CN106083725A - A kind of preparation method of high-purity allantoin - Google Patents
A kind of preparation method of high-purity allantoin Download PDFInfo
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- CN106083725A CN106083725A CN201610406131.9A CN201610406131A CN106083725A CN 106083725 A CN106083725 A CN 106083725A CN 201610406131 A CN201610406131 A CN 201610406131A CN 106083725 A CN106083725 A CN 106083725A
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- allantoin
- purity
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- carbamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the preparation method of a kind of high-purity allantoin, specifically include: allantoin solution in the hot water a) is provided；B) organic solvent is added in solution；And c) reclaim the high-purity allantoin obtained.The method of the present invention can effectively remove the impurity such as the allantoic acid, carbamide, glycoluril and the biuret that contain in allantoin, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of high-purity allantoin.
Background technology
The chemical name of allantoin (allantoin) is: Allantoinunm, belongs to and narrows azole jeterocyclic chemistry
Compound, molecular formula is C4H6N4O3, molecular weight is 158.12.
Allantoin structural formula is:
Allantoin is white or off-white color crystalline powder, and odorless is tasteless；Dissolve in the hot water, in ethanol, chloroform or ether
Insoluble.Allantoin is used as skin and the protective agent of mucosa at field of medicaments；Can be used alone or functional as composition of medicine
Composition, be used for treating epidermis chap, wound, eczema, and the drug component of gastroenteropathy, conjunctivitis eye drop etc..Changing
Cosmetic field, allantoin is also widely used.
The production method of allantoin is with glyoxalic acid and carbamide as raw material, in the presence of mineral acid or other acidic catalysts
Heating, direct polycondensation forms.
Allantoin prepares equation:
Patents has: Chinese patent CN201010553821.X discloses use phosphorous acid and closes as catalyst with sulfamic acid
The method becoming allantoin.Chinese patent CN201210376982.5 discloses use disulfate-sulphuric acid or hydrophosphate-phosphoric acid
Or individually acid salt as the method for catalyst synthetic allantoin.Chinese patent CN201210060965.0 discloses use acid
Property ionic liquid is the method for catalyst synthetic allantoin.Chinese patent CN201310663020.2 discloses use hydrogen sulfate
Sodium, sodium sulfite are as the method for catalyst synthetic allantoin.Chinese patent CN201310663367.7 discloses use phosphorus
Acid dihydride sodium, tungstophosphoric acid are as the method for catalyst synthetic allantoin.Chinese patent CN201310663368.1 discloses use
The mixture of ammonium dihydrogen phosphate and phosphomolybdic acid is as the method for catalyst synthetic allantoin.
But the improvement that these patented methods are carried out just for process recovery ratio and production cost, does not carry out allantoin and refines
The research of technique, does not the most provide the concrete preparation method of high-purity allantoin.
First German patent DE 1939924A discloses the purification process that allantoin carries out recrystallization with the water of about 15 times；
Japanese Patent Publication JP5059014 mentions crude product allantoin water, and to carry out the chloride ion that recrystallization can reduce in product residual
Stay, improve product fusing point.But the related substance situation of change that has before and after recrystallization is not studied.
Glyoxalic acid as one of allantoin synthesis material is obtained, therefore in glyoxalic acid the most all by Biformyl oxidation
A number of Biformyl can be remained.Biformyl, the most also can be with during glyoxalic acid and urea condensation prepare allantoin
Carbamide generation condensation reaction, generates glycoluril.
The reaction equation of by-product glycoluril:
Allantoin is the most unstable, meet oxidant or acid/base etc. can degrade, produce carbamide, allantoic acid and oneself in
The impurity such as uride.The materials such as carbamide, biuret, hydantoin, allantoic acid and glycoluril together constitute mainly having in allantoin
Machine impurity.
The structural formula of organic impurities in above-mentioned allantoin:
The molecular formula of carbamide is CH4N2O, molecular weight 60.06；The molecular formula of biuret is C2H5N3O2, molecular weight 103.08；In oneself
The molecular formula of uride is C3H4N2O2, molecular weight 100.08；The molecular formula of allantoic acid is C4H8N4O4, molecular weight 176.13；；Glycoluril
Molecular formula be C4H6N4O2, molecular weight 142.12.
Art methods obtains in every area percentage HPLC containing 0.422% carbamide, 0.134% biuret, 0.241% sweet
Urea, 0.208% hydantoin, and other can detect the allantoin product of impurity.Too high impurity limits allantoin at medicine
Application in field and cosmetic industry.
It is thus desirable to such a method, by simply effective purge process, such as recrystallization operation, allantoin is produced
Related impurities in product is removed, it is provided that the product purer than existing allantoin.
The invention provides the preparation method of a kind of high-purity allantoin, for purification existing allantoin product, it is provided that high
Purity, more safety and meet the allantoin of medicinal requirements.
Summary of the invention
The invention provides the preparation method of a kind of high-purity allantoin, it is characterised in that it comprises the following steps:
A) allantoin solution in the hot water is provided；
B) organic solvent is added in solution；And
C) the high-purity allantoin obtained is reclaimed.
The allantoin purification process that the present invention provides, preferably includes by allantoin heating for dissolving in the first solvent, then
Add the second solvent, the process of crystallisation by cooling.Can disposably add when adding the second solvent, it is also possible to be dividedly in some parts
Or dropping；Heating can be stopped, it is also possible to continuing heating.
The first solvent described is water；Or the solution that a kind of conventional organic solvent mixes by a certain percentage with water.Described
Two kinds of solvents are C1-4Alcohol, C3-6Ketone or their mixture.
Wherein, the solution that described conventional organic solvent mixes by a certain percentage with water, preferably methanol-water, ethanol-
Water, acetone-water, Methanol-Ethanol-Water, methanol-acetone-water.
Wherein, described C1-4Alcohol, C3-6Ketone or their mixture, preferably methanol, ethanol, propanol, isopropanol, third
Ketone, methanol/ethanol, methanol-acetone, ethanol-acetone.
The allantoin purification process that the present invention provides, during allantoin heats with the first solvent, can add
A certain proportion of activated carbon or medicinal charcoal, it is also possible to be not added with.
In the allantoin purification process that the present invention provides, the amount of the first solvent is 10-30 times of volume of allantoin weight,
Preferably 10-20 times volume.
In the allantoin purification process that the present invention provides, the heating-up temperature of allantoin and the first solvent is 50 DEG C and arrives backflow
Temperature, preferably 80-100 DEG C.
In the allantoin purification process that the present invention provides, heat time heating time is 5min-2h, preferably 0.5-1h.
In the allantoin purification process that the present invention provides, the amount of the second solvent is 1-20 times of volume of allantoin weight,
Preferably 2-5 times volume.
In the allantoin purification process that the present invention provides, the temperature of crystallize is less than 30 DEG C, preferably 10-15 DEG C.
In the allantoin purification process that the present invention provides, the time of crystallize is 0.5-10h, preferably 2-4h.
The invention provides a kind of high-purity allantoin, its carbamide containing less than about 0.5%, contracting two of less than about 0.5%
The hydantoin of the glycoluril of the allantoic acid of urea, less than about 0.5%, less than about 0.5%, less than about 0.5%.More preferably less than about 0.2%
Carbamide, the glycoluril of the allantoic acid of the biuret of less than about 0.2%, less than about 0.2%, less than about 0.2%, less than about 0.2% oneself
Interior uride.The carbamide of most preferably less than about 0.1%, the allantoic acid of the biuret of less than about 0.1%, less than about 0.1%, less than about
The glycoluril of 0.1%, the hydantoin of less than about 0.1%.
Present invention also offers the pharmaceutical composition containing this allantoin.
The present invention prepares high-purity allantoin with low-level carbamide, biuret, allantoic acid, glycoluril and hydantoin.
The allantoin prepared according to prior art contains 1.040% carbamide, 0.124% biuret, 0.747% glycoluril, 0.169% hydantoin
Deng impurity.By contrast, the purified allantoin of method provided according to the present invention contains the carbamide, less than about of less than about 0.2%
The biuret of 0.2%, the hydantoin of the glycoluril of the allantoic acid of less than about 0.2%, less than about 0.2%, less than about 0.2%.The most only
High-purity allantoin containing 0.120% hydantoin.
Detailed description of the invention
Below by concrete enforcement so that the present invention is explained further, but it is not intended to any limitation of the invention.
Embodiment 1:
74.0g glyoxalic acid, 240.2g carbamide and 200g 20% sulfuric acid solution are added in reaction bulb, is heated with stirring to 70-75 DEG C
Reaction 4h.After completing, reactant liquor is cooled to room temperature, the solid of generation is collected by filtration, repeatedly washs with moisture, 80 DEG C of drying,
To allantoin 94.9g, molar yield 60%.
Embodiment 2:
10.0g allantoin and 150ml water put in reaction bulb, heating blends the 0.5h that refluxes；Stop heating, the coldest rear addition
25ml methanol.Cooling solution, to room temperature, stirs 2h, the solid of generation is collected by filtration, washed once with dilute methanol, 80 DEG C of drums of solid
Air-dry dry, obtain high-purity allantoin 9.1g, yield 91%.
Embodiment 3:
10.0g allantoin, 200ml water and 1.00g activated carbon put in reaction bulb, heating blends the 1h that refluxes.Filter, to filter
In liquid, stream adds 50ml methanol.Cooling solution, to room temperature, stirs 4h, the solid of generation is collected by filtration, washed once with dilute methanol, Gu
80 DEG C of forced air dryings of body, obtain high-purity allantoin 8.9g, yield 89%.
Embodiment 4:
10.0g allantoin, 200ml water and 1.00g activated carbon put in reaction bulb, heating blends the 1h that refluxes.Filter, to filter
Liquid injects 100ml acetone.Cooling solution, to room temperature, stirs 2h, the solid of generation, 80 DEG C forced air dryings is collected by filtration, obtains
High-purity allantoin 8.9g, yield 89%.
Embodiment 5:
In reaction bulb, inject 20% methanol aqueous solution 2200ml, add allantoin 200g and activated carbon 10.0g, the lower heating of stirring
And the 0.5h that refluxes.Filtering, in filtrate, stream adds 1000ml acetone.Solution is cooled to room temperature, stirs 4h, generation is collected by filtration
Solid.80 DEG C of forced air dryings of solid, obtain high-purity allantoin 186g, yield 93%.
Embodiment 6:
10.0Kg allantoin, 150Kg water and 0.75Kg medicinal charcoal put in decolouring still, and agitating heating makes backflow 0.5h；Filter pressing,
Filtrate proceeds to crystallizer, controls liquid temperature 60-70 DEG C, and stream adds the methanol of 50Kg preheating.Stirring is cooled to 15-20 DEG C of crystallize, centrifugal, uses
20% methanol washed once, 70-80 DEG C of forced air drying of solid；Obtain high-purity allantoin 9.17Kg, yield 91.7%.
Embodiment 7:
The high-purity allantoin of 50.0g and 1000ml water put in reaction bulb, heating blends the 0.5h that refluxes.Filter, filter to gained
Liquid drips 200ml acetone.Cooling solution, to 15 DEG C, stirs 2h, the solid of generation is collected by filtration, with 15% washing with acetone once,
Dry.Obtain ultrapure allantoin 44.5g, yield 89%.
Embodiment 8:
The preparation of Compound Allantoin Cream
High-purity allantoin, methyl hydroxybenzoate and propyl hydroxybenzoate are dissolved in warm water, are heated to about 80 DEG C；Another by vitamin E, ointment
Substrate is heated to about 80 DEG C equally.Keep about 80 DEG C, while stirring aqueous phase is added in oil phase, add essence, continue stirring straight
To molding, subpackage.
Embodiment 9:
In order to further illustrate novelty and the feasibility of the present invention, high-purity allantoin that the present invention is prepared by we and embodiment
The most purified allantoin in 1 has carried out miscellaneous mass spectrographic comparison, it was demonstrated that high-purity allantoin that the present invention prepares has less
Impurity and higher purity.
Chromatographic column: μ Bondapak phenyl post, 125,10 μm, 3.9mm × 300mm
Mobile phase A: acetonitrile: water=96:4, phosphorus acid for adjusting pH value is 5.0
Mobile phase B: acetonitrile: methanol: water=60:5:35, phosphorus acid for adjusting pH value is 5.0
Gradient:
Flow velocity: 1.2ml/min
Detection wavelength: 200nm
Sampling volume: 20 μ L
Column temperature: 30 DEG C
Chromatographic peak relative retention time is as follows:
Figure of description
Fig. 1: the high-efficient liquid phase chromatogram of the high-purity allantoin that the method provided according to the present invention obtains
Fig. 2: the allantoin high-efficient liquid phase chromatogram produced under the conditions of prior art.
Claims (13)
1. a purification process for high-purity allantoin, including:
A) allantoin solution in the hot water is provided；
B) organic solvent is added in solution；And
C) the high-purity allantoin obtained is reclaimed.
Method the most according to claim 1, described organic solvent is C1-4Alcohol, C3-6Ketone or their mixture.
Method the most according to claim 2, wherein C1-4Alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, preferably methanol, second
Alcohol.
Method the most according to claim 2, wherein C3-6Ketone is selected from acetone, methyl acetone, butanone, preferably acetone.
Method the most according to claim 2, wherein C1-4Alcohol and C3-6The mixture of ketone is methanol-acetone, ethanol-acetone.
Method the most according to claim 1, the amount of water is 10-30 times of volume of allantoin weight, preferably 20 times volumes.
Method the most according to claim 1, C1-4The amount of alcohol is 0-20 times of volume of allantoin weight, and preferably 1-5 times volume enters
Preferably 2 times volumes of one step.
Method the most according to claim 1, C3-6The amount of ketone is 0-30 times of volume of allantoin weight, and preferably 1-10 times volume enters
Preferably 5 times volumes of one step.
Method the most according to claim 1, wherein obtains high-purity allantoin and contains the related impurities less than 0.5%.
Method the most according to claim 9, related impurities is carbamide, biuret, glycoluril, allantoic acid and interior uride.
11. methods according to claim 9, the carbamide contained in high-purity allantoin the most after purification, biuret, glycoluril,
The amount of allantoic acid and interior uride is all less than 0.2%.
12. methods according to claim 9, the carbamide contained in high-purity allantoin the most after purification, biuret, glycoluril,
The amount of allantoic acid and interior uride is all less than 0.1%.
13. 1 kinds of pharmaceutical compositions, its high-purity allantoin comprising claim 9 and pharmaceutically acceptable adjuvant.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107805222A (en) * | 2017-11-23 | 2018-03-16 | 天津市职业大学 | A kind of method of comprehensive utilization of allantoin synthesis mother liquid |
| CN111808025A (en) * | 2020-08-04 | 2020-10-23 | 李金国 | Preparation method of allantoin for cosmetics |
| CN111848523A (en) * | 2020-08-04 | 2020-10-30 | 李金国 | A method for preparing allantoin for cosmetic |
| CN111848522A (en) * | 2020-08-04 | 2020-10-30 | 李金国 | A method for producing allantoin for cosmetic |
| CN114470868A (en) * | 2022-02-22 | 2022-05-13 | 瑞昌市渝瑞实业有限公司 | Method and system for separating allantoin from yam mucus and method for preparing skin lotion |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107805222A (en) * | 2017-11-23 | 2018-03-16 | 天津市职业大学 | A kind of method of comprehensive utilization of allantoin synthesis mother liquid |
| CN107805222B (en) * | 2017-11-23 | 2020-07-17 | 天津市职业大学 | Comprehensive utilization method of allantoin synthetic mother liquor |
| CN111808025A (en) * | 2020-08-04 | 2020-10-23 | 李金国 | Preparation method of allantoin for cosmetics |
| CN111848523A (en) * | 2020-08-04 | 2020-10-30 | 李金国 | A method for preparing allantoin for cosmetic |
| CN111848522A (en) * | 2020-08-04 | 2020-10-30 | 李金国 | A method for producing allantoin for cosmetic |
| CN114470868A (en) * | 2022-02-22 | 2022-05-13 | 瑞昌市渝瑞实业有限公司 | Method and system for separating allantoin from yam mucus and method for preparing skin lotion |
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