CN109400567A - A method of synthesis glycyrrhizin - Google Patents
A method of synthesis glycyrrhizin Download PDFInfo
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- 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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- glycyrrhizin
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- 239000004378 Glycyrrhizin Substances 0.000 title claims abstract description 25
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229960004949 glycyrrhizic acid Drugs 0.000 title claims abstract description 25
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 235000019410 glycyrrhizin Nutrition 0.000 title claims abstract description 25
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000003786 synthesis reaction Methods 0.000 title claims description 13
- 230000015572 biosynthetic process Effects 0.000 title claims description 12
- SULYEHHGGXARJS-UHFFFAOYSA-N 2',4'-dihydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1O SULYEHHGGXARJS-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 10
- KLAKIAVEMQMVBT-UHFFFAOYSA-N p-hydroxy-phenacyl alcohol Natural products OCC(=O)C1=CC=C(O)C=C1 KLAKIAVEMQMVBT-UHFFFAOYSA-N 0.000 claims abstract description 8
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical compound C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical group CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- -1 hydroxyl Glycyrrhizin Chemical compound 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 239000010410 layer Substances 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 2
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 abstract description 3
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 abstract description 3
- 235000008718 isoliquiritigenin Nutrition 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 4
- UILPJVPSNHJFIK-UHFFFAOYSA-N p-methoxy-o-hydroxyacetophenone Natural products COC1=CC=C(C(C)=O)C(O)=C1 UILPJVPSNHJFIK-UHFFFAOYSA-N 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GTXRYQGMNAPQDP-UHFFFAOYSA-N butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(CCCC)C1=CC=CC=C1 GTXRYQGMNAPQDP-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 235000021374 legumes Nutrition 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic 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
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[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
- C07D311/28—Benzo[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
- C07D311/32—2,3-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
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.
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