CN113061084B - Novel method for preparing ferulic acid - Google Patents
Novel method for preparing ferulic acid Download PDFInfo
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- CN113061084B CN113061084B CN202011639485.0A CN202011639485A CN113061084B CN 113061084 B CN113061084 B CN 113061084B CN 202011639485 A CN202011639485 A CN 202011639485A CN 113061084 B CN113061084 B CN 113061084B
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- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 title claims abstract description 56
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 title claims abstract description 56
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 title claims abstract description 55
- 229940114124 ferulic acid Drugs 0.000 title claims abstract description 55
- 235000001785 ferulic acid Nutrition 0.000 title claims abstract description 55
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims abstract description 24
- 235000012141 vanillin Nutrition 0.000 claims abstract description 23
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims abstract description 23
- 230000008569 process Effects 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 229940101545 mi-acid Drugs 0.000 claims abstract description 12
- 150000007524 organic acids Chemical class 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 238000007664 blowing Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 7
- 239000007788 liquid Substances 0.000 abstract description 4
- 230000008859 change Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000220479 Acacia Species 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- OEWLZTGXBCJPKL-MSEGBBJSSA-N (e)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid;piperazine Chemical compound C1CNCCN1.COC1=CC(\C=C\C(O)=O)=CC=C1O.COC1=CC(\C=C\C(O)=O)=CC=C1O OEWLZTGXBCJPKL-MSEGBBJSSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IHKNVZISLLDMOR-UHFFFAOYSA-N O-Acetylferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1OC(C)=O IHKNVZISLLDMOR-UHFFFAOYSA-N 0.000 description 2
- IHKNVZISLLDMOR-GQCTYLIASA-N O-acetylferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1OC(C)=O IHKNVZISLLDMOR-GQCTYLIASA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- AUJXJFHANFIVKH-GQCTYLIASA-N trans-methylferulate Chemical compound COC(=O)\C=C\C1=CC=C(O)C(OC)=C1 AUJXJFHANFIVKH-GQCTYLIASA-N 0.000 description 2
- 235000015099 wheat brans Nutrition 0.000 description 2
- HZIWJAKHBOSVLV-UHFFFAOYSA-N 5-[(4-hydroxy-3-methoxyphenyl)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione Chemical compound C1=C(O)C(OC)=CC(C=C2C(OC(C)(C)OC2=O)=O)=C1 HZIWJAKHBOSVLV-UHFFFAOYSA-N 0.000 description 1
- 101001065065 Aspergillus awamori Feruloyl esterase A Proteins 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010051920 Glomerulonephropathy Diseases 0.000 description 1
- 241000112528 Ligusticum striatum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 208000010353 central nervous system vasculitis Diseases 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 244000221110 common millet Species 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- AUJXJFHANFIVKH-UHFFFAOYSA-N methyl cis-ferulate Natural products COC(=O)C=CC1=CC=C(O)C(OC)=C1 AUJXJFHANFIVKH-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- -1 oligosaccharide ferulic acid ester Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003506 piperazine hexahydrate Drugs 0.000 description 1
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- 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)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a novel method for preparing ferulic acid, belonging to the field of drug synthesis. The invention takes vanillin and Mi's acid as initial raw materials, organic acid as catalyst, and ferulic acid is obtained by reaction. The preparation process of the invention adopts cheap and easily available initial raw materials, the synthesis process is environment-friendly, and the waste liquid and organic solvent generated in the reaction system and the post-treatment are less. The operation process is simple, the feeding procedure is simple, no special equipment is needed, the steps are conventional, the control of related parameters can be within a certain range, the final yield and purity of the product can not be influenced by the change of the tiny parameters, and the process is stable and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a method for synthesizing ferulic acid.
Background
Ferulic acid is 4-hydroxy-3-methoxycinnamic acid with molecular formula of C 10 H 10 O 4 The structural formula is as follows:
the piperazine ferulate can be prepared by taking piperazine ferulate and piperazine hexahydrate as raw materials for reaction. Piperazine ferulate is the main active ingredient of the traditional Chinese medicine ligusticum wallichii, has the functions of anticoagulation, platelet aggregation prevention, microcirculation improvement, vasospasm relief and coronary artery flow increase, and is clinically suitable for the auxiliary treatment of glomerulonephropathy accompanied with microscopic haematuria and hypercoagulable state, coronary heart disease, cerebral infarction, vasculitis and the like.
The preparation of ferulic acid mainly comprises three methods: alkaline hydrolysis, enzymatic hydrolysis and chemical synthesis.
1. The alkaline hydrolysis process is one semisynthesis process of preparing ferulic acid, and the ferulic acid is cross-linked with polysaccharide and lignin via ester bond to form one part of polymer, and the alkali process or enzyme process is used to break the ester bond to release ferulic acid and the proper solvent is used for extraction. Usually, sodium hydroxide solution with low concentration is adopted, most of ferulic acid in the wheat drum can be released at a proper extraction temperature, and sodium sulfite protective agent is added or nitrogen is continuously filled in the extraction process, so that the recovery rate of the ferulic acid can be increased. In the whole process of preparing the ferulic acid, the method has the key and difficult points that the crude ferulic acid is usually extracted by an extraction method, and the ferulic acid is purified by adopting chromatographic column separation, so that the process is complicated, the purification is difficult, and the large-scale industrialization is difficult.
2. The enzyme hydrolysis method is to culture an enzyme to free ferulic acid from ferulic acid methyl ester, oligosaccharide ferulic acid ester and polysaccharide ferulic acid. For example, aspergillus niger is used as strain, a liquid submerged fermentation method is adopted to prepare a mixed enzyme preparation containing feruloyl esterase and arabinoxylase, the mixed enzyme preparation is used for acting on the wheat bran with starch removed, and the wheat bran is degraded to release ferulic acid. The preparation of ferulic acid by using biological enzyme to decompose raw materials is an ideal method with wide application prospect, but a high-efficiency production method cannot be researched at present, and further research on how to culture and enrich the special enzyme preparation with high efficiency is still needed.
3. The chemical synthesis method finds that the synthetic route of the ferulic acid mainly comprises the following 2 steps of: the first method for synthesizing the compound comprises the following steps: journal Chines e Journal of Pharmaceuticals 1997,28 of Chinese medicine industry (4)
The catalyst used in the reaction is pyridine, aniline, etc., and the solvent and the water-carrying agent are toluene. Pyridine has strong malodor and high toxicity; aniline has strong carcinogenesis; toluene is also a volatile, moderately strong, toxic organic solvent that does not meet the green chemistry requirements. The reaction takes a long time, up to several tens of hours.
The second method for synthesizing the compound comprises the following steps: chinese patent CN105566101a
The vanillin is used as a raw material, a new ferulic acid synthesis route is provided, the vanillin reacts with acetic anhydride at high temperature in the presence of potassium carbonate to generate acetylferulic acid, and the acetylferulic acid is hydrolyzed under alkaline conditions to obtain the ferulic acid.
The synthetic route still uses vanillin as a starting material, is not complex, but has some disadvantages: (1) The reaction temperature is high, and the long-time high-temperature reaction easily causes cis-conformation isomerization of the ferulic acid. (2) The reaction yield is low, the yield of the ferulic acid synthesis step is about 60%, and a large amount of unreacted vanillin is not easy to remove, so that the purity of the synthesized ferulic acid is low.
Therefore, the development of a preparation method with energy conservation, environmental protection and simple process in the field of ferulic acid synthesis has great applicability.
Disclosure of Invention
The invention provides a novel method for preparing ferulic acid, which adopts cheap and easily available starting materials on the basis of the prior reports, has the advantages of green and environment-friendly synthesis process, simple and convenient operation, high product purity, stable process and suitability for industrial production.
The invention takes vanillin and Mi's acid as initial raw materials, organic acid as catalyst, the ferulic acid is obtained by reaction, and the preparation equation is as follows:
the organic acid is specifically carboxylic acid, and can be further specifically: one or more of acetic acid, formic acid, tartaric acid and malic acid.
The molar ratio of the organic acid to vanillin is 0.1-0.5.
The solvent adopted in the reaction system is a polar solvent, preferably one or more mixed solvents of water, ethanol and methanol.
The physique ratio V/M of the solvent and vanillin in the reaction system is 3-5.
The reaction temperature is 40-80 ℃, preferably 70-80 ℃.
The molar ratio of vanillin to milbezier acid is 1:1-1:1.2.
the specific operation steps are as follows:
step 1: adding vanillin, mi's acid and an organic acid catalyst into a reaction system, reacting in a polar solvent at 40-80 ℃, cooling to room temperature after TLC monitoring reaction is completed, and filtering to obtain a ferulic acid crude product;
step 2: adding aqueous solution of organic alcohol into the ferulic acid crude product for recrystallization, crystallizing and filtering, leaching a filter cake with water, and drying by blowing to obtain the ferulic acid.
Further, the recrystallized organic alcohol in the specific step above may be one or more of ethanol or methanol or isopropanol.
Further, the volume content of the organic alcohol in the solution of the recrystallized organic alcohol water in the specific steps is 40-60%.
Further, the stability of the forced air drying in the above specific steps is 40-65 ℃.
Condensing Mi's acid under acidic condition, removing acetone, decarboxylating to obtain ferulic acid, wherein the specific reaction mechanism is as follows:
the vanillin has the chemical name of 4-hydroxy-3-methoxybenzaldehyde, also known as protomethylcatechol and vanillin, is widely applied to industries such as food, beverage, cosmetics, daily chemicals, medicines and the like, has low toxicity, is used as a starting material for preparing ferulic acid, and has high process safety.
Mild acid is a common chemical raw material and a common medical intermediate, the raw material is easy to obtain and store, and the normal state is solid, so that the use in the process operation is very convenient.
Organic acids are used as catalysts, for example carboxylic acids: acetic acid, formic acid and the like are common carboxylic acids, and the preparation method has the advantages of low price, simple components and simple preparation. Compared with the water extract of the acacia pod disclosed and reported in the literature, the water extract of the acacia pod is cheap and easy to obtain as a catalyst, is troublesome to prepare and has low yield. In addition, it is reported in the literature that whether the water extract of acacia pod can cope with the amplification effect is not known at all because the number of experimental moles of the water extract of acacia pod as a catalyst is small. In other documents, crops and wastewater are used as solvents for the reaction of vanillin and Mi's acid, and the waste liquid can be utilized, but a large amount of unknown impurities and microorganisms can be introduced into the production of medical products, so that the complexity of purification and detection is brought, and the method is not applicable to the preparation of medical raw medicines.
The preparation process of the invention adopts cheap and easily available initial raw materials, the synthesis process is environment-friendly, and the waste liquid and organic solvent generated in the reaction system and the post-treatment are less. The operation process is simple, the feeding procedure is simple, no special equipment is needed, the steps are conventional, the control of related parameters can be within a certain range, the final yield and purity of the product can not be influenced by the change of the tiny parameters, and the process is stable and suitable for industrial production.
Detailed Description
The present invention will be described in detail with reference to specific examples.
TLC was: thin layer chromatography.
Petroleum ether boiling range 60-90 deg.c.
Constitution ratio V/M is the ratio of volume to mass, in mL/g.
Example 1
10g of vanillin, 9.5g of Mi's acid, 30mL of water and 0.5g of glacial acetic acid are added into a 100mL three-necked flask as a catalyst for reaction at 75 ℃, 6hTLC (ethyl acetate: petroleum ether: 1:1) is monitored to monitor that the reaction is complete, the temperature is reduced to room temperature, and a ferulic acid crude product is obtained by filtration.
Adding 50% ethanol water solution into the ferulic acid crude product for recrystallization, crystallizing and filtering, leaching a filter cake with water, and drying by blowing at 60 ℃ to obtain 10.7g of ferulic acid with a yield of 84%.
Example 2
10g of vanillin, 9.5g of Mi's acid and 50mL of water are added into a 100mL three-necked flask, 0.3g of formic acid is added as a catalyst for reaction at 75 ℃, 7hTLC (ethyl acetate: petroleum ether: 1:1) is monitored to monitor that the reaction is complete, the temperature is reduced to room temperature, and a ferulic acid crude product is obtained by filtration.
Adding 50% ethanol water solution into the ferulic acid crude product for recrystallization, crystallizing and filtering, leaching a filter cake with water, and drying by blowing at 60 ℃ to obtain 10g of ferulic acid with the yield of 79%.
Example 3
10g of vanillin, 9.5g of Mi's acid and 30mL of water are added into a 100mL three-necked flask, 1g of tartaric acid is added as a catalyst, the mixture is reacted at 75 ℃ for 10 hours, the temperature is reduced to room temperature, and a ferulic acid crude product is obtained by filtration.
Adding 50% ethanol water solution into the ferulic acid crude product for recrystallization, crystallizing and filtering, leaching a filter cake with water, and drying by blowing at 60 ℃ to obtain 6.3g of ferulic acid with a yield of 50%.
Example 4
10g of vanillin, 9.5g of Mi's acid and 30mL of water are added into a 100mL three-necked flask, 1g of malic acid is added as a catalyst, the mixture is reacted at 75 ℃ for 10 hours, the mixture is cooled to room temperature, and a ferulic acid crude product is obtained by filtration.
Adding 50% ethanol water solution into the ferulic acid crude product for recrystallization, crystallizing and filtering, leaching a filter cake with water, and drying by blowing at 60 ℃ to obtain 6.6g of ferulic acid with the yield of 52%.
Examples 5 to 11
General conditions: 10g of vanillin, 9.5g of Mi's acid and 30mL of water are added into a 100mL three-necked flask, 0.5g of glacial acetic acid is added as a catalyst, TLC (ethyl acetate: petroleum ether: 1:1) is adopted to monitor the reaction completion, the temperature is reduced to room temperature, and the crude ferulic acid is obtained through filtration. The crude ferulic acid is purified by recrystallization or column chromatography.
At different reaction temperatures, the different results were as follows:
summarizing, it was concluded that the comparison of examples 5-11, with a constant change in temperature, affects the yield of ferulic acid, and that the reaction at above 60 ℃ leads to ferulic acid as an intermediate, 5- (4-hydroxy-3-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, at room temperature or at lower temperatures. However, when the temperature is high, the energy consumption of the reaction system is high, and polymerization impurities are generated, so that the reaction yield is reduced.
Claims (6)
1. A preparation method of ferulic acid is characterized in that vanillin and Mi's acid are used as initial raw materials, organic acid is used as a catalyst, and ferulic acid is obtained through reaction;
the organic acid is specifically carboxylic acid;
the carboxylic acid is acetic acid and formic acid;
the reaction temperature is 75-85 ℃;
the solvent in the reaction system is water.
2. The process of claim 1, wherein the molar ratio of organic acid to vanillin is 0.1-0.5.
3. The method according to claim 1, wherein the physical ratio V/M of the solvent to vanillin in the reaction system is 3-5.
4. The method according to claim 1, wherein the molar ratio of vanillin to milbezier acid is 1:1-1:1.2.
5. the preparation method according to claim 1, characterized by the specific operation steps of:
step 1: adding vanillin, mi's acid and an organic acid catalyst into a reaction system, reacting in a water solvent at 75-85 ℃, cooling to room temperature after TLC monitoring reaction is complete, and filtering to obtain a ferulic acid crude product;
step 2: adding aqueous solution of organic alcohol into the ferulic acid crude product for recrystallization, crystallizing and filtering, leaching a filter cake with water, and drying by blowing to obtain the ferulic acid.
6. The method of claim 5, wherein the organic alcohol is one or more of ethanol, methanol, and isopropanol.
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