfonic acid and 2,4, The mass ratio of 6-triaminotoluene and its hydrochloride is 4:1, the mass ratio of ammonium chloride to 2,4,6-triaminotoluene and its hydrochloride is 1:10, the hydrolysis-isomerization of enamine The reaction temperature of the reaction is 180° C., the reaction time of the enamine hydrolysis-isomerization reaction is 12 h, and the yield of the finally obtained 2,4,6-trihydroxytoluene II is 91%.

The implementation content of step 2 in this embodiment is the same as the implementation content of step 2 in the above-mentioned embodiment 6, and will not be repeated in this embodiment. In the above-mentioned Examples 17 to 20, the obtained 2,4,6-trihydroxytoluene II has a hydrogen nuclear magnetic resonance spectrum, a carbon nuclear magnetic resonance spectrum, an infrared spectrum, and a high-resolution mass spectrum, which are respectively compared with Fig. 2 , Fig. 3 , Fig. 4, Fig. 5 are identical, no longer repeatedly provide in embodiment 17～20; The proton nuclear magnetic resonance spectrogram, carbon nuclear magnetic resonance spectrogram, infrared spectrogram, high resolution mass spectrogram of the obtained phloroglucinol are respectively compared with Figure 10, Figure 11, Figure 12, and Figure 13 are the same, and will not be repeated in Embodiments 17-20.

Example 21

Step 1: Preparation of 2,4,6-trihydroxytoluene.

2,4,6-Triaminotoluene hydrochloride (100mmol, 24.65g) was dissolved in 130g of 5% dilute sulfuric acid (6.5g sulfuric acid, 123.5g deionized water), and NH ₄ Cl (45mmol, 2.4g) and heated to reflux at 105°C for 4h. Cool to room temperature after finishing the reaction. Transfer directly to the electrolyzer without further separation.

Step 2: the preparation of phloroglucinol

Add potassium dichromate (29g, 100mmol) and 24g of dilute sulfuric acid solution diluted to 40% mass fraction successively in the reaction solution, insert the cathode into the carbon electrode, insert the anode into the Cr electrode, heat to 50°C, adjust the voltage to 3.3V, adjust Current up to 550A·m ^-2 . After reacting for about 4 hours, keep stirring until the solution changes from orange to gray-green. The conversion process of raw materials is monitored by TLC chromatography column, and the electrode is removed. Re-elevate the temperature to 150° C. and reflux for 4 hours to achieve the purpose of oxidative demethylation.

Add NaOH (10g, 0.25mmol) solid to the solution to adjust the solution to alkaline, filter out the insoluble solids in the reaction solution, collect the filtrate, add concentrated hydrochloric acid to adjust the pH of the solution to acidity, put it in a refrigerator for 6 hours, filter Phloroglucinol (11.6 g, 97%) was finally obtained.

The proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the phloroglucinol I obtained in this implementation step are respectively the same as Fig. 10, Fig. 11, Fig. 12, and Fig. 13. In this implementation Examples will not be repeated.

Example 22

The implementation content of step 1 in this embodiment is the same as the implementation content of step 1 in the above-mentioned embodiment 16, and will not be repeated here.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 23, the difference is that the mass ratio of potassium dichromate to 2,4,6-trihydroxytoluene is 3:1; the dilute sulfuric acid solution is Sulfuric acid solution diluted to 15% mass fraction, the mass ratio of dilute sulfuric acid solution to 2,4,6-trihydroxytoluene is 20:1; the reaction temperature of the oxidation reaction is 30°C, the reaction time of the oxidation reaction is 1h, the anode material carbon, the cathode material is carbon, the voltage is 2.5V, and the current density is 400A·m ^-2 .

Example 23

The implementation content of step 1 in this embodiment is the same as the implementation content of step 1 in the above-mentioned embodiment 16, and will not be repeated here.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 23, the difference is that the mass ratio of potassium dichromate to 2,4,6-trihydroxytoluene is 1:2; the dilute sulfuric acid solution is Sulfuric acid solution diluted to 30% mass fraction, the mass ratio of dilute sulfuric acid solution to 2,4,6-trihydroxytoluene is 15:1; the reaction temperature of the oxidation reaction is 60°C, the reaction time of the oxidation reaction is 4h, the anode material is Pt, the cathode material is Pt, the voltage is 3V, and the current density is 500A·m ^-2 .

Example 24

The implementation content of step 1 in this embodiment is the same as the implementation content of step 1 in the above-mentioned embodiment 16, and will not be repeated here.

The implementation content of step 2 in this embodiment is similar to the implementation content of step 2 in the above-mentioned embodiment 23, the difference is that the mass ratio of potassium dichromate to 2,4,6-trihydroxytoluene is 1:10; the dilute sulfuric acid solution is Sulfuric acid solution diluted to 60% mass fraction, the mass ratio of dilute sulfuric acid solution to 2,4,6-trihydroxytoluene is 5:1; the reaction temperature of the oxidation reaction is 110°C, the reaction time of the oxidation reaction is 8h, the anode material is Cr, the cathode material is Cr, the voltage is 3.5V, and the current density is 600A·m ^-2 .

Among the above-mentioned Examples 22 to 24, the hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, infrared spectrum, and high-resolution mass spectrum of the obtained phloroglucinol are respectively the same as those in Figure 10, Figure 11, Figure 12, and Figure 13 , will not be repeated in Examples 22-24.

It should be pointed out that the steps and methods in the various embodiments of the present application are not limited to the corresponding embodiments, and the operation details and precautions of the various embodiments are corresponding to each other.

For the method embodiment, for the sake of simple description, it is expressed as a series of action combinations, but those skilled in the art should know that the present invention is not limited by the described action sequence, because according to the present invention, certain steps Other sequences or concurrently may be used. Secondly, those skilled in the art should also know that the embodiments described in the specification belong to preferred embodiments, and the actions and components involved are not necessarily required by the present invention.

A kind of method for preparing phloroglucinol by 2,4,6-triaminotoluene provided by the present invention has been described in detail above, applied specific examples in this paper to explain the principle and implementation of the present invention, the above implementation The description of the example is only used to help understand the method of the present invention and its core idea; at the same time, for those of ordinary skill in the art, according to the idea of the present invention, there will be changes in the specific implementation and scope of application. In summary As stated above, the content of this specification should not be construed as limiting the present invention.

Claims (10)

1. A method for preparing phloroglucinol by 2,4,6-triaminotoluene, characterized in that the method comprises:

   Step 1: Using 2,4,6-triaminotoluene represented by structural formula III and its hydrochloride as raw materials, carry out the hydrolysis-isomerization reaction of enamine in an acidic system to obtain 2,4-triaminotoluene represented by structural formula II ,6-trihydroxytoluene;

   Step 2: Using 2,4,6-trihydroxytoluene shown in structural formula II as a raw material, carry out an oxidative demethylation reaction to obtain the target product phloroglucinol shown in structural formula I;

   
2. The method according to claim 1, characterized in that, in the step 1, the acid selected in the acidic system includes at least one of sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid.
3. The method according to claim 2, characterized in that, when the acidic system is an acidic system composed of sulfuric acid and ammonium chloride solution, the sulfuric acid is dilute sulfuric acid diluted to 5% to 60% mass fraction, the The mass ratio of sulfuric acid to the 2,4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1, and the ammonium chloride to the 2,4,6-triaminotoluene and its hydrochloride The mass ratio of the salt is 1:5-1:10, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 90-120° C., and the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, so The reaction time of the hydrolysis-isomerization reaction of said enamine is 2～12h;

   When the acidic system is an acidic system composed of a phosphoric acid solution, the phosphoric acid solution is a phosphoric acid solution diluted to 5-60% mass fraction, and the phosphoric acid solution and the 2,4,6-triaminotoluene and its salts The mass ratio of acid salt is 20:1-4:1, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 60-180°C, the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, The reaction time of the hydrolysis-isomerization reaction of the enamine is 24～72h;

   When the acidic system is an acidic system composed of methanesulfonic acid and ammonium chloride solution, the methanesulfonic acid is methanesulfonic acid diluted to 5% to 60% by mass fraction, and the methanesulfonic acid and the 2, The mass ratio of 4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1, and the mass ratio of the ammonium chloride to the 2,4,6-triaminotoluene and its hydrochloride is 1: 5～1:10, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 60～180°C, the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, the hydrolysis-isomerization reaction of the enamine- The reaction time of isomerization reaction is 4～14h;

   When the acidic system is an acidic system composed of p-toluenesulfonic acid and ammonium chloride solution, the p-toluenesulfonic acid is p-toluenesulfonic acid diluted to 5% to 60% mass fraction, and the p-toluenesulfonic acid and The mass ratio of the 2,4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1, and the mass ratio of the ammonium chloride to the 2,4,6-triaminotoluene and its hydrochloride is The ratio is 1:5-1:10, the reaction temperature of the hydrolysis-isomerization reaction of the enamine is 60-180° C., the reaction solvent of the hydrolysis-isomerization reaction of the enamine is water, and the enamine The reaction time of the hydrolysis-isomerization reaction of the amine is 2-12 hours.
4. The method according to claim 1, characterized in that, in the step 2, the oxidative demethylation reaction comprises:

   Under the action of an oxidizing agent, the CH oxidation reaction is first carried out to obtain an oxidation reaction system containing 2,4,6-trihydroxybenzoic acid shown in structural formula IV;

   Then, the oxidation reaction system is heated to 60-180° C. to carry out in-situ decarboxylation reaction for 2-6 hours, and the target product phloroglucinol shown in structural formula I is prepared.
5. The method according to claim 4, characterized in that, in the step 2, the oxidizing agent is any one of potassium permanganate, potassium dichromate, and lead dioxide.
6. The method according to claim 5, wherein when the oxidizing agent is potassium permanganate, the oxidation system of the CH oxidation reaction is an oxidation system of potassium permanganate and magnesium sulfate aqueous solution;

   Wherein, the mass ratio of the potassium permanganate to the 2,4,6-trihydroxytoluene is 2:1～10:1; the mass ratio of the magnesium sulfate to the 2,4,6-trihydroxytoluene The ratio is 1:2-2:1; the reaction temperature of the oxidation reaction is 60-100° C., the reaction time of the oxidation reaction is 1-4 hours, and the reaction solvent of the oxidation reaction is water.
7. The method according to claim 5, characterized in that, when the oxidizing agent is lead dioxide, the oxidation system of the CH oxidation reaction is lead dioxide and potassium hydroxide aqueous solution system;

   Wherein, the mass ratio of the lead dioxide to the 2,4,6-trihydroxytoluene is 4:1 to 8:1; the mass ratio of the potassium hydroxide to the 2,4,6-trihydroxytoluene The ratio is 4:1～6:1; the reaction temperature of the oxidation reaction is 90～150°C, the reaction pressure of the oxidation reaction is 0.4～1.2MPa, the reaction time of the oxidation reaction is 0.5～3h, the The reaction solvent for the oxidation reaction is water.
8. The method according to claim 5, characterized in that, when the oxidizing agent is potassium dichromate, an in-situ oxidation reaction is carried out in the reaction system obtained after the completion of the hydrolysis-isomerization reaction by electrochemical electrode reaction , and the oxidation system of the CH oxidation reaction is an oxidant system composed of potassium dichromate and dilute sulfuric acid solution;

   Wherein, the mass ratio of the potassium dichromate to the 2,4,6-trihydroxytoluene is 3:1-1:10; the dilute sulfuric acid solution is a sulfuric acid solution diluted to 5-60% mass fraction, The mass ratio of the dilute sulfuric acid solution to the 2,4,6-trihydroxytoluene is 20:1-5:1; the reaction temperature of the oxidation reaction is 30-110°C, and the reaction time of the oxidation reaction is 1-8h, the reaction solvent of the oxidation reaction is water.
9. The method according to claim 5, characterized in that, after the in-situ decarboxylation reaction, the method further comprises: performing a second post-treatment on the decarboxylation reaction system obtained after the in-situ decarboxylation reaction, to obtain the structural formula I The target product phloroglucinol;

   Wherein, when the oxidizing agent is potassium permanganate, the second post-treatment is: adjusting the decarboxylation reaction system to alkaline, then filtering, acidifying the filtrate, concentrating the acidified filtrate and re- Crystallization; wherein, the acid used in the acidification is concentrated hydrochloric acid, the volume ratio of the concentrated hydrochloric acid to the filtrate is 1:20 to 1:5, and the temperature of the frozen crystallization is -1 to 4°C;

   When the oxidizing agent is lead dioxide, the second post-treatment is: filter the decarboxylation reaction system under reduced pressure, then filter the deleaded filtrate, acidify the filtrate after deleading, concentrate the filtrate after the acidification and concentrate liquid for recrystallization; wherein, the acid used in the acidification is concentrated hydrochloric acid, the volume ratio of the concentrated hydrochloric acid to the filtrate is 1:20 to 1:5, and the temperature of the frozen crystallization is -1 to 4°C;

   When the oxidant is potassium coincidence acid, the second post-treatment is: filter the reaction stock solution after the oxidation reaction under reduced pressure, wash the filter residue with deionized water, collect and concentrate the filtrate, and then recrystallize the concentrated solution .
10. The method according to claim 9, wherein the recrystallization of the concentrated solution comprises: freezing and crystallizing the concentrated solution; or extracting the concentrated solution with ethyl acetate, and recrystallizing the extract after concentration.

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