CN106083956A - Derivatives of astilbin and preparation method thereof - Google Patents

Derivatives of astilbin and preparation method thereof Download PDF

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Publication number
CN106083956A
CN106083956A CN201610459223.3A CN201610459223A CN106083956A CN 106083956 A CN106083956 A CN 106083956A CN 201610459223 A CN201610459223 A CN 201610459223A CN 106083956 A CN106083956 A CN 106083956A
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astilbin
derivatives
preparation
benzyl
raw material
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CN106083956B (en
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郭晓强
周闯
宋芹
姚倩
邱露
赵卫
徐孝浪
杨清
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Chengdu University
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Chengdu University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The present invention relates to derivatives of astilbin and preparation method thereof, belong to technical field of fine.With astilbin as raw material, prepare, by the mol ratio controlling benzyl bromine and astilbin, double hydroxy intermediate AB D that 5 hydroxyls of C, 5 and C 3 ' position hydroxyls of exposed monohydroxy intermediate A B S and C are the most exposed respectively.Intermediate A B S and AB D is reacted with halogeno-sugar respectively, prepares astilbin glycosides derivatives AB S X and AB D X respectively through Deprotection.Derivatives of astilbin that the present invention provides and preparation method thereof; by the phenolic hydroxyl group of astilbin and rhamnose hydroxyl are carried out selective protection and deprotection; monosaccharide or disaccharidase is introduced at the C 5 of flavanone parent nucleus; and it is simultaneously introduced monosaccharide or disaccharidase, to improve the bioavailability of astilbin at C 5 and C 3 ' position.

Description

Derivatives of astilbin and preparation method thereof
Technical field
The invention belongs to field of fine chemical, be specifically related to derivatives of astilbin and preparation method thereof.
Background technology
Astilbin (AB) is flavanone kind composition, has polyphenol and rhamnose two class hydroxyl structure, be Rhizoma Smilacis Glabrae, The effective elements of the medicine in Fructus Polygoni Orientalis etc..Research shows that astilbin has various biological activity, including suppression coenzyme A reductase Enzyme, suppression aldose reductase, edema and selectivity immunosuppressive action etc..Astilbin is soluble in methanol, ethanol etc. to be had Machine solvent, soluble,very slightly in water, 25 DEG C of water solubilities are 250ug/mL；Astilbin is only at rat vivo biodistribution availability 0.066%, belong to the compound that oral absorption is poor.Astilbin bioavailability is improved at present, its effect with practice of pharmacy Fruit is the most extremely limited.Hydroxyl and carbonyl formation intramolecular hydrogen bond in astilbin structure are the reasons causing its poorly water-soluble One of, the bioavailability of astilbin can be improved by semi-synthetic chemical modification, it is possible to achieve to its effective exploitation and profit With.
Summary of the invention
For the problems referred to above, the purpose of the present invention aims to provide a kind of derivatives of astilbin and preparation method thereof.
The present invention is by the following technical solutions:
Derivatives of astilbin, described derivant is AB-S-X and AB-D-X, and wherein the general. formula of AB-S-X is:
The general. formula of AB-D-X is:
Wherein R represents D-Glucose, D-galactose, D-MANNOSE, D-R, D-lactose, D-cellobiose or D- Maltose.
The preparation process of AB-S-X is:
C-5 position chemical reactivity is minimum, uses benzyl bromine to carry out astilbin AB in Anhydrous potassium carbonate, DMF system The Benzylation protection of part, benzyl bromine and AB mol ratio control in the range of 8:1～10:1, exposed C-5 position hydroxyl, it is thus achieved that in the middle of crucial Body AB-S；Exposed C-5 position hydroxyl, by reacting with halogeno-sugar, is finally sloughed hydroxyl protecting group and is obtained target compound AB-S- X.Monosaccharide or the disaccharidase of above-mentioned indication include: D-Glucose, D-galactose, D-MANNOSE, D-R, D-lactose, D-are fine Dimension disaccharide or D-Maltose.
Wherein, the chemical formula of AB-S is:
Wherein Bn structure is benzyl.
The preparation process of AB-D-X is:
Utilize C-5 position and C-3 ' position hydroxyl reaction activity relatively low, control benzyl bromine and mol ratio 6:1 of raw material reaction～8:1, Compound AB is carried out the Benzylation protection of part, exposed C-5 position and C-3 ' position hydroxyl, it is thus achieved that key intermediate AB-D；Again with phase The halogeno-sugar intermediate answered reacts, and sloughs benzyl through palladium carbon catalytic hydrogenation and obtains target compound AB-D-X.Above-mentioned indication Monosaccharide or disaccharidase include: D-Glucose, D-galactose, D-MANNOSE, D-R, D-lactose, D-cellobiose or D- Maltose.
Wherein, the chemical formula of AB-D is:
Wherein Bn structure is benzyl.
Due to hydrogen in being formed between C-5 position hydroxyl and C-4 carbonylic oxygen atom in flavanone structure in astilbin molecule Key, in astilbin molecule, the chemical reactivity order of phenolic hydroxyl group is: C-7 > C-4 ' > C-3 ' > C-5, and astilbin chemistry is tied Structure is:
Therefore according to phenolic hydroxyl group chemical reactivity difference in astilbin molecule, C-5 position and C-3 ' position hydroxylating are utilized The feature learning reactivity relatively low is carried out its chemical modification.
Derivatives of astilbin and preparation method thereof that the present invention provides, by the phenolic hydroxyl group of astilbin and rhamnose Hydroxyl carries out selective protection and deprotection, introduces monosaccharide or disaccharidase in the C-5 position of flavanone parent nucleus, and in C-5 position and C-3 ' position is simultaneously introduced monosaccharide or disaccharidase, to improve the bioavailability of astilbin.
Detailed description of the invention
Below in conjunction with embodiment, the detailed description of the invention of the present invention is described in detail.
Embodiment 1: the preparation of compound AB-S
Adding raw material A B 1.0g in single port bottle, 3mL DMF dissolves, and adds 2.37mL Bian bromine, 2.7g anhydrous K2CO3, 45 DEG C of stirring reaction 3h.Addition 30mL water in the reaction backward system of end, ethyl acetate extraction (20mL × 3), 20mL extracts 3 times i.e. every time；Organic facies dilute hydrochloric acid washs (15mL × 3), washes (20mL × 3), is evaporated to do, Obtain faint yellow solid 0.65g.
Embodiment 2: the preparation of compound AB-D
Adding raw material A B 1.0g in single port bottle, 4mL DMF dissolves, and adds 1.85mL Bian bromine, 2.1g anhydrous K2CO3, 25 DEG C of stirring reaction 3h.Addition 30mL water in the reaction backward system of end, ethyl acetate extraction (20mL × 3), organic facies dilute hydrochloric acid washs (15mL × 3), washes (20mL × 3), is evaporated to do, obtains faint yellow solid 0.53g.
Embodiment 3: the preparation of compound AB-S-1 (glucosan derivative)
1.0g AB-S, 0.31g acetylbromoglycose, 10mL CH is added in reaction bulb2Cl2Dissolve, add anhydrous K2CO3 1.0g, 50 DEG C of back flow reaction 4h.After reaction completely, reactant liquor is spin-dried for, is subsequently adding 30mL water, is extracted with ethyl acetate (30mL × 3), dilute hydrochloric acid washing (15mL × 3), it is evaporated to do, obtains faint yellow solid 0.61g.
Embodiment 4: the preparation of compound AB-D-1 (lactose derivatives)
1.0g AB-D, 0.48g chloro lactose, 10mL CH is added in reaction bulb2Cl2Dissolve, add anhydrous K2CO3 1.0g, 60 DEG C of back flow reaction 5h.After reaction completely, reactant liquor is spin-dried for, is subsequently adding 30mL water, is extracted with ethyl acetate (30mL × 3), dilute hydrochloric acid washing (15mL × 3), it is evaporated to do, obtains faint yellow solid 0.68g.

Claims (5)

1. derivatives of astilbin, it is characterised in that: include derivant AB-S-X and AB-D-X, the wherein general chemistry of AB-S-X Formula is:
The general. formula of AB-D-X is:
Wherein R represents D-Glucose, D-galactose, D-MANNOSE, D-R, D-lactose, D-cellobiose or D-Fructus Hordei Germinatus Sugar.
The preparation method of derivatives of astilbin the most according to claim 1, it is characterised in that described AB-S-X preparation side Method is: with astilbin as raw material, and benzyl bromine is 8:1～10:1 with the mol ratio of raw material, and carries out under the conditions of 45 DEG C～55 DEG C Reaction, prepares monohydroxy intermediate A B-S that C-5 position hydroxyl is exposed；Carry out substitution reaction with halogeno-sugar again, finally slough benzyl Protection group obtains target compound AB-S-X.
The preparation method of derivatives of astilbin the most according to claim 1, it is characterised in that described AB-D-X preparation side Method is: with astilbin as raw material, and benzyl bromine is 6:1～8:1 with the mol ratio of raw material, and carries out anti-under the conditions of 25 DEG C～35 DEG C Should, prepare C-5 position and the most exposed double hydroxy intermediate AB-D of C-3 ' position hydroxyl；Substitution reaction is carried out again, finally with halogeno-sugar Slough benzyl protecting group and obtain target compound AB-D-X.
The preparation method of derivatives of astilbin the most according to claim 2, it is characterised in that the chemistry of described AB-S Formula is:
Wherein Bn structure is benzyl.
The preparation method of derivatives of astilbin the most according to claim 3, it is characterised in that the chemistry of described AB-D Formula is:
Wherein Bn structure is benzyl.
CN201610459223.3A 2016-06-22 2016-06-22 Derivatives of astilbin and preparation method thereof Active CN106083956B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107141325A (en) * 2017-05-24 2017-09-08 成都大学 Derivatives of astilbin and preparation method thereof
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
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102285951A (en) * 2011-09-13 2011-12-21 辽宁亿灵科创生物医药科技有限公司 Luteolin derivative and application thereof to preventing and treating cardiovascular disease
CN105061531A (en) * 2015-07-29 2015-11-18 成都大学 Astilbe chinensis glycoside derivatives and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102285951A (en) * 2011-09-13 2011-12-21 辽宁亿灵科创生物医药科技有限公司 Luteolin derivative and application thereof to preventing and treating cardiovascular disease
CN105061531A (en) * 2015-07-29 2015-11-18 成都大学 Astilbe chinensis glycoside derivatives and preparation method thereof

Non-Patent Citations (2)

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Title
张吉泉等，: "5-O-取代木犀草素衍生物的合成方法.", 《化学试剂》 *
李化军等，: "3-O-甲基槲皮素的合成.", 《有机化学》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107141325A (en) * 2017-05-24 2017-09-08 成都大学 Derivatives of astilbin and preparation method thereof
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
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

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