CN106432386B - A method of using aurantiin as Material synthesis neohesperidin - Google Patents
A method of using aurantiin as Material synthesis neohesperidin Download PDFInfo
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- CN106432386B CN106432386B CN201610723564.7A CN201610723564A CN106432386B CN 106432386 B CN106432386 B CN 106432386B CN 201610723564 A CN201610723564 A CN 201610723564A CN 106432386 B CN106432386 B CN 106432386B
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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 82
- 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 82
- 238000000034 method Methods 0.000 title claims abstract description 59
- 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 49
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 33
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 33
- 239000000463 material Substances 0.000 title claims abstract description 31
- 238000002425 crystallisation Methods 0.000 claims abstract description 56
- 230000008025 crystallization Effects 0.000 claims abstract description 56
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 claims abstract description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 23
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 23
- 230000007062 hydrolysis Effects 0.000 claims abstract description 23
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 23
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 22
- 238000001816 cooling Methods 0.000 claims abstract description 19
- 239000012043 crude product Substances 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 14
- 238000010438 heat treatment Methods 0.000 claims abstract description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000000413 hydrolysate Substances 0.000 claims abstract description 6
- 235000019441 ethanol Nutrition 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 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 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- 238000007710 freezing Methods 0.000 claims description 5
- 230000008014 freezing Effects 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims 1
- 235000015895 biscuits Nutrition 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 10
- 238000001914 filtration Methods 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000000047 product Substances 0.000 abstract description 7
- 230000035484 reaction time Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 239000011261 inert gas Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 2
- 230000004044 response Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 11
- 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
- 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
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229930182478 glucoside Natural products 0.000 description 3
- 150000008131 glucosides Chemical class 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 238000010189 synthetic method Methods 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
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 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
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001514 detection method 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
- 230000003301 hydrolyzing effect Effects 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
- 238000004064 recycling Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 238000007792 addition Methods 0.000 description 1
- 150000001298 alcohols Chemical class 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
- 238000004458 analytical method Methods 0.000 description 1
- 239000002585 base Substances 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
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-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
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002045 lasting effect Effects 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
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method 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
- 230000002195 synergetic effect Effects 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
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
A method of using aurantiin as Material synthesis neohesperidin, comprising the following steps: (1) it hydrolyzes: aurantiin is dissolved in aqueous alkali, heating, pressurized hydrolysis, it is cooled to room temperature, is adjusted with acid pH value, cooling crystallization, filtering, it is dry, obtain hydrolysate --- PN；(2) it being condensed: PN is dissolved in organic solvent, isovanillin and histidine is added, back flow reaction freezes crystallization, filters, and it is dry, obtain neohesperidin crude product；(3) it refines: neohesperidin crude product being dissolved by heating with low carbon alcohol solution, cooling crystallization, filtered, filtration cakes torrefaction obtains neohesperidin fine work.It may be up to 99.5% according to the purity of neohesperidin in the method for the present invention products obtained therefrom, impurity content is few, the high income of neohesperidin；The dosage of the method for the present invention alkali and catalyst is few, and the reaction time is short, at low cost, and technical process is not necessarily to inert gas shielding, is not necessarily to anhydrous response condition, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of methods for synthesizing neohesperidin, and in particular to one kind is using aurantiin as the new orange peel of Material synthesis
The method of glycosides.
Background technique
Neohesperidin is a kind of important flavanone compound, its synthesis neohesperidin dihydro that is mainly used for looks into ear
A kind of ketone --- novel sweetener, sugariness are 1500~1800 times of sucrose, have sugariness high, heat is small, and sweet taste is lasting, surely
Qualitative good, avirulent feature is widely used in food, drug and feedstuff industry.Currently, domestic and international market is to neohesperidin two
The demand of hydrogen chalcone increasingly increases, but the raw material for synthesizing neohesperidin dihydrochalcone is but difficult to meet the need in market
It asks.
The existing method for obtaining a large amount of neohesperidins mainly has extraction method and synthetic method.Separation is extracted from natural plants
Neohesperidin is limited by resource and production cost.Due to the destruction of ecological environment and the over-exploitation of resource, extraction method is obtained
It obtains neohesperidin and does not have the production advantage.China's aurantiin is resourceful, cheap and easy to get, is that Material synthesis is newly orange with aurantiin
Skin glycosides, for we provide the new methods that one obtains a large amount of neohesperidins.
US3375242 discloses a kind of neohesperidin synthetic method, and this method is by aurantiin and excessive isovanillin
It directly mixes, synthesizes neohesperidin under the catalysis of potassium hydroxide.Though this method is simple, the loss of isovanillin is huge,
The yield of reaction is relatively low, is not suitable for industrialized production.
US3947405 discloses a kind of neohesperidin synthetic method, and this method is by-the β of phloroacetophenone -4 '-new orange peel
Glucosides (abbreviation PN) and isovanillin are dissolved in anhydrous alcohols solvent, under inert gas protection, are made using nafoxidine-acetic acid
For catalyst.But this method condition is harsh, 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 technology of neohesperidin, and this method is to be dissolved in PN and isovanillin
In 98% ethyl alcohol, major catalyst nafoxidine and co-catalyst acetic acid are successively added under nitrogen protection.But this method is reacted
Process also requires that anhydrous condition, and the recycling and recycling of 98% ethyl alcohol are difficult to realize in actual operation, and this method is received
Rate highest only 86%, does not have the advantage of industrialization.
CN101863940A discloses a kind of synthesis technology of neohesperidin, and this method is first used using aurantiin as raw material
Basic hydrolysis aurantiin obtains PN, then with the condensation of Proline-Catalyzed PN and isovanillin, to synthesize neohesperidin.In this method
Condensation step although do not need anhydrous reaction condition, still, the base amount of hydrolysing step is too big, tight to the pollution of environment
Weight；Alkali concentration is high, and the side reaction that carbonyl reduction is hydroxyl easily occurs for when hydrolysis, and it is relatively low to lead to hydrolyze yield, and only 70%；And it is catalyzed
Agent proline dosage is big, expensive, and dosage is excessive, and the cost of production is very high；Due to a large amount of additions of catalyst, post-processing is difficult
Thoroughly to remove, cause the purity of final products neohesperidin relatively low, only 97%.
Summary of the invention
The technical problem to be solved by the present invention is to overcome drawbacks described above of the existing technology, it is pure to provide a kind of product
Degree height, high income, technical process is not necessarily to inertia and anhydrous condition, at low cost, and be suitable for industrialized production is former with aurantiin
The method of material synthesis neohesperidin.
The technical solution adopted by the present invention to solve the technical problems is as follows: one kind is using aurantiin as the new orange peel of Material synthesis
The method of glycosides, comprising the following steps:
(1) it hydrolyzes: aurantiin is dissolved in aqueous alkali, heating, pressurized hydrolysis are cooled to room temperature, are adjusted with acid pH
Value, cooling crystallization filter, dry, obtain hydrolysate ----the β of phloroacetophenone -4 '-neohesperidoside；
(2) it is condensed:-the β of phloroacetophenone -4 '-neohesperidoside obtained by step (1) is dissolved in water or organic solvent,
Isovanillin and histidine is added, back flow reaction after fully reacting, freezes crystallization, filters, and it is dry, obtain neohesperidin crude product；
(3) it refines: neohesperidin crude product obtained by step (2) being dissolved by heating with low carbon alcohol solution, cooling crystallization, mistake
Filter, filtration cakes torrefaction obtain neohesperidin fine work.
Preferably, in step (1), the alkali in the aqueous alkali is sodium hydroxide or potassium hydroxide, the matter of aqueous alkali
Measuring concentration is 1~5%, and the liquid-solid ratio (mL/g) of aqueous alkali and aurantiin quality is more preferable 10~12) 8~15(.If alkali
Concentration is too low, will lead to hydrolysis not exclusively, and yield is relatively low, if the excessive concentration of alkali, will lead to alkali and neutralizes the waste with acid, this
Outside, for the product PN of hydrolysis under the alkali and high temperature action of high concentration, carbonyl can be reduced to hydroxyl, cause hydrolysis yield relatively low；
If aqueous alkali dosage is very few, aurantiin will lead to compared with indissoluble solution and hydrolysis, if aqueous alkali dosage is excessive, and will lead to anti-
Volume is excessive after answering liquid to be adjusted with acid pH value, and product PN is difficult to crystallize precipitation, and yield is relatively low.
Preferably, in step (1), the temperature of the hydrolysis is 90~140 DEG C (more preferable 110~130 DEG C), the pressure of hydrolysis
Power is the more preferable 0.1~0.3MPa of 0.01~0.40MPa(), the time of hydrolysis is the more preferable 0.5~1.0h of 0.4~1.5h().
Studies have shown that heating, pressurized hydrolysis are conducive to the C ring (pyranone structure) in flavones molecular skeleton and beat completely in a short time
It opens, the time hydrolyzed under pressurized conditions shortens dramatically；And the concentration of alkali is lower, will not induce side reaction, therefore, yield can be realized
Significantly promoted.If temperature is too low, pressure is too small or the time is too short, it is incomplete to will lead to hydrolysis；If temperature is excessively high, pressure is excessive
Or overlong time, it will all cause the waste of the energy and material.
Preferably, in step (1), the acid for adjusting pH value is hydrochloric acid, sulfuric acid or citric acid etc., and sour quality is dense
Degree is 10~30%.If the concentration of acid is too low, it will lead to after reaction solution is adjusted with acid pH value that volume is excessive, product PN is difficult to crystallize
It is precipitated, yield is relatively low；If the excessive concentration of acid, easily causes solution part acid too strong during adjusting pH value, will destroy
The molecular structure of PN and cause yield relatively low.
Preferably, in step (1), pH value is adjusted to more preferable 4~6) 2~7(.If pH value is too low, the molecule of PN will be destroyed
Structure and cause yield relatively low；If pH value is excessively high, PN is difficult to be precipitated in neutral or alkaline solution.
Preferably, in step (2), the organic solvent be methanol, ethyl alcohol, isopropanol, n-butanol, acetone, ethyl acetate,
One or both of dichloromethane or chloroform etc.；The dosage of the water or organic solvent is the-β of phloroacetophenone -4 '-new
5~30 times (more preferable 5.2~10.0 times) of orange peel glucosides quality.If water or consumption of organic solvent are very few, PN, isovanillin and
Histidine cannot sufficiently dissolve, and condensation reaction is difficult to go on smoothly；If water or consumption of organic solvent are excessive, PN, isovanillin and
Concentration of the histidine in reaction solution is relatively low, and the time of reaction will extend, and reaction solution volume is excessive, and neohesperidin is difficult to fill
Analysis is brilliant.
Preferably, in step (2), the additional amount of the isovanillin and histidine is so that-the β of phloroacetophenone -4 '-is new
The mass ratio of orange peel glucosides, isovanillin and histidine is more preferable 1:0.31~0.35 1:0.3~0.4:0.05~0.10(:
0.06~0.08).Although proline used in histidine and background technique used in the method for the present invention is all amino acid,
But also have the difference of its essence: 1) histidine is alpha amino acid (- NH2), proline is a kind of imino acid (- NH)；2) ammonia is organized
For acid in alkalinity, proline is not in alkalinity；3) histidine is polarity, hydrophilic amino acid, and proline is nonpolarity, hydrophobic amino
Acid, therefore, they are far from each other in catalytic action.Histidine mainly plays catalytic action in the reaction, inventor the study found that
Histidine other than there is amino and carboxyl as other amino acid, due to there are imidazole groups in its molecular structure (wherein
Have secondary amine), stronger alkalinity is made it have, alkaline condition adds the synergistic effect of secondary amine and carboxyl, meets catalysis
The condition of the reaction, in addition, the imidazole group in histidine molecule can not only be used for proton donor, but also as proton acceptor, and
It confesses proton and to receive the speed of proton all very fast, so histidine can serve as efficient catalysis in this aldol condensation
Agent.In the present invention, it is used due to histidine primarily as catalyst, dosage need not be excessive.
Preferably, in step (2), the temperature of the back flow reaction is 60~95 DEG C (more preferable 80~90 DEG C), reaction
Time is the more preferable 5~8h of 2~10h().If the temperature of reaction is too low or the reaction time is too short, condensation reaction may result in not
Completely；If the temperature of reaction is excessively high or the reaction time is too long, side reaction odds will be increased, reduce the receipts of condensation reaction
Rate.
Preferably, in step (2), the temperature of the freezing crystallization is 0~5 DEG C, time of crystallization is 12~for 24 hours.
Preferably, in step (3), the low-carbon alcohols are methanol, ethyl alcohol or isopropanol etc.；The body of the low carbon alcohol solution
Product concentration is more preferable 40~70%) 30~90%(, and the dosage of low carbon alcohol solution is 5~20 times of neohesperidin crude product quality
(more preferable 6~12 times).Select foundation of the low-carbon alcohols as dissolution solvent are as follows: 1) at different temperature, neohesperidin is in first
Dissolubility difference in alcohol, ethyl alcohol and isopropanol is larger, more conducively crystallizes；2) methanol, ethyl alcohol and isopropanol moderate boiling point are applicable in
In industrial production, existing certain stability, and it is easily recycled.
Preferably, in step (3), the temperature of the heating for dissolving is 60~80 DEG C.
Preferably, in step (1), the temperature of the cooling crystallization is room temperature, and the time of crystallization is 4~8h.
Preferably, in step (3), the temperature of the cooling crystallization is 20~25 DEG C, the time of crystallization is 12~for 24 hours.
In the method for the present invention step (1), it is 81.96g that the yield of PN, which hydrolyzes according to 100g aurantiin and generates the theoretical value of PN,
It calculates；In step (2), it is 128.32g calculating that the yield of neohesperidin, which is condensed according to 100gPN and generates the theoretical value of neohesperidin,.
Room temperature of the present invention is 15~25 DEG C.
The principle of the method for the present invention: C ring (pyrrole of aurantiin under the action of lye and high temperature, in flavones molecular skeleton
Mutter ketone structure) it will fully open, hydrolysis generates phloroacetophenone -4 '-β-neohesperidoside (PN), and high temperature, pressurization is used in combination
The amount ratio prior art of the mode of hydrolysis, alkali significantly reduces, and shortens hydrolysis time, the side reaction of hydrolysis is few, therefore
Improve the yield of PN；In step of condensation, the method for the present invention is pioneering to use histidine to be condensed as PN and isovanillin
Catalyst can meet the condition for being catalyzed the reaction, efficient catalyst be served as in this aldol condensation, reaction rate is high, dosage
It is few.
The method of the present invention has the beneficial effect that:
(1) according to the white crystalline powder shape of neohesperidin fine work obtained by the method for the present invention, through high performance liquid chromatography outside
The detection of mark method, the purity of gained neohesperidin may be up to 99.5 %, and impurity content is few, the high income of neohesperidin；
(2) the method for the present invention uses high temperature, pressurized hydrolysis mode in hydrolysing step, has saved the dosage of alkali, shortens anti-
Between seasonable, the yield of PN, the yield > 85% of hydrolysis are improved；It selects histidine as catalyst in condensation step, reduces
The dosage of catalyst, shortens the time of reaction, condensation reaction yield > 90%；
(3) the method for the present invention technical process is not necessarily to inert gas shielding, anhydrous response condition is not necessarily to, due to alkali and catalyst
Dosage is few, each step reaction high income, reduce production cost, be suitable for industrialized production.
Specific embodiment
Below with reference to embodiment, the invention will be further described.
Aurantiin used in the embodiment of the present invention is purchased from Hunan Hua Cheng living resources limited liability company, aurantiin it is pure
Degree is 98.2%；In step of the embodiment of the present invention (1), the yield of PN is according to the theoretical value that 100g aurantiin hydrolyzes generation PN
81.96g is calculated, and in step (2), the yield of neohesperidin is according to the theoretical value that 100gPN is condensed generation neohesperidin
128.32g calculating；PN in the embodiment of the present invention is the-β of phloroacetophenone -4 '-neohesperidoside abbreviation；The embodiment of the present invention
Used raw material and chemical reagent are obtained by routine business approach unless otherwise specified.
In the embodiment of the present invention detection method of aurantiin, PN and neohesperidin content be high performance liquid chromatography (HPLC) outside
Mark method.
Embodiment 1
(1) it hydrolyzes: 100g aurantiin being dissolved in the potassium hydroxide aqueous solution that 1000mL mass concentration is 5%, 110
DEG C, under conditions of pressure 0.1MPa, 1h is hydrolyzed, is cooled to room temperature, it is cold with the hydrochloric acid conditioning solution pH value of mass concentration 30% to 6
But to room temperature, crystallization 6h is filtered, dry, obtains 75.3g hydrolysate --- PN(purity 95.3%, yield 87.6%)；
(2) it is condensed: 75.3gPN obtained by step (1) is dissolved in 400g ethyl alcohol (volumetric concentration 95%), be added
23.87g isovanillin and 4.52g histidine, at 85 DEG C, back flow reaction 5h after fully reacting, is placed reaction liquid at 0 DEG C,
Crystallization 12h is freezed, is filtered, it is dry, obtain neohesperidin crude product 94.39g(purity 95.6%, yield 93.4%)；
(3) refine: by 94.39g neohesperidin crude product obtained by step (2), the ethyl alcohol for being 50% with 900g volumetric concentration is water-soluble
Liquid is heated to 75 DEG C of dissolutions, is cooled to 25 DEG C, for 24 hours, filtering, filtration cakes torrefaction obtains neohesperidin fine work 86.42g to crystallization.
The white crystalline powder shape of gained neohesperidin fine work, is detected, neohesperidin through high-performance liquid chromatography
Purity be 99.5%, purification yield be 95.3%.
Embodiment 2
(1) it hydrolyzes: 200g aurantiin being dissolved in the potassium hydroxide aqueous solution that 2200mL mass concentration is 4%, 120
DEG C, under conditions of pressure 0.2MPa, 1h is hydrolyzed, is cooled to room temperature, with the sulfuric acid regulation solution pH value of mass concentration 20% to 5.5,
It is cooled to room temperature, crystallization 6h, filters, it is dry, obtain 152.1g hydrolysate PN(purity 93.7%, yield 86.9%)；
(2) it is condensed: 152.1g PN obtained by step (1) is dissolved in 1500g methanol (volumetric concentration 90%), be added
48.22g isovanillin and 10.6g histidine, at 80 DEG C, back flow reaction 6h after fully reacting, is placed reaction liquid at 2 DEG C,
Crystallization 20h is freezed, is filtered, it is dry, obtain neohesperidin crude product 191.8g(purity 93.9%, yield 92.3%)；
(3) it refines: by 191.8g neohesperidin crude product obtained by step (2), the isopropanol for being 60% with 1500g volumetric concentration
Aqueous solution is heated to 80 DEG C of dissolutions, is cooled to 20 DEG C, crystallization 18h, filtering, filtration cakes torrefaction obtains neohesperidin fine work 171.1g.
The white crystalline powder shape of gained neohesperidin fine work, is detected, neohesperidin through high-performance liquid chromatography
Purity be 99.3%, purification yield be 94.3%.
Embodiment 3
(1) it hydrolyzes: 100g aurantiin being dissolved in the sodium hydrate aqueous solution that 1200mL mass concentration is 3%, 130
DEG C, under conditions of pressure 0.3MPa, 0.5h is hydrolyzed, is cooled to room temperature, it is cold with the lemon acid for adjusting pH value of mass concentration 10% to 5
But to room temperature, crystallization 6h is filtered, dry, obtains 74.7g hydrolysate PN(purity 93.6%, yield 85.3%)；
(2) it is condensed: 74.7g PN obtained by step (1) is dissolved in 740g isopropanol (volumetric concentration 90%), be added
23.87g isovanillin and 5.92g histidine, at 90 DEG C, back flow reaction 8h after fully reacting, is placed reaction liquid at 2 DEG C,
Crystallization 20h is freezed, is filtered, it is dry, obtain neohesperidin crude product 92.3g(purity 93.6%, yield 90.1%)；
(3) refine: by 92.3g neohesperidin crude product obtained by step (2), the methanol for being 55% with 923g volumetric concentration is water-soluble
Liquid is heated to 70 DEG C of dissolutions, is cooled to 20 DEG C, crystallization 18h, filtering, filtration cakes torrefaction obtains neohesperidin fine work 82.49g.
The white crystalline powder shape of gained neohesperidin fine work, is detected, neohesperidin through high-performance liquid chromatography
Purity be purity 99.5%, purification yield be 95%.
Claims (23)
1. a kind of using aurantiin as the method for Material synthesis neohesperidin, which comprises the following steps:
(1) it hydrolyzes: aurantiin is dissolved in aqueous alkali, heating, pressurized hydrolysis are cooled to room temperature, are adjusted with acid pH value, cold
But crystallization filters, dry, obtains hydrolysate ----the β of phloroacetophenone -4 '-neohesperidoside；Alkali in the aqueous alkali
For sodium hydroxide or potassium hydroxide, the mass concentration of aqueous alkali is 1~5%, and aqueous alkali and the liquid-solid ratio of aurantiin quality are
8~15；The temperature of the hydrolysis is 90~140 DEG C, and the pressure of hydrolysis is 0.01~0.40MPa, the time of hydrolysis is 0.4~
1.5h；The acid for adjusting pH value is hydrochloric acid, sulfuric acid or citric acid, and sour mass concentration is 10~30%；
(2) it is condensed:-the β of phloroacetophenone -4 '-neohesperidoside obtained by step (1) is dissolved in water or organic solvent, be added
Isovanillin and histidine, back flow reaction after fully reacting, freeze crystallization, filter, dry, obtain neohesperidin crude product；
(3) it refines: neohesperidin crude product obtained by step (2) being dissolved by heating with low carbon alcohol solution, cooling crystallization filters, filter
Biscuit is dry, obtains neohesperidin fine work.
2. according to claim 1 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: in step (1),
PH value is adjusted to 2~7.
3. according to claim 1 or claim 2 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (2)
In, the organic solvent is methanol, in ethyl alcohol, isopropanol, n-butanol, acetone, ethyl acetate, dichloromethane or chloroform
It is one or two kinds of；The dosage of the water or organic solvent is 5~30 times of-β of phloroacetophenone -4 '-neohesperidoside quality.
4. according to claim 1 or claim 2 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (2)
In, the additional amount of the isovanillin and histidine is so that-the β of phloroacetophenone -4 '-neohesperidoside, isovanillin and group
The mass ratio of propylhomoserin is 1:0.3~0.4:0.05~0.10.
5. according to claim 3 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: in step (2),
The additional amount of the isovanillin and histidine is so that-the β of phloroacetophenone -4 '-neohesperidoside, isovanillin and histidine
Mass ratio be 1:0.3~0.4:0.05~0.10.
6. according to claim 1 or claim 2 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (2)
In, the temperature of the back flow reaction is 60~95 DEG C, and the time of reaction is 2~10h.
7. according to claim 3 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: in step (2),
The temperature of the back flow reaction is 60~95 DEG C, and the time of reaction is 2~10h.
8. according to claim 4 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: in step (2),
The temperature of the back flow reaction is 60~95 DEG C, and the time of reaction is 2~10h.
9. according to claim 1 or claim 2 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (2)
In, the temperature of the freezing crystallization is 0~5 DEG C, time of crystallization is 12~for 24 hours.
10. according to claim 3 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (2)
In, the temperature of the freezing crystallization is 0~5 DEG C, time of crystallization is 12~for 24 hours.
11. according to claim 4 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (2)
In, the temperature of the freezing crystallization is 0~5 DEG C, time of crystallization is 12~for 24 hours.
12. according to claim 6 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (2)
In, the temperature of the freezing crystallization is 0~5 DEG C, time of crystallization is 12~for 24 hours.
13. according to claim 1 or claim 2 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step
(3) in, the low-carbon alcohols are methanol, ethyl alcohol or isopropanol；The volumetric concentration of the low carbon alcohol solution is 30~90%, low-carbon
The dosage of alcohol solution is 5~20 times of neohesperidin crude product quality；The temperature of the heating for dissolving is 60~80 DEG C.
14. according to claim 3 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (3)
In, the low-carbon alcohols are methanol, ethyl alcohol or isopropanol；The volumetric concentration of the low carbon alcohol solution is 30~90%, low-carbon alcohols water
The dosage of solution is 5~20 times of neohesperidin crude product quality；The temperature of the heating for dissolving is 60~80 DEG C.
15. according to claim 4 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (3)
In, the low-carbon alcohols are methanol, ethyl alcohol or isopropanol；The volumetric concentration of the low carbon alcohol solution is 30~90%, low-carbon alcohols water
The dosage of solution is 5~20 times of neohesperidin crude product quality；The temperature of the heating for dissolving is 60~80 DEG C.
16. according to claim 6 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (3)
In, the low-carbon alcohols are methanol, ethyl alcohol or isopropanol；The volumetric concentration of the low carbon alcohol solution is 30~90%, low-carbon alcohols water
The dosage of solution is 5~20 times of neohesperidin crude product quality；The temperature of the heating for dissolving is 60~80 DEG C.
17. according to claim 9 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (3)
In, the low-carbon alcohols are methanol, ethyl alcohol or isopropanol；The volumetric concentration of the low carbon alcohol solution is 30~90%, low-carbon alcohols water
The dosage of solution is 5~20 times of neohesperidin crude product quality；The temperature of the heating for dissolving is 60~80 DEG C.
18. according to claim 1 or claim 2 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step
(1) in, the temperature of the cooling crystallization is room temperature, and the time of crystallization is 4~8h；In step (3), the temperature of the cooling crystallization
It is 20~25 DEG C, time of crystallization is 12~for 24 hours.
19. according to claim 3 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (1)
In, the temperature of the cooling crystallization is room temperature, and the time of crystallization is 4~8h；In step (3), the temperature of the cooling crystallization is
20~25 DEG C, time of crystallization is 12~for 24 hours.
20. according to claim 4 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (1)
In, the temperature of the cooling crystallization is room temperature, and the time of crystallization is 4~8h；In step (3), the temperature of the cooling crystallization is
20~25 DEG C, time of crystallization is 12~for 24 hours.
21. according to claim 6 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (1)
In, the temperature of the cooling crystallization is room temperature, and the time of crystallization is 4~8h；In step (3), the temperature of the cooling crystallization is
20~25 DEG C, time of crystallization is 12~for 24 hours.
22. according to claim 9 using aurantiin as the method for Material synthesis neohesperidin, it is characterised in that: step (1)
In, the temperature of the cooling crystallization is room temperature, and the time of crystallization is 4~8h；In step (3), the temperature of the cooling crystallization is
20~25 DEG C, time of crystallization is 12~for 24 hours.
23. 3 is described using aurantiin as the method for Material synthesis neohesperidin according to claim 1, it is characterised in that: step (1)
In, the temperature of the cooling crystallization is room temperature, and the time of crystallization is 4~8h；In step (3), the temperature of the cooling crystallization is
20~25 DEG C, time of crystallization is 12~for 24 hours.
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| US3375242A (en) * | 1966-12-09 | 1968-03-26 | Agriculture Usa | Conversion of naringin to neohesperidin and neohesperidin dihydrochalcone |
| US3947405A (en) * | 1974-01-03 | 1976-03-30 | Givaudan Corporation | Process for making neohesperidine dihydrochalcone |
| CN101863940A (en) * | 2009-10-30 | 2010-10-20 | 成都华康生物工程有限公司 | New aurantiamarin synthesizing technique |
| CN104744252A (en) * | 2015-02-02 | 2015-07-01 | 天津理工大学 | Method for catalyzing condensation reaction between aromatic aldehyde and malonic diester with bionic water-containing heterogeneous catalytic system |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3375242A (en) * | 1966-12-09 | 1968-03-26 | Agriculture Usa | Conversion of naringin to neohesperidin and neohesperidin dihydrochalcone |
| US3947405A (en) * | 1974-01-03 | 1976-03-30 | Givaudan Corporation | Process for making neohesperidine dihydrochalcone |
| CN101863940A (en) * | 2009-10-30 | 2010-10-20 | 成都华康生物工程有限公司 | New aurantiamarin synthesizing technique |
| CN104744252A (en) * | 2015-02-02 | 2015-07-01 | 天津理工大学 | Method for catalyzing condensation reaction between aromatic aldehyde and malonic diester with bionic water-containing heterogeneous catalytic system |
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