CN108707163A - A kind of preparation method of steviol glucoside member - Google Patents
A kind of preparation method of steviol glucoside member Download PDFInfo
- Publication number
- CN108707163A CN108707163A CN201810596564.4A CN201810596564A CN108707163A CN 108707163 A CN108707163 A CN 108707163A CN 201810596564 A CN201810596564 A CN 201810596564A CN 108707163 A CN108707163 A CN 108707163A
- Authority
- CN
- China
- Prior art keywords
- steviol
- organic solvent
- glucoside member
- mixture
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- QFVOYBUQQBFCRH-UHFFFAOYSA-N Steviol Natural products C1CC2(C3)CC(=C)C3(O)CCC2C2(C)C1C(C)(C(O)=O)CCC2 QFVOYBUQQBFCRH-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229940032084 steviol Drugs 0.000 title claims abstract description 49
- 229930182478 glucoside Natural products 0.000 title claims description 56
- 238000002360 preparation method Methods 0.000 title claims description 20
- -1 steviol glucoside Chemical class 0.000 title claims description 19
- QFVOYBUQQBFCRH-VQSWZGCSSA-N steviol Chemical class C([C@@]1(O)C(=C)C[C@@]2(C1)CC1)C[C@H]2[C@@]2(C)[C@H]1[C@](C)(C(O)=O)CCC2 QFVOYBUQQBFCRH-VQSWZGCSSA-N 0.000 claims abstract description 53
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 claims abstract description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 27
- 230000001681 protective effect Effects 0.000 claims abstract description 26
- 239000000843 powder Substances 0.000 claims abstract description 21
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 18
- 239000000284 extract Substances 0.000 claims abstract description 17
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 10
- 230000000694 effects Effects 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 150000008131 glucosides Chemical class 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 37
- 239000007787 solid Substances 0.000 claims description 31
- 239000003960 organic solvent Substances 0.000 claims description 30
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 241000544066 Stevia Species 0.000 claims description 25
- 238000006317 isomerization reaction Methods 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 11
- QPUYECUOLPXSFR-UHFFFAOYSA-N 1-methylnaphthalene Chemical compound C1=CC=C2C(C)=CC=CC2=C1 QPUYECUOLPXSFR-UHFFFAOYSA-N 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 9
- 235000009518 sodium iodide Nutrition 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000004593 Epoxy Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 8
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 150000002460 imidazoles Chemical class 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical group C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- KFVUFODCZDRVSS-XGBBNYNSSA-N iso-steviol Chemical compound C([C@]12C[C@@](C(C2)=O)(CC[C@H]11)C)C[C@H]2[C@@]1(C)CCC[C@@]2(C)C(O)=O KFVUFODCZDRVSS-XGBBNYNSSA-N 0.000 abstract description 12
- KFVUFODCZDRVSS-UHFFFAOYSA-N isosteviol Natural products C1C(=O)C(C)(CCC23)CC21CCC1C3(C)CCCC1(C)C(O)=O KFVUFODCZDRVSS-UHFFFAOYSA-N 0.000 abstract description 12
- 244000228451 Stevia rebaudiana Species 0.000 abstract description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 235000019202 steviosides Nutrition 0.000 description 31
- 239000000047 product Substances 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000000034 method Methods 0.000 description 20
- 229940013618 stevioside Drugs 0.000 description 20
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 20
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 19
- 238000006460 hydrolysis reaction Methods 0.000 description 12
- 239000004383 Steviol glycoside Substances 0.000 description 11
- 235000019411 steviol glycoside Nutrition 0.000 description 11
- 229930182488 steviol glycoside Natural products 0.000 description 11
- 150000008144 steviol glycosides Chemical class 0.000 description 11
- 230000007062 hydrolysis Effects 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 235000003599 food sweetener Nutrition 0.000 description 9
- 239000003765 sweetening agent Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000287 crude extract Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 235000006092 Stevia rebaudiana Nutrition 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
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- 239000005720 sucrose Substances 0.000 description 3
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- 239000001512 FEMA 4601 Substances 0.000 description 2
- HELXLJCILKEWJH-SEAGSNCFSA-N Rebaudioside A Natural products O=C(O[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@@]1(C)[C@@H]2[C@](C)([C@H]3[C@@]4(CC(=C)[C@@](O[C@H]5[C@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@H](O)[C@@H](CO)O5)(C4)CC3)CC2)CCC1 HELXLJCILKEWJH-SEAGSNCFSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 244000269722 Thea sinensis Species 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
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- HELXLJCILKEWJH-UHFFFAOYSA-N entered according to Sigma 01432 Natural products C1CC2C3(C)CCCC(C)(C(=O)OC4C(C(O)C(O)C(CO)O4)O)C3CCC2(C2)CC(=C)C21OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O HELXLJCILKEWJH-UHFFFAOYSA-N 0.000 description 2
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- 150000002338 glycosides Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229930001567 kaurane Natural products 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000005059 solid analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/86—Ring systems containing bridged rings containing four rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention is by by stevia rebaudianum Leave extract powder successively acid-catalyzed hydrolysis, silated, epoxidation and reduction; obtain the isosteviol of the steviol derivative and steviol of the big positions the C19 carboxy protective of different polarities; the two is detached by the way of simple to operation; obtain the steviol derivative of the chemical pure positions C19 carboxy protective; steviol is obtained after the steviol derivative deprotection; the derivative can also distinguish C19 and C13 activity, convenient for subsequently carrying out the operation of different functional groups to differential responses site.
Description
Technical field
The invention belongs to organic synthesis fields, more particularly to a kind of preparation method of steviol derivative.
Background technology
Stevioside is the kaurane type two extracted from the blade of STEVIA REBAUDIANA (Stevia rebaudiana Bertoni)
Terpene disaccharide chain glucosides mixture, sugariness are 150-300 times of sucrose, are intense sweetener.
The production of stevioside has more than 20 years history in China, and by development in more than 20 years, China had become generation
Maximum stevioside producing country and exported country in boundary, but China's stevioside industry development level is also relatively low in general, mainly with
Based on the large area plantation and the outlet of stevioside crude extract of STEVIA REBAUDIANA, do not have the ability of deep processing, added value of product is low.And
China's export to the U.S., Japan and Southeast Asia stevioside crude product after refined added value of product significantly promoted.
It is the basis carried out for the factor for restricting stevioside industry development to cause the basic reason that China's stevioside industry development lags
Journal of Sex Research is few and Prospects of Research is poor.The unfavorable factor of stevioside industry development is restricted at present mainly including after stevioside sweetener
The large area plantation compression grain-production arable land potential threat state of the mouthfeel of astringent taste, the quality Control of stevioside and STEVIA REBAUDIANA
Family's grain security three major issues.
Solve the research and development that the undesirable fundamental way of stevia rebaudianum sugar sweetener mouthfeel is novel stevioside sweetener.To current
Until, three generations has been gone through in the development of stevioside sweetener.Earliest one on behalf of the abundant content rebaudioside-A of the content second in stevia rebaudian leaf
(Rebaudioside A, abbreviation Reb A).Due to its in stevia rebaudian leaf rich content (22-28% for accounting for crude extract), although because
Astringent taste is apparent afterwards and mouthfeel is not ideal enough, but is still being used currently as sweetener.Further study show that the lower Lay of content
Bao Di glucosides D (Rebaudioside D, abbreviation Reb D) (0.3-0.8%) as sweetener no matter from sweet tea speed or mouthfeel
Have compared with Reb A and is significantly promoted.Because its content in stevia rebaudian leaf is low and application prospect as food additives is good, Reb
D has the good reputation of ' gold in stevioside '.If the Reb D as second generation stevioside glycoside sweetener are because its 0.3-0.8%'s
Total content and can largely obtain by separation and Extraction and be applied to food industry reluctantly, then as third generation sweetener
Directly a large amount of obtain will become more difficult to rebaudioside M (Rebaudioside M, abbreviation Reb M) by separation and Extraction,
Because its content in crude extract only has 0.06%;But it is current due to its mouthfeel is no different with sucrose and sugariness is 250 times of sucrose
It is considered as ideal stevia rebaudianum sugar sweetener.
The approach for obtaining Reb D and M at present is predominantly directly extracted from natural resources, that is, stevia rebaudianum Leave extract, but same
Means obtain the lower steviol glycoside of content it is obviously helpless, even the higher Reb D of content are because of extraction cost liter
It is high and its price is made to be 5 times of Reb A.To improve the acquisition efficiency of content is low but application prospect is good steviol glycoside, reduce at
There are three types of this strategies mainly studied at present:One is Stevia seed is improved to improve the content of required stevioside, the second is
Enzyme' s catalysis, third are chemical syntheses.Seed station is a long-term process, and enzyme' s catalysis is difficult to mass production, because
It is the unique reliable approach for solving the low steviol glycoside of content and largely obtaining that this, which only has chemical synthesis,.
To realize the chemical synthesis of steviol glycoside, it is necessary first to obtain the glucoside member part of steviol glycoside, i.e. steviol, tie
Structure is shown in formula I.
Currently, steviol extracting method substantially there are three types of:Enzyme hydrolysis method, microbe fermentation method and chemical hydrolysis.
Enzyme hydrolysis method can use different enzymes to realize that C13 and C19 are simultaneously or separately hydrolyzed, enzyme hydrolysis method
Although efficient, specificity is strong, the hydrolase of purchase and screening synthesis needs higher economy and time cost, is unfavorable for
Control the extraction cost of product.Microbial hydrolytic method, the efficiency that the method hydrolysis generates steviol is generally extremely low, because of steviol
It is hydrolyzed as carbon source.Meanwhile the microbial strains for hydrolysis also are difficult to screen, and it is of a high price, it is unfavorable for cost control
System.Chemical hydrolysis, including oxidation-alkalization hydrolysis method, acid catalyzed hydrolysis and alkali catalyzed hydrolysis method, oxidation-alkalization hydrolysis method,
Sodium metaperiodate or lead tetra-acetate are mainly utilized, is aoxidized, then alkalize through 10%KOH.Although this method not will produce
Wayner-Meerwein isosteviols, but use oxidising agent commercially available at high price, it is unfavorable for cost control, meanwhile, oxidation
Process needs a large amount of solvent, is unfavorable for expanding the scale of production.Alkali catalyzed hydrolysis method, primarily directed to C19 ester type glucosides
Key, the method hydrolyzed by KOH, interrupts C19 glycosidic bonds, and product exists in a salt form, adjusts solution PH slant acidity, stevia rebaudianum
Sugar is precipitated.This method can only take half hydrolysate, and C13 glycosidic bonds can not interrupt, and be unable to get the normal products of steviol.
Acid catalyzed process is mainly interrupted C13 and C19 glycosidic bond using the acidity of HCl or H2SO4, acid hydrolysis process operation letter
Single, cheap and production efficiency is high, is to prepare the comparatively ideal method of steviol.But under acid condition, steviol is unstable,
Wayner-Meerwein reactions are easy to happen, the by-products such as isosteviol and double-bond isomerization product, obtained by-product are obtained
Object and target product is extremely difficult isolates and purifies, difficulty is caused to the separation of steviol.
(Hu Xueyi hydrochloric acid or catalyzed by amino sulfonic acid hydrolyze this and prepare steviol for husband's glycosides Southern Yangtze University Hu Xueyi et al.
[J]Fine chemistry industry, 2014,31 (4):Steviol glycoside 539-544) is hydrolyzed by hydrochloric acid catalysis, obtains the stevia rebaudianum of higher yields
Alcohol, but the work only provides the yield of HPLC, not separation confirms the by-product of hydrolysis.We repeat the work, find acid
It is not merely steviol I and isosteviol I ' to be catalyzed obtained product, further comprises the product I " of double-bond isomerization, different stevia rebaudianum
Alcohol I ' can be by column chromatography for separation, but the product I " polarity of steviol I and double-bond isomerization is close, attempts a variety of expansion
Agent can not all detach on the tlc plate, thus it is extremely difficult isolate and purify, the pure steviol of chemistry can not be obtained, to follow-up steviol glycoside
Synthesis introduce impurity, influence reaction progress.
Therefore, the most important problem of development for how obtaining the steviol of high-purity this pair of of stevia rebaudianum industry still needs
It solves.We are creative to devise series of chemical, passes through functional group conversions, obtains the big positions the C19 carboxylic of different polarities
The steviol derivative C and double-bond isomerization epoxy product B of base protection are effectively simplified the product of reaction, while making target
Product and by-product are easily isolated, and by conventional deprotection method, obtain the pure steviol of chemistry.To be solved by chemical synthesis
The low steviol glycoside of content largely obtain lay a solid foundation.
Invention content
The technical problem to be solved by the present invention is to:The acid-catalyzed hydrolysis of stevia rebaudianum Leave extract powder is distinguished by chemical method
Steviol derivative in product and other by-products, obtain the steviol and its derivative of high-purity.
In order to solve the above technical problems, the technical solution adopted by the present invention is that:A kind of preparation method of steviol glucoside member, packet
Include following steps:
(1) the sour water solution of stevia rebaudianum Leave extract powder:Stevia rebaudianum Leave extract powder is dissolved in the water, it is water-soluble that hydrochloric acid is added
Liquid, back flow reaction, after reaction, by reaction solution cooled and filtered, filter residue obtains glucoside member mixture after recrystallizing;The glucoside member
Mixture glucoside member mixture includes steviol I, isosteviol I ' and double-bond isomerization product I ", and wherein isosteviol I ' can be with
It is easier to detach, can be detached in this step, can also disposably be detached after reaction in (4) step,
(2) 19 carboxy protectives of glucoside member mixture:It is organic molten that the glucoside member mixture obtained in step (1) is dissolved in first
In agent, the glucoside member mixture of 19 carboxy protectives is obtained by the reaction with reagent RX in the presence of alkali;19 carboxy protectives
Glucoside member mixture includes the isosteviol Pg-I ' and 19 carboxyls of the steviol Pg-I of 19 carboxy protectives, 19 carboxy protectives
The double-bond isomerization product Pg-I " of protection, wherein the steviol Pg-I ' of 19 carboxy protectives is not involved in subsequent reactions, Ke Yifen
From removing, (4) step can also be remained and disposably detached after reaction,
(3) epoxidation reaction:It is organic molten that the glucoside member mixture of 19 carboxy protectives obtained in step (2) is dissolved in second
In agent, epoxidation reagent progress epoxidation reaction is added and obtains white solid;The white solid includes 19 carboxy protectives
Isosteviol ', epoxidation steviol derivative A and double-bond isomerization epoxy product B;
(4) reduction reaction:The white solid obtained in step (3) is dissolved in third organic solvent, zinc powder, acetic acid is added
Sodium, sodium iodide, glacial acetic acid and copper sulphate are reacted, and the isosteviol of 19 carboxy protectives is obtained ', steviol derivative C and
The mixture of double-bond isomerization epoxy product B;
(5) product detaches:The mixture obtained in separating step (4), respectively obtains the isosteviol of 19 carboxy protectives
Pg-I ', steviol derivative C and double-bond isomerization epoxy product B;
Wherein, R is tert-butyl diphenyl silicon substrate (TBDPS) or methyl naphthalene (Nap), and X is selected from Cl or Br.
In step (1), the mass volume ratio of the stevia rebaudianum Leave extract powder and water is 1:1.5~2.5g/mL, the salt
The rate of charge of a concentration of 10-12moL/L of aqueous acid, the stevia rebaudianum Leave extract powder and aqueous hydrochloric acid solution is 100:
0.625~0.833g/mL;The temperature of the back flow reaction is 94-96 DEG C, and the time of the back flow reaction is 26-28 hours, institute
The solvent for stating recrystallization is methanol.The glucoside member mixture obtained after filter residue recrystallization includes steviol I, isosteviol I ' and double bond
Isomerization product I ".
In step (2), first organic solvent is selected from n,N-Dimethylformamide, dichloromethane, 1,2- dichloroethanes
It is or one or more in pyridine, it is preferred that first organic solvent is n,N-Dimethylformamide;The glucoside member mixture
Mass volume ratio with the first organic solvent is 0.2~0.24g/mL;The alkali appointing in imidazoles, triethylamine, potassium carbonate
It anticipates one or more;The molar ratio of the glucoside member mixture, alkali and reagent RX is 1:1.2:1.2~1:4:4, it is preferred that be 1:
1.2:1.2~1:1.1.5:1.5.
In step (3), second organic solvent is dichloromethane or 1, and one or both of 2- dichloroethanes is described
A concentration of 0.2~the 0.3mol/L of the glucoside member mixture of 19 carboxy protectives obtained in step (2) in a second organic solvent;
The epoxidation reagent is selected from metachloroperbenzoic acid, 30% hydrogen peroxide, sodium peroxide or Oxone, it is preferred that the epoxidation
Reagent is metachloroperbenzoic acid;The glucoside member mixture and epoxidation reagent of 19 carboxy protectives obtained in the step (2)
Molar ratio be 1:1.5~1:2.
In step (4), one kind in Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol or ether of the third organic solvent or
A variety of, mass volume ratio of the white solid obtained in the step (3) in third organic solvent is 0.1~0.2g/mL, excellent
It is selected as 0.1~0.13g/mL;The white obtained in the zinc powder, sodium acetate, sodium iodide, glacial acetic acid, copper sulphate and step (3) is solid
The molar ratio of body is 5.7:1.04:1.7:10:0.1:1~6.7:2.04:2.7:20:0.2:1.
Preferably, the third organic solvent is the mixed solvent of Isosorbide-5-Nitrae-dioxane and methanol.
It is furthermore preferred that the volume ratio of the Isosorbide-5-Nitrae-dioxane and methanol is 1:1~1:2.
Described to be separated into column chromatography for separation in step (5), the eluant, eluent of the column chromatography for separation is selected from n-hexane, acetic acid
It is one or more in ethyl ester, petroleum ether or dichloromethane.
Preferably, the eluant, eluent is PE:EA=10:1,Hexane:EA=10:1,PE:DCM=1:1.
With PE:EA=10:1 is solvent, and the TLC plates of the reaction product of reaction product and step (4) in step (2) are shown
It is intended to such as Fig. 2, as it can be seen that Rf is close on the tlc plate originally in figure, the compound I and I " being not readily separated is through protection and epoxidation two
After step reaction conversion, the two class compound of B and C that Rf on TLC plates differs larger is obtained, can easily be used column chromatography.
The present invention is reacted from raw material by 4 steps, it is only necessary in final step column chromatography for separation, you can it is that chemistry is pure to obtain purity
Steviol derivative.
A kind of preparation method of steviol, including above-mentioned steps (1)~(5) further include step (6):The step (6) is
The steviol derivative C Deprotections that will be obtained in step (5);
Wherein, R is tert-butyl diphenyl silicon substrate or methyl naphthalene, and X is selected from Cl or Br.
In step (6), the Deprotection includes the following steps:By the compound C solutions obtained in step (5) in THF,
Under the TBAF effects of 1~2 molar equivalent, deprotection base.
Advantageous effect:
The invention devises series of chemical, by functional group conversions, by the minimum sweet tea of different polarities
Alantol and double-bond isomerization steviol distinguish, and obtain the big steviol derivative of different polarities so that target product and by-product
It is easily isolated, then obtains the steviol of high-purity by deprotection reaction.To solve the low steviol glycoside of content by chemical synthesis
Largely obtain lay a solid foundation.
The present invention is reacted from raw material by 4 steps, it is only necessary in final step column chromatography for separation, you can it is that chemistry is pure to obtain purity
Steviol derivative.Operation is simple, and the steviol derivative C obtained, by 13 of steviol and 19 areas
Point, it is used directly for the synthesis of steviol glycoside.
Description of the drawings
Fig. 1 flow charts of the present invention,
Fig. 2 present invention reacts TLC schematic diagrames,
The hydrogen of Fig. 3 steviols I is composed,
Fig. 4 steviols I and double-bond isomerization steviol I " mixture hydrogen spectrum,
The hydrogen of Fig. 5 isosteviols I ' is composed.
Specific implementation mode
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
Stevia rebaudianum Leave extract powder used in the present invention is the mass percent purity of Jiangxi Pu Saike companies production
For 80% stevioside leaf crude extract powder.30% hydrogen peroxide is pair that commercial available quality percent concentration is 30% in the present invention
The aqueous solution of oxygen water.Remaining raw material is commercially available.The silica gel plate chromatographic sheet that the present invention uses is (Thin Layer
Chromatography, abbreviation TLC) Huanghai Sea High Performance Thin Layer Chromatography silica gel H SGF254.
The meaning abridged in the present invention is as follows:PE is petroleum ether, and EA is ethyl acetate, and Hexane is n-hexane, DCM bis-
Chloromethanes, THF are tetrahydrofuran, and DMF is n,N-Dimethylformamide, and TBAF is tetrabutyl ammonium fluoride, and eq indicates reactant phase
For the molar equivalent of glucoside member.
Embodiment 1R is the preparation of the steviol glucoside member of TBDPS
(1) stevioside leaf crude extract powder 100g is dissolved in 250mL water, is slowly added dropwise after heating for dissolving a concentration of
In the concentrated hydrochloric acid 0.833mL to system of 12moL/L, back flow reaction 28 hours, there is white solid analysis under the conditions of stable 95 DEG C
Go out.Reaction solution filters after being completely cooled down to room temperature, and filter residue is taken to be dissolved in 60 DEG C of methanol, refrigerator low temperature recrystallization is placed, after filtering
It is glucoside member mixture 12g (0.0377mol) to obtain white powdery solids.
(2) by step (1) to white powdery solids 12g (0.0377mol) is dissolved in 50mL N, N- dimethyl
In formamide, imidazoles (1.5eq) and TBDPSCl (1.5eq) is added, 4h, ethyl acetate dilution, organic phase are reacted under nitrogen protection
Three times, saturated sodium-chloride, which is dissolved in, to be washed once, and anhydrous sodium sulfate drying after being spin-dried for solvent, obtains white foam solid for washing
12.6g(0.0226mol)
(3) the white foam solid 12.6g (0.0226mol) obtained in step (2) is dissolved in 50mL dichloromethane,
Metachloroperbenzoic acid (1.75eq) is added under ice-water bath, is slowly increased to two hours of room temperature reaction.Saturation thiosulfuric acid is added
Reaction is quenched in sodium, and organic phase is washed twice, and saturated nacl aqueous solution is washed once, and dry, obtained white is hanged in anhydrous sodium sulfate drying
Foaming solid 13g (0.0227mol).
(4) the white foam solid 13g (0.0227mol) that will be obtained in step (3), is dissolved in 100ml Isosorbide-5-Nitraes-dioxy six
(1,4- dioxane and methanol volume ratio are 1 in mixed solution in the mixed solution of ring and methanol:1) zinc powder, is added
(5.7eq), sodium acetate (1.04eq), sodium iodide (1.7eq), glacial acetic acid (10eq), copper sulphate (0.1eq), room temperature reaction are stayed overnight,
System filters, and takes filtrate, washes 3 times, and saturated sodium bicarbonate is washed 3 times, and saturated sodium-chloride is washed 1 time, and anhydrous sodium sulfate drying is spin-dried for
After solvent, residue solvent (PE:EA=10:1 or Hexane:EA=10:1 or PE:DCM=1:1 chooses any one kind of them) it carries out
Column chromatography obtains compound C-1 sterlings 6g, 10.77mmol.B-1 can obtain 5.7g 9.95mmol.
B-1:[α]D 25=-31.6 (c 1, CHCl3);1H NMR(400MHz,CDCl3)δ7.69-7.66(m,4H),7.45-
7.40 (m, 2H), 7.38-7.34 (m, 4H), 2.93 (d, J=4.8Hz, 1H), 2.78 (d, J=4.8Hz, 1H), 2.34 (brs,
1H), 2.24-2.19 (m, 1H), 2.14 (dd, J=2.0,11.2Hz, 1H), 1.35 (dd, J=2.8,11.2Hz, 1H), 1.27
(s,3H),1.14(s,9H),0.76(s,3H);13C NMR(100MHz,CDCl3)δ176.9,135.8(2C),132.1(2C),
130.1,127.7,74.9,65.4,57.1,53.9,48.8,46.7,45.8,45.2,41.7,41.5,40.8,39.5,38.6,
34.8,29.3,27.3,22.3,19.7,19.4,19.3,16.4,HRMS(ESI)calcd for C18H21IO8Na[M+Na]+
595.3214,found 595.3210.
C-1:[α]D 25=-55.3 (c 1, CHCl3);1H NMR(400MHz,CDCl3)δ7.69-7.66(m,4H),7.45-
7.34 (m, 6H), 4.97 (t, J=2.4Hz, 1H), 4.81 (t, J=2.4Hz, 1H), 2.25-2.16 (m, 2H), 2.09-2.02
(m, 2H), 1.90-1.38 (m, 9H), 1.27 (s, 3H), 1.24 (dd, J=2.4,11.2Hz, 1H), 1.14 (s, 9H), 1.08-
1.04 (m, 1H), 0.95 (d, J=8.0Hz, 1H), 0.76 (s, 3H);13C NMR(100MHz,CDCl3)δ176.9,156.3,
135.8(2C),132.2(2C),130.1,127.7,103.0,80.4,57.2,53.9,47.6,47.1,45.3,41.8,
41.6,40.8,39.5,39.3,38.7,29.4,27.3,22.4,20.6,19.4(2C),16.2;HRMS(ESI)calcd for
C18H21IO8Na[M+Na]+579.3265,found 579.3257.
Embodiment 2:R is the preparation of the steviol glucoside member of methyl naphthalene
(1) stevioside leaf crude extract powder 100g is dissolved in 250mL water, dissolve by heating, after hydrochloric acid is slowly added dropwise
In 0.41mL to system, back flow reaction 28 hours, there is white solid precipitation under the conditions of stable 95 DEG C.Mistake after being cooled to room temperature
Filter takes filter residue to be dissolved in 60 DEG C of methanol, places refrigerator low temperature recrystallization, white powdery solids 12g is obtained after filtering
(0.0377mol)。
(2) by step (1) to white powdery solids 5.6g (0.0176mol) is dissolved in 25mL N, N- diformazans
In base formamide, imidazoles (1.5eq) and NapCl (1.5eq) is added, 4h, ethyl acetate dilution, organic phase are reacted under nitrogen protection
Three times, saturated sodium-chloride, which is dissolved in, to be washed once, and anhydrous sodium sulfate drying after being spin-dried for solvent, obtains white foam solid for washing
6.6g(0.0144mol)。
(3) the white foam solid 6.6g (0.0144mol) obtained in step (2) is dissolved in 25mL dichloromethane,
Metachloroperbenzoic acid (1.75eq) is added under ice-water bath, is slowly increased to two hours of room temperature reaction.Saturation thiosulfuric acid is added
Reaction is quenched in sodium, and organic phase is washed twice, and saturated nacl aqueous solution is washed once, anhydrous sodium sulfate drying, hangs the white bubble done
Foam 6.5g (0.0141mol).
(4) the white foam solid 6.5g (0.0141mol) that will be obtained in step (3), is dissolved in 50mL Isosorbide-5-Nitraes-dioxy six
Ring:Methanol (1:1) in solution, addition zinc powder (5.7eq), sodium acetate (1.04eq), sodium iodide (1.7eq), glacial acetic acid (10eq),
Copper sulphate (0.1eq), overnight, system filtering takes filtrate, washes 3 times, and saturated sodium bicarbonate is washed 3 times, and chlorination is saturated for room temperature reaction
Sodium is washed 1 time, and anhydrous sodium sulfate drying is hanged dry.Product carries out column chromatography, obtains compound C-2 sterlings 3.1g (0.0068mol) B-2
Sterling 2.8g (0.0061mol), solvent proportioning are PE:EA=4:The Rf values of compound C-2 on the tlc plate are about 0.45 when 1,
Solvent matches:PE:EA=4:The Rf values of compound B-2 on the tlc plate are about 0.2 when 1.
B-2:[α]D 25=-59.3 (c 1, CHCl3);1H NMR(400MHz,CDCl3)δ7.86-7.83(m,4H),7.53-
7.46 (m, 3H), 5.33 (AB, 2H), 2.92 (d, J=4.4Hz, 1H), 2.78 (d, J=4.4Hz, 1H), 2.32 (t, J=
1.2Hz, 1H), 2.26 (td, J=3.6,13.2Hz, 1H), 2.15 (dd, J=2.0,11.2Hz, 1H), 1.92-1.55 (m,
10H),1.48-1.42(m,3H),1.35-1.32(m,1H),1.21(s,3H),1.08-0.93(m,3H),0.83(s,3H);13C
NMR(100MHz,CDCl3)δ177.2,133.5,133.3,133.1,128.4,128.1,127.8,127.6,126.4,
126.3,126.1,74.8,66.4,65.4,57.1,53.9,48.8,46.6,45.8,44.0,41.7,41.3,40.8,39.4,
38.1,34.8,29.0,22.0,19.6,19.2,15.8,HRMS(ESI)calcd for C18H21IO8Na[M+H]+
475.2843,found 475.2849.
C-2:[α]D 25=-51.3 (c 1, CHCl3);1H NMR(400MHz,CDCl3)δ7.86-7.83(m,4H),7.53-
7.46 (m, 3H), 5.32 (AB, 2H), 4.97 (t, J=2.4Hz, 1H), 4.81 (d, J=2.4Hz, 1H), 2.25-2.00 (m,
4H), 1.92-1.36 (m, 9H), 1.21 (s, 3H), 1.08-0.97 (m, 2H), 0.95 (d, J=8.0Hz, 1H), 0.80 (s,
3H);13C NMR(100MHz,CDCl3)δ177.4,156.2,133.6,133.3,133.2,128.4,128.1,127.8,
127.6,126.4,126.3,126.2,103.0,80.3,66.4,57.2,53.8,47.5,47.0,44.1,41.8,41.4,
40.8,39.4,39.3,38.2,29.0,22.0,20.5,19.2,15.6;HRMS(ESI)calcd for C18H21IO8Na[M+
H]+459.2894,found 459.2893.
Embodiment 3R is the preparation of the steviol glucoside member of TBDPS
Preparation method and embodiment 1 are identical, except that in step (1), stevioside leaf crude extract powder 100g is molten
In 150mL water, concentrated hydrochloric acid 0.625mL is slowly added dropwise;The temperature of the back flow reaction is 94 DEG C, and the time of the back flow reaction is
26 hours, the solvent of the recrystallization was methanol.Steviol, isosteviol and double-bond isomerization production in obtained glucoside member mixture
The molar ratio of object is 1:1.2:1.2.
In step (2), the mass volume ratio of glucoside member mixture and the first organic solvent is 0.24g/mL, and alkali is three second
The molar ratio of amine, glucoside member mixture, triethylamine and TBDPSCl is 1:1.2:1.2;
In step (3), the molar concentration of the glucoside member mixtures of 19 carboxy protectives in DCM is 0.3mol/L, epoxidation
Reagent is 30% hydrogen peroxide, and the glucoside member mixture and hydrogen peroxide molar ratio of 19 carboxy protectives are 1:2;
In step (4), the white solid that is obtained in step (3) and third organic solvent molal volume than for quality volume
Than for 0.1g/mL, catalyst group becomes zinc powder (6.7eq), sodium acetate (2.04eq), sodium iodide (2.7eq), glacial acetic acid
(20eq), copper sulphate (0.2eq), column chromatography for separation, which obtains compound C-1 sterlings 5.5g, B-1, after post-processing can obtain 5.2g.
The preparation of 4 steviol of embodiment:
Compound C-1 makees solvent through deprotection reaction, with THF, and the molar ratio range of TBAF and substrate is 1:1~1:2,
The reaction was complete for TLC detections, and three times, organic phase saturated sodium bicarbonate drying, filtering is spin-dried for column chromatography, eluant, eluent is for washing:PE:
EA=1.5:1,Hexane:EA=1.5:1 obtains the pure steviol of chemistry, yield 96.4%.1H NMR(400MHz,CDCl3)
δ 11.98 (s, 1H), 4.88 (s, 1H), 4.69 (s, 1H), 1.10 (s, 3H), 0.87 (s, 3H) are consistent with document report.
Comparative example 1:100g steviol crude extract powder is dissolved in 250mL water, sulfamic acid 1.21g, amino is added
The molar concentration of sulfonic acid is:0.05mol/L, 95 DEG C of back flow reaction 31h, reaction do not have white solid as described in document
Body is precipitated, and reverse phase plate contact plate detection, raw material is displayed without target product almost without reaction, positive phase-plate.
Comparative example 2:Bibliography:Ogawa,T.;Nozaki,M.;Matsui,M.Tetrahedron 1980,36,
2641.
Steviol glycoside (1.1g) and sodium metaperiodate (1.5g) are dissolved in (75mL), stir 16h at room temperature.Hydrogen-oxygen is then added
Change potassium (7.5g) reflux 1h, postcooling to room temperature is slowly added dropwise glacial acetic acid, neutralizes system PH>4.After extract, hang dry, column chromatography,
Obtain steviol white solid 300mg.The reaction needs a large amount of solvents and alkali, can not amplification quantity production.
The product identification of step (1) in embodiment 1:
The white powdery solids obtained in step (1) in embodiment 1 are passed through into column chromatography for separation, eluant, eluent PE:EA=
1:1, it can detach and separate isosteviol I ', I ':1H NMR(400MHz,CDCl3)δ2.01(d,1H),1.88(d,
1H), 1.12 (s, 3H), 0.87 (s, 3H), 0.73 (s, 3H) are consistent with Reported data.
Steviol I and double-bond isomerization product I " can not be detached, and the 1H NMR of mixture are shown in Fig. 4;Wherein δ 5.01, δ
It is steviol double bond hydrogen at 4.68ppm two, is the double bond hydrogen of double-bond isomerization product at δ 4.87ppm, has one at δ 1.54ppm
It is a unimodal, it is the methyl peak of C17 in double-bond isomerization product, can be seen that the ratio of I and I " is 1 from features above peak:1.
Claims (10)
1. a kind of preparation method of steviol glucoside member, which is characterized in that include the following steps:
(1) the sour water solution of stevia rebaudianum Leave extract powder:Stevia rebaudianum Leave extract powder is dissolved in the water, aqueous hydrochloric acid solution is added,
Back flow reaction, after reaction, by reaction solution cooled and filtered, filter residue obtains glucoside member mixture after recrystallizing;
(2) 19 carboxy protectives of glucoside member mixture:The glucoside member mixture obtained in step (1) is dissolved in the first organic solvent
In, the glucoside member mixture of 19 carboxy protectives is obtained by the reaction with reagent RX in the presence of alkali;
(3) epoxidation reaction:The glucoside member mixture of 19 carboxy protectives obtained in step (2) is dissolved in the second organic solvent
In, epoxidation reagent progress epoxidation reaction is added and obtains white solid;
(4) reduction reaction:The white solid obtained in step (3) is dissolved in third organic solvent, be added zinc powder, sodium acetate,
Sodium iodide, glacial acetic acid and copper sulphate are reacted, and the mixture of steviol derivative C and double-bond isomerization epoxy product B are obtained;
(5) product detaches:The mixture obtained in separating step (4), respectively obtains steviol derivative C and double-bond isomerization ring
Oxygen product B;
Wherein, R is tert-butyl diphenyl silicon substrate or methyl naphthalene, and X is selected from Cl or Br.
2. the preparation method of steviol glucoside member according to claim 1, which is characterized in that in step (1), the stevia rebaudian leaf is thick
The mass volume ratio of extract powder and water is 1:1.5~2.5g/mL, a concentration of 10-12moL/L of the aqueous hydrochloric acid solution, institute
The rate of charge for stating stevia rebaudianum Leave extract powder and aqueous hydrochloric acid solution is 100:0.625~0.833g/mL;The temperature of the back flow reaction
Degree is 94-96 DEG C, and the time of the back flow reaction is 26-28 hours, and the solvent of the recrystallization is methanol.
3. the preparation method of steviol glucoside member according to claim 1, which is characterized in that in step (2), described first is organic
Solvent is one or more in N,N-dimethylformamide, dichloromethane, 1,2- dichloroethanes or pyridine;The glucoside member is mixed
The mass volume ratio for closing object and the first organic solvent is 0.2~0.24g/mL;The alkali is in imidazoles, triethylamine, potassium carbonate
Any one or more;The molar ratio of the glucoside member mixture, alkali and reagent RX is 1:1.2:1.2~1:4:4.
4. the preparation method of steviol glucoside member according to claim 1, which is characterized in that in step (3), described second is organic
Solvent is dichloromethane or 1, one or both of 2- dichloroethanes, the glucoside member of the carboxy protective obtained in the step (2)
A concentration of 0.2~the 0.3mol/L of mixture in a second organic solvent;The epoxidation reagent be selected from metachloroperbenzoic acid,
30% hydrogen peroxide, sodium peroxide or Oxone, the glucoside member mixture and epoxy of 19 carboxy protectives obtained in the step (2)
The molar ratio for changing reagent is 1:1.5~1:2.
5. the preparation method of steviol glucoside member according to claim 1, which is characterized in that in step (4), the third is organic
Solvent is one or more in Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol or ether, and the white obtained in the step (3) is solid
Mass volume ratio of the body in third organic solvent is 0.1~0.2g/mL, the zinc powder, sodium acetate, sodium iodide, glacial acetic acid, sulphur
The molar ratio of the white solid obtained in sour copper and step (3) is 5.7:1.04:1.7:10:0.1:1~6.7:2.04:2.7:
20:0.2:1.
6. the preparation method of steviol glucoside member according to claim 5, which is characterized in that the third organic solvent is Isosorbide-5-Nitrae-
The mixed solvent of dioxane and methanol.
7. the preparation method of steviol glucoside member according to claim 6, which is characterized in that the Isosorbide-5-Nitrae-dioxane and methanol
Volume ratio be 1:1~1:2.
8. the preparation method of steviol glucoside member according to claim 1, which is characterized in that described to be separated into column in step (5)
Chromatography, one kind in n-hexane, ethyl acetate, petroleum ether or dichloromethane of the eluant, eluent of the column chromatography for separation or
It is a variety of.
9. a kind of preparation method of steviol, includes the following steps:
(1) the sour water solution of stevia rebaudianum Leave extract powder:Stevia rebaudianum Leave extract powder is dissolved in the water, aqueous hydrochloric acid solution is added,
Back flow reaction, after reaction, by reaction solution cooled and filtered, filter residue obtains glucoside member mixture after recrystallizing;
(2) 19 carboxy protectives of glucoside member mixture:The glucoside member mixture obtained in step (1) is dissolved in the first organic solvent
In, the glucoside member mixture of 19 carboxy protectives is obtained by the reaction with reagent RX in the presence of alkali;
(3) epoxidation reaction:The glucoside member mixture of 19 carboxy protectives obtained in step (2) is dissolved in the second organic solvent
In, epoxidation reagent progress epoxidation reaction is added and obtains white solid;
(4) reduction reaction:The white solid obtained in step (3) is dissolved in third organic solvent, be added zinc powder, sodium acetate,
Sodium iodide, glacial acetic acid and copper sulphate are reacted, and the mixture of steviol derivative C and double-bond isomerization epoxy product B are obtained;
(5) product detaches:The mixture obtained in separating step (4), respectively obtains steviol derivative C and double-bond isomerization ring
Oxygen product B;
(6) it is deprotected:The steviol derivative C Deprotections that will be obtained in step (5);
Wherein, R is tert-butyl diphenyl silicon substrate or methyl naphthalene, and X is selected from Cl or Br.
10. the preparation method of steviol according to claim 9, which is characterized in that
In step (1), the mass volume ratio of the stevia rebaudianum Leave extract powder and water is 1:1.5~2.5g/mL, the hydrochloric acid water
The rate of charge of a concentration of 10-12moL/L of solution, the stevia rebaudianum Leave extract powder and aqueous hydrochloric acid solution is 100:0.625~
0.833g/mL;The temperature of the back flow reaction is 94-96 DEG C, and the time of the back flow reaction is 26-28 hours, the heavy knot
Brilliant solvent is methanol;
In step (2), first organic solvent is selected from n,N-Dimethylformamide, dichloromethane, 1,2- dichloroethanes or pyrrole
It is one or more in pyridine;The mass volume ratio of the glucoside member mixture and the first organic solvent is 0.2~0.24g/mL;It is described
Any one or more of alkali in imidazoles, triethylamine, potassium carbonate;The molar ratio of the glucoside member mixture, alkali and reagent RX
It is 1:1.2:1.2~1:4:4;
In step (3), second organic solvent is dichloromethane or 1, one or both of 2- dichloroethanes, the step
(2) a concentration of 0.2~0.3mol/L of the glucoside member mixture of the carboxy protective obtained in a second organic solvent;The epoxy
It is 30% aqueous hydrogen peroxide solution, sodium peroxide or Oxone, institute to change reagent selected from metachloroperbenzoic acid, mass percent concentration
The molar ratio of the glucoside member mixture and epoxidation reagent of stating 19 carboxy protectives obtained in step (2) is 1:1.5~1:2;
In step (4), the third organic solvent is one or more in Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol or ether,
Mass volume ratio of the white solid obtained in the step (3) in third organic solvent is 0.1~0.2g/mL, the zinc
The molar ratio of the white solid obtained in powder, sodium acetate, sodium iodide, glacial acetic acid, copper sulphate and step (3) is 5.7:1.04:
1.7:10:0.1:1~6.7:2.04:2.7:20:0.2:1;
In step (6), the Deprotection includes the following steps:The compound C obtained in step (5) is dissolved in THF,
Under the TBAF effects of 1~2 molar equivalent, deprotection base.
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