CN105061531A - Astilbe chinensis glycoside derivatives and preparation method thereof - Google Patents
Astilbe chinensis glycoside derivatives and preparation method thereof Download PDFInfo
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- CN105061531A CN105061531A CN201510451877.7A CN201510451877A CN105061531A CN 105061531 A CN105061531 A CN 105061531A CN 201510451877 A CN201510451877 A CN 201510451877A CN 105061531 A CN105061531 A CN 105061531A
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Abstract
The invention discloses astilbe chinensis glycoside derivatives and a preparation method thereof, and belongs to the technical field of fine chemical engineering. The preparation method of AB-I-X comprises the following steps: taking a compound AB-1 as the raw material, adding benzyl chloride or benzyl bromide to replace the C-7 acetyl by a benzyl group so as to obtain AB-2; reducing the compound AB-2 by hydrogen in the presence of a palladium-carbon catalyst to prepare a compound AB-I, wherein through the chemical reactions mentioned above, the C-7 hydroxy group, which has the highest chemical activity, of the astilbe chinensis glycoside molecule is converted into a free state, the AB-I is a key intermediate, and a glycoside structure (AB-I-N) is introduced into the C-7 hydroxy group, and finally removing the hydroxy group protective group to obtain the target compound (AB-I-X). According to the preparation method, the phenolic hydroxyl group and rhamnose hydroxy group of astilbe chinensis glycoside are subjected to selective protection and deprotection; and then glycosyl is introduced into C-7 hydroxy group of flavanone parent nucleus to prepare astilbe chinensis glycoside derivatives (AB-I-X). Or the reaction conditions are changed so as to simultaneously introduce glycosyl into the C-7 hydroxy group and C-4' hydroxy group of flavanone parent nucleus to prepare astilbe chinensis glycoside derivatives (AB-II-X) to improve the bio-utilization degree of astilbe chinensis glycoside.
Description
Technical field
The invention belongs to technical field of fine, be specifically related to a kind of method that molecular design prepares high bioavailability astilbin glycosides derivatives and key intermediate compound thereof.
Background technology
Astilbin is flavanone kind composition, and as shown in Figure 1, astilbin is the principle active component of the Chinese medicine such as Rhizome of Glabrous Greenbrier, Princes-feather Fruit, is also extensively present in the fruit such as grape, oranges and tangerines simultaneously.Pharmaceutical research shows that Taxifolin and astilbin have the effect such as anti-oxidant, antibacterial, antiviral, antitumor, hypoglycemic and selectivity immunosuppressive action significantly.Astilbin is soluble in the organic solvents such as methyl alcohol, ethanol, ethyl acetate.But its poorly water-soluble, when 25 DEG C, solubleness is only 250 μ g/mL, belongs to soluble,very slightly sample according to Chinese Pharmacopoeia.Wang Xiaodan carries out research to astilbin pharmacokinetics and shows, the absolute bioavailability of astilbin in rat body is only 0.066%, belongs to the compound that oral absorption is poor.The method that bibliographical information improves astilbin bioavailability mainly adopts drug preparation technique, but its effect is all more limited.The intramolecular hydrogen bond formed in astilbin structure is one of reason causing its poorly water-soluble, and therefore semi-synthetic chemically modified astilbin can effectively develop it and utilize.
Summary of the invention
For the problems referred to above, object of the present invention aims to provide a kind of astilbin glycosides derivatives and preparation method thereof.
For this reason, the present invention by the following technical solutions: a kind of astilbin glycosides derivatives, described derivative is AB-I-X or AB-II-X, and wherein the general. formula of AB-I-X is
Wherein the general. formula of AB-II-X is
Wherein R represents D-Glucose, D-semi-lactosi, D-MANNOSE, D-R, D-lactose, D-cellobiose or D-Maltose.
The preparation method of described AB-I-X is: with compd A B-1 for raw material, adds Bian chlorine or Bian bromine, replaces C-7 ethanoyl be prepared into AB-2 by benzyl; Compd A B-2 palladium carbon catalytic hydrogen reduction is prepared compd A B-I, by above chemical reaction, C-7 hydroxyl the highest for chemical reactivity in astilbin molecule is dissociated, on C-7 hydroxyl, introduce glycosidic structure (AB-I-N) with AB-I for key intermediate; Last eliminating hydroxide protecting group obtains target compound (AB-I-X).
The preparation method of described AB-II-X is: with compd A B-1 for raw material, adds Bian chlorine or Bian bromine, replaces C-7 and C-4 ' ethanoyl be prepared into AB-3 by benzyl; Compd A B-3 palladium carbon catalytic hydrogen reduction is prepared compd A B-II, then on the C-7 hydroxyl and C-4 ' hydroxyl of AB-II, introduces glycosidic structure (AB-II-N); Last eliminating hydroxide protecting group obtains target compound (AB-II-X).
Use the present invention can reach following beneficial effect: the present invention, mainly through carrying out selective protection and deprotection to the phenolic hydroxyl group of astilbin and rhamnosyl hydroxyl, introduces glycosyl at the C-7 hydroxyl of flavanone parent nucleus and prepares astilbin glycosides derivatives (AB-I-X); Or introduce glycosyl at the C-7 hydroxyl of flavanone parent nucleus and C-4 ' hydroxyl simultaneously prepare astilbin glycosides derivatives (AB-II-X), to improve the bioavailability of astilbin by changing reaction conditions.
Accompanying drawing explanation
Fig. 1 is the structure iron of flavanone kind composition.
Fig. 2 is preparation method's artwork of AB-I-X.
Fig. 3 is preparation method's artwork of AB-II-X.
Embodiment
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in detail.
Embodiment: as shown in FIG. 1 to 3, derivative is AB-I-X or AB-II-X, and wherein the general. formula of AB-I-X is
Wherein the general. formula of AB-II-X is
Wherein R represents D-Glucose, D-semi-lactosi, D-MANNOSE, D-R, D-lactose, D-cellobiose or D-Maltose.
The preparation method of AB-I-X as shown in Figure 2, utilizes anhydrous acetic acid acid anhydride and pyridine to carry out acetylize protection to all hydroxyls in astilbin (AB) molecule, obtains full acetylated astilbin (AB-1); C-7 hydroxy chemical reactive behavior is the highest in the molecule, in Bian chlorine, Anhydrous potassium carbonate and acetone reaction system, the protecting group ethanoyl of C-7 hydroxyl is replaced to benzyl, is prepared into compound (AB-2); In palladium hydrocarbonize reduction selectively removing AB-2 molecule, C-7 benzyl protecting group obtains key intermediate (AB-I), by above chemical reaction, C-7 hydroxyl the highest for chemical reactivity in astilbin molecule is dissociated, with this AB-I for key intermediate can introduce glycosidic structure (AB-I-N) in specific manner on C-7 hydroxyl; Last eliminating hydroxide protecting group obtains target compound (AB-I-X).
The glycosyl intermediate of above indication comprises: 2, 3, 4, 6-tetra--O-ethanoyl-α-D-acetylbromoglycose, 2, 3, 4, 6-tetra--O-ethanoyl-α-D-bromo-galactose, 2, 3, 4, 6-tetra--O-ethanoyl-α-D-bromo seminose, 2, 3, 4-tri--O-ethanoyl-α-D-bromo pectinose, 2, 3, 6, 2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-α-D-bromo lactose, 2, 3, 6, 2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-α-D-bromo cellobiose, 2, 3, 6, 2 ', 3 ', 4 ', the active halogeno-sugar intermediate such as 6 '-seven-O-ethanoyl-α-D-bromo maltose, and glycosyl trichloroacetimidate intermediate.
The preparation method of AB-II-X is as shown in Figure 3: utilize anhydrous acetic acid acid anhydride and pyridine to carry out acetylize protection to all hydroxyls in astilbin (AB) molecule, obtain full acetylated astilbin (AB-1); C-7 hydroxyl and C-4 ' hydroxy chemical reactive behavior relatively high in the molecule, in Bian bromine, Anhydrous potassium carbonate and acetone reaction system, the protecting group ethanoyl of C-7 hydroxyl and C-4 ' hydroxyl is replaced to benzyl, is prepared into compound (AB-3); In palladium hydrocarbonize reduction selectively removing AB-3 molecule, C-7 and C-4 ' benzyl protecting group obtains key intermediate (AB-II), then on the C-7 hydroxyl and C-4 ' hydroxyl of AB-II, introduces glycosidic structure (AB-II-N); Last eliminating hydroxide protecting group obtains target compound (AB-II-X).The glycosyl intermediate of above indication comprises: 2, 3, 4, 6-tetra--O-ethanoyl-α-D-acetylbromoglycose, 2, 3, 4, 6-tetra--O-ethanoyl-α-D-bromo-galactose, 2, 3, 4, 6-tetra--O-ethanoyl-α-D-bromo seminose and 2, 3, 4-tri--O-ethanoyl-α-D-bromo pectinose, 2, 3, 6, 2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-α-D-bromo lactose, 2, 3, 6, 2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-α-D-bromo cellobiose, 2, 3, 6, 2 ', 3 ', 4 ', the active halogeno-sugar intermediate such as 6 '-seven-O-ethanoyl-α-D-bromo maltose, and glycosyl trichloroacetimidate intermediate.
Hydroxyl in astilbin molecular structure is divided into two classes, and a class is the rhamnosyl hydroxyl of flavanone parent nucleus C-3; Another kind of is the phenolic hydroxyl group, the phenolic hydroxyl group of C-5 and the phenolic hydroxyl group of C-7 that are positioned on 3, the 4-dihydroxyl phenol of C-2 on flavanone parent nucleus.Residing for hydroxyl, chemical structure position difference causes its chemical reactivity to there is larger difference, and C-3 rhamnosyl hydroxyl belongs to secondary hydroxyl group, and chemical reactivity is the poorest; Form intramolecular hydrogen bond between the phenolic hydroxyl group of C-5 and C-4 carbonylic oxygen atom, cause its chemical reactivity to be deteriorated.Comprehensive literature result, in astilbin molecule, the chemical reactivity order of hydroxyl is: C-7>C-4 ' >C-3 ' >C-5> alcoholic extract hydroxyl group (rhamnosyl).
Therefore according to hydroxy chemical reactive behavior difference in astilbin molecule, the larger feature of C-7 hydroxy chemical reactive behavior is utilized to carry out chemically modified to it.The present invention, mainly through carrying out selective protection and deprotection to the phenolic hydroxyl group of astilbin and rhamnosyl hydroxyl, introduces glycosyl at the C-7 hydroxyl of flavanone parent nucleus and prepares astilbin glycosides derivatives (AB-I-X); Or introduce glycosyl at the C-7 hydroxyl of flavanone parent nucleus and C-4 ' hydroxyl simultaneously prepare astilbin glycosides derivatives (AB-II-X), to improve the bioavailability of astilbin by changing reaction conditions.
The chemical formula of AB-1 is
The chemical formula of AB-2 is
The chemical formula of AB-I is
The chemical formula of AB-3 is
The chemical formula of AB-II is
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (7)
1. astilbin glycosides derivatives, is characterized in that: described derivative is AB-I-X or AB-II-X, and wherein the general. formula of AB-I-X is
Wherein the general. formula of AB-II-X is
Wherein R represents D-Glucose, D-semi-lactosi, D-MANNOSE, D-R, D-lactose, D-cellobiose or D-Maltose.
2. the preparation method of astilbin glycosides derivatives as claimed in claim 1, is characterized in that: the preparation method of described AB-I-X is: with compd A B-1 for raw material, adds Bian chlorine or Bian bromine, replaces C-7 ethanoyl be prepared into AB-2 by benzyl; Compd A B-2 palladium carbon catalytic hydrogen reduction is prepared compd A B-I, dissociated by C-7 hydroxyl the highest for chemical reactivity in astilbin molecule by above chemical reaction, AB-I introduces glycosidic structure (AB-I-N) for key intermediate on C-7 hydroxyl; Last eliminating hydroxide protecting group obtains target compound (AB-I-X).
3. the preparation method of astilbin glycosides derivatives as claimed in claim 1, is characterized in that: the preparation method of described AB-II-X is: with compd A B-1 for raw material, adds Bian chlorine or Bian bromine, replaces C-7 and C-4 ' ethanoyl be prepared into AB-3 by benzyl; Compd A B-3 palladium carbon catalytic hydrogen reduction is prepared compd A B-II, then on the C-7 hydroxyl and C-4 ' hydroxyl of AB-II, introduces glycosidic structure (AB-II-N); Last eliminating hydroxide protecting group obtains target compound (AB-II-X).
4. the preparation method of the astilbin glycosides derivatives according to Claims 2 or 3, is characterized in that: the chemical formula of described AB-1 is
5. the preparation method of astilbin glycosides derivatives according to claim 2, is characterized in that: the chemical formula of AB-2 is
The chemical formula of described AB-I is
6. the preparation method of astilbin glycosides derivatives according to claim 2, is characterized in that: the chemical formula of described AB-3 is
The chemical formula of described AB-II is
7. the preparation method of the astilbin glycosides derivatives according to Claims 2 or 3, is characterized in that: described AB-1 carries out acetylize protection by anhydrous acetic acid acid anhydride and pyridine to all hydroxyls in astilbin (AB) molecule and obtains.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083956A (en) * | 2016-06-22 | 2016-11-09 | 成都大学 | Derivatives of astilbin and preparation method thereof |
| CN109762037A (en) * | 2019-03-04 | 2019-05-17 | 成都大学 | A kind of astilbin aminopyridine analog derivative targeted prodrug and its preparation method and application |
| CN109762038A (en) * | 2019-03-04 | 2019-05-17 | 成都大学 | A kind of astilbin amino acid derivatives targeted prodrug and its preparation method and application |
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| CN1724552A (en) * | 2005-07-08 | 2006-01-25 | 南京大学 | Preparation method of astilbin |
| CN101638424A (en) * | 2008-07-28 | 2010-02-03 | 山东绿叶天然药物研究开发有限公司 | Derivatives of astilbin and preparation method thereof |
| CN101804064A (en) * | 2010-04-08 | 2010-08-18 | 成都军区昆明总医院 | Application of dihydroquercetin and glucoside compounds to preparing drug-resistance bacteria medicine |
| CN102234300A (en) * | 2010-04-26 | 2011-11-09 | 广州医学院 | Methods for extracting astilbin and dihydroquercetin from engelhardia roxburghiana wall leaves and application of extractives thereof |
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2015
- 2015-07-29 CN CN201510451877.7A patent/CN105061531A/en active Pending
Patent Citations (4)
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| CN1724552A (en) * | 2005-07-08 | 2006-01-25 | 南京大学 | Preparation method of astilbin |
| CN101638424A (en) * | 2008-07-28 | 2010-02-03 | 山东绿叶天然药物研究开发有限公司 | Derivatives of astilbin and preparation method thereof |
| CN101804064A (en) * | 2010-04-08 | 2010-08-18 | 成都军区昆明总医院 | Application of dihydroquercetin and glucoside compounds to preparing drug-resistance bacteria medicine |
| CN102234300A (en) * | 2010-04-26 | 2011-11-09 | 广州医学院 | Methods for extracting astilbin and dihydroquercetin from engelhardia roxburghiana wall leaves and application of extractives thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083956A (en) * | 2016-06-22 | 2016-11-09 | 成都大学 | Derivatives of astilbin and preparation method thereof |
| CN106083956B (en) * | 2016-06-22 | 2019-03-15 | 成都大学 | Derivatives of astilbin and preparation method thereof |
| CN109762037A (en) * | 2019-03-04 | 2019-05-17 | 成都大学 | A kind of astilbin aminopyridine analog derivative targeted prodrug and its preparation method and application |
| CN109762038A (en) * | 2019-03-04 | 2019-05-17 | 成都大学 | A kind of astilbin amino acid derivatives targeted prodrug and its preparation method and application |
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