CN109400567A - A method of synthesis glycyrrhizin - Google Patents

A method of synthesis glycyrrhizin Download PDF

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Publication number
CN109400567A
CN109400567A CN201811476362.2A CN201811476362A CN109400567A CN 109400567 A CN109400567 A CN 109400567A CN 201811476362 A CN201811476362 A CN 201811476362A CN 109400567 A CN109400567 A CN 109400567A
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China
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added
glycyrrhizin
synthesis
reaction
protection
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CN201811476362.2A
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Inventor
杨双兵
刘玉亭
赵成安
付林
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HUAZHONG PHARMACEUTICAL CO Ltd
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HUAZHONG PHARMACEUTICAL CO Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D311/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/322,3-Dihydro derivatives, e.g. flavanones

Abstract

The present invention relates to a kind of methods of synthetic chemical glycyrrhizin.Using 2,4-dihydroxyacetophenone and 4-HBA ethyl ester as raw material, glycyrrhizin can be obtained by hydroxyl protection, ketone ester condensation, cyclisation and hydroxyl deprotection, reduction reaction.This method avoids the premise of synthesizing isoliquiritigenin, and method simple possible, raw material is cheap, high income, convenient for industrialization.

Description

A method of synthesis glycyrrhizin
Technical field
The present invention relates to a kind of methods for synthesizing glycyrrhizin, belong to organic synthesis field.
Background technique
Glycyrrhizin is because initially from glycyrrhizic legume, the drying root and rhizome extract separation of swollen fruit Radix or glycyrrhiza glabra It gains the name out.
Glycyrrhizin is an important flavanone compound in Radix Glycyrrhizae, has antitumor, antiviral, free radical resisting, suppression The bioactivity such as lipid peroxidation processed, wherein antitumor is the hot spot of Recent study.Numerous studies discovery, flavone compound Antitumor action can be played by inducing apoptosis of tumour cell;Existing research shows that glycyrrhizin has and inhibits human cervical carcinoma HeLa The proliferation of cell and the effect induced cell apoptosis.Currently, it is widely used to medicine, food and cosmetic industry.
Summary of the invention
The purpose of the present invention is to provide a kind of methods for synthesizing glycyrrhizin, have synthesized Radix Glycyrrhizae with more succinct method Element.Compared to traditional synthetic method: after utilizing condensation synthesizing isoliquiritigenin, then carrying out cyclization into glycyrrhizin;This method The premise of synthesizing isoliquiritigenin is avoided, method is easy, and raw material is easy to get, and cheap, yield is higher, to reduce the need to Radix Glycyrrhizae It asks, meets ever-increasing market demand.
The present invention is using 2,4-dihydroxyacetophenone and 4-HBA ethyl ester as raw material, the protection through perhydroxyl radical, ketone ester Condensation, cyclization and deprotection, reduction reaction, can be obtained product glycyrrhizin.Reaction equation is as follows:
Wherein: Base is that imidazoles or diisopropylethylamine are one such;Hydroxy protecting agent tri isopropyl chlorosilane or uncle Butyl diphenyl chlorosilane is one such.
The specific steps of the present invention are as follows:
(1) protection of 2,4-dihydroxyacetophenone: 30g 2,4-dihydroxyacetophenone is added in reaction flask, and solvent is added and stirs After mixing dissolution, then the protection reagent of hydroxyl is slowly added dropwise after addition alkali thereto, after 1-12h is stirred at room temperature, water is added, Organic layer is separated, is concentrated to get protection product after dry;
(2) protection of 4-HBA ethyl ester: 50g 4-HBA ethyl ester is added in reaction flask, and solvent is added After stirring and dissolving, then the protection reagent of hydroxyl is slowly added dropwise after addition alkali thereto, after 1-12h is stirred at room temperature, is added Water separates organic layer, is concentrated to get protection product after dry;
(3) ketone ester is condensed: (1) and (2) being dissolved in organic solvent according to certain molar ratio, nucleopilic reagent is added, in 0-100 It is stirred to react 2-12h between degree, after reaction, is poured into ice water, organic solvent extraction is added, separates organic layer Afterwards, it is concentrated to get addition product;
(4) it is cyclized and is deprotected: (3) are added in 80-120ml acetic acid, catalyst 2ml is added, is stirred between 50-100 DEG C Reaction 2-5h is mixed, reaction solution is poured into ice water, there are a large amount of solids to be precipitated, filtering, drying obtains cyclised products;
(5) reduction of ethylene linkage: (4) are added in the solvent being mixed in a certain ratio, and the water-soluble of reducing agent is added under low temperature After liquid, it is stirred to react 1-3h, acetic acid, water, methylene chloride extraction are added into reaction solution;Radix Glycyrrhizae is obtained after separating organic layer concentration Element.
Wherein step (1), (2), (3), (4), the organic solvent in (5) are methanol, ethyl alcohol, isopropanol, methylene chloride, chlorine Imitative, ethyl acetate, acetone, tetrahydrofuran, n,N-Dimethylformamide or with two or more above-mentioned solvents with arbitrary proportion institute The mixed solvent of composition.
Wherein the reaction temperature of step (1) is 20-60 DEG C;The reaction temperature of step (2) is 20-50 DEG C;Step (3) it is anti- Answering temperature is 0-60 DEG C;The reaction temperature of step (4) is 60-90 DEG C;The reaction temperature of step (5) is-30-10 DEG C.
Wherein the reaction time of step (1) is 3-6h;The reaction time of step (2) is 2-5h;The reaction time of step (3) For 2-6h;The reaction time of step (4) is 5-12h;The reaction time of step (5) is 1-2h.
Wherein step (1), hydroxy protecting agent described in (2) are tri isopropyl chlorosilane, tert-butyl diphenyl chlorine silicon Alkane is one such.
Wherein molar ratio described in step (3) is step (1) product: step (2) product 1.1:1 ~ 1.3:1;Described Nucleopilic reagent are as follows: sodium hydride, hydrofining, lithium hexamethyldisilazide or sodium hexamethyldisilazide are one such.
Wherein catalyst described in step (4) is the concentrated sulfuric acid, concentrated phosphoric acid, trifluoroacetic acid or methanesulfonic acid therein one Kind.
Wherein the ratio of mixed solvent methanol and methylene chloride described in step (5) is methanol: methylene chloride: 2:3 ~ 1:2; The reducing agent are as follows: sodium borohydride, potassium borohydride, lithium borohydride or borine are one such.
The invention has the following advantages that
1. the method for the present invention is simple, easy, reaction condition is mild, safety;
2. raw material of the present invention is easy to get, cheap, it is suitble to industrialized production;
3. 4-HBA ethyl ester and 2,4-dihydroxyacetophenone are carried out hydroxyl protection by the present invention, by-product generation is reduced Risk, improve the yield of glycyrrhizin.
Specific embodiment
Embodiment 1
(1) imidazoles of 63.9g2,4- resacetophenone and 71.4g the protection of 2,4- resacetophenone: is added to reaction In bottle, after methylene chloride stirring and dissolving is added, the tri isopropyl chlorosilane of 170g is added, then after 25 DEG C or so stirring 5h, After the water stirring 15min of 500ml is added, standing separates dichloromethane layer, and after organic phase is dry, evaporated under reduced pressure obtains white solid 176.7g yield 90.5%;
(2) 49.4g 4- this Ethyl formate of hydroxyl and 24.3g imidazoles the protection of 4-HBA ethyl ester: are added to reaction flask In, after methylene chloride stirring and dissolving is added, 60.2g tri isopropyl chlorosilane, then after 25 DEG C are stirred to react 4h, TLC is added Raw material end of reaction is detected, after 350ml water stirring 20min is added into system, standing separates dichloromethane layer, and organic phase is dry Afterwards, light yellow solid 87.3g, yield 91.1% are concentrated under reduced pressure to give;
(3) ketone ester is condensed: by 64.5g(2) and 350mlN, dinethylformamide is added in reaction flask, after dissolution completely;It will System is down to 0 DEG C, and sodium hydride 10.1g(60% oil dispersed is added thereto);1h is stirred after addition, then 93g(1 is added dropwise) The solution of n,N-Dimethylformamide makes it rise to heating naturally after being added dropwise, stir 5h, and TLC detects raw material end of reaction, It is poured into 600ml ice water, methylene chloride extraction is concentrated under reduced pressure to give 126.3g product, yield after organic phase is dry 85.2%;
(4) cyclization and deprotection: 74.2g condensation product is added in 400ml glacial acetic acid, after stirring and dissolving is complete, is added The concentrated sulfuric acid of 1.2ml;System is warming up to 90 DEG C, after being stirred to react 8h, after being cooled to room temperature, is poured into ice water, two Chloromethanes extraction is concentrated under reduced pressure to give 23.4g product, yield 92.1% after organic phase is dry;
(5) reduction of ethylene linkage: 18g(4) is added in 120ml methylene chloride and 80ml methanol mixed solution, and stirring is completely molten System is cooled to -30 DEG C, the aqueous solution of 4g sodium borohydride is added dropwise, is stirred to react 2h after being added dropwise, added into system by Xie Hou After being warmed to room temperature, water is added in the glacial acetic acid for entering 14ml, and methylene chloride extraction obtains after reduced pressure after organic phase is dry 16.2g glycyrrhizin, yield 89.2%.
Embodiment 2
(1) protection of 2,4- resacetophenone: 60.9g 2,4- resacetophenone and 129.3g diisopropylethylamine are added Enter into reaction flask, chloroform is added after mixing evenly, the tert-butyl diphenyl chlorosilane of 231g is added, then on 25 DEG C of left sides After right stirring 3h, water is added, chloroform extraction, after organic phase is dry, evaporated under reduced pressure obtains white solid 229.6g, yield 91.2%;
(2) protection of 4-HBA ethyl ester: 66.5g 4- this Ethyl formate of hydroxyl and 62.1g diisopropylethylamine are added Into reaction flask, chloroform is added after mixing evenly, 121g tert-butyl diphenyl chlorosilane is added, it is then anti-in 25 DEG C of stirrings After answering 5h, TLC detects raw material end of reaction, water is added, chloroform extraction, after organic phase is dry, evaporated under reduced pressure obtains light yellow Solid 146.5g, yield 90.5%;
(3) ketone ester is condensed: by 74.8g(2) and 96.2g(1), 500ml tetrahydrofuran is added in reaction flask;System is down to 0 DEG C, lithium hexamethyldisilazide (1mol/L) 440ml is added thereto;1h is stirred after addition, makes it after being added dropwise Naturally heating is risen to, 4h is stirred, TLC detects raw material end of reaction, is poured into 600ml ice water, and methylene chloride extraction has After machine is mutually dried, it is concentrated under reduced pressure to give 131.4g product, yield 87%;
(4) cyclization and deprotection: 78.7g condensation product is added in 385ml glacial acetic acid, and after stirring and dissolving is complete, 5ml is added Methanesulfonic acid;System is warming up to 90 DEG C, after being stirred to react 6h, after being cooled to room temperature, is poured into ice water, methylene chloride Extraction is concentrated under reduced pressure to give 23.2g product, yield 91.6% after organic phase is dry;
(5) reduction of ethylene linkage: 15g(4) is added in 100ml methylene chloride and 50ml methanol mixed solution, and stirring is completely molten System is cooled to -25 DEG C, the aqueous solution of 4.8g potassium borohydride is added dropwise, 3h is stirred to react after being added dropwise, into system by Xie Hou The glacial acetic acid of 10ml is added, after being warmed to room temperature, water is added, methylene chloride extraction obtains after reduced pressure after organic phase is dry 13.3g glycyrrhizin, yield 88%.

Claims (10)

1. a kind of method for synthesizing glycyrrhizin, using 4-HBA ethyl ester and 2,4-dihydroxyacetophenone as raw material, by hydroxyl Glycyrrhizin can be obtained in base protection, ketone ester condensation, cyclisation and deprotection, reduction reaction, and specific synthesis step is as follows:
(1) protection of 2,4-dihydroxyacetophenone: 2,4-dihydroxyacetophenone is added in reaction flask, and it is molten that stirring solvent is added Xie Hou, then alkali is added thereto, the protection reagent of hydroxyl is slowly added dropwise, after 1-12h is stirred at room temperature, water is added, has separated Machine layer is concentrated to get protection product after dry;
(2) protection of 4-HBA ethyl ester: 4-HBA ethyl ester is added in reaction flask, and stirring solvent is added After dissolution, then alkali is added thereto, the protection reagent of hydroxyl is slowly added dropwise, after 1-12h is stirred at room temperature, water is added, separates Organic layer is concentrated to get protection product after dry;
(3) ketone ester is condensed: (1) and (2) being dissolved in organic solvent according to certain molar ratio, nucleopilic reagent is added, in 0-100 It is stirred to react 2-12h between degree, after reaction, is poured into ice water, organic solvent extraction is added, separates organic layer Afterwards, it is concentrated to get addition product;
(4) it is cyclized and is deprotected: (3) are added in acetic acid, catalyst is added, 2-5h is stirred to react between 50-100 DEG C, Reaction solution is poured into ice water, there are a large amount of solids to be precipitated, filtering, drying obtains cyclised products;
(5) reduction of ethylene linkage: (4) are added in the solvent being mixed in a certain ratio, and the water-soluble of reducing agent is added under low temperature After liquid, it is stirred to react 1-3h, acetic acid, water, methylene chloride extraction are added into reaction solution;Radix Glycyrrhizae is obtained after separating organic layer concentration Element.
2. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: step (1), (2), (3), (4), (5) In organic solvent be methanol, ethyl alcohol, isopropanol, methylene chloride, chloroform, ethyl acetate, acetone, tetrahydrofuran, N, N- diformazan Base formamide or with two or more above-mentioned solvents with mixed solvent composed by arbitrary proportion.
3. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: the reaction temperature of step (1) is 20-60 ℃;The reaction temperature of step (2) is 20-50 DEG C;The reaction temperature of step (3) is 0-60 DEG C;The reaction temperature of step (4) is 60-90℃;The reaction temperature of step (5) is-30-10 DEG C.
4. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: the reaction time of step (1) is 3-6h; The reaction time of step (2) is 2-5h;The reaction time of step (3) is 2-6h;The reaction time of step (4) is 5-12h;Step (5) reaction time is 1-2h.
5. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: hydroxyl described in step (1), (2) Protection reagent is tri isopropyl chlorosilane, and tert-butyl diphenyl chlorosilane is one such.
6. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: molar ratio described in step (3) is Step (1) product: step (2) product 1.1:1 ~ 1.3:1.
7. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: nucleopilic reagent described in step (3) Are as follows: sodium hydride, hydrofining, lithium hexamethyldisilazide or sodium hexamethyldisilazide are one such.
8. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: catalyst described in step (4) is The concentrated sulfuric acid, concentrated phosphoric acid, trifluoroacetic acid or methanesulfonic acid are one such.
9. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: mixed solvent first described in step (5) The proportion methanol of alcohol and methylene chloride: methylene chloride is 2:3 ~ 1:2.
10. a kind of method of synthesis glycyrrhizin according to right 1, it is characterised in that: reducing agent described in step (5) are as follows: Sodium borohydride, potassium borohydride or lithium borohydride are one such.
CN201811476362.2A 2018-12-05 2018-12-05 A method of synthesis glycyrrhizin Pending CN109400567A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2006002422A2 (en) * 2004-06-24 2006-01-05 Novartis Vaccines And Diagnostics Inc. Compounds for immunopotentiation
CN101570528A (en) * 2009-06-18 2009-11-04 吕秋军 Glycyrrhizin derivatives and preparation and use thereof
CN103193749A (en) * 2013-04-19 2013-07-10 中国科学院新疆理化技术研究所 Preparation method of polyhydroxy flavonoids compound
CN106536468A (en) * 2014-07-02 2017-03-22 肥后春男 Process for producing liquiritigenin precursor
CN108164532A (en) * 2016-12-07 2018-06-15 季昀 Organic compound with class tetrahedron configuration
CN108440264A (en) * 2018-04-24 2018-08-24 湖北凌晟药业有限公司 A kind of synthetic method of isoliquiritigenin

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1384100A (en) * 1996-02-13 2002-12-11 艾博特公司 Benzo-1,3-dioxole and benzofuran substituted pentazane derivative
WO2006002422A2 (en) * 2004-06-24 2006-01-05 Novartis Vaccines And Diagnostics Inc. Compounds for immunopotentiation
CN101570528A (en) * 2009-06-18 2009-11-04 吕秋军 Glycyrrhizin derivatives and preparation and use thereof
CN103193749A (en) * 2013-04-19 2013-07-10 中国科学院新疆理化技术研究所 Preparation method of polyhydroxy flavonoids compound
CN106536468A (en) * 2014-07-02 2017-03-22 肥后春男 Process for producing liquiritigenin precursor
CN108164532A (en) * 2016-12-07 2018-06-15 季昀 Organic compound with class tetrahedron configuration
CN108440264A (en) * 2018-04-24 2018-08-24 湖北凌晟药业有限公司 A kind of synthetic method of isoliquiritigenin

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