WO2023015629A1 - Procédé de préparation de phloroglucinol à partir de 2,4,6-triaminotoluène - Google Patents

Procédé de préparation de phloroglucinol à partir de 2,4,6-triaminotoluène Download PDF

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WO2023015629A1
WO2023015629A1 PCT/CN2021/116397 CN2021116397W WO2023015629A1 WO 2023015629 A1 WO2023015629 A1 WO 2023015629A1 CN 2021116397 W CN2021116397 W CN 2021116397W WO 2023015629 A1 WO2023015629 A1 WO 2023015629A1
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reaction
hydrolysis
trihydroxytoluene
acid
triaminotoluene
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黄木华
张志豪
邓汉林
罗贤升
彭山青
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北京理工大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/045—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen
    • C07C37/05—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen by substitution of a NH2 group

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  • 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.
  • 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.
  • phloroglucinol is mainly prepared by oxidation of 1,3,5-triisopropylbenzene, hydrolysis of 1,3,5-trihalobenzene, and biosynthesis.
  • 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.
  • 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;
  • the acid selected in the acidic system includes at least one of sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid.
  • 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 °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 the reaction is 2 to 12 hours;
  • 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
  • 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;
  • 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
  • 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 reaction time of isomerization reaction is 4 ⁇ 14h;
  • 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
  • the mass ratio of the 2,4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1
  • 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
  • the enamine The reaction time of the hydrolysis-isomerization reaction of the amine is 2-12 hours.
  • the oxidative demethylation reaction includes:
  • 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;
  • 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.
  • the oxidizing agent is any one of potassium permanganate, lead dioxide, and potassium dichromate.
  • the oxidation system of the CH oxidation reaction is an oxidation system of potassium permanganate and magnesium sulfate aqueous solution;
  • 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.
  • the oxidation system of the CH oxidation reaction is an aqueous system of lead dioxide and potassium hydroxide;
  • 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.
  • 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;
  • 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.
  • 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;
  • 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;
  • 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;
  • 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.
  • 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).
  • 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 decarbox
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • the hydroxyl functional group is introduced through the hydrolysis-isomerization reaction of enamine.
  • it can accurately replace the target site and reduce its by-products under high temperature conditions.
  • it can enhance the oxidation resistance of raw materials, and it is easier to improve the stability of product intermediates in the production process.
  • 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.
  • 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.
  • 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.
  • 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°C
  • 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;
  • 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°C, the reaction solvent of enamine hydrolysis-isomerization reaction is water, the enamine hydrolysis-isomerization reaction The reaction time is 24 ⁇ 72h;
  • 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
  • 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°C
  • the reaction solvent of the hydrolysis-isomerization reaction of enamine is water
  • the reaction time of the hydrolysis-isomerization reaction of enamine is 4 ⁇ 14h;
  • 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
  • the mass ratio of 4,6-triaminotoluene and its hydrochloride is 20:1 to 4:1
  • 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°C
  • the reaction solvent of enamine hydrolysis-isomerization reaction is water
  • the enamine hydrolysis-isomerization reaction The reaction time is 2 ⁇ 12h.
  • the oxidizing agent is any one of potassium permanganate, lead dioxide, and potassium dichromate.
  • the method provided in this embodiment further includes: obtaining 2,4,6-trihydroxytoluene represented by the structural formula II through the first post-treatment.
  • 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 .
  • 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.
  • the oxidation system of the CH oxidation reaction is the oxidation system of potassium permanganate and magnesium sulfate aqueous solution
  • 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.
  • the oxidation system of the CH oxidation reaction is the aqueous system of lead dioxide and potassium hydroxide
  • 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.
  • the oxidizing agent is potassium dichromate
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Step 1 Preparation of 2,4,6-trihydroxytoluene.
  • 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.
  • the reaction 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.
  • Step 2 the preparation of phloroglucinol
  • 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.
  • 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 .
  • 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%.
  • 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%.
  • 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
  • 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%.
  • 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%.
  • 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
  • the reaction time is 10h.
  • the final 2 The yield of 4,6-trihydroxytoluene II was 91%.
  • 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%.
  • 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
  • the reaction time is 12h.
  • the final 2 The yield of 4,6-trihydroxytoluene II was 94%.
  • 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.
  • 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.
  • Step 1 Preparation of 2,4,6-trihydroxytoluene.
  • Step 2 the preparation of phloroglucinol
  • 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.
  • 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
  • the yield of trihydroxytoluene II is 89%.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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 phosphoric acid solution is a phosphoric acid solution diluted to 60% by mass
  • 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
  • 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 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.
  • Step 1 Preparation of 2,4,6-trihydroxytoluene.
  • 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.
  • 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
  • the yield of the final 2,4,6-trihydroxytoluene II is 87%.
  • 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.
  • 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
  • the yield of the finally obtained 2,4,6-trihydroxytoluene II was 88%.
  • 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.
  • 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
  • the yield of the final 2,4,6-trihydroxytoluene II is 90%.
  • 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.
  • 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
  • the yield of the finally obtained 2,4,6-trihydroxytoluene II is 91%.
  • 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 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.
  • Step 1 Preparation of 2,4,6-trihydroxytoluene.
  • 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.
  • 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
  • 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
  • the yield of the finally obtained 2,4,6-trihydroxytoluene II is 84%.
  • 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.
  • 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
  • the yield of the finally obtained 2,4,6-trihydroxytoluene II is 88%.
  • 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.
  • 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
  • the yield of the finally obtained 2,4,6-trihydroxytoluene II is 90%.
  • 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.
  • 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
  • the yield of the finally obtained 2,4,6-trihydroxytoluene II is 91%.
  • 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 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.
  • 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
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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 .
  • 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.
  • 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 .

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Abstract

L'invention concerne un procédé de préparation de phloroglucinol à partir de 2,4,6-triaminotoluène. Le procédé comprend : l'utilisation de 2,4,6-triaminotoluène et d'un chlorhydrate de celui-ci en tant que matières premières pour effectuer une réaction d'hydrolyse-isomérisation de triénamine afin d'obtenir du 2,4,6-trihydroxytoluène ; puis la mise en œuvre d'une réaction de déméthylation oxydative sur le 2,4,6-trihydroxytoluène afin d'obtenir du phloroglucinol produit cible. Dans le procédé, un acide bon marché et facilement disponible est utilisé comme réactif dans la conversion de 2,4,6-triaminotoluène et d'un chlorhydrate de celui-ci en 2,4,6-trihydroxytoluène, l'hydrolyse-isomérisation de la triénamine est obtenue à 77-90 %, et la réaction de déméthylation du 2,4,6-trihydroxytoluène est obtenue avec un rendement de 71 à 97 % afin d'obtenir du phloroglucinol produit cible. En résumé, le procédé innove une voie synthétique de phloroglucinol de façon simple, efficace, sûre et modérée, et pose une fondation solide pour obtenir une préparation à faible coût et à grande échelle de phloroglucinol.
PCT/CN2021/116397 2021-08-13 2021-09-03 Procédé de préparation de phloroglucinol à partir de 2,4,6-triaminotoluène WO2023015629A1 (fr)

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