CN114890871A - Preparation method of trimethyl phloroglucinol crude product and preparation method of trimethyl phloroglucinol - Google Patents
Preparation method of trimethyl phloroglucinol crude product and preparation method of trimethyl phloroglucinol Download PDFInfo
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- 229940030049 trimethylphloroglucinol Drugs 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000012043 crude product Substances 0.000 title claims abstract description 16
- MNBSXKSWDLYJHN-UHFFFAOYSA-N 2,4,6-trimethylbenzene-1,3,5-triol Chemical compound CC1=C(O)C(C)=C(O)C(C)=C1O MNBSXKSWDLYJHN-UHFFFAOYSA-N 0.000 title claims abstract 22
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000000047 product Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 41
- 239000012141 concentrate Substances 0.000 claims description 37
- 238000010438 heat treatment Methods 0.000 claims description 32
- 238000001816 cooling Methods 0.000 claims description 31
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 claims description 30
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 30
- 229960001553 phloroglucinol Drugs 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 238000001914 filtration Methods 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000011049 filling Methods 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 239000008213 purified water Substances 0.000 claims description 7
- 238000005303 weighing Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000007865 diluting Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 abstract description 4
- 231100000252 nontoxic Toxicity 0.000 abstract description 3
- 230000003000 nontoxic effect Effects 0.000 abstract description 3
- 238000007069 methylation reaction Methods 0.000 abstract description 2
- 230000009972 noncorrosive effect Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 53
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 231100000086 high toxicity Toxicity 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- CKAPSXZOOQJIBF-UHFFFAOYSA-N hexachlorobenzene Chemical compound ClC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl CKAPSXZOOQJIBF-UHFFFAOYSA-N 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- YWDUZLFWHVQCHY-UHFFFAOYSA-N 1,3,5-tribromobenzene Chemical compound BrC1=CC(Br)=CC(Br)=C1 YWDUZLFWHVQCHY-UHFFFAOYSA-N 0.000 description 1
- ZDPACSAHMZADFZ-UHFFFAOYSA-N 1-[3-(2,4,6-Trimethoxybenzoyl)propyl]pyrrolidinium chloride Chemical compound [Cl-].COC1=CC(OC)=CC(OC)=C1C(=O)CCC[NH+]1CCCC1 ZDPACSAHMZADFZ-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical group O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002113 buflomedil hydrochloride Drugs 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
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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
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/16—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing a crude product of trimethyl phloroglucinol and a method for preparing the trimethyl phloroglucinol. And the reaction product obtained in the first step and dimethyl carbonate are subjected to a second step methylation reaction, and the dimethyl carbonate is non-toxic and non-corrosive, so that the production safety is greatly improved, the environment is protected, and the quality and yield of the final finished product are improved. Solves the problems of low safety of the existing preparation method of trimethyl phloroglucinol, avoids using strong corrosive reagents such as hydrochloric acid and the like, and adopts dimethyl carbonate to replace highly toxic dimethyl sulfate.
Description
The present application claims priority from the chinese patent application entitled "a method for producing trimethylphloroglucinol" filed by the chinese patent office on 2021, month 07, and 06, having application number CN202110760402.1, the entire contents of which are incorporated herein by reference.
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of a trimethyl phloroglucinol crude product and a preparation method of trimethyl phloroglucinol.
Background
Trimethylbenzotriphenol, the chemical name of which is 1, 3, 5-trimethoxybenzene, is an important organic synthesis intermediate, and is widely applied to the synthesis of medicines, pesticides and fine chemical products, such as the synthesis of a vasodilator buflomedil hydrochloride. Meanwhile, trimethyl phloroglucinol is an effective antispasmodic drug, can directly act on smooth muscle, enables sphincter and urethral smooth muscle to be more sensitive to phloroglucinol through synergistic effect, and has the effect of enhancing spasmolysis and analgesia.
At present, there are two main methods reported in China for synthesizing trimethyl phloroglucinol: firstly, hexachlorobenzene is used as a raw material to prepare trimethyl phloroglucinol through two steps of etherification and dechlorination, however, hexachlorobenzene has high toxicity, metal sodium and methanol are required to react to form sodium methoxide in the preparation process, the metal sodium is too active and is not beneficial to safe operation, and the yield of the route is low; secondly, 1, 3, 5-tribromobenzene is used as a raw material to prepare trimethyl phloroglucinol through methoxylation reaction, however, the raw material is expensive, and metal sodium and methanol also need to be used for reaction in the preparation process.
US patent No. 3449503 discloses the preparation of trimethylphloroglucinol by using phloroglucinol as the starting material, introducing hydrogen chloride into methanol to perform catalytic reaction to generate a partial methylated product, and using potassium carbonate as a catalyst and dimethyl sulfate as a methylation reagent. However, the method has large consumption of hydrogen chloride, and a large amount of hydrogen chloride gas can volatilize in the reaction process, so that the method has strong corrosivity; in addition, dimethyl sulfate is a highly toxic reagent and is unsafe to use.
The document "Green Synthesis Process of 1, 3, 5-trimethoxybenzene" (synthetic chemistry, 2015, 23 (8): 753-756, discloses the use of phloroglucinol as raw material, dimethyl carbonate as methylating agent, in K 2 CO 3 /(Bu) 4 Under the catalysis of NBr, 1, 3, 5-trimethoxy benzene (namely trimethyl phloroglucinol) is synthesized. In fact, phloroglucinol is quite unstable under the above conditions, and thus the target compound cannot be obtained according to the literature method.
Therefore, it is urgently needed to provide a new preparation method of trimethyl phloroglucinol to overcome the defects of the existing synthesis method.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing a crude trimethylphloroglucinol product and a method for preparing trimethylphloroglucinol, so as to solve the technical problems of low safety, high toxicity of reagents and low yield of finished products in the existing method for preparing trimethylphloroglucinol.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a trimethyl phloroglucinol crude product, which comprises the following steps:
(1) adding methanol into a reactor, and adding a catalyst sulfuric acid while stirring; adding anhydrous phloroglucinol into the reactor, stirring until the phloroglucinol is dissolved, filling nitrogen, and heating for reaction for 2-8 hours; cooling to room temperature, diluting with water or inorganic salt water solution, extracting with extraction solvent for three times, mixing extractive solutions, and vacuum distilling to recover solvent to obtain concentrate;
(2) and (2) taking the concentrate in the step (1), adding dimethyl sulfoxide to dissolve the concentrate, filling nitrogen to protect the concentrate, adding potassium carbonate, heating the concentrate, weighing dimethyl carbonate, adding the dimethyl carbonate in batches, heating the mixture to react for 1-6 hours after the dimethyl carbonate is added, then carrying out reduced pressure distillation to remove excessive dimethyl carbonate, cooling the mixture to room temperature, dropwise adding purified water while stirring, cooling and crystallizing while stirring after the dimethyl carbonate is dropwise added, filtering, and washing filter residues with water to obtain a trimethyl phloroglucinol crude product.
The invention provides a preparation method of trimethyl phloroglucinol, which comprises the following steps:
(1) adding methanol into a reactor, and adding a catalyst sulfuric acid while stirring; adding anhydrous phloroglucinol into the reactor, stirring until the phloroglucinol is dissolved, filling nitrogen, and heating for reaction for 2-8 hours; cooling to room temperature, diluting with water or inorganic salt water solution, extracting with extraction solvent for three times, mixing extractive solutions, and vacuum distilling to recover solvent to obtain concentrate.
(2) And (2) taking the concentrate in the step (1), adding dimethyl sulfoxide to dissolve the concentrate, filling nitrogen to protect the concentrate, adding potassium carbonate, heating the concentrate, weighing dimethyl carbonate, adding the dimethyl carbonate in batches, heating the concentrate to react for 1-6 hours after the addition, then carrying out reduced pressure distillation to remove excessive dimethyl carbonate, cooling the mixture to room temperature, dropwise adding purified water while stirring, cooling and crystallizing while stirring after the dropwise addition is finished, filtering, and washing filter residues with water to obtain a trimethyl phloroglucinol crude product.
(3) Preparing a primary refined product of trimethyl phloroglucinol: and (3) adding a recrystallization solvent into the crude trimethyl phloroglucinol in the step (2), heating and dissolving, adding activated carbon for decoloring, filtering while hot, cooling and crystallizing while stirring, and filtering to obtain a primary refined trimethyl phloroglucinol product.
(4) And (3) adding a recrystallization solvent into the primary refined trimethyl phloroglucinol product obtained in the step (3), heating and dissolving, adding activated carbon for decoloring, filtering while hot, cooling and crystallizing while stirring, filtering, washing filter residues with a cold recrystallization solvent, and drying under reduced pressure to obtain a finished trimethyl phloroglucinol product.
Optionally, in the step (1), the molar ratio of the catalyst sulfuric acid to the anhydrous phloroglucinol is 2-10: 1.
Optionally, in the step (1), the feeding ratio of the methanol to the anhydrous phloroglucinol is 5-20: 1 (v/w).
Optionally, in the step (1), the heating reaction temperature is 50-120 ℃.
Optionally, in the step (2), the heating reaction temperature is 100-160 ℃.
Optionally, in the step (2), the molar ratio of the dimethyl carbonate to the anhydrous phloroglucinol in the step (1) is 2-15: 1.
Optionally, in the step (2), the molar ratio of the potassium carbonate to the anhydrous phloroglucinol in the step (1) is 2-12: 1.
Optionally, in the step (2), the mass ratio of the purified water to the dimethyl sulfoxide is 1-6: 1.
Alternatively, in step (3) and step (4), the recrystallization solvent independently comprises methanol, ethanol, isopropanol, acetone, diethyl ether, petroleum ether, ethyl acetate, or an aqueous solution of the above solvents.
According to the technical scheme, the embodiment of the invention has the following advantages:
1. according to the preparation method of trimethyl phloroglucinol provided by the invention, the used reagent in the preparation process is basically nontoxic, and the damage to the health of researchers is greatly reduced in production.
2. The preparation method of trimethyl phloroglucinol provided by the invention takes phloroglucinol as a raw material, adopts sulfuric acid to replace hydrogen chloride as a catalyst for the first-step reaction, is very simple and convenient to operate, reduces by-products, and reduces the damage to production equipment.
3. According to the invention, dimethyl carbonate is adopted to replace dimethyl sulfate in the second step of reaction, and the dimethyl carbonate is non-toxic and non-corrosive, so that the production safety is greatly improved, the method is green and environment-friendly, and the yield of the final finished product is improved.
4. In the preparation method of trimethyl phloroglucinol provided by the invention, as phloroglucinol is difficult to react with dimethyl carbonate to obtain trimethyl phloroglucinol in the actual production, the inventor finds that the problem that phloroglucinol is difficult to react with dimethyl carbonate can be solved by firstly reacting phloroglucinol with methanol and then carrying out the second step reaction with dimethyl carbonate, and the preparation method has the advantages of few byproducts, simple and safe operation and easy post-treatment.
The invention provides a preparation method of trimethyl phloroglucinol, which is used for solving the technical problems of low safety in the production process, high toxicity of used reagents and low yield of finished products of the existing preparation method of trimethyl phloroglucinol.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments described in the present invention, and it is obvious for those skilled in the art to obtain other drawings according to these drawings.
FIG. 1 is a scheme showing the synthesis of trimethylphloroglucinol in the examples of the present invention;
FIG. 2 is a high performance liquid chromatogram of trimethylphloroglucinol prepared in example 1 of the present invention.
Detailed Description
In order to make those skilled in the art better understand the technical solutions of the present invention, the following embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
Example 1
The embodiment provides a preparation method of trimethyl phloroglucinol, which comprises the following steps:
(1) adding 200mL of methanol into a reaction bottle, and slowly dripping 64g of concentrated sulfuric acid while stirring; adding 20.2g of anhydrous phloroglucinol into a reactor, stirring until the phloroglucinol is dissolved, filling nitrogen, heating to 80 ℃, and carrying out reflux reaction for 6 hours.
Cooling to room temperature, adding 20% sodium chloride solution 200mL, extracting with methyl tert-butyl ether (3 times, the amount of methyl tert-butyl ether is 100mL, 50mL and 50mL respectively), mixing extractive solutions, and distilling at 60 deg.C to recover solvent to obtain concentrate.
(2) Taking the concentrate in the step (1), adding 180mL of dimethyl sulfoxide to dissolve the concentrate, filling nitrogen, adding 66.4g of potassium carbonate, and heating to 130 ℃. Weighing 57.8g of dimethyl carbonate, adding the dimethyl carbonate for three times at an interval of 0.5h every time, continuing to react for 1h after the addition is finished, distilling to remove unreacted excessive dimethyl carbonate, cooling to 25 ℃, dropwise adding 360mL of cold water while stirring, cooling to 5 ℃ after the dropwise addition is finished, crystallizing for 1h, filtering, and washing filter residues with water to obtain a trimethyl phloroglucinol crude product.
(3) Taking a crude product of trimethyl phloroglucinol, adding 120mL of 25% (v/v) ethanol aqueous solution, heating and dissolving at 50 ℃, adding 2.4g of activated carbon for decoloring for 10min, filtering while hot, cooling to 5 ℃ under stirring, continuing stirring for 1h, and filtering to obtain a primary refined product.
(4) Taking the primary refined product, adding 80mL of 25% (v/v) ethanol aqueous solution, heating and dissolving at 50 ℃, adding 0.8g of activated carbon for decoloring for 10min, filtering while hot, cooling to 5 ℃ under stirring, continuing stirring for 1h, filtering, washing filter residue with 15mL of 25% (v/v) ethanol aqueous solution, and drying at 30 ℃ under reduced pressure to obtain 18.85g of white crystals (yield 70.1%). Detecting a trimethyl phloroglucinol finished product by adopting a high performance liquid chromatography, wherein the high performance liquid chromatography conditions are as follows: the chromatographic column is Welch Ultimate AQ-C18, the detection wavelength is 230nm, the flow rate is 1.0mL/min, the mobile phase is acetonitrile-water (50: 50), and the column temperature is 40 ℃. The purity was 99.94%.
Example 2
The embodiment provides a preparation method of trimethyl phloroglucinol, which comprises the following steps:
(1) adding 200mL of methanol into a reaction bottle, and slowly dripping 72g of 98% sulfuric acid solution while stirring; adding 20.2g of anhydrous phloroglucinol into a reactor, stirring until the phloroglucinol is dissolved, filling nitrogen, heating to 90 ℃, and carrying out reflux reaction for 4 hours.
Cooling to room temperature, adding 20% sodium chloride solution 200mL, extracting with methyl tert-butyl ether (3 times, the amount of methyl tert-butyl ether is 100mL, 50mL and 50mL respectively), mixing extractive solutions, and distilling at 60 deg.C to recover solvent to obtain concentrate.
(2) Taking the concentrate in the step (1), adding 180mL of dimethyl sulfoxide to dissolve the concentrate until the concentrate is clear, filling nitrogen, adding 44.3g of potassium carbonate, and heating to 120 ℃. Weighing 72.2g of dimethyl carbonate, adding the dimethyl carbonate for three times at an interval of 0.5h every time, continuing to react for 2h after the addition is finished, distilling to remove unreacted excessive dimethyl carbonate, cooling to 25 ℃, taking 540mL of cold water to drop in while stirring, cooling to 5 ℃ after the dropping is finished, crystallizing for 1h, filtering, and washing filter residues with water to obtain a trimethyl phloroglucinol crude product.
(3) Taking a crude product of trimethyl phloroglucinol, adding 140mL of 25% (v/v) methanol aqueous solution, heating and dissolving at 50 ℃, adding 2.8g of activated carbon for decoloring for 10min, filtering while hot, cooling to 5 ℃ under stirring, continuing stirring for 1h, and filtering to obtain a primary refined product.
(4) Taking the primary refined product, adding 100mL of 25% (v/v) methanol aqueous solution, heating at 50 ℃ for dissolving, adding 1.1g of activated carbon for decoloring for 10min, filtering while hot, cooling to 5 ℃ while stirring, continuing to stir for 1h, filtering, washing filter residue with 20mL of 25% (v/v) methanol aqueous solution, and drying at 40 ℃ to obtain 17.82g of white crystals (yield 66.2%). The high performance liquid chromatography is adopted to detect the trimethyl phloroglucinol finished product, and the purity is 99.92%. The conditions of the high performance liquid chromatography were the same as in example 1.
Example 3
The embodiment provides a preparation method of trimethyl phloroglucinol, which comprises the following steps:
(1) adding 12L of methanol into a reaction kettle, and slowly dripping 3.84kg of 98% sulfuric acid solution while stirring; adding 1.21kg of anhydrous phloroglucinol into a reactor, stirring until the phloroglucinol is dissolved, filling nitrogen, heating to 90 ℃, and carrying out reflux reaction for 4 hours.
Cooling to room temperature, adding 20% sodium chloride solution 12L, extracting with methyl tert-butyl ether (3 times, the amount of methyl tert-butyl ether is 6L, 3L and 3L respectively), mixing extractive solutions, and distilling at 60 deg.C to recover solvent to obtain concentrate.
(2) And (2) taking the concentrate in the step (1), adding 10.8L of dimethyl sulfoxide to dissolve the concentrate until the concentrate is clear, filling nitrogen, adding 3.98kg of potassium carbonate, and heating to 140 ℃. Weighing 4.33kg of dimethyl carbonate, adding the dimethyl carbonate for three times at an interval of 0.5h every time, continuing to react for 2h after the addition is finished, distilling to remove unreacted excessive dimethyl carbonate, cooling to 25 ℃, dropwise adding 21.6L of cold water while stirring, cooling to 5 ℃ after the dropwise addition is finished, crystallizing for 1h, filtering, and washing filter residues with water to obtain a trimethyl phloroglucinol crude product.
(3) Taking a crude product of trimethyl phloroglucinol, adding 7.2L of 25% (v/v) ethanol aqueous solution, heating and dissolving at 50 ℃, adding 144g of activated carbon for decoloring for 10min, filtering while hot, cooling to 5 ℃ under stirring, continuing stirring for 1h, and filtering to obtain a primary refined product.
(4) Taking the primary refined product, adding 6L of 25% (v/v) ethanol aqueous solution, heating and dissolving at 50 ℃, adding 60g of activated carbon for decoloring for 10min, filtering while hot, cooling to 5 ℃ while stirring, continuing to stir for 1h, filtering, washing filter residue with 900ml of 25% (v/v) ethanol aqueous solution, and drying at 40 ℃ to obtain 1.11kg of white crystals (yield is 68.8%). The high performance liquid chromatography is adopted to detect the trimethyl phloroglucinol finished product, and the purity is 99.95 percent. The conditions of the high performance liquid chromatography were the same as in example 1.
The embodiment is the industrial scale-up production of the preparation method of trimethyl phloroglucinol, and it can be seen that the yield and purity of the small-batch production of trimethyl phloroglucinol in the embodiment and the embodiments 1-2 are almost the same, which indicates that the preparation method of trimethyl phloroglucinol provided by the invention has higher production and application values in industrial production.
The above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A preparation method of a trimethyl phloroglucinol crude product is characterized by comprising the following steps:
(1) adding methanol into a reactor, and adding a catalyst sulfuric acid while stirring; adding anhydrous phloroglucinol into the reactor, stirring until the phloroglucinol is dissolved, filling nitrogen, and heating for reaction for 2-8 hours; cooling to room temperature, diluting with water or inorganic salt water solution, extracting with extraction solvent for three times, mixing extractive solutions, and vacuum distilling to recover solvent to obtain concentrate;
(2) and (2) taking the concentrate in the step (1), adding dimethyl sulfoxide to dissolve the concentrate, filling nitrogen to protect the concentrate, adding potassium carbonate, heating the concentrate, weighing dimethyl carbonate, adding the dimethyl carbonate in batches, heating the mixture to react for 1-6 hours after the dimethyl carbonate is added, then carrying out reduced pressure distillation to remove excessive dimethyl carbonate, cooling the mixture to room temperature, dropwise adding purified water while stirring, cooling and crystallizing while stirring after the dimethyl carbonate is dropwise added, filtering, and washing filter residues with water to obtain a trimethyl phloroglucinol crude product.
2. The preparation method of trimethyl phloroglucinol is characterized by comprising the following steps:
(1) adding methanol into a reactor, and adding a catalyst sulfuric acid while stirring; adding anhydrous phloroglucinol into the reactor, stirring until the phloroglucinol is dissolved, filling nitrogen, and heating for reaction for 2-8 hours; cooling to room temperature, diluting with water or inorganic salt water solution, extracting with extraction solvent for three times, mixing extractive solutions, and vacuum distilling to recover solvent to obtain concentrate;
(2) taking the concentrate in the step (1), adding dimethyl sulfoxide to dissolve the concentrate, filling nitrogen to protect the concentrate, adding potassium carbonate, heating the concentrate, weighing dimethyl carbonate, adding the dimethyl carbonate in batches, heating the concentrate to react for 1 to 6 hours after the dimethyl carbonate is added, then distilling the concentrate under reduced pressure to remove excessive dimethyl carbonate, cooling the concentrate to room temperature, dropwise adding purified water while stirring, cooling and crystallizing the concentrate while stirring after the purified water is dropwise added, filtering the concentrate, and washing filter residues with water to obtain a trimethyl phloroglucinol crude product;
(3) preparing a primary refined product of trimethyl phloroglucinol: taking the crude trimethyl phloroglucinol in the step (2), adding a recrystallization solvent, heating for dissolving, adding activated carbon for decoloring, filtering while hot, cooling for crystallizing while stirring, and filtering to obtain a primary refined trimethyl phloroglucinol product;
(4) and (3) adding a recrystallization solvent into the primary refined trimethyl phloroglucinol product obtained in the step (3), heating and dissolving, adding activated carbon for decoloring, filtering while hot, cooling and crystallizing while stirring, filtering, washing filter residues with a cold recrystallization solvent, and drying under reduced pressure to obtain a finished trimethyl phloroglucinol product.
3. The method for preparing trimethylphloroglucinol according to claim 1 or 2, wherein in the step (1), the molar ratio of the catalyst sulfuric acid to the anhydrous phloroglucinol is 2-10: 1.
4. The method for preparing trimethylphloroglucinol according to claim 1 or 2, wherein the feeding ratio of the methanol to the anhydrous phloroglucinol in the step (1) is 5-20: 1 (v/w).
5. The method for producing trimethylphloroglucinol according to claim 1 or 2, wherein in the step (1), the heating reaction temperature is 50 to 120 ℃.
6. The method for producing trimethylphloroglucinol according to claim 1 or 2, wherein in the step (2), the heating reaction temperature is 100 to 160 ℃.
7. The method for preparing trimethylphloroglucinol according to claim 1 or 2, wherein the molar ratio of the dimethyl carbonate in the step (2) to the anhydrous phloroglucinol in the step (1) is 2-15: 1.
8. The method for preparing trimethylphloroglucinol according to claim 1 or 2, wherein the molar ratio of the potassium carbonate to the anhydrous phloroglucinol in step (1) in step (2) is 2-12: 1.
9. The method for preparing trimethylphloroglucinol according to claim 1 or 2, wherein in the step (2), the mass ratio of the purified water to the dimethyl sulfoxide is 1-6: 1.
10. The method of preparing trimethylphloroglucinol according to claim 2, wherein the recrystallization solvent independently comprises methanol, ethanol, isopropanol, acetone, diethyl ether, petroleum ether, ethyl acetate or an aqueous solution of the above solvents in step (3) and step (4).
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