CN102336798A - Synthetic method of ginsenoside Rh3 - Google Patents
Synthetic method of ginsenoside Rh3 Download PDFInfo
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- CN102336798A CN102336798A CN2010102282023A CN201010228202A CN102336798A CN 102336798 A CN102336798 A CN 102336798A CN 2010102282023 A CN2010102282023 A CN 2010102282023A CN 201010228202 A CN201010228202 A CN 201010228202A CN 102336798 A CN102336798 A CN 102336798A
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- PHLXREOMFNVWOH-YAGNRYSRSA-N Ginsenoside Rh3 Chemical compound O([C@H]1CC[C@]2(C)[C@H]3C[C@@H](O)[C@H]4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@@H]4C(\C)=C/CC=C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PHLXREOMFNVWOH-YAGNRYSRSA-N 0.000 title claims abstract description 17
- PHLXREOMFNVWOH-DNQFHFKUSA-N Ginsenoside Rh3 Natural products O([C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@@H]1C(C)(C)[C@H]2[C@@](C)([C@@H]3[C@](C)([C@@]4(C)[C@H]([C@H](O)C3)[C@@H](/C(=C/C/C=C(\C)/C)/C)CC4)CC2)CC1 PHLXREOMFNVWOH-DNQFHFKUSA-N 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000002808 molecular sieve Substances 0.000 claims abstract description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000002841 Lewis acid Substances 0.000 claims abstract description 4
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 76
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- -1 ginsenoside Rh 3 compound Chemical class 0.000 claims description 21
- 238000006206 glycosylation reaction Methods 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 239000003921 oil Substances 0.000 claims description 10
- 239000011973 solid acid Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 239000000377 silicon dioxide Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-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 5
- 239000002585 base Substances 0.000 claims description 5
- 238000003379 elimination reaction Methods 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 4
- 239000011968 lewis acid catalyst Substances 0.000 claims description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052796 boron Inorganic materials 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052709 silver Inorganic materials 0.000 claims description 3
- 239000004332 silver Substances 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
- 150000004645 aluminates Chemical class 0.000 claims 1
- 229910052786 argon Inorganic materials 0.000 claims 1
- 229910052728 basic metal Inorganic materials 0.000 claims 1
- 150000003818 basic metals Chemical class 0.000 claims 1
- 229960001701 chloroform Drugs 0.000 claims 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 239000000499 gel Substances 0.000 claims 1
- 239000001307 helium Substances 0.000 claims 1
- 229910052734 helium Inorganic materials 0.000 claims 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- 239000011347 resin Substances 0.000 claims 1
- 229920005989 resin Polymers 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 2
- 239000008103 glucose Substances 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 239000011949 solid catalyst Substances 0.000 abstract 1
- 229940089161 ginsenoside Drugs 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000003480 eluent Substances 0.000 description 9
- 229930182494 ginsenoside Natural products 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 229910001958 silver carbonate Inorganic materials 0.000 description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229930182490 saponin Natural products 0.000 description 3
- 235000017709 saponins Nutrition 0.000 description 3
- CKUVNOCSBYYHIS-IRFFNABBSA-N (20S)-ginsenoside Rh2 Chemical compound O([C@H]1CC[C@]2(C)[C@H]3C[C@@H](O)[C@H]4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@@H]4[C@@](C)(O)CCC=C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O CKUVNOCSBYYHIS-IRFFNABBSA-N 0.000 description 2
- 241000208340 Araliaceae Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000008434 ginseng Nutrition 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 2
- 150000007949 saponins Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- IXWUPTJSAZCADA-UHFFFAOYSA-N S(=O)(=O)(C1=CC=CC=C1)ClC Chemical compound S(=O)(=O)(C1=CC=CC=C1)ClC IXWUPTJSAZCADA-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000002929 anti-fatigue Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- YVECGMZCTULTIS-PBXRRBTRSA-N glucal Chemical compound OC[C@H]1OC=C[C@@H](O)[C@@H]1O YVECGMZCTULTIS-PBXRRBTRSA-N 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000011964 heteropoly acid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 150000003587 threonine derivatives Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention relates to a synthetic method of ginsenoside Rh3. The synthetic method comprises the following steps of: with protopanoxadiol as a starting raw material, firstly, selectively protecting 12-hydroxyl to obtain a 12-substitueted protopanoxadiol; dehydrating 20-hydroxyl of 12-substitueted protopanoxadiol under the acid condition to form double bonds; carrying out glucosidation on the double bonds, a glucose-based donor and a molecular sieve under the catalytic action of Lewis acid or a solid catalyst; secondly, removing a protecting group; and finally, separating and purifying to obtain the ginsenoside Rh3. The method has the advantages of mild reaction condition, low cost, simpleness in operation, environment friendliness, strong practicability and suitability for industrial production; in addition, a reaction product has high selectivity, high yield and high purity.
Description
Technical field
The present invention relates to a kind of compound method of rare ginsenoside of biologically active, specifically: the ginsenoside Rh 3, i.e. 3 β-O-Da Ma-20 (22), 24-diene-glucopyranoside, the compound method that its structure is as follows.
Background technology
Genseng is widely used in motherland's medical science, and is with a long history, and Shennong Bencaojing is classified as top grade.Modern pharmacology discovers that the main active ingredient of genseng is a ginsenoside.Up-to-date pharmaceutical research shows; Ginsenoside for apoptotic protection, reverse leukemia cell's resistance, antifatigue, delay senility, regulate cns, enhance immunity power, improve the cardiovascular and cerebrovascular blood supply insufficiency, suppress growth of tumour cell etc. and have good effect; Kind surplus the ginsenoside that has separated at present and identified reaches 60; The content of various saponin(es, exist the position to be not quite similar, and pharmacological action have similar, have opposite, what have has unique pharmacological action.Discovery ginsenoside Rh2s such as KIM Y S can be induced different HL-60 cells with Rh3, make it to become the granulocyte on morphologic and the function; Dong-Hyun Kim etc. discovers that ginsenoside Rh 3 has good anti-inflammatory action.In order to give full play to each monomeric biological activity, to need further each monomer to be prepared, just can be applied to the new drug development field.
Synthesizing of ginsenoside, critical step is glycosylation reaction.(spy opens flat 8-208688 like (1) Japanese Patent; 1996) with protopanoxadiol as semi-synthetic 20 (the S)-ginsenoside Rh2s of raw material, the linear synthetic route of this method was six steps, the silver carbonate that in glycosylation reaction, has used equivalent is as catalyzer; Price is valuable; Make that this method cost is higher, and the reaction product stereoselectivity of this catalyzer is bad, considers all to be unfavorable for scale operation from cost and yield two aspects.(2) Korea S's genseng Dohanykutato Intezet adopts the dried powder of alkaline alcoholic solution hydrolysis Ginseng Leaf and Gen; Obtain 20 (S)-ginsenoside aglycons; And then in the presence of catalyzer such as silver carbonate with the glucose condensation to prepare 20 (S)-ginsenoside Rh2s, this method also has been to use silver carbonate as catalyzer, price is valuable; Make this method cost higher, and use silver carbonate to do the mixture of the reaction product of catalyzer as Q, two kinds of glycosidic link configurations of B.(3) Chinese patent 20041005329.2 reports; With the protopanoxadiol is raw material; Its 12 hydroxyls are protected; Use the catalyzer as glycosylation reaction such as expensive lewis acid catalyst such as fluoro hydrocarbyl sulfonic, silica-based hydrofluoric ether sulphonate, fluoro hydrocarbyl sulfonic silver or unsettled boron trifluoride-ether complex, and reaction needs control low temperature, cost is higher relatively.
Solid acid has caused people's extensive concern as a kind of new green environment protection type catalyzer.Up to the present, nine types of solid acids such as immobilized liquid acid, simple oxide, sulfide, metal-salt, zeolite solid acid, heteropolyacid solid acid, Zeo-karb, clay pit, solid super-strong acid have been developed.Wherein, Strongly acidic cation-exchange Amberlyst-15, NKC-9, Nafion-H etc. are widely used in the glycosylation reaction of organic synthesis; It at room temperature gets final product a series of O such as catalysis simple alcohols/sulphur is liquor-saturated, phenol/toluene-, monose, Threonine/serine derivative, and the S-nucleophilic reagent is connected with full acetylated glycosyl tribromo-acetyl imines ester with glucal respectively, and highly-solid selectively ground generates O; S-oligosaccharides glycosides and glycosyl amino acid, yield reaches 50-98%.With existing method relatively, this catalystsystem has characteristics such as mild condition, operation sieve be single, environmentally friendly, practical, for the glycosylation reaction of ginsenoside provides a new approach.
Ginsenoside Rh 3 content in genseng is very little, is a kind of rare ginsenoside, and its chemical synthesis process does not appear in the newspapers.Chen Yingjie etc. find ginsenoside Rh3 from the Ginseng Leaf, and identify its structure; Lv Di etc. are raw material with the panoxadiol saponins, adopt the ginsenoside enzyme of plant origin, and enzyme process changes the glycols saponin glycosyl, produce ginsenoside Rh's 3 mixtures; From Radix Panacis Quinquefolii, isolate ginsenoside Rh 3 first from stepping on upright the grade.
Summary of the invention
For this reason, the object of the present invention is to provide ginsenoside Rh 3, i.e. protopanoxadiol 3 β-O-Da Ma-20 (22), the compound method of 24-diene-glucopyranoside.Present method has the advantages that cost is low, reaction conditions is gentle, the beta comfiguration glycosidic link selectivity of reaction product high, productive rate is high, purity is high, and simple to operate, environmentally friendly, practical, is the method that is fit to suitability for industrialized production.
Method of the present invention can be represented with following reaction formula:
Compound method of the present invention is to be starting raw material with the protopanoxadiol; 12 hydroxyls of selective protection at first; Obtain 12 substituted protopanoxadiols, the hydroxyl that 12 substituted protopanoxadiols are 20 dewaters under acidic conditions and forms two keys, under the katalysis of Lewis acid or solid acid catalyst, carries out glycosylation reaction for body, molecular sieve with glucone again; Slough the protection base then, after separation and purification obtains ginsenoside Rh 3.
Compound method of the present invention is a raw material with the protopanoxadiol, comprises the steps:
1. protopanoxadiol
(a1) and contain the compound R H reaction of blocking group, obtaining structural formula does
(a2) 12 substituted protopanoxadiols, R is C in the structural formula
2-C
6The substituted arene acyl group of alkyl substituted acyl, arene acyl group or alkane, C
3-C
6Alkyl replace silica-based, C
6-C
16Aromatic base replace silica-basedly, in reaction, the mol ratio of compound (a1) and compound R H is 1: 1.2-5.0, temperature of reaction is 10-25 ℃, the reaction times is 2-20 hour, reacting organic solvent is C
2-C
6Chloroparaffin, triethylamine, pyridine, N, one or more mixture in the dinethylformamide, consumption are that 1mol compound (a1) rises organic solvent with 3-5, the yield of reaction is 85-95%.
2. compound (a2) carries out elimination reaction with dewatering agent, and dewatering agent is C
2-C
6Alkyl carboxylic acid halides or sulfonic acid halide, like Acetyl Chloride 98Min., single halogenated C
2-C
6The alkyl carboxylic acid halides, like chloroacetyl chloride, C
6-C
16Aryl carboxylic acid halides or sulfonic acid halide, like Benzoyl chloride 99min., Methyl benzenesulfonyl chlorine, substituted C
6-C
16Aryl carboxylic acid halides or sulfonic acid halide, C
2-C
16Organic acid anhydride, substituted C
2-C
16Organic acid anhydride, like trifluoroacetic anhydride, generating structure formulas such as inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, Hydrogen bromide, Vanadium Pentoxide in FLAKES, thiophosphoric anhydride do
Compound (a3).Compound (a2) is 1 with the mol ratio of dewatering agent: 1.5-5.0, and temperature of reaction is 20-60 ℃, and the reaction times is 2-20 hour, and the reaction organic solvent is C
2-C
6Chloroparaffin, triethylamine, pyridine, acetone, dioxane, THF in one or more mixture, add quencher cancellation reaction when reaction finishes, product is with column chromatography or recrystallization purifying, the yield of reaction is 65-95%.
3. compound (a3) gives body (b1), Lewis acid or solid acid catalyst, molecular sieve under protection of inert gas with glucone; In organic solvent, carry out glycosylation reaction, the generating structure formula is the compound (a4) of
.In glycosylation reaction, it is 1 that compound (a3), glucone are given the mol ratio of body (b1), catalyzer: 0.5-5.0: 0.01-1.0, and the weight ratio of compound (a3) and molecular sieve is 1: 0-7.0; Temperature of reaction is 5-35 ℃; Reaction times is 0.5-10 hour, and the reaction solvent consumption is that 1mol compound (a3) rises organic solvent with 3-5, adds quencher cancellation reaction when reaction finishes; Product is with column chromatography or recrystallization purifying, and the yield of reaction is 80-90%.
Lewis acid catalyst is C
3-C
9Halogen acid amide, C
1-C
6Fluoro hydrocarbyl sulfonic, C
1-C
8Silica-based fluoro alkyl sulphonate, C
1-C
6Fluoro hydrocarbyl sulfonic silver, boron trifluoride-ether complex or their mixture, for example N-iodo succimide (NIS), silver trifluoromethanesulfonate, the trimethyl silicon based ester of trifluoromethanesulfonic acid etc.Solid acid catalyst is Amberlyst-15, NKC-9 or Nafion-H.
R is the substituted arene acyl group of arene acyl group or alkane, C in the structural formula
2-C
6Alkyl substituted acyl, C
3-C
6Alkyl replace silica-based, C
6-C
16Aromatic base replace silica-based; R1 is C
2-C
8Alkyl substituted acyl, benzoyl-or benzyl.
4. compound (a4) carries out deprotection reaction with alkali metal cpd in polar solvent; Generate ginsenoside Rh 3
(a5); In deprotection reaction, compound (a4) is 1 with the mol ratio of alkali metal cpd: 3-10, and temperature of reaction is 20-60 ℃; Reaction times is 2-10 hour; The consumption of solvent is that 1mol compound (a4) rises solvent with 5-10, and the product of generation is through recrystallization purifying, and the yield of reaction is 80-90%.
Advantage of the present invention: the reaction conditions of the inventive method is relatively gentleer, and synthetic route is succinct, reasonable, and reaction raw materials cheaply is easy to get, cost is low, and simple to operate, environmentally friendly, practical; The beta comfiguration glycosidic link selectivity of the product of the inventive method is high, and product yield is higher, and the yield of glycosylation reaction can reach 85%; Final product adopts the method for recrystallization; Can obtain the higher product of purity, therefore, the inventive method is to be suitable for the method that large-scale industrialization is produced.
Embodiment
Further specify the present invention below in conjunction with embodiment.It should be understood that embodiments of the invention are to be used to explain the present invention rather than limitation of the present invention.Under the prerequisite of spirit of the present invention and principle, all belong to the present invention and require the scope protected inventing any change that indivedual technological steps carry out and changing.
Embodiment 1:12-replaces the synthetic of protopanoxadiol (a2)
(1) synthetic (being that R is an ethanoyl) of 12-ethanoyl protopanoxadiol
Protopanoxadiol (a1) (according to the preparation of document Journal of Chinese Universities 2006/27/03 method) 46g (0.1mol) is dissolved in the pyridine (500ml), adds diacetyl oxide 15.2g (0.15mol), 25 ℃ of stirred overnight under the room temperature; The LC-MS demonstration reacts completely; Add frozen water 500ml cancellation reaction, concentrating under reduced pressure, water is used ethyl acetate extraction; Be washed till neutrality with saturated aqueous common salt again, anhydrous sodium sulfate drying.Concentrating under reduced pressure, and the crude product silica gel column chromatography (eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 4: 1), get compound (a2) 42.7g, yield 85%, HPLC purity is 93%.
The materialization data of compound (a2) are following:
1H-NMR (300MHz, CDCl
3): δ 5.16 (t, 1H), 4.75 (t, 1H), 2.48 (m, 2H), 2.22 (d, 1H), 2.07-1.88 (m, 9H), 1.71-1.24 (m, 24H), 1.13-0.94 (m, 14H).
(2) synthetic (being that R is a benzoyl-) of 12-benzoyl-protopanoxadiol
Protopanoxadiol (a1) (according to the preparation of document Journal of Chinese Universities 2006/27/03 method) 4.6g (0.01mol) is dissolved in the pyridine (50ml), and 0 ℃ adds Benzoyl chloride 99min. 5.1g (0.03mol), 25 ℃ of stirred overnight down; Thin-layer chromatography detects, and demonstration reacts completely, and adds frozen water 50ml cancellation reaction; Concentrating under reduced pressure; Water is used ethyl acetate extraction, is washed till neutrality with saturated aqueous common salt again, anhydrous sodium sulfate drying.Concentrating under reduced pressure, and the crude product silica gel column chromatography (eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 4: 1), get compound (a2) 4.72g, yield 85%, HPLC purity is 94%.
The materialization data of compound (a2) are following:
1H-NMR (300MHz, CDCl
3): δ 7.98-7.36 (m, 5H), 5.14 (t, 1H), 4.72 (t, 1H), 2.46 (m, 2H), 2.20 (d, 1H), 2.05-1.85 (m, 6H), 1.70-1.22 (m, 24H), 1.12-0.86 (m, 14H).
Embodiment 2: elimination reaction
(1) compound (a2) 503mg (0.001mol) is dissolved in the 20ml THF, adds 20% dilute sulphuric acid 2ml, and 50 ℃ were reacted 4 hours; Add sodium hydrogencarbonate cancellation reaction, be cooled to room temperature, the pressure reducing and steaming solvent; Water is used ethyl acetate extraction, and saturated aqueous common salt is washed till neutrality, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, crude product silica gel column chromatography (eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 10: 1) get product compound (a3) 340mg yield 70%.
(2) compound (a2) 503mg (0.01mol) is dissolved in the 20ml methylene dichloride, oxalyl chloride 2.35g (0.03mol), and 50 ℃ were reacted 2 hours; Add aqueous ammonium chloride solution cancellation reaction, be cooled to room temperature, the pressure reducing and steaming solvent; Water is used ethyl acetate extraction, and saturated aqueous common salt is washed till neutrality, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, crude product silica gel column chromatography (eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 10: 1) get product compound (a3) 350mg, yield 72%.
(3) compound (a2) 503mg (0.01mol) is dissolved in 20ml 1, in the 4-dioxane, and sulfur oxychloride 2.38g (0.02mol); 25 ℃ of reactions 2 hours add the shrend reaction of going out, the pressure reducing and steaming solvent; Water is used ethyl acetate extraction, and saturated aqueous common salt is washed till neutrality, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, crude product silica gel column chromatography (eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 10: 1) get product compound (a3) 330mg yield 68%.
(4) compound (a2) 503mg (0.01mol) is dissolved in the 20ml acetone, trifluoroacetic anhydride 5.25g (0.025mol), and 45 ℃ were reacted 2 hours; Add S-WAT cancellation reaction, cool to room temperature, the pressure reducing and steaming solvent; Water is used ethyl acetate extraction, and saturated aqueous common salt is washed till neutrality, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, crude product silica gel column chromatography (eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 10: 1) get product compound (a3) 352mg, yield 72%.
The materialization data of compound (a3) are following:
1H-NMR (300MHz, CDCl
3): δ 5.06 (t, 1H), 4.91 (t, 1H), 3.19 (m, 2H), 2.66 (m, 2H), 2.48 (t, 1H), 1.91-1.25 (m, 30H), 1.13-0.71 (m, 14H).
Embodiment 3: glycosylation reaction (solid acid catalyst)
(1) compound (a3) 4.85g (0.01mol) and compound (b1) (according to the journal 2005/22/05 method preparation of document Shenyang Pharmaceutical University) 5.9g (0.012mol) is dissolved in the 100ml anhydrous methylene chloride; Add
molecular sieve 1g; At room temperature stirred 0.5 hour; Add Amberlyst 15 1.5g, 20 ℃ of stirring reactions 2 hours.Reaction finishes back adding triethylamine cancellation reaction, filters, and filtrating concentrates, 200-300 order silica gel column chromatography, and eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 2: 1, get compound (a4) 6.68g, yield 82%, it is 92.3% that HPLC measures purity.
(2) compound (a3) 4.85g (0.01mol) and compound (b1) (according to the journal 2005/22/05 method preparation of document Shenyang Pharmaceutical University) 5.9g (0.012mol) is dissolved in the 100ml anhydrous methanol; Add
molecular sieve 1g; At room temperature stirred 0.5 hour; Add Nafion-H0.8g, 20 ℃ of stirring reactions 2 hours.Reaction finishes back adding triethylamine cancellation reaction, filters, and filtrating concentrates, 200-300 order silica gel column chromatography, and eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 2: 1, get compound (a4) 6.51g, yield 80%, it is 93.1% that HPLC measures purity.
The materialization data of compound (a4) are following:
ESI：815.5(M+H)。
Embodiment 4: glycosylation reaction (lewis acid catalyst)
Compound (a3) 4.85g (0.01mol) and compound (b1) 5.9g (0.012mol) are dissolved in the 100ml anhydrous methylene chloride; Add
molecular sieve 1g; Under nitrogen protection, stirred 0.5 hour; Add the trimethyl silicon based ester 0.08ml of trifluoromethanesulfonic acid (0.416mmol), 0 ℃ of stirring reaction 0.5 hour.Reaction finishes the back and adds triethylamine cancellation reaction.Filter, filtrating concentrates, 200-300 order silica gel column chromatography, and eluent: the volume ratio of sherwood oil and ETHYLE ACETATE 2: 1, get compound (a4) 6.34g, yield 78%, it is 92.8% that HPLC measures purity.
The materialization data of compound (a4) are following: with embodiment 3.
Embodiment 4: deprotection reaction
(1) compound (a4) 8.15g (0.01mol) is dissolved in the 100ml methyl alcohol, stirs to add sodium methylate 32.4g (0.6mol) down in batches, and 50 ℃ were reacted 8 hours, and reaction finishes.Reaction solution concentrate white solid, use the acetonitrile recrystallization, obtain compound (a5) 4.96g, yield 82.1%, HPLC mensuration purity is 96.2%.
(2) compound (a4) 8.15g (0.01mol) is dissolved in the 100ml THF, stirs to add sodium hydroxide 24g (0.6mol) down in batches, and 50 ℃ were reacted 10 hours, and reaction finishes.Reaction solution concentrate white solid, use the acetonitrile recrystallization, obtain compound (a5) 4.96g, yield 82.1%, HPLC mensuration purity is 96.4%.
Its materialization data are coincident with literature value: Chin Pharm J, 2000 February, Vol.35 No.2.
The materialization data of compound (a5) are following:
ESI：605(M+H)。
1H-NMR(300MHz，C
5D
5N)：δ5.49(t，1H)，5.21(t，1H)，4.95(d，1H)，4.58(d，1H)，4.40(t，1H)，4.20(t，2H)，4.01(t，2H)，3.78(t，1H)，3.35(dd，1H)2.75(t，2H)，0.79-2.20(42H)；
13C?NMR(300MHz，C
5D
5N)：δ139.90，131.20，124.30，122.95，107.75，88.75，78.26，75.73，72.91，71.87，70.95，63.07，56.37，54.75，51.68，50.38，48.56，40.29，39.64，39.12，36.95，35.14，32.03，31.32，28.36，28.15，27.45，26.74，25.68，18.46，17.72，17.03，16.79，16.46，15.84，13.20。
Claims (13)
1. a ginsenoside Rh 3 compound method is a raw material with the protopanoxadiol, it is characterized in that comprising the steps:
(a) protopanoxadiol
(a1) and contain the compound R H reaction of blocking group, obtaining structural formula does
(a2) 12 substituted protopanoxadiols, R is C in the structural formula
2-C
6The substituted arene acyl group of alkyl substituted acyl, arene acyl group or alkane, C
3-C
6Alkyl replace silica-based, C
6-C
16Aromatic base replace silica-basedly, in reaction, the mol ratio of compound (a1) and compound R H is 1: 1.2-5.0, temperature of reaction is 10-25 ℃, the reaction times is 2-20 hour, reacting organic solvent is C
2-C
6Chloroparaffin, triethylamine, pyridine, N, one or more mixture in the dinethylformamide, consumption are that 1mol compound (a1) rises organic solvent with 3-5;
(b) compound (a2) carries out elimination reaction with dewatering agent, and the generating structure formula does
(a3) product, compound (a2) is 1 with the mol ratio of dewatering agent: 1.5-5.0, temperature of reaction is 20-60 ℃, and the reaction times is 2-20 hour, and the reaction organic solvent is C
2-C
6Chloroparaffin, triethylamine, pyridine, acetone, dioxane, THF in one or more mixture, consumption is that 1mol compound (a2) rises organic solvent with 3-5; Add quencher cancellation reaction when reaction finishes, product is with column chromatography or recrystallization purifying;
(c) compound (a3) is that
glucone (b1) gives body, Lewis acid or solid acid catalyst, molecular sieve under protection of inert gas with structural formula; In organic solvent, carry out glycosylation reaction; The generating structure formula is
product (a4); In glycosylation reaction; The mol ratio of compound (a3), compound (b1) and catalyzer is 1: 0.5-5.0: 0.01-1.0; The weight ratio of compound (a3) and molecular sieve is 1: 0-7.0; Temperature of reaction is 5-35 ℃; Reaction times is 0.5-10 hour; The reaction solvent consumption is that 1mol compound (a3) rises organic solvent with 3-5, adds quencher cancellation reaction when reaction finishes, and product is with column chromatography or recrystallization purifying;
R is the substituted arene acyl group of arene acyl group or alkane, C in the structural formula
2-C
6Alkyl substituted acyl, C
3-C
6Alkyl replace silica-based, C
6-C
16Aromatic base replace silica-based; R
1Be C
2-C
6Alkyl substituted acyl, benzoyl-or benzyl; R
2Be OC (NH) CCl
3Or SEt.
(d) compound (a4) carries out deprotection reaction with alkali metal cpd in solvent; Generate ginsenoside Rh 3
(a5); In deprotection reaction; Compound (a4) is 1 with the mol ratio of alkali metal cpd: 3-10, and temperature of reaction is 20-60 ℃, the reaction times is 2-10 hour; The consumption of solvent is that 1mol compound (a4) rises solvent with 5-10, and the product of generation is through recrystallization purifying.
2. compound method as claimed in claim 1 is characterized in that dewatering agent used in said elimination reaction is C
2-C
6Alkyl carboxylic acid halides, substituted C
2-C
6Alkyl carboxylic acid halides, C
6-C
16Aryl carboxylic acid halides, substituted C
6-C
16Aryl carboxylic acid halides, C
2-C
16Organic acid anhydride, substituted C
2-C
16Organic acid anhydride, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, Hydrogen bromide, Vanadium Pentoxide in FLAKES, thiophosphoric anhydride.
3. compound method as claimed in claim 1 is characterized in that quencher used in said elimination reaction is water, aqueous ammonium chloride solution, sodium hydrogencarbonate, S-WAT.
4. compound method as claimed in claim 1 is characterized in that lewis acid catalyst used in said glycosylation reaction is C
3-C
9Halogen acid amide, C
1-C
6Fluoro hydrocarbyl sulfonic, C
2-C
8Silica-based fluoro alkyl sulphonate, C
1-C
6Fluoro hydrocarbyl sulfonic silver, boron trifluoride-ether complex or their mixture, for example N-iodo succimide (NIS), silver trifluoromethanesulfonate, the trimethyl silicon based ester of trifluoromethanesulfonic acid etc.
5. compound method as claimed in claim 1 is characterized in that solid acid catalyst used in said glycosylation reaction is Amberlyst-15, NKC-9 or Nafion-H.
6. compound method as claimed in claim 1 is characterized in that molecular sieve used in described glycosylation reaction is
type aluminate molecular sieve or its powder.
7. compound method as claimed in claim 1 is characterized in that inertia protective material used in described glycosylation reaction is nitrogen, argon gas or helium.
8. compound method as claimed in claim 1 is characterized in that organic solvent used in described glycosylation reaction is C
2-C
6Chloroparaffin or toluene.
9. compound method as claimed in claim 1 is characterized in that the quencher that in described glycosylation reaction, adds is Trimethylamine 99, triethylamine, sodium hydrogencarbonate, S-WAT or Sulfothiorine.
10. compound method as claimed in claim 1 is characterized in that the used weighting agent of column chromatography is silica gel, aluminum oxide, macroporous resin or gel in described glycosylation reaction.
11. compound method as claimed in claim 1 is characterized in that wash-out is used in column chromatography purification described in the said glycosylation reaction solvent is one or more a mixture in sherwood oil, methylene dichloride, ETHYLE ACETATE, trichloromethane, methyl alcohol, normal hexane or the hexanaphthene.
12. compound method as claimed in claim 1 is characterized in that basic metal thing used in said deprotection reaction is sodium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, Pottasium Hydroxide or Lithium Hydroxide MonoHydrate.
13. compound method as claimed in claim 1 is characterized in that polar solvent used in said deprotection reaction is one or more the mixture in methylene dichloride, ETHYLE ACETATE, acetone, THF, methyl alcohol, ethanol, ethylene glycol monomethyl ether, the water.
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