CN106432386A - Method for synthesizing neohesperidin by taking naringin as raw material - Google Patents
Method for synthesizing neohesperidin by taking naringin as raw material Download PDFInfo
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- CN106432386A CN106432386A CN201610723564.7A CN201610723564A CN106432386A CN 106432386 A CN106432386 A CN 106432386A CN 201610723564 A CN201610723564 A CN 201610723564A CN 106432386 A CN106432386 A CN 106432386A
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- neohesperidin
- aurantiin
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- material synthesis
- hydrolysis
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- ARGKVCXINMKCAZ-UZRWAPQLSA-N neohesperidin 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)O3)O[C@H]3[C@@H]([C@H](O)[C@@H](O)[C@H](C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UZRWAPQLSA-N 0.000 title claims abstract description 65
- 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 title claims abstract description 65
- 238000000034 method Methods 0.000 title claims abstract description 50
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 title claims abstract description 35
- 239000002994 raw material Substances 0.000 title abstract description 5
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 title abstract 3
- 229940052490 naringin Drugs 0.000 title abstract 3
- 229930019673 naringin Natural products 0.000 title abstract 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 239000003513 alkali Substances 0.000 claims abstract description 25
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 22
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 238000009833 condensation Methods 0.000 claims abstract description 11
- 230000005494 condensation Effects 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000007710 freezing Methods 0.000 claims abstract description 5
- 230000008014 freezing Effects 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims description 29
- 238000006460 hydrolysis reaction Methods 0.000 claims description 29
- 238000002425 crystallisation Methods 0.000 claims description 26
- 230000008025 crystallization Effects 0.000 claims description 26
- XLEYFDVVXLMULC-UHFFFAOYSA-N 2',4',6'-trihydroxyacetophenone Chemical compound CC(=O)C1=C(O)C=C(O)C=C1O XLEYFDVVXLMULC-UHFFFAOYSA-N 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 22
- 238000003786 synthesis reaction Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000413 hydrolysate Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 229930182470 glycoside Natural products 0.000 claims description 4
- 150000002338 glycosides Chemical class 0.000 claims description 4
- 235000015895 biscuits Nutrition 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 235000001759 Citrus maxima Nutrition 0.000 claims 1
- 244000276331 Citrus maxima Species 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 9
- 239000000047 product Substances 0.000 abstract description 7
- 238000001914 filtration Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 4
- 239000011261 inert gas Substances 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001035 drying Methods 0.000 abstract 3
- 239000012065 filter cake Substances 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 238000010992 reflux Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 7
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229930182478 glucoside Natural products 0.000 description 3
- 150000008131 glucosides Chemical class 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000005882 aldol condensation reaction Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229930003944 flavone Natural products 0.000 description 2
- 235000011949 flavones Nutrition 0.000 description 2
- 150000002213 flavones Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003335 secondary amines Chemical group 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical group O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000001329 FEMA 3811 Substances 0.000 description 1
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
- VOLMSPGWNYJHQQ-UHFFFAOYSA-N Pyranone Natural products CC1=C(O)C(=O)C(O)CO1 VOLMSPGWNYJHQQ-UHFFFAOYSA-N 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical group 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- -1 flavanone compound Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- ITVGXXMINPYUHD-CUVHLRMHSA-N neohesperidin dihydrochalcone Chemical compound C1=C(O)C(OC)=CC=C1CCC(=O)C(C(=C1)O)=C(O)C=C1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ITVGXXMINPYUHD-CUVHLRMHSA-N 0.000 description 1
- 229940089953 neohesperidin dihydrochalcone Drugs 0.000 description 1
- 235000010434 neohesperidine DC Nutrition 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for synthesizing neohesperidin by taking naringin as a raw material. The method comprises the following steps: (1) hydrolyzing: dissolving the naringin into an aqueous alkali; heating, pressurizing and hydrolyzing; cooling to room temperature and adjusting the pH (Potential of Hydrogen) value with an acid; cooling and crystallizing; filtering and drying to obtain a hydrolyzed product-PN; (2) carrying out condensation: dissolving the PN into an organic solvent; adding isovanillin and histidine; carrying out a refluxing reaction; freezing and crystallizing; filtering and drying to obtain a neohesperidin crude product; (3) refining: heating and dissolving the neohesperidin crude product with a low-carbon alcohol water solution; cooling and crystallizing; filtering and drying a filter cake to obtain a neohesperidin fine product. According to the method provided by the invention, the purity of the neohesperidin in the product can reach 99.5 percent, the content of impurities is less and the yield of the neohesperidin is high; the dosage of an alkali and a catalyst in the method is less, the reaction time is short and the cost is low; in a technological process, protection of inert gas is not needed and anhydrous reaction conditions are not needed, so that the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method of synthesis neohesperidin is and in particular to one kind is with aurantiin for the new orange peel of Material synthesis
The method of glycosides.
Background technology
Neohesperidin is a kind of important flavanone compound, and its synthesis neohesperidin dihydro that is mainly used for looks into ear
A kind of novel sweetener of ketone, its sugariness is 1500～1800 times of sucrose, has sugariness height, and heat is little, and sweet taste is lasting, surely
Qualitative good, avirulent feature, it is widely used in food, medicine and feedstuff industry.At present, domestic and international market is to neohesperidin two
The demand of hydrogen chalcone increasingly increases, but the raw material of synthesis neohesperidin dihydrochalcone is but difficult to meet the need in market
Ask.
The existing method obtaining a large amount of neohesperidins mainly has extraction method and synthetic method.Extract from natural plants and separate
Neohesperidin is limited by resource and production cost.Due to the destruction of ecological environment and the over-exploitation of resource, extraction method obtains
Obtain neohesperidin and do not possess the production advantage.China's aurantiin aboundresources, cheap and easy to get, it is that Material synthesis are newly orange with aurantiin
Skin glycosides, for we providing the new method of a large amount of neohesperidins of acquisition.
The method that US3375242 discloses a kind of synthesis of neohesperidin, the method is by aurantiin and excessive isovanillin
Directly mix, synthesize neohesperidin under the catalysis of potassium hydroxide.Though the method is simple, the loss of isovanillin is huge,
The yield of reaction is low, is not suitable for industrialized production.
The method that US3947405 discloses a kind of synthesis of neohesperidin, the method is by phloroacetophenone -4 '-β-new orange peel
Glucosides（Abbreviation PN）It is dissolved in anhydrous alcohols solvent with isovanillin, under inert gas shielding, made using nafoxidine-acetic acid
For catalyst.But, the method condition is harsh, and the reaction time is long, and reaction requires to carry out under conditions of absolute, has very big
Limitation.
CN103408620A discloses a kind of synthesis technique of neohesperidin, and the method is to be dissolved in PN and isovanillin
In 98% ethanol, successively add major catalyst nafoxidine and co-catalyst acetic acid under nitrogen protection.But, the method is reacted
Process also requires that anhydrous condition, the recovery of 98% ethanol and recycling are difficult in practical operation, and the method is received
Rate highest only 86%, does not possess the advantage of industrialization.
CN101863940A discloses a kind of synthesis technique of neohesperidin, and the method is with aurantiin as raw material, first uses
Basic hydrolysis aurantiin obtains PN, then the condensation with Proline-Catalyzed PN and isovanillin, thus synthesizing neohesperidin.In the method
Although condensation step do not need anhydrous reaction condition, the alkali consumption of hydrolysing step is too big, and the pollution to environment is tight
Weight；Alkali concn is high, during hydrolysis, the side reaction that carbonyl reduction is hydroxyl easily occurs, and leads to hydrolysis yield low, and only 70%；And be catalyzed
Agent proline consumption is big, expensive, and consumption is excessive, and the cost of production is very high；Due to a large amount of interpolations of catalyst, post processing is difficult
Removed with thorough, lead to the purity of final products neohesperidin low, only 97%.
Content of the invention
The technical problem to be solved is to overcome the drawbacks described above of prior art presence, provide a kind of product pure
Degree is high, high income, and without inertia and anhydrous condition, low cost, be suitable for industrialized production is former with aurantiin to technical process
The method of material synthesis neohesperidin.
The technical solution adopted for the present invention to solve the technical problems is as follows：One kind is with aurantiin for the new orange peel of Material synthesis
The method of glycosides, comprises the following steps：
（1）Hydrolysis：Aurantiin is dissolved in aqueous alkali, heating, pressurized hydrolysis, is cooled to room temperature, with acid for adjusting pH value, cold
But crystallization, filters, and is dried, obtains hydrolysate phloroacetophenone -4 '-β-neohesperidoside；
（2）Condensation：By step（1）Gained phloroacetophenone -4 '-β-neohesperidoside is dissolved in water or organic solvent, adds
Isovanillin and histidine, back flow reaction, after reaction completely, freeze crystallization, filter, be dried, obtain neohesperidin crude product；
（3）Refined：By step（2）Gained neohesperidin crude product low carbon alcohol solution heating for dissolving, cooling crystallization, filters, filter
Biscuit is dry, obtains neohesperidin fine work.
Preferably, step（1）In, the alkali in described aqueous alkali is NaOH or potassium hydroxide, the matter of aqueous alkali
Amount concentration is 1～5%, the liquid-solid ratio of aqueous alkali and aurantiin quality（mL/g）For 8～15（More preferably 10～12）.If alkali
Concentration is too low, will lead to hydrolysis not exclusively, yield is low, if the excessive concentration of alkali, will lead to the waste of alkali and neutralization acid, this
Outward, under the alkali and high temperature action of high concentration, carbonyl can be reduced to hydroxyl to the product PN of hydrolysis, leads to hydrolysis yield low；
If aqueous alkali consumption is very few, aurantiin will be led to compared with indissoluble solution and hydrolysis, if aqueous alkali consumption is excessive, will lead to anti-again
After answering liquid acid for adjusting pH value, volume is excessive, and product PN is difficult to crystallization and separates out, and yield is low.
Preferably, step（1）In, the temperature of described hydrolysis is 90～140 DEG C（More preferably 110～130 DEG C）, the pressure of hydrolysis
Power is 0.01～0.40MPa（More preferably 0.1～0.3MPa）, the time of hydrolysis is 0.4～1.5h（More preferably 0.5～1.0h）.
Research shows, heating, pressurized hydrolysis are conducive to the C ring in flavones molecular skeleton（Pyranone structure）Beat completely at short notice
Open, under pressurized conditions, the time of hydrolysis shortens dramatically；And the concentration of alkali is relatively low, side reaction will not be induced, therefore, yield can achieve
Significantly lifted.If temperature is too low, pressure is too small or the time is too short, hydrolysis will be led to not exclusively；If temperature is too high, pressure is excessive
Or overlong time, all will result in the waste of the energy and material.
Preferably, step（1）In, the described acid for adjusting pH value is hydrochloric acid, sulfuric acid or citric acid etc., and the quality of acid is dense
Spend for 10～30%.If the concentration of acid is too low, after leading to reactant liquor acid for adjusting pH value, volume is excessive, and product PN is difficult to crystallize
Separate out, yield is low；If the excessive concentration of acid, locally acidity is too strong to easily cause solution during adjusting pH value, will destroy
The molecular structure of PN and lead to yield low.
Preferably, step（1）In, regulation pH value to 2～7（More preferably 4～6）.If pH value is too low, the molecule of PN will be destroyed
Structure and lead to yield low；If pH value is too high, PN is difficult to separate out in neutrality or alkaline solution.
Preferably, step（2）In, described organic solvent be methyl alcohol, ethanol, isopropanol, n-butanol, acetone, ethyl acetate,
One of dichloromethane or chloroform etc. or two kinds；The consumption of described water or organic solvent is phloroacetophenone -4 '-β-new
5～30 times of orange peel glucosides quality（More preferably 5.2～10.0 times）.If water or consumption of organic solvent are very few, PN, isovanillin and
Histidine can not fully dissolve, and condensation reaction is difficult to be smoothed out；If water or consumption of organic solvent are excessive, PN, isovanillin and
Concentration in reactant liquor for the histidine is low, and the time of reaction will extend, and reaction solution volume is excessive, and neohesperidin is difficult to fill
Analysis is brilliant.
Preferably, step（2）In, the addition of described isovanillin and histidine is to make phloroacetophenone -4 '-β-new
The mass ratio of orange peel glucosides, isovanillin and histidine is 1:0.3～0.4:0.05～0.10（More preferably 1:0.31～0.35:
0.06～0.08）.Although the histidine that the inventive method is used is all amino acid with the proline used in background technology,
But also there is the difference of its essence：1）Histidine is alpha amino acid（-NH2）, proline is a kind of imino acid（-NH）；2）Group ammonia
In alkalescence, proline is not in alkalescence for acid；3）Histidine is polarity, hydrophilic amino acid, and proline is nonpolar, hydrophobic amino
Acid, therefore, they are far from each other in catalytic action.Histidine acts primarily as catalytic action in the reaction, and inventor's research finds,
In addition to having amino and carboxyl as other amino acid, there is imidazole group due in its molecular structure in histidine（Wherein
There is secondary amine）So as to have stronger alkalescence, the condition of alkalescence adds the synergy of secondary amine and carboxyl, meets catalysis
The condition of this reaction, additionally, the imidazole group in histidine molecule can not only be used for proton donor, but also as proton acceptor, and
It is all very fast with the speed accepting proton to confess proton, so histidine can serve as efficient catalysis in this aldol condensation
Agent.In the present invention, because histidine uses primarily as catalyst, therefore, consumption need not be excessive.
Preferably, step（2）In, the temperature of described back flow reaction is 60～95 DEG C（More preferably 80～90 DEG C）, reaction
Time is 2～10h（More preferably 5～8h）.If the temperature of reaction is too low or the reaction time is too short, may result in condensation reaction not
Completely；If the temperature of reaction is too high or the reaction time is long, side reaction odds will be increased, reduce the receipts of condensation reaction
Rate.
Preferably, step（2）In, the temperature of described freezing crystallization is 0～5 DEG C, and the time of crystallization is 12～24h.
Preferably, step（3）In, described low-carbon alcohols are methyl alcohol, ethanol or isopropanol etc.；The body of described low carbon alcohol solution
Long-pending concentration is 30～90%（More preferably 40～70%）, the consumption of low carbon alcohol solution is 5～20 times of neohesperidin crude product quality
（More preferably 6～12 times）.Select low-carbon alcohols as the foundation of dissolution solvent be：1）At different temperature, neohesperidin is in first
Dissolubility difference in alcohol, ethanol and isopropanol is larger, more conducively crystallizes；2）Methyl alcohol, ethanol and isopropanol moderate boiling point, are suitable for
In industrial production, existing certain stability, it is easily recycled again.
Preferably, step（3）In, the temperature of described heating for dissolving is 60～80 DEG C.
Preferably, step（1）In, the temperature of described cooling crystallization is room temperature, and the time of crystallization is 4～8h.
Preferably, step（3）In, the temperature of described cooling crystallization is 20～25 DEG C, and the time of crystallization is 12～24h.
The inventive method step（1）In, the yield of PN hydrolyzes theoretical value 81.96g producing PN according to 100g aurantiin
Calculate；Step（2）In, the yield of neohesperidin is condensed the theoretical value 128.32g calculating producing neohesperidin according to 100gPN.
Room temperature of the present invention is 15～25 DEG C.
The principle of the inventive method：C ring in the presence of alkali lye and high temperature, in its flavones molecular skeleton for the aurantiin（Pyrrole
Mutter ketone structure）To fully open, hydrolysis generates phloroacetophenone -4 '-β-neohesperidoside（PN）, it is used in combination high temperature, pressurization
The mode of hydrolysis, the amount ratio existing process of alkali significantly reduces, and shortens hydrolysis time, and the side reaction of hydrolysis is few, therefore
Improve the yield of PN；In step of condensation, the inventive method is initiated and histidine is used as PN and isovanillin condensation
Catalyst, can meet the condition being catalyzed this reaction, serve as efficient catalyst in this aldol condensation, and reaction rate is high, consumption
Few.
The having the beneficial effect that of the inventive method：
（1）According to the white crystalline powder shape of the inventive method gained neohesperidin fine work, through high-performance liquid chromatography
Detection, the purity of gained neohesperidin may be up to 99.5 %, and impurity content is few, the high income of neohesperidin；
（2）The inventive method adopts high temperature, pressurized hydrolysis mode in hydrolysing step, has saved the consumption of alkali, when shortening reaction
Between, improve the yield of PN, the yield ＞ 85% of hydrolysis；Select histidine as catalyst in condensation step, decrease and urge
The consumption of agent, shortens the time of reaction, condensation reaction yield ＞ 90%；
（3）The inventive method technical process without inert gas shielding, without anhydrous response condition, due to the use of alkali and catalyst
Amount less, each step reaction high income, reduce production cost, be suitable for industrialized production.
Specific embodiment
With reference to embodiment, the invention will be further described.
The aurantiin that the embodiment of the present invention is used is purchased from Hunan Hua Cheng living resources limited company, aurantiin pure
Spend for 98.2%；Embodiment of the present invention step（1）In, the yield of PN hydrolyzes the theoretical value producing PN according to 100g aurantiin
81.96g calculating, step（2）In, the yield of neohesperidin is condensed the theoretical value producing neohesperidin according to 100gPN
128.32g calculating；PN in the embodiment of the present invention be phloroacetophenone -4 '-β-neohesperidoside abbreviation；The embodiment of the present invention
The raw material being used and chemical reagent, if no special instructions, are all obtained by routine business approach.
In the embodiment of the present invention, the detection method of aurantiin, PN and neohesperidin content is high performance liquid chromatography（HPLC）Outward
Mark method.
Embodiment 1
（1）Hydrolysis：100g aurantiin is dissolved in the potassium hydroxide aqueous solution that 1000mL mass concentration is 5%, at 110 DEG C, pressure
Under conditions of power 0.1MPa, hydrolyze 1h, be cooled to room temperature, with the hydrochloric acid conditioning solution pH value of mass concentration 30% to 6, be cooled to
Room temperature, crystallization 6h, filters, is dried, obtains 75.3g hydrolysate PN（Purity 95.3%, yield is 87.6%）；
（2）Condensation：By step（1）Gained 75.3gPN is dissolved in 400g ethanol（Volumetric concentration is 95%）In, add 23.87g different
Vanillic aldehyde and 4.52g histidine, at 85 DEG C, back flow reaction 5h, after reaction completely, place reaction liquid at 0 DEG C, freeze crystallization
12h, filters, and is dried, obtains neohesperidin crude product 94.39g（Purity 95.6%, yield is 93.4%）；
（3）Refined：By step（2）Gained 94.39g neohesperidin crude product, the ethanol water being 50% with 900g volumetric concentration,
It is heated to 75 DEG C of dissolvings, be cooled to 25 DEG C, crystallization 24h, filters, filtration cakes torrefaction, obtains neohesperidin fine work 86.42g.
Gained neohesperidin fine work white crystalline powder shape, through high-performance liquid chromatography detection, neohesperidin
Purity be 99.5%, refined yield be 95.3%.
Embodiment 2
（1）Hydrolysis：200g aurantiin is dissolved in the potassium hydroxide aqueous solution that 2200mL mass concentration is 4%, at 120 DEG C, pressure
Under conditions of power 0.2MPa, hydrolyze 1h, be cooled to room temperature, with the sulfuric acid regulation solution pH value of mass concentration 20% to 5.5, cool down
To room temperature, crystallization 6h, filter, be dried, obtain 152.1g hydrolysate PN（Purity 93.7%, yield is 86.9%）；
（2）Condensation：By step（1）Gained 152.1g PN is dissolved in 1500g methyl alcohol（Volumetric concentration is 90%）In, add 48.22g
Isovanillin and 10.6g histidine, at 80 DEG C, back flow reaction 6h, after reaction completely, place reaction liquid at 2 DEG C, freezing analysis
Brilliant 20h, filters, and is dried, obtains neohesperidin crude product 191.8g（Purity 93.9%, yield is 92.3%）；
（3）Refined：By step（2）Gained 191.8g neohesperidin crude product, the isopropanol being 60% with 1500g volumetric concentration is water-soluble
Liquid, is heated to 80 DEG C of dissolvings, is cooled to 20 DEG C, and crystallization 18h filters, filtration cakes torrefaction, obtains neohesperidin fine work 171.1g.
Gained neohesperidin fine work white crystalline powder shape, through high-performance liquid chromatography detection, neohesperidin
Purity be 99.3%, refined yield be 94.3%.
Embodiment 3
（1）Hydrolysis：100g aurantiin is dissolved in the sodium hydrate aqueous solution that 1200mL mass concentration is 3%, at 130 DEG C, pressure
Under conditions of power 0.3MPa, hydrolyze 0.5h, be cooled to room temperature, with the lemon acid for adjusting pH value of mass concentration 10% to 5, be cooled to
Room temperature, crystallization 6h, filters, is dried, obtains 74.7g hydrolysate PN（Purity 93.6%, yield is 85.3%）；
（2）Condensation：By step（1）Gained 74.7g PN is dissolved in 740g isopropanol（Volumetric concentration is 90%）In, add 23.87g
Isovanillin and 5.92g histidine, at 90 DEG C, back flow reaction 8h, after reaction completely, place reaction liquid at 2 DEG C, freezing analysis
Brilliant 20h, filters, and is dried, obtains neohesperidin crude product 92.3g（Purity 93.6%, yield is 90.1%）；
（3）Refined：By step（2）Gained 92.3g neohesperidin crude product, the methanol aqueous solution being 55% with 923g volumetric concentration, plus
Heat dissolves to 70 DEG C, is cooled to 20 DEG C, crystallization 18h, filters, filtration cakes torrefaction, obtains neohesperidin fine work 82.49g.
Gained neohesperidin fine work white crystalline powder shape, through high-performance liquid chromatography detection, neohesperidin
Purity be purity 99.5%, refined yield be 95%.
Claims (10)
1. a kind of with aurantiin for the method for Material synthesis neohesperidin it is characterised in that comprising the following steps：
（1）Hydrolysis：Aurantiin is dissolved in aqueous alkali, heating, pressurized hydrolysis, is cooled to room temperature, with acid for adjusting pH value, cold
But crystallization, filters, and is dried, obtains hydrolysate phloroacetophenone -4 '-β-neohesperidoside；
（2）Condensation：By step（1）Gained phloroacetophenone -4 '-β-neohesperidoside is dissolved in water or organic solvent, adds
Isovanillin and histidine, back flow reaction, after reaction completely, freeze crystallization, filter, be dried, obtain neohesperidin crude product；
（3）Refined：By step（2）Gained neohesperidin crude product low carbon alcohol solution heating for dissolving, cooling crystallization, filters, filter
Biscuit is dry, obtains neohesperidin fine work.
2. according to claim 1 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step（1）In,
Alkali in described aqueous alkali is NaOH or potassium hydroxide, and the mass concentration of aqueous alkali is 1～5%, aqueous alkali and shaddock
The liquid-solid ratio of skin glycosides quality is 8～15.
3. according to claim 1 or claim 2 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step（1）
In, the temperature of described hydrolysis is 90～140 DEG C, and the pressure of hydrolysis is 0.01～0.40MPa, and the time of hydrolysis is 0.4～1.5h.
4. according to one of claims 1 to 3 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step
Suddenly（1）In, the described acid for adjusting pH value is hydrochloric acid, sulfuric acid or citric acid, and the mass concentration of acid is 10～30%；Adjust pH
It is worth to 2～7.
5. according to one of Claims 1 to 4 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step
Suddenly（2）In, described organic solvent is methyl alcohol, ethanol, isopropanol, n-butanol, acetone, ethyl acetate, dichloromethane or three chloromethanes
One of alkane or two kinds；The consumption of described water or organic solvent be phloroacetophenone -4 '-β-neohesperidoside quality 5～
30 times.
6. according to one of Claims 1 to 5 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step
Suddenly（2）In, the addition of described isovanillin and histidine is to make phloroacetophenone -4 '-β-neohesperidoside, isovanillin
Mass ratio with histidine is 1:0.3～0.4:0.05～0.10.
7. according to one of claim 1～6 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step
Suddenly（2）In, the temperature of described back flow reaction is 60～95 DEG C, and the time of reaction is 2～10h.
8. according to one of claim 1～7 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step
Suddenly（2）In, the temperature of described freezing crystallization is 0～5 DEG C, and the time of crystallization is 12～24h.
9. according to one of claim 1～8 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step
Suddenly（3）In, described low-carbon alcohols are methyl alcohol, ethanol or isopropanol；The volumetric concentration of described low carbon alcohol solution is 30～90%, low
The consumption of carbon alcohol solution is 5～20 times of neohesperidin crude product quality；The temperature of described heating for dissolving is 60～80 DEG C.
10. according to one of claim 1～9 with aurantiin for the method for Material synthesis neohesperidin it is characterised in that：Step
Suddenly（1）In, the temperature of described cooling crystallization is room temperature, and the time of crystallization is 4～8h；Step（3）In, the temperature of described cooling crystallization
Spend for 20～25 DEG C, the time of crystallization is 12～24h.
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| CN109503685A (en) * | 2018-12-28 | 2019-03-22 | 成都欧康医药股份有限公司 | A method of neohesperidin is synthesized with Fructus Citri grandis extract |
| CN114478657A (en) * | 2022-02-18 | 2022-05-13 | 厦门大学 | Synthesis method of neohesperidin |
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| CN101863940A (en) * | 2009-10-30 | 2010-10-20 | 成都华康生物工程有限公司 | New aurantiamarin synthesizing technique |
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