CN103664536A - Synthetic method of hydroxytyrosol - Google Patents
Synthetic method of hydroxytyrosol Download PDFInfo
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- CN103664536A CN103664536A CN201210342015.7A CN201210342015A CN103664536A CN 103664536 A CN103664536 A CN 103664536A CN 201210342015 A CN201210342015 A CN 201210342015A CN 103664536 A CN103664536 A CN 103664536A
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- methylene
- dioxy
- hydroxytyrosol
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- methylenedioxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medicament synthesis, and in particular relates to a chemical synthetic method of hydroxytyrosol. The chemical synthetic method comprises the steps of (1) protecting two phenolic hydroxyl groups of catechol by using dichloromethane, and enabling catechol to react with dichloromethane to prepare 1,2-methylenedioxybenzene; (2) enabling 1,2-methylenedioxybenzene to react with various monoesters of oxalyl chloride to prepare 3,4-methylenedioxy phenylglyoxylic acid ester; (3) preparing 3,4-methylenedioxy phenylacetic acid by using 3,4-methylenedioxy phenylglyoxylic acid ester through a Wollff-kishner-Huang Minglong reduction reaction; and (4) reducing the 3,4-methylenedioxy phenylacetic acid by using lithium aluminum hydride, lithium borohydride or sodium borohydride to prepare 3,4-methylenedioxy phenethyl alcohol, and then removing methylene protection of the 3,4-methylenedioxy phenethyl alcohol by using boron tribromide or palladium on activated carbon to prepare hydroxytyrosol. A reactive reagent used in the synthetic method disclosed by the invention is easy to obtain and low in price, the reaction condition is mild, and the final yield of the whole reaction is 23%.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of chemical synthesis process of Hydroxytyrosol.
Background technology
Hydroxytyrosol (hydroxytyrosol) has another name called 3,4 dihydroxyphenyl ethanols, and it is mainly with the form of carboxylate Oleuropein, to be present in each position of olive, and Oleuropein can obtain free Hydroxytyrosol after hydrolysis.Be a kind of natural polyphenolic compound, there is very strong oxidation-resistance.In recent years, studies confirm that in a large number both at home and abroad that Hydroxytyrosol has is much of value to active (1) Hydroxytyrosol of the bio-pharmacology of HUMAN HEALTH and is reducing blood pressure, and there is positive promoter action preventing cardiovascular disease aspect; (2) Hydroxytyrosol is helpful to bone growth and development and function; (3) Hydroxytyrosol also has application aspect anti-cancer and cancer-preventing; (4) Hydroxytyrosol has bacteriostatic action; (5) Hydroxytyrosol can effectively reduce and suppress the harm of smoking to human body.Due to its remarkable physiologically active, be deeply subject in recent years the attention of biological and medical circle.
Hydroxytyrosol is mainly obtained by following mode at present: the waste water that (1) produces from squeezing sweet oil, extract Hydroxytyrosol.The advantage of this method is that the waste water that production sweet oil is produced carries out utilization of waste material, reduces the pollution to environment.But this method need consume a large amount of solvents, and Hydroxytyrosol yield is lower, is not too applicable to suitability for industrialized production; (2) utilize biological fermentation process to obtain Hydroxytyrosol.The method relates to genetic engineering bacterium, and technical requirements is higher, and the production cycle is long, and technology is also immature at present; (3) utilize the method for chemosynthesis to prepare Hydroxytyrosol.The artificial synthesis of the Hydroxytyrosol of bibliographical information is mainly to prepare by reduction DOPAC or oxidation tyrosol in recent years.But above route raw material less stable, cost is higher.Pyrocatechol also be take as raw material in DSM company, has applied for preparing the process patent of Hydroxytyrosol, but in route, uses the expensive chemical reagent such as palladium carbon, therefore need to study a kind of method of more cost effective synthesis of hydroxy tyrosol.
Summary of the invention
The object of the invention is to provide a kind of synthetic method of Hydroxytyrosol more economically, when assurance and the overall productive rate of other method of having announced are constant, greatly reduces the cost of synthesis of hydroxy tyrosol.
For achieving the above object, the technical solution used in the present invention is: a kind of synthetic method of Hydroxytyrosol, comprises the following steps:
(1) with methylene dichloride, protect two phenolic hydroxyl groups of pyrocatechol: pyrocatechol reacts preparation 1,2-methylenedioxybenzenes with methylene dichloride;
(2) take the raw material that the various monoesters of the oxalyl chloride shown in general structure a are Friedel-Crafts reaction, with 1,2-methylenedioxybenzenes reaction preparation, 3,4-methylene-dioxy benzoylformic acid ester, the R in a is C
1-C
6alkyl or C
6h
5cH
2.
(3) 3,4-methylene-dioxy benzoylformic acid esters are by Wolff-Kishner-Huang Min-lon reduction reaction preparation 3,4-methylene-dioxy toluylic acid;
(4) use lithium aluminium hydride or lithium borohydride or sodium borohydride reduction 3,4-methylene-dioxy toluylic acid is prepared 3,4-methylene-dioxy phenylethyl alcohol, then with the methylene radical protection that boron tribromide or palladium carbon are taken off 3,4-methylene-dioxy phenylethyl alcohol, prepares Hydroxytyrosol.
The preparation method of concrete a kind of Hydroxytyrosol comprises the following steps:
(1) Tetrabutyl amonium bromide (TBAB) is dissolved in to dimethyl sulfoxide (DMSO), be heated to 110 ℃ of backflows, drip wherein the dimethyl sulphoxide solution of pyrocatechol simultaneously, and 50% inorganic alkali solution, after sustained reaction finishes, add water, continue to add thermal distillation, collect 99~104 ℃ of cuts, by distillate process 1,2-methylenedioxybenzenes;
Wherein, described mineral alkali is sodium hydroxide or potassium hydroxide, and the mol ratio of phase-transfer catalyst TBAB and pyrocatechol is 0.05~0.1: 1;
(2) aluminum chloride is added in anhydrous methylene chloride, be stirred to suspension.Under condition of ice bath, drip wherein oxalyl chloride monoesters, after fully stirring, then drip piperonyl cyclonene in system, after room temperature condition reaction finishes, add the shrend reaction of going out, separating-purifying, obtains 3,4-methylene-dioxy benzoylformic acid ester;
Wherein, described 1, the mol ratio of 2-methylenedioxybenzenes, aluminum trichloride (anhydrous) and oxalyl chloride monoesters is 1: 1.15: 1.05~1.15;
(3) 3,4-methylene-dioxy benzoylformic acid ester and hydrazine hydrate are dissolved in to ethylene glycol, slowly heat up, reflux, after reaction finishes, adds ground potassium hydroxide after being cooled to room temperature, heating, intensification limit, limit steams low-boiling-point substance, after finishing, back flow reaction is several hours again, is cooled to room temperature, drips dilute hydrochloric acid solution and adjusts pH to 2~3, preliminary aftertreatment, with ethyl acetate-sherwood oil system recrystallization, obtain 3,4-methylene-dioxy toluylic acid;
(4) according to prior art; use lithium aluminium hydride or lithium borohydride or sodium borohydride reduction 3,4-methylene-dioxy toluylic acid is prepared 3,4-methylene-dioxy phenylethyl alcohol; then with the methylene radical protection that boron tribromide or palladium carbon are taken off 3,4-methylene-dioxy phenylethyl alcohol, prepare Hydroxytyrosol.
The present invention compared with prior art tool has the following advantages and effect:
The reaction reagent that the present invention uses is easy to get, cheapness, and reaction conditions is gentle, and the ultimate yield of whole reaction is 23%, and reaction cost reduces greatly, has good industrial applications prospect.
Accompanying drawing explanation
Fig. 1 is the synthetic route schematic diagram of preparing Hydroxytyrosol in embodiment mono-;
Fig. 2 is in embodiment mono-1, the proton nmr spectra analysis chart of 2-methylenedioxybenzenes;
Fig. 3 is in embodiment mono-3, the proton nmr spectra analysis chart of 4-methylene-dioxy benzoylformic acid ethyl ester;
Fig. 4 is in embodiment mono-3, the proton nmr spectra analysis chart of 4-methylene-dioxy toluylic acid;
Fig. 5 is in embodiment mono-3, the proton nmr spectra analysis chart of 4-methylene-dioxy phenylethyl alcohol;
Fig. 6 is the proton nmr spectra analysis chart of Hydroxytyrosol in embodiment mono-.
Embodiment
Below in conjunction with drawings and Examples, the present invention is described further:
Embodiment mono-: according to the synthesis of hydroxy of synthetic route shown in Fig. 1 tyrosol
1, preparation 1,2-methylenedioxybenzenes (3)
In 250ml there-necked flask, add DMSO (80ml), methylene dichloride (20ml), TBAB (1.9g, 6mmol), be slowly warming up to 110 ℃, slightly see while refluxing, in reactor, slowly drip and be dissolved with pyrocatechol (11g, DMSO 0.1mol) (60mL) solution drips 50% aqueous sodium hydroxide solution (sodium hydroxide 8g, 0.2mol simultaneously, water 8mL), about 2h dropwises, the more about 1h of sustained reaction, and TLC monitoring reaction finishes.
In reaction flask, add 100mL water, continue heating, collect the cut of 99-104 ℃.This cut is the azeotrope of water and 1,2-methylenedioxybenzenes, and the muddy shape that is white in color, after overhead product clarification, has not contained 1,2-methylenedioxybenzenes.Distillate is processed to obtain to water white transparency shape liquid (9.97g, 81.7%).
Carry out nmr analysis, obtain Fig. 2, result is as follows:
1H-NMR(CDCl
3):δ/ppm?5.97(2H,s,
CH 2 ),6.87(4H,s,Ar
H).
Above result shows, products therefrom is 1,2-methylenedioxybenzenes.
2, preparation 3,4-methylene-dioxy benzoylformic acid ethyl ester (4)
In 250ml there-necked flask, add anhydrous methylene chloride (60mL), aluminum chloride (5.85g, 0.043mol), is stirred to suspension.Slowly drip ethyl oxalyl chloride (5.88g, 0.043mol), in about 30min, dropwise, stirring at room 10min, it is faint yellow that solution is.Under ice bath, dropwise add 3 (5g, 0.041mol), about 10min dropwises, and removes ice bath, room temperature reaction 1h, and TLC monitoring reaction finishes.
Under ice bath, slowly add the water of 3 times of equivalents, be extracted with ethyl acetate three times, merge organic phase, organic phase is successively through 5% sodium bicarbonate aqueous solution (30ml * 2) and water (40ml * 2) washing, after anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and the product obtaining uses column chromatography, [V (sherwood oil): V (ethyl acetate)=40: 1] obtains faint yellow oily matter (6.5g, 72.3%).
Carry out nmr analysis, obtain Fig. 3, result is as follows:
1H-NMR(CDCl
3):δ/ppm?1.41-1.45(3H,t,CH
2 CH 3 ),4.42-4.47(2H,m,
CH 2 CH
3),6.10(2H,s,
CH 2 ),6.90-6.92(1H,d,Ar
H),7.49-7.50(1H,d,Ar
H),7.62-7.64(1H,dd,Ar
H).
Above result shows, products therefrom is 3,4-methylene-dioxy benzoylformic acid ethyl ester.
3, preparation 3,4-methylene-dioxy toluylic acid (5)
In 250ml three-necked bottle, add 4 (6.7g, 0.03mol), ethylene glycol (60ml) and 85% hydrazine hydrate (8.85g, 0.15mol), be slowly warming up to 120 ℃ of reaction 2h.After being cooled to room temperature, add potassium hydroxide (5g, 0.09mol), be heated to 180 ℃, intensification limit, limit steams low-boiling-point substance (about 2h), then back flow reaction 4h.After reaction finishes, be cooled to room temperature, add 6mol/L hydrochloric acid and be adjusted to pH 2~3.Add water (60ml), be extracted with ethyl acetate (50ml * 4), merge organic phase.Wash with water after (50ml * 2), suction filtration after anhydrous sodium sulfate drying, filtrate decompression is concentrated into dry, and ethyl acetate-sherwood oil for residuum (1: 1) recrystallization obtains white solid (3.39g, 62.8%).
Carry out nmr analysis, obtain Fig. 4, result is as follows:
1H-NMR(CDCl3):δ/ppm?3.59(2H,s,
CH 2 COOH),5.97(2H,s,
CH 2 ),6.73-6.75(1H,dd,Ar
H),6.78(1H,s,Ar
H),6.80-6.81(1H,d,Ar
H).
Above result shows, products therefrom is 3,4-methylene-dioxy toluylic acid.
4, preparation 3,4-methylene-dioxy phenylethyl alcohol (6)
In 100ml there-necked flask, add 5 (3g, 0.017mol), anhydrous tetrahydro furan (30mL), is placed under condition of ice bath and mixes.Carefully add lithium aluminum hydride aluminium (1.7g, 0.05mol), back flow reaction 4h, TLC monitoring reaction finishes.
Under condition of ice bath, slowly add the NaOH solution (1mol/L) of 3 times of equivalents, the water of 3 times of equivalents.Filter, use washed with dichloromethane filter cake, concentrated, mix silicagel column on sample, sherwood oil: ethyl acetate=3: 1 obtains the slightly transparent oily matter (2.28g, 81%) of displaing yellow.
1H-NMR(CDCl
3):δ/ppm?1.55(1H,s,CH
2CH
2 OH),2.79-2.82(2H,t,
CH 2 CH
2OH),3.82-3.85(2H,t,CH
2 CH 2 OH),5.95(2H,s,
CH 2 ),6.69-6.71(1H,dd,ArH),6.74-6.75(1H,d,Ar
H),6.77-6.79(1H,d,Ar
H).
Above result shows, products therefrom is 3,4-methylene-dioxy phenylethyl alcohol.
5, prepare Hydroxytyrosol (1)
In 50ml reaction flask, add 6 (0.2g, 1.20mmol), anhydrous methylene chloride (25ml), is cooled to-40 ℃, drips dichloromethane solution (containing the boron tribromide 1.78mol/L) 4.3ml of boron tribromide with syringe.Dropwise, under room temperature, react 2h, TLC detection reaction finishes.Under ice bath, drip 10ml methyl alcohol cancellation reaction, concentrated, debris column chromatography for separation, obtains Hydroxytyrosol 1, is white powder (0.141g, 76%).
1H-NMR(CDCl
3):δ/ppm?3.03-3.07(2H,t,
CH 2 CH
2OH),3.49-3.53(2H,t,CH
2 CH 2 OH),5.04(1H,s,Ar
OH),5.14(1H,s,Ar
OH),6.64-6.66(1H,dd,Ar
H),6.73-6.74(1H,d,Ar
H),6.80-6.82(1H,d,Ar
H).
Above result shows, products therefrom is Hydroxytyrosol.
Claims (2)
1. a synthetic method for Hydroxytyrosol, is characterized in that, comprises the following steps:
(1) with methylene dichloride, protect two phenolic hydroxyl groups of pyrocatechol: pyrocatechol reacts preparation 1,2-methylenedioxybenzenes with methylene dichloride;
(2) take the raw material that the various monoesters of the oxalyl chloride shown in general structure a are Friedel-Crafts reaction, with 1,2-methylenedioxybenzenes reaction preparation, 3,4-methylene-dioxy benzoylformic acid ester, the R in a is C
1-C
6alkyl or C
6h
5cH
2.
(3) 3,4-methylene-dioxy benzoylformic acid esters are by Wolff-Kishner-Huang Min-lon reduction reaction preparation 3,4-methylene-dioxy toluylic acid;
(4) use lithium aluminium hydride or lithium borohydride or sodium borohydride reduction 3,4-methylene-dioxy toluylic acid is prepared 3,4-methylene-dioxy phenylethyl alcohol, then with the methylene radical protection that boron tribromide or palladium carbon are taken off 3,4-methylene-dioxy phenylethyl alcohol, prepares Hydroxytyrosol.
2. synthetic method according to claim 1, is characterized in that, comprises the following steps:
(1) Tetrabutyl amonium bromide (TBAB) is dissolved in to dimethyl sulfoxide (DMSO), be heated to 110 ℃ of backflows, drip wherein the dimethyl sulphoxide solution of pyrocatechol simultaneously, and 50% inorganic alkali solution, after sustained reaction finishes, add water, continue to add thermal distillation, collect 99~104 ℃ of cuts, by distillate process 1,2-methylenedioxybenzenes;
Wherein, described mineral alkali is sodium hydroxide or potassium hydroxide, and the mol ratio of phase-transfer catalyst TBAB and pyrocatechol is 0.05~0.1: 1;
(2) aluminum chloride is added in anhydrous methylene chloride, be stirred to suspension.Under condition of ice bath, drip wherein oxalyl chloride monoesters, after fully stirring, then drip piperonyl cyclonene in system, after room temperature condition reaction finishes, add the shrend reaction of going out, separating-purifying, obtains 3,4-methylene-dioxy benzoylformic acid ester;
Wherein, described 1, the mol ratio of 2-methylenedioxybenzenes, aluminum trichloride (anhydrous) and oxalyl chloride monoesters is 1: 1.15: 1.05~1.15;
(3) 3,4-methylene-dioxy benzoylformic acid ester and hydrazine hydrate are dissolved in to ethylene glycol, slowly heat up, reflux, after reaction finishes, adds ground potassium hydroxide after being cooled to room temperature, heating, intensification limit, limit steams low-boiling-point substance, after finishing, back flow reaction is several hours again, is cooled to room temperature, drips dilute hydrochloric acid solution and adjusts pH to 2~3, preliminary aftertreatment, with ethyl acetate-sherwood oil system recrystallization, obtain 3,4-methylene-dioxy toluylic acid;
(4) according to prior art; use lithium aluminium hydride or lithium borohydride or sodium borohydride reduction 3,4-methylene-dioxy toluylic acid is prepared 3,4-methylene-dioxy phenylethyl alcohol; then with the methylene radical protection that boron tribromide or palladium carbon are taken off 3,4-methylene-dioxy phenylethyl alcohol, prepare Hydroxytyrosol.
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Cited By (10)
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CN104387240A (en) * | 2014-11-19 | 2015-03-04 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of 2-(3,4-dihydroxyphenyl) ethanol |
CN105837424A (en) * | 2016-03-31 | 2016-08-10 | 常州大学 | Synthetic method for 1-chloro-3-methyl-3-buten-2-one |
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CN108164398A (en) * | 2018-01-26 | 2018-06-15 | 山东省药学科学院 | A kind of improved method of hydroxytyrosol synthesis technology |
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CN105837424A (en) * | 2016-03-31 | 2016-08-10 | 常州大学 | Synthetic method for 1-chloro-3-methyl-3-buten-2-one |
CN106397387A (en) * | 2016-09-20 | 2017-02-15 | 苏州弘森药业股份有限公司 | Method for preparing pepper ring |
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