CN104861029A - Preparation method of ammonium 18alpha,beta-H-glycyrrhetate and hydrate thereof - Google Patents
Preparation method of ammonium 18alpha,beta-H-glycyrrhetate and hydrate thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of ammonium 18alpha,beta-H-glycyrrhetate and a hydrate thereof. The method selecting 75% crude glycyrrhizic acid as a raw material comprises the following steps: purifying the crude glycyrrhizic acid to obtain purified glycyrrhizic acid with the content of above 98%, converting 18alpha,beta-H-glycyrrhizic acid into 18alpha-H-glycyrrhizic acid, and controlling different pH values of the 18alpha-H-glycyrrhizic acid to generate the following different salts: diammonium 18alpha-H-glycyrrhetate, triammonium 18alpha-H-glycyrrhetate and hydrate thereof, and converting 18beta-H-glycyrrhizic acid to generate monoammonium 18beta-H-glycyrrhetate and hydrate thereof. The method has the advantages of simple operation, mild reaction condition, easy control of the quality, high conversion rate, and suitableness for large scale preparation.
Description
Technical field
The present invention relates to the preparation method of a kind of 18 α, β-H-ammonium glycyrrhizunate and hydrate thereof.
Background technology
Potenlini is also known as Radix Glycyrrhizae triterpenoid saponin, glycyrrhizin, derive from the root welding technology of glycyrrhizic legume (Glycyrrhiza uralensis Fisch.), be topmost activeconstituents in Radix Glycyrrhizae, be the sweet ingredient of Radix Glycyrrhizae, content reaches 3.63-13.06%.The glycosides that it is made up of glycyrrhetinic acid and 2 molecule glucose aldehydic acid.Being Triterpenoids sapogenins compound, is be transformed by dammarane's positive ion, and the D ring of dammarane's positive ion, through ring expansion, forms the C-18 carbonium ion that A-B-C-D ring is six-ring.The aqueous solution is slightly acidic, the pH2.5-3.5 of 2% solution, is insoluble in water, Diluted Alcohol, is soluble in hot water, in thick jelly after cooling.Compound glycyrrbizic acid (SNMC, trade(brand)name: U.S. energy) is that Japan developed in 1948, and take Potenlini as the preparation of main component, within 1958, for chronic hepatitis, the curative effect of SNMC obtains the support of liver pathology, and has the curative effect reaching 22 years.Be mainly used in food, also have application in other industries such as medicine, makeup and cigarette in addition.Potenlini structural formula is as follows:
Carboxyl acidity on pentacyclic triterpene is the most weak, and the glucuronic acid carboxyl acidity be directly connected with pentacyclic triterpene is the strongest, and another glucuronic acid carboxyl acidity is taken second place.Glucuronic acid carboxyl has met a S, S atom has met again an O and S in addition, O-S and S-S all has electrophilic feature, the electronics of carboxyl by these two atoms attract to cause H legibility from, so acidity is strong compared with the carboxyl on pentacyclic triterpene, acid as two glucuronic acid carboxyls, due to the glucuronic acid carboxyl sky resistance of end.Carry out salify structural modification to Potenlini, can obtain multiple glycyrrhetate, Potenlini has three carboxyls, if become ammonium salt in fact may there are single ammonium, two ammoniums and three ammoniums.Have and better face to come using value.
Ammonium glycyrrhizunate structural formula is as follows:
Wherein R1 and R3 is-H, R2 is-NH
4 +time be monoammonium glycyrrhizinate; R1 is-H, R2 and R3 is-NH
4 +time be diammonium glycyrrhizinate; R1, R2 and R3 are-NH
4 +time be Potenlini three ammonium.
Monoammonium glycyrrhizinate (monoammonium glycyrrhizinate) molecular formula: C
42h
65nO
16, be called for short MAG, molecular weight: 839.9626, CAS No.53956-04-0, white or pale yellow crystals type powder, special sweet taste.Be dissolved in Diluted Alcohol, monoammonium glycyrrhizinate, to the capable stronger avidity of hepatic cholesterol metabolic enzyme, has the effect of obvious cortin sample, as anti-inflammatory, antianaphylaxis and protective membrane structure etc.; Reduce ALT, AST release, induce γ-LFN and interleukin-II, improve NK cytoactive and OKT4/OKT8 ratio and activate reticuloendothelial system; Suppress the release of histamine; The formation of T suppression cell membrane phospholipid enzyme A2 (PL-A2) and prostaglandin E2 (PGE2) and granulomatous reaction; Suppress generation and the formation of free radical and lipid peroxidation, reduce the activity of dried meat ammonia hydroxylase; Regulate calcium channel, protection lysosome membrane and plastosome, alleviate damage and the necrosis of cell; Promote that epithelial cell produces mucopolysaccharide; To by arsenical, cling to the toxic hepatitis that appropriate class medicine, tetracol phenixin etc. cause, there is reduction gpt, recover hepatocyte function, prevent the effects such as Steatosis; Promote bile pigment metabolism and removing jaundice and detoxification, reduce collagen fiber hyperplasia, prevent liver cirrhosis etc.Monoammonium glycyrrhizinate S is different with monoammonium glycyrrhizinate A purity, and monoammonium glycyrrhizinate S purity height is injection, and A is crude product.Monoammonium glycyrrhizinate sugariness is 200 ~ 300 times of sucrose, there is strong Radix Glycyrrhizae peat-reek, there is low calorie, safety non-toxic and stronger medicinal health care function, the most desirable sweeting agent of hypertension, obesity, diabetes, cardiac's use, of many uses in medicine, foodstuff additive and makeup etc.The preparation of monoammonium glycyrrhizinate has the leaching of traditional acetone method, Ethanol Method, ammonia, hot dipping, cold soaking, ion-exchange-resin process and ultrafiltration process and with alcohol extraction preparing high-purity monoammonium glycyrrhizinate.Different process extracts impact comparatively greatly to monoammonium glycyrrhizinate, and methyl alcohol toxicity is comparatively large, and refine as solvent, products obtained therefrom purity lower (90%), yield is lower (65 ~ 75%) also, purification difficult.Acidic ethanol makes solvent easily coking aborning, variable color, raw material caking, yield is low, and acidic ethanol liquid is prepared with concentrated hydrochloric acid and 95% ethanol, is greater than or less than 3.5 ~ 4.0 by concentrated nitric acid or pH value, all be unfavorable for aftertreatment, Extracting temperature is too high can increase the impurity such as colloid and pigment.Be not suitable for industrialization.In the leaching process of monoammonium glycyrrhizinate, excess moisture, can remain a large amount of pigment, saccharic in mother liquor, not only affect quality product, also can make difficult solvent recovery.Introducing moisture can be overcome by the precipitation that liquefied ammonia replaces strong aqua to carry out alkalizing, but improve product yield.Acidic ethanol is Extraction solvent, just Glacial acetic acid process before recrystallization, and can obtain white crystals, purity 98% through once heavily tying product, yield can reach more than 61%.Ammonia alcohol method gained Potenlini powder exists with part ammonium salt, should not refine with solvent method.The product that hot dipping is carried contains more impurity, is difficult to remove in a solvent, and the impurity in products of cold-maceration is low, but yield is also low.First alcohol and water can affect sedimentary crystallization, should avoid being mixed into of methyl alcohol especially when extraction and crystallization.Triammonium glycyrrhizinate can not be dry or be long placed in, and should take advantage of wetly to use Glacial acetic acid process as early as possible, makes it be converted into mono-ammonium.The impurity such as pigment and colloid can be removed simultaneously.The effect of this step process directly affects crystallization and product color purity
[1-11].
Diammonium glycyrrhizinate (Diammonium Glycyrrhizinate) molecular formula: C
42h
68n
2o
16, white crystals sprills, odorless, taste is sweet, easily molten in water, and soluble,very slightly is in ethanol almost insoluble in chloroform or ether, standard No.: WS-019 (X-015)-94, has stronger anti-inflammatory, protects liver plasma membrane and improves the effect of liver function.The Serum ALT stoping semi-lactosi ammonium, tetracol phenixin etc. to cause increases, and improves hepatic tissue and damages, become a kind of Novel medicine protecting the liver, protect liver.Natural Potenlini exists with 18 α-H bodies and 18 β-H bodies, two kinds of configurations, and 18 α-H body burdens are very low, and 18 α-H-diammonium glycyrrhizinates are the di-ammonium salts made by 18 α-H-Potenlinis.Potenlini preparation in the market mainly contains 18 α-H body two ammoniums and 18 β-H body monoammonium glycyrrhizinates composition.18 α-H body two ammonium chemical names: the sweet aldehydic acid di-ammonium salts of the positive volatile oil of 20 β-H-carboxyl-11-oxygen-12-alkene-3 β base-2 '-O-β-D-Glucopyranose sweet aldehydic acid base-α-D-Glucopyranose.18 β-H bodies are mainly mono-ammonium.α body is stronger than β body anti-inflammatory action, and liver targeting is high, and untoward reaction is little, high safety, is more suitable for the treatment of clinical hepatopathy.Radix Glycyrrhizae acids bulk drug or preparation is not recorded in American Pharmacopeia USP35-NF30 version, Japanese Pharmacopoeia 16 editions and Chinese Pharmacopoeia 2010 editions.Only the mixture of monoammonium glycyrrhizinate is measured in national drug mark (WS1-XG-2002), and not mentioned related substances.In EP7.0 with BP2012, monoammonium glycyrrhizinate quality standard is identical, has only recorded monoammonium glycyrrhizinate salt bulk drug, specifies the mixture that monoammonium glycyrrhizinate is epimer.Determine that its principal constituent is 18 β-Gly, and composition higher for other 2 kinds of content is defined as related substances, be attributed to related substance A and 18 α-Gly respectively.18 α-Gly and 18 β-Gly are a pair epimers.
The diammonium glycyrrhizinate synthetic route of current bibliographical information and method mainly contain 3 kinds, (1) according to 18 α-H-Potenlinis easily and the formation of methanol methyl esters and separating out, from the mixed solution of 18 β-H-Potenlinis and 18 α-H-Potenlinis, 18 α-H-Potenlinis are isolated.This method can obtain high purity product, but has a large amount of propyl carbinol and remain in water layer, and cost is higher.(2) taking the method for n-butanol extraction equally, is 18 β-H-Potenlinis and 18 α-H-Potenlini mixtures, needs repeatedly recrystallization just can obtain qualified product.(3) the solubility property difference in organic phase and water according to 18 β-H-glycyrrhetates and 18 α-H-glycyrrhetates, take inhomogeneous reaction to isolate 18 α-H-glycyrrhetates, technique is simple, but owing to adopting organic reagent, be separated not thorough, bottom product in mother liquor, affects yield
[12-16].
Potenlini three ammonium (Three glycyrrhizic acid ammoniu) molecular formula: C
42h
71n
3o
16, white or pale yellow crystals type powder, odorless, taste is sweet, easily molten in water, and soluble,very slightly is in ethanol almost insoluble in chloroform or ether.There is certain anti-inflammatory, protect liver plasma membrane and improve the effect of liver function; pharmacological evaluation proves; obviously can alleviate amino half lactic acid of D-to the damage of liver with improve the chronic injury of immune factor to liver; distribute the highest with lung, liver, kidney in vivo; other tissue distribution are very low; discharge from ight soil mainly through bile, part is discharged from respiratory tract with form of carbon dioxide, and it is a small amount of for discharging in urine.China is among the people is customarily used in sauce and jam product, pickled prod etc.There is hair care and educate the unusual effect sent out, can be used as the additive of hair nutrition goods and skin care, use in skincare product have sun-proof, brighten, function that is antipruritic, more scar
[17-19].
Reference:
[1] Deng Baowei. from glycyrrhizic acid inclusion compound extracting Radix Glycyrrhizae acid Unit ammonium salt [J]. Chinese Journal of Pharmaceuticals, 1990,21 (4): 157
[2] Wang Jinqiu, Zhou Weichun, Song Jinbiao etc. process for refining research [J] of monoammonium glycyrrhizinate. forest chemical engineering communication, 2001,35 (1): 8-13
[3] Tong Liansheng, Tian Yun. produce monoammonium glycyrrhizinate [J] .HEILONGJIANG M EDICINE ANDPHARM ACY Aug.2004 from glycyrrhizic acid inclusion compound, 27 (4): 51
[4] history peak, Xu Jing, Zhou Baohua etc.The preparation of monoammonium glycyrrhizinate and purifying newly descend skill research [J]. foodstuffs industry science and technology, 2011,32 (4): 324-326
[5] Ma Zhen, Wang Zunyuan, Shen Zhengrong etc. the preparation [J] of Reference Control for Assay of Monoammonium Glycyrrhizinate. Chinese Journal of Pharmaceuticals, 2001,32 (4): 172-174
[6] Yang Jie, Chu Yanping, Zhang Shujing etc. monoammonium glycyrrhizinate is on the impact [J] of toad isolated heart function. Qiqihar Medical College's journal, 2012,33 (9): 1121-1122
[7] Wang Yanan, Zheng Bingqing, Qu Xinyan etc. the experimental study [J] of monoammonium glycyrrhizinate salt pair microwave radiation rat blood injury protection effect. world's combination of Chinese tradiational and Western medicine magazine, 2013,8 (5): 445-447
[8] Wu Anxin, Yang Weidong, Chen Shiwu. the technical study [J] of monoammonium glycyrrhizinate. Chinese Journal of Pharmaceuticals, 1997,28 (11): 486-488
[8] Zhao Yanyan, Liu Liyan, Han Yuanyuan etc. monoammonium glycyrrhizinate salt bulk drug principal constituent isomer and with related substance simultaneously separation detection and structural identification [J]. Acta Pharmaceutica Sinica, 2013,48 (8): 1286-1291
[9] Shi Hongchang, Zhang Jingde. the preparation [J] of pure monoammonium glycyrrhizinate. Chinese Journal of Pharmaceuticals, 1998,29 (11): 487-488
[10] Chen Zhenhong. preparation method [P] .CN200810072825.9 of the sour Unit ammonium salt of sweet grass
[11] Bai Fengyun, Zhang Yong, Wang Xiaodong etc. a kind of preparation method [P] .CN201310121182.3 of monoammonium glycyrrhizinate
[12] preparation [J] of the firm .18 α of Li Liwei, Dai Xuyong, Cheng Zhi-H-diammonium glycyrrhizinate. Chinese Journal of Modern Applied Pharmacy magazine, 2008,25 (4): 309-312
[13] Li Hao, Zhang Jianfeng, Zhang Wei etc. diammonium glycyrrhizinate causes the impact [J] of acute lung injury of rats TLR-4 expression to paraquat poisoning. snake will, 2014,26 (1): 1-3
[14] Li Hong. the routine clinical observation on the therapeutic effect of diammonium glycyrrhizinate Treatment chronic Hepatitis B 92 [J]. contemporary Chinese medicinal application, 2013,7 (5): 74-75
[15] Li Zhu, Li Jianhe, Yi Lidan etc. the preparation of injection diammonium glycyrrhizinate, quality control and study on the stability [J]. contemporary Chinese medical journal, 2011,21 (26): 3258-3263
[16] Zhou Jingliang, Zhang Xiaoliang. preparation method [P] .200410074039.4 of diammonium glycyrhetate
[17] He Xiujuan, the kinetics that the .N K A macroporous adsorbent resins such as flood grows into forest, Qi Yu adsorb Triammonium glycyrrhizinate and thermodynamic study [J]. Shihezi Univ's journal (natural science edition), 2013,31 (3): 393-396
[18] Wang Meilan. extraction preparation [J] of Triammonium glycyrrhizinate. Strait Pharmaceutical Journal, 1996,8 (3): 66
[19] Yang Jun, paddy is ascended glad, opens and waits quietly. technology of large-scale refining production of glycyrrhetate [P] .200910044332.9
Traditional technology adopts Potenlini and ammoniacal liquor or liquefied ammonia to generate Potenlini three ammonium, displaces acid two more weak carboxyls in Potenlini, obtain monoammonium glycyrrhizinate, then by monoammonium glycyrrhizinate ammonification, obtain diammonium glycyrrhizinate by Glacial acetic acid acidifying.The present invention selects 75% glycyrrhizic acid inclusion compound to be raw material, by crude product Potenlini is refined, obtain the Potenlini fine work of content more than 98%, 18 β-H-Potenlinis are converted into 18 α-H-Potenlinis, 18 α-H-Potenlinis are by controlling different pH value, generate different salt-18 α-H-diammonium glycyrrhizinates, 18 α-H-Potenlini three ammonium and hydrates thereof, 18 β-H-Potenlinis can generate 18 β-H-monoammonium glycyrrhizinate and hydrates thereof.Whole technological operation is simple, and reaction conditions is gentle, and quality is easy to control, and transformation efficiency is high, is applicable to extensive preparation.
Summary of the invention
For overcoming the deficiency in background technology, the present invention aims to provide the preparation method of a kind of 18 α, β-H-ammonium glycyrrhizunate and hydrate thereof.
Technical solution of the present invention is:
A preparation method for ammonium glycyrrhizunate, comprises the steps:
(1) by stir at 50 ~ 60 DEG C one of in the glycyrrhizic acid inclusion compound ethanol of 5,4,3 times amount (W/W), acetone or propyl carbinol extraction 2.0,1.5,1.0h, united extraction liquid, add the EDTA of 0.5%, add one of the hydrogen peroxide or gac of 3 ~ 5% (W/W), at 50 ~ 60 DEG C, be incubated 30min, filter, filtrate reduced in volume is to proportion 1.15 ~ 1.20, leave standstill, crystallization, obtains fine work Potenlini.
(2) massfraction that the Potenlini after refining adds 3 ~ 4 times amount (W/W) is 10 ~ 20% sodium hydroxide, 10 ~ 20% potassium hydroxide, triethylamine and N, one of in N-dimethylformamide, heat 4 ~ 8h at reflux, add sulfuric acid or hydrochloric acid, phosphoric acid regulates pH1 ~ 3, controls reacting liquid temperature and is no more than 5 DEG C, insulated and stirred 30min, filter, dry, obtain white solid 18 α-H-Potenlini.
(3) by Potenlini fine work with the dehydrated alcohol heating for dissolving of 5 ~ 8 times amount (W/W), add liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, one of in ammonium oxalate and ammonium chloride, regulate pH4 ~ 5, at 50 ~ 70 DEG C of heating 1 ~ 2h, reduction vaporization, be concentrated into material relative density 1.05 ~ 1.10, stop heating, move in Settling tanks, add ethanol, alcoholic degree is made to reach about 80%, abundant mixing, leave standstill, it is made to precipitate completely, then put into suction filtration machine to filter, use ethanol rinse filter cake, drain, filtrate recycling ethanol, recycle, filter cake is peeled off, move in porcelain dish, send in vacuum drier, dry under 40 ~ 50 DEG C of temperature condition, obtain 18 β-H body monoammonium glycyrrhizinates
(4) Potenlini fine work is with the deionized water heating for dissolving of 5 ~ 8 times amount (W/W), one of to add in liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, ammonium oxalate and ammonium chloride, regulate pH4 ~ 5, at 50 ~ 70 DEG C of heating 1 ~ 2h, be cooled to room temperature, hold over night, centrifugal, use a small amount of glacial acetic acid and absolute ethanol washing respectively, obtain light yellow monoammonium glycyrrhizinate crude product.Crude product in 70 DEG C of thermosols, adds activated carbon decolorizing, suction filtration with 90% ethanol, filtrate is concentrated into rear crystallisation by cooling, centrifugal white crystal ,-(35 ± 5) DEG C, freezing 4 ~ 6h under normal pressure, then dry 5h at 40 DEG C, obtain 18 β-H body monoammonium glycyrrhizinate hydrates.
(5) 18 α-H-Potenlinis are with the dehydrated alcohol heating for dissolving of 5 ~ 8 times amount (W/W), add liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, one of in ammonium oxalate and ammonium chloride, regulate pH6 ~ 7 at 50 ~ 70 DEG C of heating 4 ~ 6h, be evaporated to dry, add 5 ~ 10 times amount (W/W) 20 ~ 40% ethanol to dissolve, hydrogen peroxide is added under stirring, that the concentration of hydrogen peroxide reaches 3 ~ 4%, decolour 2h at 40 ~ 50 DEG C, filter, filtrate reduced in volume is to material proportion 1, 15 ~ 1.20, place more than 12h, crystallization, crystal is with ethanol rinse, filter cake is sent in vacuum drier, dry 2 ~ 4h at 40 ~ 60 DEG C, obtain 18 α-H-diammonium glycyrrhizinates.
(6) with the deionized water heating for dissolving of 5 ~ 8 times amount (W/W), one of to add in liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, ammonium oxalate and ammonium chloride, regulate pH8 ~ 9, to yellow mercury oxide not generation, filter, filter cake is with in the solution input decolouring still after deionized water dissolving, add the powdered carbon of amount of filtrate 0.5%, at 60 ~ 80 DEG C of intermittent stirrings, filter after decolouring 1 ~ 2h, obtain destainer, active breeze recycle.Filtrate reduced in volume, to proportion 1.15 ~ 1.20, one of to add in a small amount of methyl alcohol, ethanol or acetone, stirs evenly gently, leave standstill crystallization, crystal is with a little ethanol rinse, and crystal is sent in vacuum drier, at 40 ~ 60 DEG C, dry 2 ~ 4h, obtains 18 α-H-Potenlini three ammoniums.
(7) with the dehydrated alcohol heating for dissolving of 5 ~ 8 times amount (W/W), one of to add in liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, ammonium oxalate and ammonium chloride, regulate pH8 ~ 9, to yellow mercury oxide not generation, filter, filter cake is with in the solution input decolouring still after deionized water dissolving, add the powdered carbon of amount of filtrate 0.5%, at 60 ~ 80 DEG C of intermittent stirrings, filter after decolouring 1 ~ 2h, obtain destainer, active breeze recycle.Filtrate reduced in volume is to proportion 1.15 ~ 1.20, one of to add in a small amount of methyl alcohol, ethanol and acetone, stir evenly gently, leave standstill knot product, product body is with a little ethanol rinse, crystal is placed in charging tray, in putting on lyophilize pallet in freeze drier ,-(35 ± 5) DEG C, freezing 4 ~ 6h under normal pressure, then dry 5h at 40 DEG C, obtains 18 α-H-Potenlini three ammonium hydrates.
Embodiment
Refining of Potenlini: the ethanol 250mL glycyrrhizic acid inclusion compound 500g of content 75% being added volume fraction 95%, stir at 50 ~ 60 DEG C and extract 2.0h, filtered filtration residue stirs with 200mL volume fraction 95% ethanol and extracts 1.5h at 50 ~ 60 DEG C, and filtered filtration residue stirs with 150mL volume fraction 95% ethanol and extracts 1.0h at 50 ~ 60 DEG C.United extraction liquid, adds the EDTA of 0.5%, adds 3 ~ 5% (W/W) powdered carbon, 50 ~ 60 DEG C of insulation 30min, filter, filtrate reduced in volume is to relative density 1.15 ~ 1.20, leave standstill, crystallization, peels off crystallisate, move in porcelain dish, send in vacuum drier, dry under 40 ~ 50 DEG C of temperature condition, obtain 18 α, the fine work 396g of β-H-Potenlini mixture, content 98.8%.
Potenlini configuration conversion: by the fine work 200g of Potenlini mixture, DMF 800mL, join in 1000mL there-necked flask, heating reflux reaction 8h, be cooled to about 0 DEG C, stir the sulfuric acid tune pH3.0 that lower slowly dropping massfraction is 50%, control reacting liquid temperature and be no more than 5 DEG C, generate white solid, insulated and stirred 30min, filter, drying, obtains white solid 18 α-H-Potenlini 185g, content 99.6%.
The preparation of 18 β-H-monoammonium glycyrrhizinates: by the Potenlini after refining with the dehydrated alcohol heating for dissolving of 6 times amount (W/W), add bicarbonate of ammonia, regulate pH4 ~ 5, at 50 ~ 70 DEG C of heating 4 ~ 6h, reduction vaporization, is concentrated into material relative density 1.05 ~ 1.10, stop heating, move in Settling tanks, add ethanol, make alcoholic degree reach about 80%, abundant mixing, leave standstill, make it precipitate completely, then put into suction filtration machine and filter, use ethanol rinse filter cake, drain, filtrate recycling ethanol, recycle.Yellow mercury oxide is under agitation regulated pH4 ~ 5 with Glacial acetic acid, leaves standstill, drain, with a small amount of absolute ethanol washing filter cake, obtain 18 β-H-monoammonium glycyrrhizinate crude products.In 18 β-H-monoammonium glycyrrhizinate crude products, add 90% ethanol, stirring and refluxing, then add gac, backflow 30min, filtered while hot, filtrate places 12h, and adularescent crystal is separated out, filter, crystallisate is peeled off, moves in porcelain dish, send in vacuum drier, dry under 40 ~ 50 DEG C of temperature condition, obtain 18 β-H body monoammonium glycyrrhizinates.
The preparation of 18 β-H-monoammonium glycyrrhizinate hydrates: the Potenlini after refining is with dissolve with ethanol, be cooled to room temperature, filtrate is sent in ammonification cylinder, add volatile salt under agitation and regulate pH4 ~ 5, at 50 ~ 70 DEG C of heating 1 ~ 2h, be cooled to room temperature, hold over night, centrifugal, use a small amount of glacial acetic acid and absolute ethanol washing respectively, obtain light yellow monoammonium glycyrrhizinate crude product.This crude product is added deionized water, in 70 DEG C of thermosols, add gac backflow 30min, suction filtration, filtrate is concentrated into crystallisation by cooling after half volume, centrifugal white crystal, put on lyophilize pallet ,-(35 ± 5) DEG C, freezing 4 ~ 6h under normal pressure, then dry 5h at 40 DEG C, obtains 18 β-H body monoammonium glycyrrhizinate hydrates.
The preparation of 18 α-H-diammonium glycyrrhizinates: 18 α-H-Potenlini 100g take volume fraction as the ethanol 700mL heating for dissolving of 95%, add ammonium acetate 20 ~ 30g and regulate pH6 ~ 7, at 50 ~ 70 DEG C of heated and stirred 4 ~ 6h, be evaporated to dry, add 5 ~ 10 times amount (W/W) 20 ~ 40% ethanol to dissolve, hydrogen peroxide is added under stirring, the concentration of hydrogen peroxide is made to reach 3 ~ 4%, decolour 2h at 40 ~ 50 DEG C, filter, filtrate reduced in volume is to material proportion 1.15 ~ 1.20, place more than 12h, crystallization, crystallisate is to send in vacuum drier after ethanol rinse, vacuum-drying 2 ~ 4h at 40 ~ 60 DEG C, obtain 18 α-H-diammonium glycyrrhizinates.
The preparation of 18 α-H-Potenlini three ammoniums: 18 α-H-Potenlinis are with the acetone heating for dissolving of 5 ~ 8 times amount (W/W), add liquefied ammonia and regulate pH8 ~ 9, insulation leaves standstill to yellow mercury oxide not generation, filter, filter cake, with in the solution input decolouring still after deionized water dissolving, adds the powdered carbon of amount of filtrate 0.5%, at 60 ~ 80 DEG C of intermittent stirrings, filter after decolouring 1 ~ 2h, obtain destainer, active breeze recycle.Filtrate reduced in volume, to proportion 1.15 ~ 1.20, adds a small amount of methyl alcohol, ethanol, acetone, stir evenly gently, leave standstill crystallization, crystal is with a little ethanol rinse, and crystal is sent in vacuum drier, at 40 ~ 60 DEG C, dry 2 ~ 4h, obtains 18 α-H-Potenlini three ammoniums, is called for short TAO.
The preparation of 18 α-H-Potenlini three ammonium hydrates: 18 α-H-Potenlini 80g are with 400mL dehydrated alcohol heating for dissolving, add liquefied ammonia and regulate pH8 ~ 9, to yellow mercury oxide not generation, filter, filter cake, with in the solution input decolouring still after deionized water dissolving, adds the powdered carbon of amount of filtrate 0.5%, at 60 ~ 80 DEG C of intermittent stirrings, filter after decolouring 30min, obtain destainer, active breeze recycle.Filtrate reduced in volume, to proportion 1.15 ~ 1.20, leaves standstill, crystallization, crystallisate is placed in charging tray, puts on the lyophilize pallet of freeze drier ,-(35 ± 5) DEG C, freezing 4 ~ 6h under normal pressure, then dry 5h at 40 DEG C, obtain 18 α-H-Potenlini three ammonium hydrates.
Claims (8)
1. the preparation method of 18 α, β-H-ammonium glycyrrhizunate and hydrate thereof, general structure is as follows:
Wherein R1 and R3 is-H, R2 is-NH
4 +time be monoammonium glycyrrhizinate; R1 is-H, R2 and R3 is-NH
4 +time be diammonium glycyrrhizinate; R1, R2 and R3 are-NH
4 +time be Potenlini three ammonium.
Be raw material with glycyrrhizic acid inclusion compound, the method includes the steps of:
(1) glycyrrhizic acid inclusion compound is refining.
The preparation of (2) 18 α-H-Potenlinis.
The preparation of (3) 18 β-H-monoammonium glycyrrhizinates.
The preparation of (4) 18 β-H-monoammonium glycyrrhizinate salt hydrate.
The preparation of (5) 18 α-H diammonium glycyrhetates.
The preparation of (6) 18 α-H-Triammonium glycyrrhizinates.
The preparation of (7) 18 α-H-Triammonium glycyrrhizinate hydrates.
2. a kind of 18 α as claimed in claim 1, the preparation method of β-H-ammonium glycyrrhizunate and hydrate thereof, it is characterized in that, in step (1) by stir at 50 ~ 60 DEG C one of in the glycyrrhizic acid inclusion compound ethanol of 5,4,3 times amount (W/W), acetone or propyl carbinol extraction 2.0,1.5,1.0h, united extraction liquid, add the EDTA of 0.5%, add one of the hydrogen peroxide or gac of 3 ~ 5% (W/W), 30min is incubated at 50 ~ 60 DEG C, filter, filtrate reduced in volume is to proportion 1.15 ~ 1.20, refining, crystallization, obtains fine work Potenlini.
3. a kind of 18 α as claimed in claim 1, the preparation method of β-H-ammonium glycyrrhizunate and hydrate thereof, it is characterized in that, the massfraction that Potenlini after refining in step (2) adds 3 ~ 4 times amount (W/W) is 10 ~ 20% sodium hydroxide, 10 ~ 20% potassium hydroxide, triethylamine and N, heat 4 ~ 8h at reflux one of in N-dimethylformamide, add sulfuric acid or hydrochloric acid, phosphoric acid regulates pH1 ~ 3, control reacting liquid temperature and be no more than 5 DEG C, insulated and stirred 30min, filter, dry, obtain white solid 18 α-H-Potenlini.
4. a kind of 18 α as claimed in claim 1, the preparation method of β-H-ammonium glycyrrhizunate and hydrate thereof, it is characterized in that, in step (3) by Potenlini fine work with the dehydrated alcohol heating for dissolving of 5 ~ 8 times amount (W/W), add liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, one of in ammonium oxalate and ammonium chloride, regulate pH4 ~ 5, at 50 ~ 70 DEG C of heating 1 ~ 2h, reduction vaporization, be concentrated into material relative density 1.05 ~ 1.10, alcohol precipitation, alcoholic degree is made to reach about 80%, suction filtration, filter cake regulates pH4 ~ 5 with Glacial acetic acid, again with volume fraction 80 ~ 90 dissolve with ethanol, add activated carbon decolorizing, filter, crystallization, crystallisate vacuum-drying under 40 ~ 50 DEG C of temperature condition, obtain 18 β-H body monoammonium glycyrrhizinates.
5. a kind of 18 α as claimed in claim 1, the preparation method of β-H-ammonium glycyrrhizunate and hydrate thereof, it is characterized in that, in step (4) by Potenlini fine work with the dehydrated alcohol heating for dissolving of 5 ~ 8 times amount (W/W), one of to add in liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, ammonium oxalate and ammonium chloride, regulate pH4 ~ 5, at 50 ~ 70 DEG C of heating 1 ~ 2h, be cooled to room temperature, hold over night, centrifugal, use a small amount of glacial acetic acid and absolute ethanol washing respectively, obtain light yellow monoammonium glycyrrhizinate crude product.Crude product with deionized water in 70 DEG C of thermosols, add activated carbon decolorizing, suction filtration, filtrate is concentrated into crystallisation by cooling after material proportion 1,15 ~ 1.20, centrifugal white crystal,-(35 ± 5) DEG C, freezing 4 ~ 6h under normal pressure, then dry 5h at 40 DEG C, obtain 18 β-H body monoammonium glycyrrhizinate hydrates.
6. a kind of 18 α as claimed in claim 1, the preparation method of β-H-ammonium glycyrrhizunate and hydrate thereof, it is characterized in that, in step (5), 18 α-H-Potenlinis are with the dehydrated alcohol heating for dissolving of 5 ~ 8 times amount (W/W), add liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, one of in ammonium oxalate and ammonium chloride, regulate pH6 ~ 7 at 50 ~ 70 DEG C of heating 4 ~ 6h, be evaporated to dry, add 5 ~ 10 times amount (W/W) 20 ~ 40% ethanol to dissolve, hydrogen peroxide is added under stirring, that the concentration of hydrogen peroxide reaches 3 ~ 4%, decolour 2h at 40 ~ 50 DEG C, filter, filtrate reduced in volume is to material proportion 1, 15 ~ 1.20, place more than 12h, crystallization, crystallisate is with ethanol rinse, vacuum-drying 2 ~ 4h at 40 ~ 60 DEG C, obtain 18 α-H-diammonium glycyrrhizinates.
7. a kind of 18 α as claimed in claim 1, the preparation method of β-H-ammonium glycyrrhizunate and hydrate thereof, it is characterized in that, in step (6), 18 α-H-Potenlinis are with the acetone heating for dissolving of 5 ~ 8 times amount (W/W), add liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, one of in ammonium oxalate and ammonium chloride, regulate pH8 ~ 9, precipitation, filter, filter cake is with deionized water dissolving, add the powdered carbon of amount of filtrate 0.5%, filter after stirring decolouring 1 ~ 2h at 60 ~ 80 DEG C, filtrate reduced in volume is to proportion 1.15 ~ 1.20, add a small amount of methyl alcohol, one of in ethanol and acetone, stir evenly gently, leave standstill crystallization, crystallisate is vacuum-drying 2 ~ 4h at 40 ~ 60 DEG C, obtain 18 α-H-Potenlini three ammoniums.
8. a kind of 18 α as claimed in claim 1, the preparation method of β-H-ammonium glycyrrhizunate and hydrate thereof, it is characterized in that, in step (7), 18 α-H-Potenlinis are with the dehydrated alcohol heating for dissolving of 5 ~ 8 times amount (W/W), add liquefied ammonia, ammonium acetate, volatile salt, bicarbonate of ammonia, one of in ammonium oxalate and ammonium chloride, regulate pH8 ~ 9, precipitation, filter, filter cake is with deionized water dissolving, add the powdered carbon of amount of filtrate 0.5%, filter after stirring decolouring 1 ~ 2h at 60 ~ 80 DEG C, filtrate reduced in volume is to proportion 1.15 ~ 1.20, leave standstill, crystallization, crystallisate is at-(35 ± 5) DEG C lyophilize 4 ~ 6h, then dry 5h at 40 DEG C, obtain 18 α-H-Potenlini three ammonium hydrates.
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| CN105237609A (en) * | 2015-10-19 | 2016-01-13 | 新疆天山制药工业有限公司 | Mono-ammonium glycyrrhizinate and preparing method thereof |
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| CN106336446A (en) * | 2016-08-24 | 2017-01-18 | 江苏天晟药业股份有限公司 | Preparation method of potassium glycyrrhizate |
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| CN113004366A (en) * | 2021-03-05 | 2021-06-22 | 陕西富捷药业有限公司 | Novel method for producing diammonium glycyrrhizinate |
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| CN105237609A (en) * | 2015-10-19 | 2016-01-13 | 新疆天山制药工业有限公司 | Mono-ammonium glycyrrhizinate and preparing method thereof |
| CN106045968A (en) * | 2016-05-26 | 2016-10-26 | 河南精康制药有限公司 | Method for preparing Sparfloxacin |
| CN106336446A (en) * | 2016-08-24 | 2017-01-18 | 江苏天晟药业股份有限公司 | Preparation method of potassium glycyrrhizate |
| CN106336446B (en) * | 2016-08-24 | 2018-07-03 | 江苏天晟药业股份有限公司 | A kind of preparation method of potassium glycyrrhizana |
| CN106380506B (en) * | 2016-08-29 | 2018-07-03 | 江苏天晟药业股份有限公司 | A kind of preparation method of 18 alpha type glycyrrhizic acid di-ammonium salts |
| CN106478762A (en) * | 2016-08-29 | 2017-03-08 | 江苏天晟药业股份有限公司 | A kind of preparation method of diammonium glycyrhetate |
| CN106380506A (en) * | 2016-08-29 | 2017-02-08 | 江苏天晟药业股份有限公司 | Preparation method of 18 alpha type diammonium glycyrrhizinate |
| CN106420778A (en) * | 2016-09-13 | 2017-02-22 | 中国药科大学 | Diammonium-glycyrrhizinate-caused hypokalemia resistance application of pharmaceutical composition of spironolactone and diammonium glycyrrhizinate |
| CN108929359A (en) * | 2018-06-20 | 2018-12-04 | 陕西富捷药业有限公司 | A kind of recrystallization method of ammonium glycyrrhizinate |
| CN110818765A (en) * | 2018-08-07 | 2020-02-21 | 重庆圣华曦药业股份有限公司 | Method for isomerizing cis-glycyrrhizic acid |
| CN111393499A (en) * | 2020-03-25 | 2020-07-10 | 河南豫辰药业股份有限公司 | Method for removing triterpenoid impurities in diammonium glycyrrhizinate bulk drug |
| CN112047987A (en) * | 2020-03-31 | 2020-12-08 | 张家港保税区麦福生物制品有限公司 | Preparation method of mono-ammonium glycyrrhizinate |
| CN113004366A (en) * | 2021-03-05 | 2021-06-22 | 陕西富捷药业有限公司 | Novel method for producing diammonium glycyrrhizinate |
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