High-efficiency and energy-saving preparation process of phloroglucinol

Abstract

The present application relates to a kind of high efficiency energy-saving preparation process of phloroglucinol.The preparation process uses phenol as raw material, generates 2,6-dichlorophenol and dichlorophenol isomer through chlorination reaction, then is alkaline hydrolysis and acidification into product phloroglucinol, after the intermediate dichlorophenol is generated in the chlorination reaction of raw material phenol, it is not concentrated and separated, directly add base to carry out alkaline hydrolysis reaction, realize chlorination-alkaline hydrolysis two-step reaction continuous production.The present application uses alkaline hydrolysis reaction to also convert the original dichlorophenol isomer impurity in situ into product phloroglucinol, realizes waste to treasure, improves yield about 8-10%;In the preparation process, 2,6-dichlorophenol intermediate is not separated, it is directly used in the next step alkaline hydrolysis reaction, the operation unit such as the solvent, crystallization, centrifugation, drying, packaging etc. for its concentration replacement is saved, at the same time, the pungent odor generated in the large production process of 2,6-dichlorophenol is fundamentally avoided, and the environmental pollution problem in the production process of phloroglucinol is avoided.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical manufacturing technology, specifically to a highly efficient and energy-saving process for preparing phloroglucinol. Background Technology

[0002] Phloroglucinol, chemical name 1,3,5-trihydroxybenzene CAS: 108-73-6 It belongs to the class of gastrointestinal antispasmodics and acts on spasmodic smooth muscle, thus having an antispasmodic effect. It can be used for acute spasmodic pain caused by dysfunction of the digestive system and biliary tract, acute spasmodic urethral, ​​bladder, and renal colic, gynecological spasmodic pain, and as an adjunct treatment for uterine contractions during pregnancy. The commonly used dosage form is injection. In addition, phloroglucinol is also an important fine chemical product, mainly used in the synthesis of flavonoid isoflavone antitumor drugs, dye coupling agents, tire tackifiers, and nitrogen-based composite ink raw materials.

[0003] Currently, the main methods for the chemical synthesis of resorcinol include: ① using TNT or benzene halides as raw materials, followed by amination and hydrolysis. This method uses relatively expensive and difficult-to-obtain raw materials; ② using 1,3,5-tribromobenzene or hexachlorobenzene as raw materials, followed by alkane oxidation, complexation, and hydrolysis to prepare resorcinol. This method has a low yield and generates a large amount of waste acid that needs to be treated; ③ using benzene and propylene as starting materials for alkylation to generate TIP, which is then oxidized to form 1,3,5-tris(2-hydroxyperoxy-2-methylethyl)benzene (THPO). THPO is then decomposed into resorcinol under acidic conditions. This method produces acetone as a byproduct, which is difficult to treat, and the reaction yield is low, with intermediates easily oxidized; ④ using dihydroxychlorobenzene as a raw material, followed by alkaline hydrolysis and then acidification to obtain the resorcinol. Although this method is simple, the raw materials are expensive and not suitable for industrial production; ⑤ using 2,6-dichlorophenol to prepare the target compound through elimination, addition, and acidification reactions. During the reaction, the reactor needs to be filled with nitrogen for protection.

[0004] Chinese patent CN110423186A discloses a method for producing phloroglucinol, using 2,6-dichlorophenol as the reactant, reacting in the presence of a copper salt catalyst and 1,2,4-trimethylbenzene solvent. The reaction solution is subjected to a three-gradient cooling process, and hot water is added in the first and second stages for layer separation. Activated carbon adsorption columns are used for decolorization, and metal ion adsorbents are used to remove copper and potassium ions. However, this synthesis process requires numerous operating units, has a long production time and low efficiency, requires significant equipment investment, and the use of heavy metal copper salts as catalysts causes considerable pollution. Furthermore, the production process generates unpleasant gases, making it unsuitable for large-scale production.

[0005] Therefore, it is necessary to invent a highly efficient and energy-saving process for preparing phloroglucinol to solve the above problems. Summary of the Invention

[0006] The purpose of this invention is to provide a highly efficient and energy-saving process for preparing phloroglucinol with high energy utilization and high production efficiency, thereby realizing the large-scale production of high-purity phloroglucinol.

[0007] To achieve the above objectives, the present invention provides the following technical solution: A highly efficient and energy-saving process for preparing phloroglucinol includes the following steps: S1. Add phenol and reaction solvent A to the reactor, stir and heat to 80~85℃; introduce Cl2, and stop introducing chlorine after a total of 4~5 h to end the reaction; stir and introduce N2 to remove the remaining Cl2 and HCl for 1~2 h; under N2 protection, directly add alkali to continue alkaline hydrolysis, and the reaction is complete in 10~12 h. S2. Cool the reaction system to below 120℃, add water dropwise and stir for half an hour until the reaction system is homogeneous and allowed to stand for separation. Add the extractant to the aqueous layer, stir for 1 hour to extract, allow to stand for separation, and take the aqueous phase for HPLC analysis. If the content of 2,6-dichlorophenol is ≥0.3%, repeat the above extraction steps until the content of 2,6-dichlorophenol is <0.3%. Continue to cool to ≤40℃, adjust the pH of the reaction system to 10 with concentrated hydrochloric acid, then centrifuge and filter, and rinse the filter cake with water. Collect the lower aqueous phase, add ethyl acetate, stir and extract for 1 hour, and allow to stand for separation. Collect the lower aqueous phase, control the temperature to ≤40℃, continue to adjust the pH of the lower aqueous phase to 2-3 with concentrated hydrochloric acid, and finally cool to 0-5℃, keep warm and stir for 1 hour, centrifuge and filter, and rinse the filter cake with cold water to obtain a light yellow solid filter cake. Place the obtained filter cake in a drying oven at 40℃ and dry for 15-20 hours to obtain phloroglucinol. Wherein, the reaction solvent A is any one or a combination of nitrobenzene, m-dichlorobenzene, and o-dichlorobenzene.

[0008] Furthermore, the alkali is any one or a mixture of several of KOH, NaOH, and triethylamine.

[0009] Further, the extractant is any one or a mixture of several of the following: n-heptane, n-octane, nonane, decanane, cyclohexane, cyclobutane, cyclopentane; ethyl acetate, isobutyl acetate, isopropyl acetate, amyl acetate, cyclohexyl acetate, ethyl propionate, and butyl propionate.

[0010] The beneficial effects of this invention are as follows: This invention provides a highly efficient and energy-saving process for preparing phloroglucinol. The process uses phenol as a raw material, generating 2,6-dichlorophenol and its dichloro isomer through a chlorination reaction, followed by direct alkaline hydrolysis to produce the product phloroglucinol. After the chlorination of the raw phenol to generate the dichlorophenol intermediate, it is directly subjected to alkaline hydrolysis without concentration or separation, achieving continuous production through a two-step chlorination-alkaline hydrolysis reaction. This invention utilizes the alkaline hydrolysis reaction to convert the original dichlorophenol isomer impurity into the product phloroglucinol in situ, turning waste into treasure and increasing the yield by approximately 8-10%. The preparation process eliminates the need to separate the chlorinated intermediate 2,6-dichlorophenol, directly using it in the next alkaline hydrolysis reaction. This not only saves a large number of operational units such as concentration, solvent replacement, crystallization, centrifugation, drying, and packaging, but also fundamentally avoids the unpleasant and irritating odor generated during the large-scale production of 2,6-dichlorophenol, thus avoiding the environmental pollution problems associated with phloroglucinol production.

[0011] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, and to make the above and other objects, technical features and beneficial effects of the present invention more obvious and understandable, the following preferred embodiments are described in detail with reference to the accompanying drawings. Attached Figure Description

[0012] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, some of the drawings in the following description are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0013] Figure 1 This is the main reaction formula for the synthesis process of high-purity phloroglucinol in Example 1 of the present invention. Detailed Implementation

[0014] The present invention will now be described in detail with reference to specific embodiments to make its features and advantages clearer. However, it should be noted that the embodiments are for understanding the concept of the invention, and the scope of the invention is not limited to the embodiments listed herein. The technical solution of the present invention will be further explained and described below with reference to specific embodiments and accompanying drawings.

[0015] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available. Example 1

[0016] Add phenol (2.0 kg, 21.25 mol) and m-dichlorobenzene (10 kg) to a 20 L reactor, stir and heat to 80-85 °C, then begin introducing Cl2 through a chlorine flow meter (for 4-5 hours). During the reaction, the solution color changes from colorless to pale yellow. Stop introducing chlorine after a cumulative chlorine flow of approximately 3.05 kg, ending the reaction. Stir and introduce N2 to purge any remaining Cl2 and HCl from the chlorination system for 1-2 hours. Under N2 protection, add KOH (10 kg, 178.22 mol) for alkaline hydrolysis, slowly heat to reflux, and the reaction system changes from a clear liquid to a turbid liquid, with the reaction completed in approximately 10-12 hours.

[0017] When the temperature drops below 120℃, add 8 kg of water dropwise over approximately 30 minutes. After stirring for half an hour until homogeneous, allow the mixture to stand and separate into layers. Add 2 kg of n-heptane to the aqueous layer, stir for 1 hour to extract, and allow the mixture to stand and separate into layers. Perform HPLC analysis on the aqueous phase. If the content of 2,6-dichlorophenol is ≥0.3%, repeat the above extraction steps until the content of 2,6-dichlorophenol is <0.3%. Continue cooling, controlling the temperature to ≤40℃, and adjust the pH to 10 with concentrated hydrochloric acid. Then centrifuge and filter, rinsing the filter cake with water. Collect the lower aqueous phase, add 2 kg of ethyl acetate, stir and extract for 1 hour, and allow the mixture to stand and separate into layers. Collect the lower aqueous phase, control the temperature to ≤40℃, continue adjusting the pH to 2-3 with concentrated hydrochloric acid in the lower aqueous phase, and finally cool to 0-5℃, maintain the temperature and stir for 1 hour. Centrifuge and filter, rinsing the filter cake with cold water to obtain a pale yellow solid. The obtained pale yellow solid was dried in a drying oven at 40°C for 15–20 h to obtain 1.8 kg of pale yellow crude phloroglucinol, with a yield of 70–75%. Example 2

[0018] Add phenol (2.0 kg, 21.25 mol) and nitrobenzene to a 20 L reactor, stir and heat to 80-85°C, then begin introducing Cl2 through a chlorine flow meter (for approximately 4-5 hours). During the reaction, the solution color changes from colorless to pale yellow. Stop introducing chlorine after a cumulative chlorine flow of approximately 3.05 kg, ending the reaction. Stir and introduce N2 to purge any remaining Cl2 and HCl from the chlorination system for 1-2 hours. Under N2 protection, add KOH (10 kg, 178.22 mol) for alkaline hydrolysis, slowly heating to reflux. The reaction system changes from a clear liquid to a turbid liquid, and the reaction is complete in approximately 10-12 hours.

[0019] When the temperature drops below 120℃, add 8 kg of water dropwise over approximately 30 minutes. After stirring for half an hour until homogeneous, allow the mixture to stand and separate into layers. Add 2 kg of n-octane to the aqueous layer, stir for 1 hour to extract, and allow the mixture to stand and separate into layers. Perform HPLC analysis on the aqueous phase. If the content of 2,6-dichlorophenol is ≥0.3%, repeat the above extraction steps until the content of 2,6-dichlorophenol is <0.3%. Continue cooling, controlling the temperature to ≤40℃, and adjust the pH to 10 with concentrated hydrochloric acid. Then centrifuge and filter, rinsing the filter cake with water. Collect the lower aqueous phase, add 2 kg of ethyl acetate, stir and extract for 1 hour, and allow the mixture to stand and separate into layers. Collect the lower aqueous phase, control the temperature to ≤40℃, continue adjusting the pH to 2-3 with concentrated hydrochloric acid in the lower aqueous phase, and finally cool to approximately 0-5℃, maintain the temperature and stir for 1 hour. Centrifuge and filter, rinsing the filter cake with cold water to obtain a pale yellow solid. The obtained pale yellow solid was dried in a drying oven at 40°C for 15–20 h to obtain 1.76 kg of pale yellow crude phloroglucinol, with a yield of 70–75%. Example 3

[0020] Add phenol (2.0 kg, 21.25 mol) and o-dichlorobenzene to a 20 L reactor, stir and heat to 80-85°C, then begin introducing Cl2 through a chlorine flow meter (for approximately 4-5 hours). During the reaction, the solution color changes from colorless to pale yellow. Stop introducing chlorine after a cumulative chlorine flow of approximately 3.05 kg, ending the reaction. Stir and introduce N2 to purge any remaining Cl2 and HCl from the chlorination system for 1-2 hours. Under N2 protection, add KOH (10 kg, 178.22 mol) for alkaline hydrolysis, slowly heating to reflux. The reaction system changes from a clear liquid to a turbid solution, and the reaction is complete in approximately 10-12 hours.

[0021] When the temperature drops below 120℃, add 8 kg of water dropwise over approximately 30 minutes. After stirring for half an hour until homogeneous, allow the mixture to stand and separate into layers. Add 2 kg of cyclohexane to the aqueous layer, stir for 1 hour to extract, and allow the mixture to stand and separate into layers again. Perform HPLC analysis on the aqueous phase. If the content of 2,6-dichlorophenol is ≥0.3%, repeat the above extraction steps until the content of 2,6-dichlorophenol is <0.3%. Continue cooling, controlling the temperature to ≤40℃, and adjust the pH to 10 with concentrated hydrochloric acid. Then centrifuge and filter, rinsing the filter cake with water. Collect the lower aqueous phase, add 2 kg of ethyl acetate, stir and extract for 1 hour, and allow the mixture to stand and separate into layers again. Collect the lower aqueous phase, control the temperature to ≤40℃, continue adjusting the pH to 2-3 with concentrated hydrochloric acid in the lower aqueous phase, and finally cool to approximately 0-5℃, maintain the temperature and stir for 1 hour. Centrifuge and filter, rinsing the filter cake with cold water to obtain a pale yellow solid. The obtained pale yellow solid was dried in a drying oven at 40°C for 15–20 h to obtain 1.78 kg of pale yellow crude phloroglucinol, with a yield of 70–75%.

[0022] In summary, this invention provides a highly efficient and energy-saving process for preparing phloroglucinol. This process uses phenol as a raw material, generating the dichloroisomer 2,4-dichlorophenol through a chlorination reaction, followed by alkaline hydrolysis to produce the final product, phloroglucinol. This invention utilizes alkaline hydrolysis to convert the original dichloroisomer impurity into phloroglucinol, achieving in-situ waste-to-resource conversion and increasing the yield by approximately 10%. The preparation process eliminates the need to separate the chlorinated intermediate 2,6-dichlorophenol, saving numerous steps such as crystallization, centrifugation, drying, and packaging. Furthermore, it allows for direct use in the subsequent alkaline hydrolysis reaction, fundamentally avoiding the unpleasant odor generated during the large-scale production of 2,6-dichlorophenol and mitigating the environmental pollution problems associated with phloroglucinol production.

[0023] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0024] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A highly efficient and energy-saving process for preparing phloroglucinol, characterized in that, Includes the following steps: S1. Add phenol and reaction solvent A to the reactor, stir and heat to 80~85℃; introduce Cl2, and stop introducing chlorine after a total of 4~5 h to end the reaction; stir and introduce N2 to remove the remaining Cl2 and HCl for 1~2 h; under N2 protection, directly add alkali to continue alkaline hydrolysis, and the reaction is complete in 10~12 h. S2. Cool the reaction system to below 130℃, add water dropwise and stir for half an hour until the reaction system is homogeneous and allowed to stand for separation. Add the extractant to the aqueous layer, stir for 1 hour to extract, allow to stand for separation, and take the aqueous phase for HPLC analysis. If the content of 2,6-dichlorophenol is ≥0.3%, repeat the above extraction steps until the content of 2,6-dichlorophenol is <0.3%. Continue to cool to ≤40℃, adjust the pH of the reaction system to 10 with concentrated hydrochloric acid, then centrifuge and filter, and rinse the filter cake with water. Collect the lower aqueous phase, add ethyl acetate, stir and extract for 1 hour, and allow to stand for separation. Collect the lower aqueous phase, control the temperature to ≤40℃, continue to adjust the pH of the lower aqueous phase to 2-3 with concentrated hydrochloric acid, and finally cool to 0-5℃, keep warm and stir for 1 hour, centrifuge and filter, rinse the filter cake with cold water to obtain a light yellow solid filter cake. Place the obtained filter cake in a drying oven at 40℃ and dry for 15-20 hours to obtain phloroglucinol. Wherein, the reaction solvent A is any one or a combination of nitrobenzene, m-dichlorobenzene, and o-dichlorobenzene.

2. The high-efficiency and energy-saving phloroglucinol preparation process as described in claim 1, characterized in that, The alkali is any one or a mixture of several of KOH, NaOH, and triethylamine.

3. The high-efficiency and energy-saving phloroglucinol preparation process as described in claim 1, characterized in that, The extractant is any one or a mixture of several of the following: n-heptane, n-octane, nonane, decanane, cyclohexane, cyclobutane, cyclopentane, ethyl acetate, isobutyl acetate, isopropyl acetate, pentyl acetate, cyclohexyl acetate, ethyl propionate, and butyl propionate.

Images