WO2013143494A1 - Procédé de préparation de ginsénosides protopanaxatriols - Google Patents

Procédé de préparation de ginsénosides protopanaxatriols Download PDF

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WO2013143494A1
WO2013143494A1 PCT/CN2013/073489 CN2013073489W WO2013143494A1 WO 2013143494 A1 WO2013143494 A1 WO 2013143494A1 CN 2013073489 W CN2013073489 W CN 2013073489W WO 2013143494 A1 WO2013143494 A1 WO 2013143494A1
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group
protected
hydroxyl
triol
substituted
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PCT/CN2013/073489
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Chinese (zh)
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俞飚
孙建松
牛一鸣
李荣耀
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中国科学院上海有机化学研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention relates to the synthesis of 6 and 12 monosaccharide chains and 3/20 and 6/20 disaccharide chain-20(S)-protopanaxatriol ginsenosides. Background technique
  • ginseng As a valuable Chinese medicine, ginseng has been used in China for two thousand years. With the development of modern biotechnology, ginseng saponin contained in ginseng has been identified as the main active ingredient of ginseng.
  • ginsenosides can be mainly divided into two categories: original ginseng diol ginsenosides (PPDS). And Panaxatriols (PPTS) ((a) Christensen, LP Adv. Food Nutri. Res. 2009, 55, 1. (b) Qi, L. -W.; Wang, C. -Z .; Yuan, C. -S. Nat. Prod. Rep. 201 1 , 28, 467 ⁇ ), structure as
  • the first is chemical synthesis, which is mainly used to synthesize the synthesis of the less toxic ginseng glycol ginsenosides ((a) Atopkina, LN; Denisenko, VA; Uvarova, NI; Elyakov, GB Carbohvdr. Res. 1988 , 777, 101. (b) Atopkina, LN; Uvarova, NI; Elyakov, GB Carbohydr. Res. 1997, 303, 449.
  • ginsenosides which is mainly for the synthesis of the original ginseng triol ginsenosides
  • Danieli, ⁇ Falcone, L.; Monti, D.; Riva, S.; Gebhardt, S.; Schubert-Zsilavecz, MJ Org. Chem. 2001, 66, 262.
  • Ko, S. -R.; Choi, K. -J.; Suzuki, K.; Suzuki , Y. Chem. Pharm. Bull. 2003, 51, 404. In view of the fact that enzymes involved in enzymatic synthesis are generally expensive and difficult to obtain, enzymatic synthesis is not an ideal solution to sample supply.
  • triol ginsenosides In stark contrast to the supply bottleneck of triol ginsenosides, recent studies on the activity of triol ginsenosides have shown that ginsenosides inhibit leukemia cell proliferation (Popovich, DG; Kitts, DD Arch. Biochem. Biophys. 2002). , 406, 1 ⁇ ), immunomodulation (Yu, J.-L.; Dou, D.-Q.; Chen, X.-H.; Yang, H.-Z.; Guo, N.; Cheng, G .-F. Planta Med. 2005, 77, 202) and other aspects have shown excellent medicinal prospects, so there is an urgent need to develop a chemical synthesis method that provides reliable and efficient supply of ginseng triol ginsenosides. Summary of the invention
  • a method for preparing a protopanaxatriol ginsenoside comprises the following steps:
  • the original ginseng triol is used as a raw material to protect the hydroxyl group of the original ginseng triol, thereby exposing the 20-position hydroxyl group and at least one of the hydroxyl groups at the 3, 6 and 12 positions to obtain a partial hydroxy-protected proto-ginseng III.
  • Alcohol receptor
  • step (b) The partial hydroxy-protected protopanaxatriol receptor obtained in step (a) is glycosylated with a fully protected glycosyl donor to obtain a native ginseng to which a fully protected glycosyl group is attached and a portion of the hydroxyl group is protected. a triol ginsenoside; (c) deprotecting the ginseng triol ginsenoside obtained by the step (b) with a fully protected glycosyl group and a partial hydroxy group protected, thereby obtaining protopanaxatriol Ginsenosides.
  • the step protects the hydroxyl group of the original ginseng triol to regioselectively protect the hydroxyl group of the original ginseng triol.
  • the structure of the glycosyl donor is as follows:
  • R 6 is a fully protected ⁇ -D-glucosyl, ⁇ -D-glucosyl, ⁇ -D-galactosyl, aD-galactosyl, ⁇ -D-mannosyl, aD-mannosyl, ⁇ - -Du-- ⁇ , ⁇ a u--D- ⁇ s group, ⁇ ⁇ -- ⁇ -2-aminoglucosylglucosyl, aD-2-glucosamine, aL-rat Liglycosyl, ⁇ -L-rhamnosyl, aa--DD--Aralala oligosaccharide, ⁇ --DD--Aralabalose glycosyl, aa--LL -- arabinose, ⁇ -L-arabinosyl, aL-fucosyl, ⁇ -LL--stone rock algalose glycosyl, ⁇ -DD--glucosamine Alalduronic acid group, aa--DD--glucur
  • the silicon group is a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.
  • the R 5 is n-butyl or cyclopropyl.
  • the ginseng triol is used as a raw material to protect the hydroxyl group of the original ginseng triol, thereby exposing the hydroxyl group at the 20th position, and exposing at least one of the hydroxyl groups at the 3rd position, the 6th position, and the 12th position.
  • the original ginseng triol receptor with partial hydroxyl groups is obtained, and the reaction route is as follows:
  • R 3 are independently selected from substituted or unsubstituted C 6 —i.
  • Alkenyl, substituted or unsubstituted C w Any of the aryl groups, and, and any of them is H;
  • substitution refers to a mono-, di- or tri-substitution using a group selected from the group consisting of C w . ⁇ , C w . Oxyloxy, C ⁇ . Alkenyl, C ⁇ . Cyclodecyl, C. Aryl, nitro, halogen, amino, silicon.
  • the halogen is F Cl Br or I
  • the aromatic hydrocarbon acyl group is a benzoyl group.
  • the substituted aromatic hydrocarbon acyl group is p-methoxybenzoyl, p-chlorobenzoyl, p-bromobenzoyl, p-iodobenzoyl, or p-nitrobenzoyl.
  • the silicon group is a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.
  • the protection of the hydroxyl group is carried out in an organic solvent, which is dichloro Formamidine, toluene, tetrahydrofuran, or dimethylformamide.
  • the 12-position hydroxyl group having the highest activity in the original ginseng triol is first blocked with a protecting group; and then the 3-position hydroxyl group in the active center is blocked with a protecting group to obtain a bare original of 6 and 20 hydroxyl groups.
  • the same protecting group is introduced at the 3, 6, and 12 positions in the original ginseng triol, and then the protecting group at the 12 position is selectively removed to obtain the original ginseng triol exposed at the 12th and 20th positions.
  • the 12-position hydroxyl group having the highest activity in the original ginseng triol is first blocked with a protecting group; then the protecting group is used to block the active hydroxyl group 3 hydroxyl group, and the protecting group is used to protect the least active 6-position hydroxyl group, and finally Selective removal of the protecting group at position 3 yields the original ginsenotriol receptors at the 3 and 20 dihydroxyl exposures.
  • the protecting group in step (a) is selected from the group consisting of: tert-butyldimethylsilyl (TBS), acetyl Ac, trimethylacetyl, allyl.
  • tetrabutylammonium fluoride TBAF tris(diethylamino)difluorotrimethylphosphonium silicate TASF, HF pyridine complex or p-toluenesulfonic acid is used.
  • TSOH removes the silicon-based protecting group.
  • the palladium metal catalyst used for removing the allyl protecting group is Pd(OAc) 2 , PdCl 2 or Pd(PPh 3 ) 4 .
  • the acyl protecting group is removed under basic conditions, and the base is NaOMe, sodium hydroxide, lithium hydroxide or potassium hydroxide.
  • all glycosidation reactions are under the protection of an inert gas, in an organic solvent, in the presence of a molecular sieve, the glycosyl donor and the partial hydroxyl group obtained by the step are protected by the protopanaxatriol receptor,
  • the Lewis acid promotes the reaction carried out.
  • the inert gas is nitrogen, argon or helium.
  • the inert gas is high purity nitrogen, high purity argon or high purity helium.
  • the high purity means that the purity of the gas is 99.999%, wherein the gas is nitrogen, argon or helium.
  • the organic solvent is toluene, dichloromethane, diethyl ether, or acetonitrile.
  • the organic solvent is dry toluene, methylene chloride, diethyl ether, or acetonitrile, and the drying means that the organic solvent is an anhydrous organic solvent or an organic solvent having a water content of 500 ppm.
  • the organic solvent is methylene chloride.
  • the molecular sieve is a 3-5 A molecular sieve or a pickled 3-5 A molecular sieve.
  • the molecular sieve is an activated 3-5 A molecular sieve or a pickled 3-5 A molecular sieve.
  • the Lewis acid is a gold-containing complex, and the Lewis acid is used in an amount of 0.01 to 1 equivalent of the amount of the protopanaxatriol receptor to which the partial hydroxyl group is protected.
  • the glycosidation reaction time in the step (b) is from 0.5 to 12 hours.
  • the gold-containing complex is PPh 3 AuOTf or PPh 3 AuNTf 2 , preferably, PPh 3 AuNTf 2 for easy operation.
  • the Lewis acid is used in an amount of 0.05 to 0.5 equivalents, preferably 0.1 to 0.2 equivalents, based on the amount of the partially hydroxy-protected protopanaxatriol receptor.
  • the method further comprises the step of separating and purifying the protopanaxatriol ginsenoside prepared in the step (c).
  • the purification comprises column chromatography purification.
  • a method for preparing a ginseng triol ginsenoside comprises the following steps:
  • step (b) The partial hydroxy-protected protopanaxatriol receptor obtained in step (a) is glycosylated with a fully protected glycosyl donor to obtain a native ginseng to which a fully protected glycosyl group is attached and a portion of the hydroxyl group is protected.
  • step (c) Deprotecting the protopanaxatriol ginsenoside which is obtained by the step (b) and having a fully protected glycosyl group and a part of the hydroxyl group protected, thereby obtaining the original ginseng triol ginsenoside.
  • the protopanaxatriol ginsenoside is selected from the group consisting of a monosaccharide chain at position 6 , a monosaccharide chain at position 12, a disaccharide chain at position 6 and 20, or Ginsenosides with a double sugar chain at the 3 and 20 positions.
  • the 20-position hydroxyl group is exposed in the step.
  • step (a) at least one of the 20-position hydroxyl group and the bare 3 position, 6-position and 12-position in step (a)
  • ⁇ _ it is alkyl with 6, c 3 _i. Cyclodecyl or c 3 _i. Aryl;
  • R 6 is a fully protected ⁇ -D-glucosyl, ⁇ -D-glucosyl, ⁇ -D-galactosyl, aD-galactosyl, ⁇ -D-mannosyl, aD-mannosyl, ⁇ - D-xylosyl, aD-xylosyl, ⁇ -indol-2-glucosyl, aD-2-glucosyl, aL-rhamnosyl, ⁇ -L-rhamnosyl, aD-arabinose Base, ⁇ -D-arabinosyl, aL-arabinosyl, ⁇ -L-arabinosyl, aL-fucosyl, ⁇ -L-fucosyl, ⁇ -D-glucuronic acid, aD - glucuronic acid group, ⁇ -D-galacturonic acid group, or aD-galacturonic acid group; said full protection means all hydroxy groups with acetyl
  • the R 5 is n-butyl or cyclopropyl.
  • the ginseng triol is used as a raw material to protect the hydroxyl group of the original ginseng triol, thereby exposing the hydroxyl group at the 20 position and at least one of the hydroxyl groups at the 3, 6 and 12 positions.
  • each group is as defined above.
  • the step of protecting the partially hydroxy-protected protopanaxatriol receptor comprises:
  • R 6 is a fully protected ⁇ -D-glucosyl, ⁇ -D-glucosyl, ⁇ -D-galactosyl, aD-galactosyl, ⁇ -D-mannosyl, aD-mannosyl, ⁇ - D-xylosyl, aD-xylosyl, ⁇ -indol-2-glucosyl, aD-2-glucosyl, aL-rhamnosyl, ⁇ -L-rhamnosyl, aD-arabinose Base, ⁇ -D-arabinosyl, aL-arabinosyl, ⁇ -L-arabinosyl, aL-fucosyl, ⁇ -L-fucosyl, ⁇ -D-glucuronic acid, aD - glucuronic acid group, ⁇ -D-galacturonic acid group, or aD-galacturonic acid group; said full protection means all hydroxy groups with acetyl
  • the R 5 is n-butyl or cyclopropyl.
  • the invention provides a novel method for chemically synthesizing protosan ginseng triol ginsenoside, which is reliable, high-efficiency, high in yield and high in stereoselectivity.
  • the method is substantially as described in Examples 1-4. It should be understood that within the scope of the present invention, the above various technical features of the present invention and the following (as in the embodiment; The various technical features described can be combined with each other to form a new or preferred technical solution. Due to space limitations, we will not repeat them here. detailed description
  • the inventors of the present application have extensively and intensively studied and first synthesized the original ginseng triol as a raw material.
  • 6th place has a monosaccharide chain
  • 12 has a monosaccharide chain
  • 6 and 20 have a double sugar chain
  • 3 and 20 have a double sugar chain ginsenoside.
  • the 12-position hydroxyl group is the most active, the activity of the 3, 6, and 12 hydroxyl groups is not much different, and it is difficult to regioselectively protect the hydroxyl group, so it is difficult to achieve glycosidation at the 3, 6, and 12 hydroxyl groups.
  • Ginsenosides also known as ginsenosides
  • Ginsenoside is the main component of ginseng.
  • ginsenosides obtained by separation are named Ro, Ral,
  • the preparation method of the original ginseng triol ginsenoside provided by the invention comprises the following steps:
  • the original ginseng triol is used as a raw material to protect the hydroxyl group of the original ginseng triol, thereby exposing the 20-position hydroxyl group and at least one of the hydroxyl groups at the 3, 6 and 12 positions to obtain a partial hydroxy-protected proto-ginseng III.
  • Alcohol receptor
  • step (b) The partial hydroxy-protected protopanaxatriol receptor obtained in step (a) is glycosylated with a fully protected glycosyl donor to obtain a native ginseng to which a fully protected glycosyl group is attached and a portion of the hydroxyl group is protected.
  • step (c) Deprotecting the protopanaxatriol ginsenoside which is obtained by the step (b) and having a fully protected glycosyl group and a part of the hydroxyl group protected, thereby obtaining the original ginseng triol ginsenoside.
  • the step (a) protects the hydroxyl group of the original ginseng triol to regioselectively protect the hydroxyl group of the original ginseng triol.
  • the structure of the glycosyl donor is as follows:
  • ⁇ _ it is alkyl with 6, c 3 _i. Cyclodecyl or c 3 _i. Aryl;
  • R 6 is a fully protected ⁇ -D-glucosyl, ⁇ -D-glucosyl, ⁇ -D-galactosyl, aD-galactosyl, ⁇ -D-mannosyl, aD-mannosyl, ⁇ - D-xylosyl, aD-xylosyl, ⁇ -indol-2-glucosyl, aD-2-glucosyl, aL-rhamnosyl, ⁇ -L-rhamnosyl, aD-arabinose Base, ⁇ -D-arabinosyl, aL-arabinosyl, ⁇ -L-arabinosyl, aL-fucosyl, ⁇ -L-fucosyl, ⁇ -D-glucuronic acid, aD a glucuronic acid group, a ⁇ -D-galacturonic acid group, or an aD-galacturonic acid group; said full protection means that all of the hydroxyl
  • the R 5 is n-butyl or cyclopropyl.
  • the ginseng triol is used as a raw material to protect the hydroxyl group of the original ginseng triol, thereby exposing the hydroxyl group at the 20th position, and exposing at least one of the hydroxyl groups at the 3rd position, the 6th position, and the 20th position.
  • R 3 are independently selected from substituted or unsubstituted C 6 —i.
  • Alkenyl, substituted or unsubstituted C w An aryl group, and any one of them is H;
  • the substitution refers to a mono-, di- or tri-substitution using a group selected from the group consisting of C w .
  • the halogen is F, Cl, Br or I.
  • the aromatic hydrocarbon acyl group is a benzoyl group.
  • the substituted aromatic hydrocarbon acyl group is p-methoxybenzoyl, p-chlorobenzoyl, p-bromobenzoyl, p-iodobenzoyl, or p-nitrobenzoyl.
  • the silicon group is a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.
  • the protection of the p-hydroxy group is carried out in an organic solvent, which is methylene chloride, toluene, tetrahydrofuran, or dimethylformamide.
  • an organic solvent which is methylene chloride, toluene, tetrahydrofuran, or dimethylformamide.
  • the 12-position hydroxyl group having the highest activity in the original ginseng triol is first blocked with a protecting group; and then the 3-position hydroxyl group in the active center is blocked with a protecting group to obtain a bare original of 6 and 20 hydroxyl groups.
  • Ginseng triol receptor or
  • the same protecting group is introduced at the 3, 6, and 12 positions in the original ginseng triol, and then the protecting group at the 12 position is selectively removed to obtain the original ginseng triol exposed at the 12th and 20th positions.
  • the 12-position hydroxyl group having the highest activity in the original ginseng triol is blocked with a protecting group; then the protecting group is used to block the active hydroxyl group 3 hydroxyl group, and the protecting group is used to protect the least active 6-position hydroxyl group, and finally the selective hydroxyl group is removed.
  • the original ginsenotriol receptors of the 3 and 20 bis-hydroxyl exposures were obtained.
  • the protecting group in step (a) is selected from the group consisting of: tert-butyldimethylsilyl (TBS), acetyl Ac, trimethylacetyl, allyl.
  • tetrabutylammonium fluoride TBAF tris(diethylamino)difluorotrimethylphosphonium silicate TASF, HF pyridine complex or p-toluenesulfonic acid is used.
  • TSOH removes the silicon-based protecting group.
  • the palladium metal catalyst used for removing the allyl protecting group is Pd(OAc) 2 , PdCl 2 or Pd(PPh 3 ) 4 .
  • the acyl protecting group is removed under basic conditions, and the base is NaOMe, sodium hydroxide, lithium hydroxide or potassium hydroxide.
  • the glycosidation reaction is an original ginsenotriol receptor protected by a glycosyl donor and a step obtained in the presence of a molecular sieve in the presence of a molecular sieve under an inert gas, The reaction carried out under the promotion of Lewis acid.
  • the inert gas is nitrogen, argon or helium.
  • the inert gas is high purity nitrogen, high purity argon or high purity helium.
  • the high purity means that the purity of the gas is 99.999%, wherein the gas is nitrogen, argon or helium.
  • the organic solvent is toluene, dichloromethane, diethyl ether, or acetonitrile.
  • the organic solvent is dry toluene, methylene chloride, diethyl ether, or acetonitrile, and the drying means that the organic solvent is an anhydrous organic solvent or an organic solvent having a water content of 500 ppm.
  • the organic solvent is methylene chloride.
  • the molecular sieve is a 3-5 A molecular sieve or a pickled 3-5 A molecular sieve.
  • the molecular sieve is an activated 3-5 A molecular sieve or a pickled 3-5 A molecular sieve.
  • the Lewis acid is a gold-containing complex, and the Lewis acid is used in an amount of 0.01 to 1 equivalent of the amount of the protopanaxatriol receptor to which the partial hydroxyl group is protected.
  • the glycosidation reaction time in the step (b) is from 0.5 to 12 hours.
  • the gold-containing complex is PPh 3 AuOTf or PPh 3 AuNTf 2 , preferably, PPh 3 AuNTf 2 for easy operation.
  • the Lewis acid is used in an amount of 0.05 to 0.5 equivalents, preferably 0.1 to 0.2 equivalents, based on the amount of the partially hydroxy-protected protopanaxatriol receptor.
  • the method further comprises the step of separating and purifying the protopanaxatriol ginsenoside prepared in the step (c).
  • the purification comprises column chromatography purification.
  • the method for preparing ginsenoside of the present invention comprises the steps of:
  • step (c) removing all of the protecting groups on the protected ginsenoside linked to the fully protected glycosyl group obtained in step (b), obtaining 6 groups with a monosaccharide chain, 12 positions with a monosaccharide chain, Ginsenosides with a double sugar chain at the 6th and 20th positions, or a double sugar chain at the 3 and 20 positions.
  • the method for preparing ginsenoside of the present invention comprises the steps of:
  • R 2 is independently selected from substituted or unsubstituted C w .
  • An aromatic hydrocarbon acyl group a substituted or unsubstituted C 2 -6 decanoyl group, a silicon group, a substituted or unsubstituted C w .
  • Sulfhydryl substituted or unsubstituted C.
  • Aryl substituted or unsubstituted C 3 _ 1Q cyclodecyl, substituted or unsubstituted C 3 _ 1Q alkenyl; said substitution means mono-substitution using a group selected from the group below, Substitution or trisubstituted: c w .
  • the thiol, c w Oxyloxy, c 3 _i. Alkenyl,
  • R 31 is a largely hindered silicon group, a substituted or unsubstituted C 6 - 1Q aromatic hydrocarbon acyl group, or a substituted or unsubstituted C 2 -6 fluorenyl group; the substitution means a group selected from the group consisting of the following groups Perform mono-, di- or tri-substituted: ⁇ , C w . Oxyloxy, C ⁇ . Alkenyl, C ⁇ . Cyclic sulfhydryl, Cw. Aryl, nitro, halogen, amino, silicon.
  • R 32 is a small hindered silicon group, substituted or unsubstituted. Sulfhydryl, substituted or unsubstituted. Cyclodecyl, substituted or unsubstituted C 3 _ 1Q alkenyl, substituted or unsubstituted C 6 _ 1Q aryl; said substitution means mono-substitution with a group selected from the group below, Substitution or trisubstituted: C w . ⁇ , C w . Oxyloxy, c 3 _i. Alkenyl, C ⁇ . Cyclic sulfhydryl, Cw. Aryl, nitro, halogen, amino, silicon.
  • R is a ⁇ -D-glucosyl group, a-D-glucosyl group, ⁇ -D-galactosyl group, aD-galactosyl group, ⁇ -D-mannosyl group, aD-mannosyl group, ⁇ which are all protected by a hydroxyl group.
  • -D-xylosyl aD-xylosyl, ⁇ -indol-2-glucosyl, aD-2-glucosyl, aL-rhamnosyl, ⁇ -L-rhamnosyl, aD-Arabic Glycosyl, ⁇ -D-arabinosyl, aL-arabinosyl, ⁇ -L-arabinosyl, aL-fucosyl, ⁇ -L-fucosyl, ⁇ -D-glucuronic acid, aD-glucuronic acid group, ⁇ -D-galacturonic acid group, or aD-galacturonic acid group; all of the hydroxyl groups are protected by acetyl, benzoyl, benzyl, or silicon-based pairs The hydroxyl group is protected.
  • R' is a ⁇ -D-glucosyl group, aD-glucosyl group, ⁇ -D-galactosyl group, aD-galactose, all of which are exposed to a hydroxyl group. , ⁇ -D-mannosyl, ⁇ -D-mannosyl, ⁇ -D-xylosyl, aD-xylosyl, ⁇ -indol-2-glucosyl, aD-2-glucosyl, aL-rhamnosyl, ⁇ -L-rhamnosyl, aD-arabinosyl, ⁇ -D-arabinosyl, aL-arabinosyl, ⁇ -L-arabinosyl, ⁇ -L-arabinosyl, aL-arabinosyl, ⁇ -L-arabinosyl, aL-fucosyl , ⁇ -L-fucosyl, ⁇ -D-glucur
  • the largely hindered silicon group is preferably a triethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.
  • the small hindered silicon group is preferably a trimethylsilyl group.
  • R 31 is C ⁇ .
  • R 31 is benzoyl, p-methoxybenzoyl, p-nitrobenzoyl, or trimethylacetyl.
  • R 32 is trimethylsilyl, benzyl, phenyl, C 3 -6 alkenyl, or d- 6 fluorenyl. In another preferred embodiment, R 32 is an allyl group. In another preferred embodiment, the preparation of the protopanaxatriol receptor formula A1 compound, including the steps
  • the 12-hydroxyl protected protopanaxatriol is reacted with an acid halide, a silyl chloride, or a halogenated hydrocarbon under the action of a base, and a protecting group at the 3-position hydroxyl group is introduced to obtain a compound of the formula A1. .
  • R 31 The definition of R 31 , is as described above.
  • R 31 is benzoyl, p-methoxybenzoyl, p-nitrobenzoyl, or trimethylacetyl.
  • R 31 is a trimethylacetyl group.
  • ! ⁇ is tert-butyldimethylsilyl.
  • the organic solvent is a halogenated CM embankment, preferably, is chloro embankment d_ 4, more preferably, it is of dichloromethane.
  • the acid halide is a C 7 - 1Q aryl acid halide, a substituted aryl acid halide, a C 2 - 1Q mercapto acid halide; the substitution means a mono-substitution using a group selected from the group below, Substitution or trisubstituted: C W . ⁇ ,. Alkoxy group, C 3 _ 1Q alkenyl group, C ⁇ . Cyclodecyl, C. Aryl, nitro, halogen, amino, silicon.
  • the acid halide is benzoyl chloride, p-methylbenzoyl chloride, p-nitrobenzoyl chloride, chloroacetyl or trimethylacetyl chloride.
  • the silicoyl chloride is c 3 _ 16 fluorenyl substituted silyl chloride or c 6 _ 2 .
  • the halogenated hydrocarbon is. Halogenated oxime, c 2 _i. Halogenated olefin, c 3 _i. Halogenated alkyne, .
  • the base is pyridine, triethylamine, DMAP, imidazole, sodium hydride, potassium hydride, LDA or LiHMDS.
  • the protecting group R 31 or Ri is introduced from the acid halide, and the base used is preferably pyridine, triethylamine, DMAP.
  • the base used for introducing the protecting group R from the silyl chloride is preferably triethylamine, or imidazole.
  • the base used for introducing the protecting group from the halogenated hydrocarbon is preferably sodium hydride, potassium hydride, LDA or LiHMDS.
  • the molar ratio of the original ginseng triol and the protecting group-containing reagent (such as an acid halide;) in the raw material is 1:0.9-10, preferably,
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 12 hours.
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 30 ° C, more preferably 0 to 25 ° C.
  • the molar ratio of the 12-hydroxyl protected protopanaxatriol to the protecting group-containing reagent is 1:0.9-10, preferably 1:0.9-5. More preferably, it is 1: 1-1.5.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 12 hours.
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 ° C, more preferably 0 to 0.
  • the preparation of the protopanaxatriol receptor formula A2 compound comprises the steps of:
  • R 2 is as defined above, and
  • the protecting group-containing reagent is an acid anhydride, an acid halide, a silyl chloride or a halogenated hydrocarbon;
  • the base is pyridine, triethylamine, DMAP, imidazole, sodium hydride, potassium hydride, LDA or LiHMDS; a protecting group, R 2 , R 3 is introduced from the acid halide.
  • the base used is preferably pyridine, triethylamine, DMAP.
  • a protecting group, R 2 , R 3 is introduced from the silicon-based chlorine.
  • the base used is preferably triethylamine, or imidazole.
  • the base used is preferably sodium hydride, potassium hydride, LDA or LiHMDS.
  • the molar ratio of protopanaxatriol to a protecting group-containing reagent such as an acid anhydride, acid halide, silyl chloride, or halogenated hydrocarbon;
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 ° C, more preferably 0 to 20 ° C.
  • the acid halide is a C 7 — 1Q aryl acid halide, a substituted aryl acid halide, a C 2 — 1Q mercapto acid halide; and the substitution refers to a group selected from the group consisting of The group is mono-, di- or tri-substituted: C W . Sulfhydryl, CL!O decyloxy, C ⁇ . Alkenyl, C ⁇ . Cyclic sulfhydryl, C W . Aryl, nitro, halogen, amino, silicon.
  • the acid halide is benzoyl chloride, p-methylbenzoyl chloride, p-nitrobenzoyl chloride, chloroacetyl, or trimethylacetyl chloride.
  • the anhydride is acetic anhydride Ac 2 0.
  • said R 2 , R 3 is an acetyl group.
  • the 12 hydroxyl groups are selectively removed. , among them,
  • R 3 In the case of an acyl group, R 3 is removed under basic conditions.
  • An acyl protecting group, the base being NaOMe, sodium hydroxide, lithium hydroxide or potassium hydroxide; preferably sodium methoxide (NaOMe);
  • R 3 When it is a silicon group, tetrabutylammonium fluoride TBAF, tris(diethylamino)difluorotrimethylphosphonium silicate TASF,
  • R 3 is removed by using a palladium metal catalyst Pd(OAc) 2 , PdCl 2 or Pd(PPh 3 ) 4 . .
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 ° C, more preferably 0 to 20 ° C;
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 12 hours.
  • the preparation of the protopanaxatriol receptor formula A2 compound comprises the steps of:
  • step a (b) introducing a protecting group at the 3 and 6 hydroxyl groups at a time in the product of step a and
  • Ri is selected from: a substituted or unsubstituted C 6 _ 1Q aromatic hydrocarbon acyl group, a substituted or unsubstituted C 2 -6 fluorenyl group, a silicon group, a substituted or unsubstituted fluorenyl group, a substituted or unsubstituted C 6 _ 1Q aryl, substituted or unsubstituted c 3 _i. Cyclodecyl, substituted or unsubstituted c 3 _i. Alkenyl; said substitution means mono-, di- or tri-substituted with a group selected from the group consisting of: Cw. ⁇ , C w . Oxyloxy,. Alkenyl, C ⁇ . Cyclodecyl, C w . Aryl, nitro, halogen, amino, silicon.
  • the hydrocarbon group is preferably a benzyl group, a phenyl group, an alkenyl group of C 3 -6 or a fluorenyl group.
  • the base of the step (a) is pyridine, triethylamine, DMAP, imidazole, sodium hydride, potassium hydride, LDA or LiHMDS; preferably sodium hydride, potassium hydride, LDA or LiHMDS.
  • the molar ratio of the original ginseng triol to the halogenated hydrocarbon is from 1: 1.0 to 10, preferably from 1: 1.0 to 5. More preferably, it is 1: 1-1.5.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 12 hours.
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 V, more preferably 0 to 20 ° C.
  • the molar ratio of the product of step a to the protecting group-containing reagent is from 1:2.0 to 40, preferably from 1:2.0 to 30, more preferably, Is 1:3.0-20;
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 ° C, more preferably 0 to 20 ° C.
  • the preparation of the protopanaxatriol receptor formula A3 compound comprises the steps of:
  • step (c) the product of step (b) is reacted with an acid anhydride, an acid halide, a silyl chloride, or a halogenated hydrocarbon under the action of a base to introduce a protecting group R 2 at the 6-position hydroxyl group ;
  • step (d) removing the silicon-based protecting group at the 3-position of the product of step (c) to give a compound of formula A3.
  • R 32 is alkyl with the Cu, C 2 _ 1 () alkenyl, C 3 _ 1 () alkynyl, C 6 _ 1 () aryl.
  • R 2 The definition of R 2 is as described above.
  • R 32 is an allyl group.
  • the step (b) is introduced into a silicon-based protecting group at the 3-position hydroxyl group, and the silicon-based protecting group is a trimethylsilyl group, a triethylsilyl group, a tert-butyl group.
  • the silyl decyl group or the tert-butyl diphenyl silicon group is preferably a tert-butyldimethylsilyl group.
  • R 2 is an acetyl group.
  • the halogenated hydrocarbon is a halogenated Cwo the embankment, C 2 _ 1Q of halogenated olefins, C 3 _ 1Q halogenated alkyne, C 6 _ 10 halogenated aromatic hydrocarbon.
  • the base is sodium hydride, potassium hydride, LDA (lithium diisopropylamide) or LiHMDS (lithium hexamethyldisilazide);
  • the molar ratio of the original ginseng triol triol to the halogenated hydrocarbon is from 1:0.9 to 10, preferably from 1:0.9 to 5. More preferably, it is 1: 1-1.5.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 12 hours.
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 ° C, more preferably 0 to 20 ° C.
  • the silicon-based chlorine is c 3 _ 16 fluorenyl substituted or c 6 _ 2 .
  • An aryl-substituted silyl chloride; the base used is triethylamine, imidazole;
  • the molar ratio of the product obtained to the step of the halogenated hydrocarbon is from 1:0.8 to 10, preferably from 1:1.0 to 5. More preferably, it is 1: 1-1.5.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 12 hours.
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 V, more preferably 0 to 20 ° C.
  • the acid halide is a C 7 — 1Q aryl acid halide, a substituted aryl acid halide, a C 2 — 1Q mercapto acid halide; and the substitution refers to a group selected from the group consisting of the following groups.
  • the acid halide is benzoyl chloride, p-methylbenzoyl chloride, p-nitrobenzoyl chloride, chloroacetyl or trimethylacetyl chloride.
  • the anhydride is acetic anhydride.
  • the silicon-based chlorine is c 3 _ 16 fluorenyl substituted or c 6 _ 2 .
  • the halocarbon is Cwo embankment halo, C 2 _ 1Q of halogenated olefins, C 3 _ 1Q halogenated alkyne, C 6 _ 1Q haloaryl Hydrocarbon
  • the bases used were pyridine, triethylamine and DMAP.
  • the molar ratio of the product obtained in the step (b) to the halogenated hydrocarbon is from 1:0.1 to 10, preferably from 1:0.5 to 5. More preferably, it is 1: 1.5-4.
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 ° C, more preferably 0 to 20 ° C.
  • the organic solvent used in the above reaction is a C1-C4 halogenated hydrazine or a pyridine.
  • the preparation of the protopanaxatriol receptor formula A4 compound comprises the steps of:
  • R 32 is as described above.
  • 2 is C w . ⁇ base, C ⁇ . Alkenyl, C ⁇ . Alkynyl group, C w . Aryl.
  • R 32 is an allyl group.
  • ! ⁇ is a silicon group
  • the silicon group is selected from the group consisting of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl, preferably tert-butyl Silicon germanium.
  • the halogenated hydrocarbon is a halogenated hydrazine, a C 2 _ 1Q halogenated olefin, a C 3 _ 1Q halogenated alkyne, and a C 6 _ 1Q halogenated aromatic hydrocarbon.
  • the base is sodium hydride, potassium hydride, LDA (lithium diisopropylamide) or LiHMDS (lithium hexamethyldisilazide);
  • the molar ratio of the original ginseng triol triol to the halogenated hydrocarbon is from 1:0.1 to 3, preferably from 1:0.5 to 2. More preferably, it is 1: 1-1.5.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 12 hours.
  • the reaction temperature is -20 to 50 ° C, preferably -10 to 25 ° C, more preferably 0 to 20 ° C.
  • the present invention can not only achieve high-efficiency discrimination of a plurality of hydroxyl groups in protopanaxatriol containing a plurality of hydroxyl groups, but also have high yield and stereoselectivity in constructing glycosidic bonds.
  • the present invention will greatly advance the research on the activity mechanism of the original ginseng triol ginsenosides and the progress of drug development.
  • the above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. Revealed in the present specification All of the features may be combined with any combination of forms, and the various features disclosed in the specification may be replaced by any alternative feature that provides the same, equal or similar purpose. Therefore, unless otherwise stated, the disclosed features are only a general example of equivalent or similar features.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are only intended to illustrate the invention and not to limit the scope of the invention.
  • the experimental methods in the present invention which do not specify the specific conditions are usually carried out according to conventional conditions or in accordance with the conditions recommended by the manufacturer.
  • the experimental conditions for introducing a protecting group for the protection of a hydroxyl group and the experimental conditions for removing the protecting group may employ a hydroxy protecting and deprotecting condition conventionally used in the art.
  • the original ginseng triol 100 mg, 0.21 mmol was dissolved in 3 ml of anhydrous DMF, and triethylamine (146 ⁇ , 0.42 mmol) and PivCl (52 ⁇ L, 0.42 mmol) were slowly added dropwise under ice bath. After 2 hours, the reaction was quenched with water, extracted with a large amount of ethyl acetate, washed with water (3*30 mL), washed with saturated brine, dried over anhydrous sodium sulfate and dried 2 (yield 80%).
  • compound 1 (500 mg, 1.05 mmol) was dissolved in 3 mL of anhydrous pyridine. 3 mL of acetic anhydride was slowly added dropwise in an ice bath. After half an hour, the reaction was quenched with 1 mol/L hydrochloric acid. The mixture was diluted with EtOAc (3 mL, dry.
  • the above-obtained elimination product was dissolved in dry tetrahydrofuran (5 mL), and then a solution of TBAF in tetrahydrofuran was added to the reaction system, and the mixture was stirred at room temperature for 5 hours, and then subjected to conventional post-treatment to obtain a silicon-based intermediate.

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Abstract

L'invention concerne un procédé de préparation de ginsénosides protopanaxatriols, comprenant les étapes suivantes : (a) la protection de l'hydroxyle du protopanaxatriol, l'exposition d'un hydroxyle en position 20 et d'un hydroxyle en position 3, en position 6 et/ou en position 12 pour obtenir un récepteur de protopanaxatriol dont une partie des hydroxyles est protégée; (b) la réalisation d'une réaction de glycosylation du récepteur de protopanaxatriol obtenu à l'étape (a) dont une partie des hydroxyles est protégée avec un donneur de glycosyle entièrement protégé afin d'obtenir les ginsénosides protopanaxatriols connectés avec un glycosyle entièrement protégé et dont les hydroxyles sont protégés; (c) la déprotection des ginsénosides protopanaxatriols obtenus à l'étape (b) connectés avec un glycosyle entièrement protégé et dont les hydroxyles sont protégés, afin d'obtenir les ginsénosides protopanaxatriols. Le procédé de synthèse chimique de la présente invention est nouveau, fiable et efficace, et présente un rendement et une stéréosélectivité élevés.
PCT/CN2013/073489 2012-03-30 2013-03-29 Procédé de préparation de ginsénosides protopanaxatriols WO2013143494A1 (fr)

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WO2006010307A1 (fr) * 2004-07-29 2006-02-02 Shanghai Innovative Research Center Of Traditional Chinese Medicine Synthese du 20 (s)-ginsenoside rh2
CN102336800A (zh) * 2011-07-22 2012-02-01 中国科学院上海有机化学研究所 一种20位接糖的原人参三醇类人参皂苷及类似物的合成方法

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CN102336800A (zh) * 2011-07-22 2012-02-01 中国科学院上海有机化学研究所 一种20位接糖的原人参三醇类人参皂苷及类似物的合成方法

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