CN103030647A - Method for synthesizing glabridin - Google Patents
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Abstract
The invention relates to a method for synthesizing glabridin. The method comprises the following steps: using acetophenone protected by phenol hydroxy as a raw material, carrying out a Willgerodt-Kindler reaction to obtain aryl phenylacetic acid, and carrying out a Friedel-Crafts reaction to obtain an isoflavones compound; causing the isoflavones compound to carry out Pd/C catalytic hydrogenation to obtain a isoflavanone compound; and causing the isoflavanone compound to carrying out a crclizationreaction, a conyl reduction reaction and a removing phenolic hydroxyl group protection group reaction to obtain the glabridin. The operation and the serparation of the steps of the method are simple, the yield is higher, the used reagents are common reagents, are cheap and are easily obtained, the path is shorter, and the tptal yield is not lower than 20 percent.
Description
Technical field
The present invention relates to a kind of synthetic method of glabridin, belong to the fine chemical technology field.
Background technology
Glabridin is topmost isoflavones components in the glycyrrhiza glabra, only is present in the cork layer and rotten root of glycyrrhiza glabra root, accounts for 11% in the glycyrrhiza glabra isoflavones.Stable in properties under the glabridin normal temperature, have whitening, antibiotic, anti-oxidant, anticancer, spasmolytic, anti-inflammatory, anti-quick, protect the liver, remove the effect such as free radical, and certain reducing blood-fat and hypotensive effect are arranged, in the control of arteriosclerosis and cardiovascular disorder, also demonstrate good medicinal DEVELOPMENT PROSPECT.
The chemical synthesis of the glabridin of report has two lines at present.Be that raw material makes glabridin with 2,4-, two mesyloxy toluylic acids among the patent JP2006008604A, synthetic route is as follows:
The method goes on foot through 6, total recovery 25.8%, but the reaction of per step has all related to the column chromatography separation, and cost is higher, and has used highly toxic ethylene dichloride equal solvent, brings very large pollution to environment, is difficult to carry out suitability for industrialized production.
2007, the people such as Keepyung Nahm reported an other synthetic route (Bull.Korean Chem.Soc., 2007,28,481), make glabridin take 2,4-dihydroxyacetophenone as raw material, and synthetic route is as follows:
This route makes glabridin through ten step reactions, yield 6.2%, and wherein committed step compound 1 and 2 condensation reaction need to be carried out under-78 ℃, are not suitable for scale operation.
Summary of the invention
Purpose of the present invention is intended to overcome technical deficiency and synthetic method that a kind of glabridin is provided, take through the methyl phenyl ketone of phenolic hydroxyl group protection as raw material, make glabridin through six-step process.
The technical scheme that the present invention takes is:
A kind of synthetic method of glabridin comprises that step is as follows:
The Willgerodt-Kindler reaction occurs in the methyl phenyl ketone that (1) 2,4-dialkoxy is replaced and sulphur powder, morpholine under the reflux condition, reaction makes the toluylic acid that 2,4-dialkoxy replaces by sodium hydroxide alkaline hydrolysis, adjust pH, filtration;
Friedel-Crafts reaction occurs in the toluylic acid and the Resorcinol that (2) 2,4-dialkoxy are replaced under the effect of boron trifluoride diethyl etherate, product is without separation, adds DMF after being cooled to room temperature, then splashes into MeSO under 50~55 ℃ of conditions
2The mixed solution of Cl and DMF reacts 5-6h under 70~80 ℃ after dripping off again, recrystallization after the solvent evaporated, get compound 7-hydroxyl-2 ', 4 '-dialkoxy isoflavones (being compound 3);
(3) with 7-hydroxyl-2 ', 4 '-the dialkoxy isoflavones add the Pd/C catalyzer through the Pd/C catalytic hydrogenation make 7-hydroxyl-2 ', 4 '-dialkoxy isoflavan (being compound 4);
(4) with 7-hydroxyl-2 ', 4 '-dialkoxy isoflavan and 3-methyl-2-alkene butyraldehyde carry out annulation, separating-purifying must be with the isoflavones (being compound 5) of dihydropyrane ring;
(5) will add reductive agent with the isoflavones (being compound 5) of dihydropyrane ring and the reaction medium reflux is carried out carbonyl reduction, get alkoxyl group glabridin (being compound 6);
(6) alkoxyl group glabridin (compound 6) is added the deprotecting regent ice-water bath stirs or heating reflux reaction is sloughed phenolic hydroxyl group and protected to get glabridin.
In the above-mentioned synthetic method, in the step (1) 2, the molar ratio range of the methyl phenyl ketone that the 4-dialkoxy replaces and sulphur powder, morpholine, sodium hydroxide is 1:(2~2.5): (2~2.5): (0.8~1.2).The time of Willgerodt-Kindler reaction is 7-9h.Described alkaline hydrolysis is the sodium hydroxide solution backflow alkaline hydrolysis 7-9h that adds concentration 10~20wt% under the room temperature.Described adjust pH is for to transfer pH=1~2 with concentrated hydrochloric acid.Preferred 2, the 4-dimethoxy-acetophenone of the methyl phenyl ketone that 2,4-dialkoxy replaces.
In the step (2) 2, toluylic acid, Resorcinol, MeSO that the 4-dialkoxy replaces
2The molar ratio range of Cl is 1:(0.9~1): 6~8 times of the toluylic acid quality that (3~5), boron trifluoride diethyl etherate consumption are 2, the 4-dialkoxy replaces.Add the DMF consumption under the room temperature and be 0.3~0.8 times of boron trifluoride diethyl etherate quality.MeSO
2The mixed solution of Cl and DMF is by MeSO
2Cl mixes with DMF mass ratio 1:1.Described Friedel-Crafts reaction is 80~95 ℃ of reaction 2-3h.Wherein boron trifluoride diethyl etherate is both as solvent, again as lewis acid catalyst.Recrystallization solvent is selected alcohols, ester class, halohydrocarbon, such as ethyl acetate, isopropyl acetate, ethanol, methyl alcohol, Virahol, propyl carbinol, methylene dichloride, trichloromethane; First-selected alcohols is such as ethanol.
The described Pd/C catalytic hydrogenation of step (3) is take acetic acid as solvent, catalytic hydrogenation 10-12h under 1atm pressure, reflux conditions.Pd/C and 7-hydroxyl-2 ', 4 '-molar ratio range of dialkoxy isoflavones is 0.1~0.4:1.The acetic acid consumption be 7-hydroxyl-2 ', 4 '-40~80 times of dialkoxy isoflavones quality.
The described 7-hydroxyl-2 of step (4) ', 4 '-molar ratio range of dialkoxy isoflavan and 3-methyl-2-alkene butyraldehyde is 1:(1.1~1.5).Annulation is take pyridine or picoline as solvent, reacts 12-14h under the reflux conditions, solvent load be 7-hydroxyl-2 ', 4 '-20~50 times of dialkoxy isoflavan quality; Perhaps make solvent with toluene, under phenylo boric acid and the acetic acid catalysis, back flow reaction 6-8h, the toluene consumption be 7-hydroxyl-2 ', 4 '-30~60 times of dialkoxy isoflavan quality, 7-hydroxyl-2 ', 4 '-dialkoxy isoflavan, phenylo boric acid molar ratio range are 1:1.2~1.6, acetic acid is 1:20~30 with volume of toluene than scope.
Reductive agent described in the step (5) is NaBH
4/ AlCl
3, LiAlH
4, LiAlH
4/ AlCl
3The time, reaction medium is selected from tetrahydrofuran (THF), ether.Compound 5 is 1:5~15 with the reductive agent molar ratio range, and the reaction medium consumption is 20~50 times of compound 5 quality, and temperature of reaction is the reflux temperature of reaction medium, and the TLC monitoring reaction course reacted completely in 3~6 hours.
When the reductive agent described in the step (5) was Zn (Hg), compound 5 was 1:10~15 with the reductive agent molar ratio range, and reaction medium is the 35-37% concentrated hydrochloric acid, back flow reaction 20~30 hours, TLC monitoring reaction course.
Reductive agent described in the step (5) is NH
2NH
2During/NaOH, compound 5 is 1:5~15 with the reductive agent molar ratio range, and reaction medium is glycol ether, and 190~210 ℃ were reacted the TLC monitoring reaction course 6~9 hours.
Compound 6 described in the step (6), deprotecting regent molar ratio range are 1:8~15, the preferred boron tribromide of deprotecting regent, Hydrogen bromide, trimethyl silicane iodine, hydroiodic acid HI.
Concrete synthetic route of the present invention is as follows, and in the statement hereinafter, specific synthetic product is according to the numbering in the structural formula, represents with Arabic numerals.Me represents methyl.
Wherein, R=Me.
The present invention take through the methyl phenyl ketone of phenolic hydroxyl group protection as raw material, six-step process makes glabridin, yield is higher, wherein 7-hydroxyl-2 ', 4 '-preparation of dialkoxy isoflavones adopts one kettle way, and is simple efficient.
Each step operation of the inventive method separates simple, and productive rate is higher, and agents useful for same is common agents, and is cheap and easy to get, and route is shorter, and total recovery is not less than 20%.
Embodiment
Below by embodiment in detail the present invention is described in detail, but the scope of the invention is not limited to following embodiment.
Embodiment 1
(1) synthetic 2,4-dimethoxyphenylacetic acid (compound 2)
With compound 2,4-dimethoxy-acetophenone (0.1mol), sulphur powder (0.2mol), morpholine (0.2mol) place reaction flask stirring heating backflow 7h, be cooled to room temperature, add the dissolving of 200mL methylene dichloride, with 6N salt acid elution (100mL * 2), collect organic phase underpressure distillation desolventizing, get brown oil.Add 20wt% sodium hydroxide solution stirring and refluxing 7h, be cooled to room temperature, transfer pH=1~2 with concentrated hydrochloric acid, filter and collect the gained solid, get compound 2, yield 85%.
(2) synthetic 7-hydroxyl-2 ', 4 '-dimethoxy isoflavones (compound 3)
Compound 2(0.1mol) and Resorcinol (0.1mol) mix, under fresh boron trifluoride diethyl etherate (60mL) katalysis, 85 ℃ of reaction 3h generate coupled product.Behind the cool to room temperature, add dry DMF (50mL), 55 ℃ of lower dimethyl formamide solutions (about 90g) that drip methylsulfonyl chloride (0.4mol) finish rear in 70 ℃ of reaction 6h.The underpressure distillation desolventizing, the residue ethyl alcohol recrystallization obtains compound 3, yield 63%.
(3) synthetic 7-hydroxyl-2 ', 4 '-dimethoxy isoflavan (compound 4)
Compound 3(0.05mol), 10%Pd/C(0.005mol) be mixed in acetic acid (100mL) and pass into hydrogen, be heated to backflow, under 1atm, reduce 10h, filtration, pressure reducing and steaming acetic acid, get the brown crude product, crude product gets whitening compound 4 through the toluene recrystallization, yield 62%.
(4) synthetic compound 5
Compound 4 (0.02mol), 3 - methyl-2 - ene-butyraldehyde (0.024mol) were mixed in anhydrous pyridine (100mL), the reflux 12h, cooled to room temperature and, after 6N hydrochloric acid, extracted with ethyl acetate, without after drying over anhydrous sodium sulfate and the solvent steam, to give a brown oil, which was dissolved in hexane and freeze crystallization 12h, to give a pale yellow solid, i.e. compound 5, yield 74%.
(5) synthetic compound 6
Under 0 ℃, nitrogen protection, add tetrahydrofuran (THF) 200mL to compound 5 (0.01mol); be filled with stirring and dissolving; add lithium aluminium hydride (10eq) in batches; complete rear backflow 3h; be cooled to room temperature; add ethyl acetate cancellation reaction, concentrated solvent separates to get compound 6, yield 76% by column chromatography.
(6) synthetic glabridin
Under nitrogen protection, add methylene dichloride 200mL to compound 6 (0.01mol), be filled with stirring and dissolving, drip the BBr that contains 0.1mol
3Dichloromethane solution 50mL, ice-water bath stirs 2h.After completion of the reaction, the reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent afforded the crude product steam, from toluene / light yellow solid was recrystallized from cyclohexane, i.e. glabridin, yield 87%.
1H?NMR(DMSO,600MHz):δ9.39(s,1H),9.11(s,1H),6.86(d,1H,J=7.8Hz),6.83(d,1H,J=8.4Hz),6.54(d,1H,J=9.6Hz),6.33(s,1H),6.29(d,1H,J=8.4Hz),6.19(d,1H,J=8.4Hz),5.64(d,1H,J=10.2Hz),4.23(d,1H,J=10.2Hz),3.93(t,1H,J=10.2Hz),3.29(t,1H,J=10.2Hz),2.89(dd?appeared?t,1H,J=11.4Hz),2.69(dd,1H,J=16.2and4.2Hz),1.76(s,6H);
13C?NMR(DMSO,125MHz):δ157.31,156.28,151.65,149.67,129.76,129.62,127.99,117.85,116.86,115.17,109.99,108.53,106.70,102.92,75.65,70.17,31.31,30.41,27.77,27.66;ESI-MS:m/z(%)=347(100)[M+Na
+].
Embodiment 2
Compound 2,3,4,6 and glabridin synthetic with embodiment 1, different is the preparation of compound 5.
Compound 5: Compound 4 (0.02mol), 3 - methyl-2 - ene-butyraldehyde (0.024mol) were mixed in dry pyridine (80mL), the reflux 10h, cooled to room temperature, after 6N hydrochloric acid , extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent steam, to give a brown oil, which was dissolved in hexane and freeze crystallization 12h, to give a pale yellow solid, i.e. compound 5, in 77% yield.
Embodiment 3
Compound 2,3,4,6 and glabridin synthetic with embodiment 1, different is the preparation of compound 5.
Preparation of Compound 5: Under a nitrogen atmosphere, the compound 4 (0.01mol), 3 - methyl-2 - ene-butyraldehyde (0.012mol), phenylboronic acid (0.012mol), 50mL acetic acid mixed in 250mL of toluene, refluxed for 7h watershed , steam under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography to afford compound 5, 71% yield.
Embodiment 4
Compound 2,3,4,5 and glabridin synthetic with embodiment 1, different is the preparation of compound 6.
The preparation of compound 6: add sodium borohydride (10eq), aluminum chloride (5eq) in the 100mL tetrahydrofuran (THF), stir under the room temperature, slowly drip compound 5(1eq) tetrahydrofuran solution, complete rear backflow 5h adds dilute hydrochloric acid cancellation reaction.The concentrated tetrahydrofuran (THF) of removing obtains compound 6, yield 61% by dichloromethane extraction, anhydrous sodium sulfate drying, column chromatography separation.
Embodiment 5
Compound 2,3,4,5 and glabridin synthetic with embodiment 1, different is the preparation of compound 6.
The preparation of compound 6: in freshly prepd zinc amalgam, add concentrated hydrochloric acid, with compound 5(1eq) be suspended in the reaction solution, backflow 24h, every 6h adds the 10mL concentrated hydrochloric acid in the reaction process.Reaction finishes to separate by dichloromethane extraction, anhydrous sodium sulfate drying, column chromatography, gets compound 6, yield 76%.
Embodiment 6
Compound 2,3,4,5,6 synthesizes with embodiment 1, and different is the preparation of last glabridin.
Synthetic glabridin
Compound 5 (0.01mol) is joined in 40% Hydrogen bromide, be filled with stirring, reflux 12h.After completion of the reaction, the reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate and steam to remove the solvent, the residue was purified by silica gel column chromatography to obtain a pale yellow solid, which glabridin, yield 77%.
Claims (10)
1. the synthetic method of a glabridin is characterized in that, comprises that step is as follows:
The Willgerodt-Kindler reaction occurs in the methyl phenyl ketone that (1) 2,4-dialkoxy is replaced and sulphur powder, morpholine under the reflux condition, reaction makes the toluylic acid that 2,4-dialkoxy replaces by sodium hydroxide alkaline hydrolysis, adjust pH, filtration;
Friedel-Crafts reaction occurs in the toluylic acid and the Resorcinol that (2) 2,4-dialkoxy are replaced under the effect of boron trifluoride diethyl etherate, product is without separation, adds DMF after being cooled to room temperature, then splashes into MeSO under 50~55 ℃ of conditions
2The mixed solution of Cl and DMF reacts 5-6h under 70~80 ℃ after dripping off again, recrystallization after the solvent evaporated, get compound 7-hydroxyl-2 ', 4 '-the dialkoxy isoflavones;
(3) with 7-hydroxyl-2 ', 4 '-the dialkoxy isoflavones add the Pd/C catalyzer through the Pd/C catalytic hydrogenation make 7-hydroxyl-2 ', 4 '-the dialkoxy isoflavan;
(4) with 7-hydroxyl-2 ', 4 '-dialkoxy isoflavan and 3-methyl-2-alkene butyraldehyde carry out annulation, separating-purifying must be with the isoflavones of dihydropyrane ring;
(5) will add reductive agent with the isoflavones of dihydropyrane ring and the reaction medium reflux is carried out carbonyl reduction, get the alkoxyl group glabridin;
(6) the alkoxyl group glabridin is added the deprotecting regent ice-water bath stirs or heating reflux reaction is sloughed phenolic hydroxyl group and protected to get glabridin.
2. the synthetic method of a kind of glabridin according to claim 1 is characterized in that, in the step (1) 2, the molar ratio range of the methyl phenyl ketone that the 4-dialkoxy replaces and sulphur powder, morpholine, sodium hydroxide is 1:2~2.5:2~2.5:0.8~1.2.
3. the synthetic method of a kind of glabridin according to claim 1 and 2 is characterized in that, and is described 2, and the methyl phenyl ketone that the 4-dialkoxy replaces selects 2,4-dimethoxy-acetophenone.
4. the synthetic method of a kind of glabridin according to claim 1 is characterized in that, in the step (2) 2, and toluylic acid, Resorcinol, MeSO that the 4-dialkoxy replaces
2The molar ratio range of Cl is 1:0.9~1:3~5, and the boron trifluoride diethyl etherate consumption is 6~8 times of 2,4-dialkoxy substituted phenylacetic acid quality, adds the DMF consumption under the room temperature and be 0.3~0.8 times of boron trifluoride diethyl etherate quality, MeSO
2The mixed solution of Cl and DMF is by MeSO
2Cl mixes with DMF mass ratio 1:1.
5. the synthetic method of a kind of glabridin according to claim 1 is characterized in that, the described Friedel-Crafts reaction of step (2) is 80~95 ℃ of reaction 2-3h.
6. the synthetic method of a kind of glabridin according to claim 1 is characterized in that, the described Pd/C catalytic hydrogenation of step (3) is take acetic acid as solvent, catalytic hydrogenation 10-12h under 1atm pressure, reflux conditions; Pd/C and 7-hydroxyl-2 ', 4 '-molar ratio range of dialkoxy isoflavones is 0.1~0.4:1, the acetic acid consumption be 7-hydroxyl-2 ', 4 '-40~80 times of dialkoxy isoflavones quality.
7. the synthetic method of a kind of glabridin according to claim 1 is characterized in that, the described 7-hydroxyl-2 of step (4) ', 4 '-molar ratio range of dialkoxy isoflavan and 3-methyl-2-alkene butyraldehyde is 1:1.1~1.5.
8. the synthetic method of a kind of glabridin according to claim 1, it is characterized in that the described annulation of step (4) is take pyridine or picoline as solvent, reacts 12-14h under the reflux conditions, solvent load be 7-hydroxyl-2 ', 4 '-20~50 times of dialkoxy isoflavan quality; Perhaps make solvent with toluene, under phenylo boric acid and the acetic acid catalysis, back flow reaction 6-8h, the toluene consumption be 7-hydroxyl-2 ', 4 '-30~60 times of dialkoxy isoflavan quality, 7-hydroxyl-2 ', 4 '-dialkoxy isoflavan, phenylo boric acid molar ratio range are 1:1.2~1.6, acetic acid is 1:20~30 with volume of toluene than scope.
9. the synthetic method of a kind of glabridin according to claim 1 is characterized in that, the reductive agent described in the step (5) is selected from NaBH
4/ AlCl
3, LiAlH
4, LiAlH
4/ AlCl
3, Zn (Hg), NH
2NH
2/ NaOH.
10. the synthetic method of a kind of glabridin according to claim 1 is characterized in that, deprotecting regent selects boron tribromide, Hydrogen bromide, trimethyl silicane iodine or hydroiodic acid HI in the step (6).
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