CN117586317A - Preparation method of high-purity methyl hesperidin - Google Patents
Preparation method of high-purity methyl hesperidin Download PDFInfo
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- CN117586317A CN117586317A CN202311592285.8A CN202311592285A CN117586317A CN 117586317 A CN117586317 A CN 117586317A CN 202311592285 A CN202311592285 A CN 202311592285A CN 117586317 A CN117586317 A CN 117586317A
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- hesperidin
- methyl hesperidin
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- tetramethyl
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- GUMSHIGGVOJLBP-SLRPQMTOSA-N methyl hesperidin Chemical compound C1=C(OC)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 GUMSHIGGVOJLBP-SLRPQMTOSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 claims abstract description 21
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 claims abstract description 21
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 claims abstract description 21
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 claims abstract description 21
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 claims abstract description 21
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229940025878 hesperidin Drugs 0.000 claims abstract description 21
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- -1 tetramethyl quaternary ammonium salt Chemical class 0.000 claims abstract description 16
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 238000000746 purification Methods 0.000 claims abstract description 7
- 238000004090 dissolution Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims description 10
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 claims description 4
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 claims description 4
- 230000011987 methylation Effects 0.000 abstract description 15
- 238000007069 methylation reaction Methods 0.000 abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 12
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012022 methylating agents Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NDTCCAGOOOOBNJ-ZHVSJPNKSA-N C1=C(O)C(OC)=CC=C1\C=C\C(=O)C(C(=C1)O)=C(O)C=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 Chemical compound C1=C(O)C(OC)=CC=C1\C=C\C(=O)C(C(=C1)O)=C(O)C=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 NDTCCAGOOOOBNJ-ZHVSJPNKSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002740 effect on eyes Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006485 reductive methylation reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of methyl hesperidin, and relates to a preparation method of high-purity methyl hesperidin, which comprises the following preparation steps: s1, adding hesperidin into N, N-dimethylformamide, stirring for dissolution, adding tetramethyl quaternary ammonium salt, stirring, heating for reaction to obtain a reaction solution, and S2, carrying out vacuum concentration on the reaction solution obtained in the step S1 to obtain a methyl hesperidin crude product; s3, dissolving the crude methyl hesperidin obtained in the step S2 in a purification solvent, and filtering to obtain the methyl hesperidin. According to the invention, the tetramethyl quaternary ammonium salt is used as a methylation reagent, so that the efficient chemoselective methylation of the hesperidin can be realized, the concentration is carried out, and then the methyl hesperidin is obtained by recrystallisation by using an organic solvent, wherein the purity is more than 98%, the yield is more than 70%, the reaction process is safe, the operation is simple and convenient, the efficiency is high, the environment is protected, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of methyl hesperidin, and relates to a preparation method of high-purity methyl hesperidin.
Background
The preparation method of the methyl hesperidin mainly comprises a chemical synthesis method and a plant extraction method, and because the content of the methyl hesperidin in natural plants is extremely low, the main source of the methyl hesperidin is prepared by a method of methylation of the hesperidin.
The chemical synthesis method of methyl hesperidin comprises a dimethyl sulfate synthesis method, a dimethyl carbonate synthesis method and the like: 1 dimethyl sulfate synthesis:
(1) The industrial design institute Yang Ailing in wenzhou city adopts dimethyl sulfate as a methylation reagent, and the dimethyl sulfate is added into a mixed system of hesperidin, water and sodium hydroxide in batches, and the yield of the method is only 40%;
(2) The electronic technology university Wang adopts dimethyl sulfate as a methylation reagent, and comprehensive researches on the synthesis, extraction and extraction process conditions of methyl hesperidin are carried out, but the preparation method uses a large amount of extraction solvent, so that the environmental protection is greatly pressurized, the n-butanol smell of the extraction solvent is great, and certain confusion is brought to industrialization;
(3) The method comprises the steps of dissolving hesperidin in an aqueous solution of calcium hydroxide to generate hesperidin chalcone, carrying out methylation by dimethyl sulfate, and separating and purifying to obtain methyl hesperidin, wherein the yield of the product can reach 75%, but the dimethyl sulfate belongs to a high-toxicity substance, so that the product has a strong stimulation effect on eyes and upper respiratory tracts of people and has strong corrosiveness on skin. In addition, liver, kidney, cardiac muscle, etc. may be seriously damaged, and contact allergic dermatitis may be caused; today, in pursuing green chemical production processes, whether in laboratory small-scale synthesis or in factory large-scale production of methyl hesperidin, dimethyl sulfate is adopted as a methylation reagent, a relatively backward production process is adopted;
2 synthesis of dimethyl carbonate:
the university of Chinese medicine Chen Jianqiu et al adopts low-toxicity dimethyl carbonate to replace dimethyl sulfate as a methylation reagent, firstly, hesperidin is dissolved in pyridine, the methylation reagent and a catalyst are respectively added, and a polyamide column is used for separation and purification, so that a crude product is obtained, the yield is 23.3%, and the yield is not high.
Based on the method, the invention provides a preparation method of methyl hesperidin with high efficiency, environmental protection, high yield and high product purity.
Disclosure of Invention
The invention aims to solve the technical problems and provide a preparation method of high-purity methyl hesperidin, which adopts hesperidin and tetramethyl quaternary ammonium salt to react under heating in the presence of N, N-dimethylformamide solution to prepare a methyl hesperidin crude product, and the methyl hesperidin crude product is recrystallized to obtain the high-purity methyl hesperidin, wherein the yield is more than 70 percent and the content is more than 98 percent.
The technical scheme for solving the technical problems is as follows:
the invention provides a preparation method of high-purity methyl hesperidin, which comprises the following preparation steps:
s1, adding hesperidin into N, N-dimethylformamide, stirring for dissolution, adding tetramethyl quaternary ammonium salt, stirring, and heating for reaction to obtain a reaction solution;
s2, carrying out vacuum concentration on the reaction liquid obtained in the step S1 to obtain a methyl hesperidin crude product;
s3, dissolving the crude methyl hesperidin obtained in the step S2 in a purification solvent, and filtering to obtain the methyl hesperidin.
Further, in step S1, the tetramethyl quaternary ammonium salt is one of tetramethyl ammonium fluoride, tetramethyl ammonium iodide, tetramethyl ammonium bromide and tetramethyl ammonium chloride.
Further, in step S1, the temperature of the heating reaction is controlled to 80-100 ℃.
Further, in step S1, the heating reaction time is 12 hours.
Further, in step S1, the molar ratio of hesperidin to tetramethyl quaternary ammonium salt is 1: (1-3.5).
Further, in step S3, the purification solvent is ethanol, methanol, acetonitrile or acetone.
Further, in step S3, the purified solvent obtained after filtration is concentrated and crystallized to obtain methyl hesperidin.
The beneficial effects of the invention are as follows:
1. the method adopts the tetramethyl quaternary ammonium salt as the methylating agent, is efficient and environment-friendly, reduces the pollution to the environment, and ensures that the yield of the methyl hesperidin prepared by the method reaches more than 70 percent and the content (purity) reaches more than 98 percent;
2. the preparation method disclosed by the invention is safe in reaction process, simple and convenient to operate, efficient and environment-friendly, suitable for industrial production, free from n-butanol and related organic solvents for extraction, and capable of reducing solvent residues, so that the product is safer and higher in purity.
Detailed Description
The principles and features of the present invention are described below with examples given for the purpose of illustration only and are not intended to limit the scope of the invention.
Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or may be prepared by existing methods.
The sources of part of raw materials of the invention are as follows:
n, N-Dimethylformamide (DMF) was purchased from Chengdu Corp.
The invention provides a preparation method of high-purity methyl hesperidin, which comprises the following preparation steps:
s1, adding hesperidin into N, N-dimethylformamide, stirring for dissolution, adding tetramethyl quaternary ammonium salt, stirring, heating for reaction to obtain reaction liquid,
s2, carrying out vacuum concentration on the reaction liquid obtained in the step S1 to obtain a methyl hesperidin crude product;
s3, dissolving the crude methyl hesperidin obtained in the step S2 in a purification solvent, and filtering to obtain the methyl hesperidin.
The tetramethyl quaternary ammonium salt is used as a methylating agent to realize the efficient chemoselective methylation of the hesperidin,
methylation typically involves the use of labile, volatile or toxic methylating agents such as methyl iodide, dimethyl sulfate, etc., and also requires an excess of a strong base; alternative processes include reductive methylation with formaldehyde or methylation with methanol under transition metal catalysis, but the former requires an excess of a reducing agent and a strong acid (such as trifluoroacetic acid), and the latter has relatively low conversion and severe reaction conditions. Peroxide or PO (OMe) 3 can also be used as a methylating agent, but special transition metal catalysts are required, and these disadvantages limit the scope of applicability of these methods, and the present invention can achieve efficient chemoselective methylation of alcohols using tetramethyl ammonium fluoride (TMAF) as a methylating agent.
The method does not use n-butanol and related organic solvents for extraction, reduces solvent residues, and ensures that the product is safer and has higher purity.
As an alternative embodiment, in step S1, the tetramethyl quaternary ammonium salt is one of tetramethyl ammonium fluoride, tetramethyl ammonium iodide, tetramethyl ammonium bromide and tetramethyl ammonium chloride.
As an alternative embodiment, in step S1, the temperature of the heating reaction is controlled between 80 and 100 ℃. The temperature is lower than 80 ℃, the reaction time is longer, and the reaction does not occur when the temperature is reduced to room temperature.
As an alternative embodiment, in step S1, the heating reaction time is 12 hours.
As an alternative embodiment, in step S1, the molar ratio of hesperidin to tetramethyl quaternary ammonium salt is 1: (1-3.5).
As an alternative embodiment, in step S3, the purification solvent is ethanol.
Specifically, the crude methyl hesperidin is dissolved in 85% ethanol, and stirred at minus 5 ℃ to increase crystallization amount.
As an alternative embodiment, in step S3, the purified solvent obtained after filtration is concentrated and crystallized to obtain methyl hesperidin.
Preferably, methyl hesperidin is also present in the purified solvent obtained after filtration, and is concentrated and crystallized to separate out residual methyl hesperidin.
The present invention will be described in detail with reference to examples and experimental data, wherein the following examples are not given to particular conditions, and are generally determined according to national standards. If the corresponding national standard does not exist, the method is carried out according to the general international standard, the conventional condition or the condition recommended by the manufacturer.
Example 1
10L of DMF and 1Kg of hesperidin are added into a 20L reaction kettle, stirred and dissolved, 0.38kg of tetramethyl ammonium fluoride is added at room temperature, stirred for 12 hours at 100 ℃, cooled to room temperature, stirred for 1 hour, filtered, and the solvent is distilled off from the filtrate under reduced pressure, thus obtaining brown massive solid. Dissolving the solid in 5L of 85% ethanol, stirring for 5 hours at minus 5 ℃, increasing crystallization amount to ensure that insoluble substances are completely changed into loose suspended substances, filtering, and obtaining 0.88 kg of product by vacuum drying, wherein the filter cake is yellow solid, and HPLC: purity 98.2% and yield 87%.
Example 2
10L of DMF and 0.5Kg of hesperidin are added into a 20L reaction kettle, stirred and dissolved, 0.15kg of tetramethyl ammonium bromide is added at room temperature, stirred for 12 hours at 100 ℃, cooled to room temperature, stirred for 1 hour, filtered, and the solvent is distilled off from the filtrate under reduced pressure, thus obtaining brown massive solid. This solid was dissolved in 2.5l of 85% ethanol and stirred for 1 hour at minus 5 ℃ to completely turn the insoluble matter into a loose suspension, filtered, the filter cake was a yellow solid, and dried in vacuo to give 0.41 kg of product, HPLC: purity 98.3% and yield 82%.
Example 3
10L of DMF and 0.5Kg of hesperidin are added into a 20L reaction kettle, stirred and dissolved, 0.12kg of tetramethyl ammonium iodide is added at room temperature, stirred for 12 hours at 100 ℃, cooled to room temperature, stirred for 1 hour, filtered, and the solvent is distilled off from the filtrate under reduced pressure, thus obtaining brown massive solid. This solid was dissolved in 2.5l of 85% ethanol and stirred for 5 hours at minus 5 ℃ to completely turn the insoluble matter into a loose suspension, filtered, the filter cake was a yellow solid, dried in vacuo to give 0.4 kg of product, HPLC: purity 98.3% and yield 81%.
Example 4
10L of DMF and 0.5Kg of hesperidin are added into a 20L reaction kettle, stirred and dissolved, 0.14kg of tetramethyl ammonium chloride is added at room temperature, stirred for 12 hours at 100 ℃, cooled to room temperature, stirred for 1 hour, filtered, and the solvent is distilled off from the filtrate under reduced pressure, thus obtaining brown massive solid. This solid was dissolved in 2.5l of 85% ethanol and stirred for 5 hours at minus 5 ℃ to completely turn the insoluble matter into a loose suspension, filtered, the filter cake was a yellow solid, and dried in vacuo to give 0.386 kg of product, HPLC: purity 98.5% and yield 77%.
Example 5
10L of DMF and 1Kg of hesperidin are added into a 20L reaction kettle, stirred and dissolved, 0.38kg of tetramethyl ammonium fluoride is added at room temperature, stirred for 12 hours at 80 ℃, cooled to room temperature, stirred for 1 hour, filtered, and the solvent is distilled off from the filtrate under reduced pressure to obtain brown massive solid. The solid was dissolved in 5l of 85% ethanol and stirred for 5 hours at minus 5 ℃ to completely turn insoluble matter into loose suspension, filtered, the filter cake was yellow solid, dried in vacuo to yield 0.77 kg of product, HPLC: purity 98.1% and yield 75%.
Comparative example 1
10L of 1, 4-dioxane and 1Kg of hesperidin are added into a 20L reaction kettle, stirred and dissolved, 0.17Kg of tetramethyl ammonium fluoride is added at room temperature, stirred for 12 hours at 100 ℃, cooled to room temperature, stirred for 1 hour, filtered, and the solvent is distilled off from the filtrate under reduced pressure to obtain brown massive solids. The solid was dissolved in 5l of 85% ethanol and stirred for 5 hours at minus 5 ℃ to completely turn the insoluble matter into a loose suspension, filtered, the filter cake was a yellow solid, and dried in vacuo to give 0.37 kg of product, HPLC: purity 98.1% and yield 36%.
From comparative example 1 and example 1, it can be obtained that methyl hesperidin is obtained by dissolving hesperidin in DMF and then carrying out methylation by tetramethyl ammonium fluoride, and the yield and purity are higher.
As can be seen from the above, the optimum conditions for the process of the present invention are TMAF (2.5 eq.) with DMF (0.4M) as solvent and heating to 100 ℃.
In conclusion, the method adopts the tetramethyl quaternary ammonium salt as the methylation reagent, is efficient and environment-friendly, reduces the pollution to the environment, and ensures that the yield of the methyl hesperidin prepared by the method reaches more than 70 percent and the content reaches more than 98 percent; the preparation method disclosed by the invention is safe in reaction process, simple and convenient to operate, efficient and environment-friendly, suitable for industrial production, free from n-butanol and related organic solvents for extraction, and capable of reducing solvent residues, so that the product is safer and higher in purity.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (7)
1. The preparation method of the high-purity methyl hesperidin is characterized by comprising the following preparation steps:
s1, adding hesperidin into N, N-dimethylformamide, stirring for dissolution, adding tetramethyl quaternary ammonium salt, stirring, and heating for reaction to obtain a reaction solution;
s2, carrying out vacuum concentration on the reaction liquid obtained in the step S1 to obtain a methyl hesperidin crude product;
s3, dissolving the crude methyl hesperidin obtained in the step S2 in a purification solvent, and filtering to obtain the methyl hesperidin.
2. The method for preparing high-purity methyl hesperidin according to claim 1, wherein in the step S1, the tetramethyl quaternary ammonium salt is one of tetramethyl ammonium fluoride, tetramethyl ammonium iodide, tetramethyl ammonium bromide and tetramethyl ammonium chloride.
3. The method for preparing high purity methyl hesperidin according to claim 1, wherein in step S1, the temperature of the heating reaction is controlled to 80-100 ℃.
4. The method for preparing high-purity methyl hesperidin according to claim 1, wherein in the step S1, the heating reaction time is 12 hours.
5. The method for preparing high-purity methyl hesperidin according to claim 1, wherein in step S1, the molar ratio of hesperidin to tetramethyl quaternary ammonium salt is 1: (1-3.5).
6. The method for preparing high-purity methyl hesperidin according to claim 1, wherein in step S3, the purifying solvent is ethanol 。
7. The method for preparing high-purity methyl hesperidin according to claim 1, wherein in step S3, the purified solvent obtained after filtration is concentrated and crystallized to obtain methyl hesperidin.
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