CN102234304B - Ursolic acid salt, preparation method thereof, and crystal thereof - Google Patents
Ursolic acid salt, preparation method thereof, and crystal thereof Download PDFInfo
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- 0 C1*CCNC1 Chemical compound C1*CCNC1 0.000 description 1
- SYHPSWALPMFJNF-FMDLRWIUSA-N C[C@H]1[C@H](C)[C@@]2(C)C3=CC[C@H]([C@@](C)(CC4)[C@@H](CC5)C(C)(C)[C@H]4O)[C@]5(C)[C@]3(C)CC[C@@]2(C)CC1 Chemical compound C[C@H]1[C@H](C)[C@@]2(C)C3=CC[C@H]([C@@](C)(CC4)[C@@H](CC5)C(C)(C)[C@H]4O)[C@]5(C)[C@]3(C)CC[C@@]2(C)CC1 SYHPSWALPMFJNF-FMDLRWIUSA-N 0.000 description 1
- FSLPMRQHCOLESF-SFMCKYFRSA-N C[C@H]1[C@H](C)[C@H]2C3=CC[C@H]([C@@](C)(CC4)[C@@H](CC5)C(C)(C)[C@H]4O)[C@]5(C)[C@]3(C)CC[C@@]2(C)CC1 Chemical compound C[C@H]1[C@H](C)[C@H]2C3=CC[C@H]([C@@](C)(CC4)[C@@H](CC5)C(C)(C)[C@H]4O)[C@]5(C)[C@]3(C)CC[C@@]2(C)CC1 FSLPMRQHCOLESF-SFMCKYFRSA-N 0.000 description 1
Abstract
The invention discloses an ursolic acid salt, a preparation method thereof, and a crystal thereof. The ursolic acid salt provided by the invention is a piperazine ursolic acid salt with the following chemical structure. The ursolic acid salt provided by the invention has good solubility, high dissolution rate, low hygroscopicity, high physical and chemical stability, and excellent prospect in clinic applications. The method has high crystallization technology operability and high bioavailability. The invention also provides a form of the medicinal ursolic acid salt with an excellent prospect in clinic applications.
Description
Technical field
The present invention is specifically related to a kind of ursolic acid salt, its preparation method and crystal thereof.
Background technology
The main pharmacological of ursolic acid have its main pharmacological have reducing blood-fat, atherosclerosis, reduction blood sugar, anti-inflammatory and antiviral, anti-oxidant, protect the liver, enhancing body immunologic function, antitumor etc.The seventies in last century, in hyperlipidaemia, fatty liver, had clinical application very widely in the diseases such as viral hepatitis and tumour for since clinical treatment.Safe fat peace capsule taking ursolic acid as main effective constituent has become at present domestic main Chinese medicine two kind new medicines that are used for the treatment of hyperlipidaemia etc.
Physico-chemical property aspect, ursolic acid is ursane type pentacyclic triterpenoid, its powder white crystalline, odorless, tasteless, water insoluble.Press the classification of biological agent categorizing system, this compound belongs to low solubility-hypertonicity medicine, i.e. BCS-II class medicine.The subject matter of ursolic acid is poorly water-soluble, and its solubleness in water is less than 0.001mg/mL, and due to poorly water-soluble, oral ursolic acid can be absorbed (bioavailability is less than 1%) hardly.In addition, show by preformulation study, ursolic acid easily changes into amorphous form, and has the polymorphic of solvate to exist, more difficult control quality stability in production technique.
Improving drug solubility has a lot of methods, as passed through structural modification, practice of pharmacy etc.In order to change its bioavailability, main employing is to improve its solubleness by preparation means at present.In the retrieval of Chinese patent, have ursolic acid is made to fabaceous lecithin nano-granule freeze-dried powder pin (02147711.6), cyanoacrylate nano particle freeze-dried powder injection, (02147712.4), ursolic acid polylactic acid nano particle lyophilized injectable powder (02147713.2), fat micro sphere preparation (200610020604.8), phospholipid complex (200610010228.4), dripping pill (200610129969.4 and 200310116883.4), fat milk injection (200510114817.2) etc.But often technique is comparatively complicated to improve solubleness by technology of pharmaceutics means, cost is higher.And its derivative and prodrug have chemical modification object amino alcohol (200710158384.X), chemical modification object amine (200710158385.4), chemical modification object amino acid (200610047235.1), chemical modification object amino alcohol (200610047236.6), chemical modification object amine, heterocycle (200610047237.0), hydrophilic polyglycol supported ursolic acid (200710048614.7), ursolic acid derivative (200910027213.2), 18-dehydroursolic acid (03119751.5), 3 β-succinyl-18-dehydroursolic acid disodium salt (03113998.1) etc.These derivatives and prodrug lack the support of necessary pharmacology data and clinical efficacy.
On the basis of change structure not, the method for alternative raising solubleness also has the screening of salt type.So-called salt type screening, refers to medicine and different guest molecule (acid or alkali) reactions is generated to salt, between medicine and soda acid molecule, mainly has an effect with ionic linkage form.In " American Pharmacopeia " 2006 editions products that record, the medicine of free form accounts for 44%, and the medicine existing with the form of salt accounts for 56%.Salt type not only can improve solubleness or the dissolution rate of medicine; also can improve other undesirable physical chemistry of medicine or biopharmacy character, as reduced water absorbability, improve physical and chemical stability, change fusing point, improve nonferromagnetic substance, be convenient to prepare purifying, realize slow controlled release, improve the sense of taste and compatibleness, prolong drug patent protection period etc.
But the patent that the screening of domestic application salt type improves the solubleness of ursolic acid has no report.This patent is synthetic through a series of salt to ursolic acid, comprises sodium salt, sylvite, piperazine salt, choline salt, calcium salt, magnesium salts, tert-butylamine salt, the preferred piperazine salt with good physical chemical property.
Summary of the invention
Technical problem to be solved by this invention is poor in order to overcome in existing ursolic acid degree of crystallinity, poorly water-soluble, the deficiency that bioavailability is low, and strong, the unsettled defect of ursolic acid salt water absorbability, and a kind of ursolic acid salt, its preparation method and crystal thereof are provided.Ursolic acid salt of the present invention not only solubleness and dissolution rate good, and water absorbability is low, physical and chemical stability is high, crystallization processes is workable, has higher bioavailability, has good potential applicability in clinical practice.
The present invention solves the problems of the technologies described above one of adopted technical scheme: a kind of ursolic acid salt, and it is ursolic acid piperazine salt, has following chemical structural formula:
The invention still further relates to a kind of crystal of above-mentioned ursolic acid piperazine salt, in the X-ray powder diffraction pattern of this crystal, source of radiation is CuK α
1, in angle of diffraction 2 θ=5.095, there is main peak at 5.649,10.582,10.987,11.881,14.380,15.383 degree places; And in 2 θ=13.019, can there be weak peak at 16.426,17.422,19.519,20.471,21.061,22.265,22.925,26.005 degree places; Wherein 2 θ value limit of error are ± 0.3.
The present invention solves the problems of the technologies described above another adopted technical scheme: a kind of preparation method of ursolic acid piperazine salt, comprises the following steps: in polar solvent or medium polar solvent, ursolic acid and piperazine are carried out to neutralization reaction.
Neutralization reaction of the present invention can adopt method and the condition of the acid-base neutralisation reaction of this area routine, and the present invention is also optimized reaction raw materials and reaction conditions, specific as follows described in.
In neutralization reaction of the present invention, the mol ratio of the charging capacity of ursolic acid and the charging capacity of piperazine is preferably 1: 0.5～1: 1.2.The selection of reaction solvent is according to the character of ursolic acid self, and after salify, the character of salt is come preferably.According to the solubleness of ursolic acid self, described polar solvent is preferably selected from one or more in methyl-sulphoxide, N,N-DIMETHYLACETAMIDE and dimethyl formamide, and medium polar solvent is preferably selected from Isosorbide-5-Nitrae-dioxane and/or tetrahydrofuran (THF).Reaction solvent is 10～204ml/g with the volume mass ratio of ursolic acid, is preferably 10～100ml/g.Described neutralization reaction is preferably under agitation carried out, and the speed of stirring is preferably 100～1000rpm.The reaction times of described neutralization reaction is as conventional the same in this area, be preferably complete with detection reaction till, be generally 1～24 hour; The temperature of reaction of described neutralization reaction is as conventional in this area, preferably for reaching following 5～10 degrees Celsius of reaction solvent boiling point used, or be heated to reaction solvent boiling point used by the method for reflux, and the present invention is preferably 55～180 DEG C, better is 60～170 DEG C.
After neutralization reaction of the present invention finishes, reaction soln can obtain the crystal of ursolic acid piperazine salt of the present invention through crystallization.Wherein the method for crystallization can be the crystallization method of this area routine, preferably solvent evaporation method, anti-solvent method, method of cooling, anti-solvent-method of cooling, anti-solvent-crystal seed method, cooling-crystal seed method or anti-solvent-cooling-crystal seed method.Solvent evaporation method is generally only suitable in preliminary screening.Anti-solvent method, method of cooling, anti-solvent-method of cooling, anti-solvent-crystal seed method, cooling-crystal seed method and anti-solvent-cooling-crystal seed method, is adapted at industry member and is widely used.
Described anti-solvent method refers to and in ursolic acid salt reaction soln, adds the different anti-solvent of specific inductivity, makes the method for the crystallization of drug salts.For anti-solvent method, the selection of the kind of solvent and anti-solvent, adds the temperature of anti-solvent, consumption, and speed, the concentration of mother liquor etc. is all worth investigating in detail.The anti-solvent of using is mainly selected according to the consistency of solvent, polarity, volatility, boiling point.The anti-solvent using in described anti-solvent method is selected from one or more in water, acetonitrile, acetone, Virahol, ethyl acetate, methyl ethyl ketone, methyl tertiary butyl ether, isopropyl acetate, hexanaphthene, normal hexane, heptane and pentane, better is selected from one or more in water, acetonitrile and heptane.Preferably 1～10 times of solvent volume amount of the add-on of anti-solvent, better is 3～5 times.Condition when each condition in above-mentioned anti-solvent method can be independent use the method, also can be the condition adopting while being combined with other crystallization method.
Described method of cooling refers to the reaction soln of ursolic acid salt is heated to certain temperature, then by this reaction soln with given pace Slow cooling, make the method for the crystallization of drug salts.In method of cooling, reaction soln temperature preferably can be heated to following 5～10 degrees Celsius of solvent for use boiling point, also can be heated to solvent for use boiling point by the method for reflux.Preferably, cool to room temperature or ice bath zero degree.Cooling speed preferably value is 2～10 DEG C/h, and that better is 3～5 DEG C/h, and that best is 5 DEG C/h.Cooling speed directly affects the speed that nucleus forms.In a nucleation process, if rate of cooling is too fast, the crystal of generation likely breaks out nucleation or produces time stable form and amorphous, and the latter can bring the problem of mixed crystal, physical stability, chemical stability fermentation.Therefore control rate of cooling very important.Condition when each condition in above-mentioned method of cooling can be independent use the method, also can be the condition adopting while being combined with other crystallization method.
Better, mix and use anti-solvent method and method of cooling, i.e. anti-solvent-method of cooling.Described anti-solvent-method of cooling refers at certain time point of cooling crystallization and adds anti-solvent with certain speed, to improve or to maintain certain degree of supersaturation, thereby improves the efficiency of crystallization and the method for productive rate.In the situation that productive rate is too low, in the process of cooling crystallization, can adds anti-solvent to improve degree of supersaturation, thereby improve efficiency and the productive rate of crystallization.Or, better, mix and use anti-solvent method and crystal seed method, i.e. anti-solvent-crystal seed method.Described anti-solvent-crystal seed method refers to and in the reaction soln of ursolic acid salt, adds a certain amount of a certain size crystal seed and different anti-solvent of specific inductivity, makes the method for the crystallization of drug salts.Or, better, mix and use method of cooling and crystal seed method, i.e. cooling-crystal seed method.Described cooling-crystal seed method refers to the reaction soln of ursolic acid salt is heated to certain temperature, then by this solution with given pace Slow cooling, can add at a certain temperature a certain amount of a certain size crystal seed, make the method for the crystallization of drug salts.
In the present invention, the use of crystal seed can be avoided a unmanageable nucleation, is widely used at the amplification test of Chemicals with in producing.Crystal seed refers to the crystal with certain crystal formation with certain technique small serial production, is broken into some scale, for using at crystallization amplification technique, to avoid the crystal particles of a nucleation through crystallization processes itself or further processing powder.Described crystal seed can obtain with the synthetic and crystallization processes of less or identical scale the crystal of the crystal formation of the same race of certain size, is then ground into the crystal of less desired size by the method for physics or machinery, is crystal seed.Dropping into the size of temperature, mode, quantity and the crystal seed of crystal seed all should investigate in detail.In the present invention, in described crystal seed method, the temperature that adds crystal seed preferably value is 30～120 DEG C, more preferably 35～100 DEG C; Adding the amount of crystal seed can value be 0.1～1%, more preferably 0.3～0.7%, and described per-cent is the per-cent that crystal seed amount accounts for ursolic acid piperazine salt theoretical yield; Add preferably 10～500 μ m of particle diameter of crystal seed, more preferably 20～400 μ m.In all processes of crystallization, crystallization is preferably carried out under whipped state, and stir speed (S.S.) is 100～1000rpm preferably, more preferably 300～700rpm.Stir speed (S.S.) can transform by mathematical method in lab scale and amplification test.
Better, mix and use anti-solvent method, method of cooling and crystal seed method, i.e. anti-solvent-cooling-crystal seed method.Described anti-solvent-cooling-crystal seed method refers to that certain time point of cooling crystallization drops into crystal seed, to lure the generation of crystallization into, and add anti-solvent at another time point of cooling crystallization with certain speed, to improve or to maintain certain degree of supersaturation, thereby improve the efficiency of crystallization and the method for productive rate.
In the present invention, described crystal after separating out method routinely filter, washing, is drying to obtain crystal shape ursolic acid piperazine salt of the present invention.
The raw material that the present invention is used or reagent except special instruction, all commercially available obtaining.
Positive progressive effect of the present invention is: than prior art, ursolic acid piperazine salt of the present invention not only solubleness and dissolution rate good, and water absorbability is low, stability is high, has higher bioavailability, has good potential applicability in clinical practice.
Brief description of the drawings
Fig. 1 is the polarizing microscope figure of the crystal of the ursolic acid piperazine salt that makes of embodiment 1.
Fig. 2 is the DSC/TGA figure of the crystal of the ursolic acid piperazine salt that makes of embodiment 1.
Fig. 3 is the X-ray powder diffraction pattern of the crystal of the ursolic acid piperazine salt that makes of embodiment 1.
Fig. 4 be the ursolic acid piperazine salt that makes of embodiment 1 crystal dynamic moisture sorption isotherm graphic representation.
Fig. 5 is the solubleness (artificial simulation intestinal juice after feed is shown in Chinese Pharmacopoeia or American Pharmacopeia for artificial simulation gastric juices, on an empty stomach lower artificial simulation intestinal juice) of the crystal of the ursolic acid piperazine salt of the ursolic acid piperazine salt that makes of embodiment 1.
Embodiment
Further illustrate the present invention with embodiment below, but the present invention is not limited.
The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer." room temperature " described in embodiment refers to the temperature of the operation room of testing, and is generally 5～30 DEG C.
Embodiment 1
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 4L1,4-dioxane, 75 DEG C are heated to dissolve, add Isosorbide-5-Nitrae-dioxane solution (piperazine 9.43g, the i.e. 0.1095mol of piperazine, Isosorbide-5-Nitrae-dioxane 0.438L), constant temperature, 100rpm stirs 2h, is down to room temperature, crystallize out with the rate of cooling of 5 DEG C/h, filter, with the washing of Isosorbide-5-Nitrae-dioxane, 45 DEG C of vacuum-drying 24h, obtain white solid, i.e. ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 85%.
Embodiment 2
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 4L N,N-DIMETHYLACETAMIDE, 75 DEG C are heated to dissolve, add the ethyl acetate solution (piperazine 9.43g, i.e. 0.1095mol, ethyl acetate 0.438L) of piperazine, constant temperature, 300rpm stirs 15min, is down to room temperature with the rate of cooling of 2 DEG C/h, crystallize out, filter, with the washing of water saturation ethyl acetate, 45 DEG C of vacuum-drying 24h, obtain white solid, i.e. ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 91%.Gained crystal particle diameter is 500 μ m, is ground into the different-grain diameter crystal seeds such as 10 μ m, 30 μ m, 50 μ m, 100 μ m, 300 μ m, for following examples with ball mill, Universalpulverizer, micronizer mill, hammer crusher or impact grinder etc.
Embodiment 3
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 4L methyl-sulphoxide, 180 DEG C are heated to dissolve, add aqueous isopropanol (the piperazine 9.43g of piperazine, be 0.1095mol, Virahol 0.438L), constant temperature, 200rpm stirs 15min, be down to 120 DEG C with the rate of cooling of 5 DEG C/h, add the crystal seed (0.1094g of particle diameter at 10 μ m, evenly be suspended in 100mL water, this crystal seed account for ursolic acid piperazine salt theoretical yield 0.1%), be down to 4 DEG C with the rate of cooling of 5 DEG C/h, crystallize out, filter, with 45 DEG C of vacuum-drying 24h of washed with isopropyl alcohol, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 93%.
Embodiment 4
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 20L dimethyl formamide, 70 DEG C are heated to dissolve, add the ethyl acetate solution (piperazine 9.43g, i.e. 0.1095mol, ethyl acetate 0.438L) of piperazine, constant temperature, 400rpm stirs 15min, is down to room temperature with the rate of cooling of 3 DEG C/h, crystallize out, filter, with ethyl acetate washing, 45 DEG C of vacuum-drying 24h, obtain white solid, i.e. ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 94%.
Embodiment 5
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 10L tetrahydrofuran (THF), 55 DEG C are heated to dissolve, add methyl ethyl ketone solution (the piperazine 9.43g of piperazine, be 0.1095mol, methyl ethyl ketone 0.438L), constant temperature, 500rpm stirs 15min, be down to 55 DEG C with the rate of cooling of 5 DEG C/h, add the crystal seed (0.4g of particle diameter at 50 μ m, evenly be suspended in 100mL heptane, this crystal seed account for ursolic acid piperazine salt theoretical yield 0.3655%), slowly add the 20L heptane of 55 DEG C, be down to 4 DEG C with the rate of cooling of 7 DEG C/h, crystallize out, filter, wash with methyl ethyl ketone, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 94%.
Embodiment 6
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 20L1, 4-dioxane, 60 DEG C are heated to dissolve, add 1 of piperazine, 4-dioxane solution (piperazine 22.63g, be 0.263mol, 1, 4-dioxane 0.438L), constant temperature, 600rpm stirs 15min, be down to 45 DEG C with the rate of cooling of 4 DEG C/h, add the crystal seed (1.0g of particle diameter at 100 μ m, evenly be suspended in 100mL1, in 4-dioxane, this crystal seed account for ursolic acid piperazine salt theoretical yield 0.9138%), slowly add the 60L acetonitrile of 45 DEG C, be down to 4 DEG C with the rate of cooling of 5 DEG C/h, crystallize out, filter, wash with acetonitrile, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 93%.
Embodiment 7
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 20L methyl-sulphoxide, 170 DEG C are heated to dissolve, add ethanolic soln (the piperazine 22.63g of piperazine, be 0.263mol, ethanol 0.438L), constant temperature, 700rpm stirs 15min, be down to 100 DEG C with the rate of cooling of 6 DEG C/h, add the crystal seed (0.6g of particle diameter at 300 μ m, evenly be suspended in 50mL ethanol, this crystal seed account for ursolic acid piperazine salt theoretical yield 0.5483%), slowly add the 60L water of 55 DEG C, be down to 4 DEG C with the rate of cooling of 5 DEG C/h, crystallize out, filter, wash with water, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 95%.
Embodiment 8
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 3L1,4-dioxane, 75 DEG C are heated to dissolve, add 1 of piperazine, 4-dioxane solution (piperazine 22.63g, i.e. 0.263mol, 1,4-dioxane 0.438L), constant temperature, 800rpm stirs 15min, is down to 45 DEG C with the rate of cooling of 7 DEG C/h, add 30L normal hexane, be down to 4 DEG C with the rate of cooling of 5 DEG C/h, crystallize out, filters, wash with normal hexane, 45 DEG C of vacuum-drying 24h, obtain white solid, i.e. ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 90%.
Embodiment 9
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 3L1,4-dioxane, 75 DEG C are heated to dissolve, add 1 of piperazine, 4-dioxane solution (piperazine 22.63g, i.e. 0.263mol, 1,4-dioxane 0.438L), constant temperature, 800rpm stirs 15min, is down to 45 DEG C with the rate of cooling of 7 DEG C/h, add 30L hexanaphthene, be down to 4 DEG C with the rate of cooling of 5 DEG C/h, crystallize out, filters, wash with hexanaphthene, 45 DEG C of vacuum-drying 24h, obtain white solid, i.e. ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 91%.
Embodiment 10
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 1L tetrahydrofuran (THF), 60 DEG C are heated to dissolve, add tetrahydrofuran solution (the piperazine 22.63g of piperazine, be 0.263mol, tetrahydrofuran (THF) 0.438L), constant temperature, 900rpm stirs 15min, slowly add the 20L ethyl acetate of 60 DEG C, be down to 4 DEG C with the rate of cooling of 8 DEG C/h, crystallize out, filters, by heptane wash, 45 DEG C of vacuum-drying 24h, obtain white solid, i.e. ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 90%.
Embodiment 11
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 20L N,N-DIMETHYLACETAMIDE, 75 DEG C are heated to dissolve, add isopropyl acetate solution (the piperazine 22.63g of piperazine, be 0.263mol, isopropyl acetate 0.438L), constant temperature, 1000rpm stirs 15min, add with the rate of cooling of 9 DEG C/h and be down to 55 DEG C, add the crystal seed (0.9g of particle diameter at 300 μ m, evenly be suspended in 100mL isopropyl acetate, this crystal seed account for ursolic acid piperazine salt theoretical yield 0.8224%), be down to 4 DEG C with the rate of cooling of 9 DEG C/h, crystallize out, filter, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 93%.
Embodiment 12
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 15L dimethyl formamide, 55 DEG C are heated to dissolve, add acetone soln (the piperazine 22.63g of piperazine, be 0.263mol, acetone 0.438L), constant temperature, 500rpm stirs 15min, be down to 45 DEG C with the rate of cooling of 10 DEG C/h, add the crystal seed (1.0g of particle diameter at 300 μ m, evenly be suspended in 100mL acetone, this crystal seed account for ursolic acid piperazine salt theoretical yield 0.9138%), add the 45L acetone of 45 DEG C, be down to 4 DEG C with the rate of cooling of 10 DEG C/h, crystallize out, filter, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 85%.
Embodiment 13
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 20L tetrahydrofuran (THF), 55 DEG C are heated to dissolve, add tetrahydrofuran solution (the piperazine 22.63g of piperazine, be 0.263mol, tetrahydrofuran (THF) 0.438L), constant temperature, 500rpm stirs 15min, be down to 30 DEG C with the rate of cooling of 5 DEG C/h, add the crystal seed (0.5g of particle diameter at 500 μ m, evenly be suspended in 100mL tetrahydrofuran (THF), this crystal seed account for ursolic acid piperazine salt theoretical yield 0.4569%), add the 60L methyl ethyl ketone of 30 DEG C, be down to 4 DEG C with the rate of cooling of 5 DEG C/h, crystallize out, filter, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 87%.
Embodiment 14
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 4L1, 4-dioxane, 75 DEG C are heated to dissolve, add aqueous isopropanol (the piperazine 22.63g of piperazine, be 0.263mol, Virahol 0.438L), constant temperature, 500rpm stirs 15min, be down to 30 DEG C with the rate of cooling of 5 DEG C/h, add the crystal seed (1.094g of particle diameter at 30 μ m, evenly be suspended in 100mL Virahol, this crystal seed account for ursolic acid piperazine salt theoretical yield 1%), add the 60L Virahol of 30 DEG C, be down to 4 DEG C with the rate of cooling of 5 DEG C/h, crystallize out, filter, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 93%.
Embodiment 15
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 10L1, 4-dioxane, stirring at room temperature is to dissolving, add aqueous isopropanol (the piperazine 14.15g of piperazine, be 0.164mol, Virahol 0.438L), constant temperature, 500rpm stirs 15min, add the crystal seed (1.094g of particle diameter at 30 μ m, evenly be suspended in 100mL Virahol, this crystal seed account for ursolic acid piperazine salt theoretical yield 1%), add 15L isopropyl acetate and the 15L methyl tertiary butyl ether of 30 DEG C, crystallize out, filter, 45 DEG C of vacuum-drying 24h, obtain white solid, it is ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 82%.
Embodiment 16
Synthesizing of ursolic acid piperazine salt: 100g (0.219mol) ursolic acid is dropped in reactor, add 10L1,4-dioxane, stirring at room temperature, to dissolving, adds aqueous isopropanol (piperazine 18.86g, the i.e. 0.219mol of piperazine, Virahol 0.438L), constant temperature, 500rpm stirs 15min, add the 30L acetone of 30 DEG C, crystallize out, filters 45 DEG C of vacuum-drying 24h, obtain white solid, i.e. ursolic acid piperazine salt.Ursolic acid piperazine salt productive rate is 78%.
The physicochemical property of checking the ursolic acid piperazine salt of above-mentioned preparation below by test example, further illustrate beneficial effect of the present invention.
Test example 1 polarized light microscopic method
Crystallization prepared by embodiment 1, application polarizing microscope detects, and eyepiece amplifies 10 times, object lens magnify 20, detected result is shown in Fig. 1.As seen from Figure 1: crystal has obvious birefringent phenomenon; Its crystal habit is needle-like; Its particle diameter is within the scope of 20～100 μ m.
The differential thermal analysis system of test example 2 and thermogravimetric analysis
Crystallization prepared by embodiment 1, carry out means of differential scanning calorimetry (differential scanningcalorimeter, DSC) with thermogravimetric analysis (thermogravimetric analysis, TGA), means of differential scanning calorimetry testing conditions is: temperature rise rate is 5 DEG C/min; Intensification scope is 25～350 DEG C; Nitrogen flow rate 50mL/min; Thermogravimetric analysis testing conditions is: temperature rise rate is 5 DEG C/min; Intensification scope is 25～350 DEG C; Balance nitrogen flow rate 40mL/min; Sample nitrogen flow rate 60mL/min; Detected result is shown in Fig. 2.As seen from Figure 2: it is 212.28 DEG C that crystal loses piperazine temperature, while being heated to 220 DEG C, ursolic acid piperazine salt loses 16.63% weight; Lose after piperazine, ursolic acid is degraded in 287.35 DEG C of meltings.
Test example 3X-ray powder diffraction method
Crystallization prepared by embodiment 1, carries out the detection of X-ray powder diffraction, and testing conditions is: X-ray source: (wavelength is CuK
); Operating voltage: 40KV; Working current intensity: 40mA; Detector: LynxEye detector; Scanning angle: 4～40 ° (2-theta); Step value: 0.05 °; Sweep velocity: 1 second/step-length, detected result was shown in Fig. 3.As seen from Figure 3: crystal characteristic X-ray powder diffraction style is in 2 θ=5.095,2-theta angle, and there is main peak at 5.649,10.582,10.987,11.881,14.380,15.383 degree places; And in 2 θ=13.019, can there be weak peak at 16.426,17.422,19.519,20.471,21.061,26.005 degree places.
Test example 4 water absorbability assay methods
Crystallization prepared by embodiment 1, measures water absorbability, and detecting step and condition are as follows: dynamically moisture content moisture absorption instrument (DVS Advantage, Surface Measurement System Ltd.); Experimental temperature: 25 DEG C; Humidity range of DO: the relative humidity of 0% relative humidity to 95%; Step value: 5% relative humidity; Weightening finish tension metrics: in 5 minutes, changes in weight is less than 0.01%; The longest starting time: 120 minutes.Detected result is shown in Fig. 4.As seen from Figure 4: crystal increases weight 1.544% between the relative humidity of 0% relative humidity to 95%, and ursolic acid piperazine salt has advantages of agent of low hygroscopicity.
Test example 5 solubility test methods
Crystallization prepared by embodiment 1, measure solubleness, detecting step or condition are specific as follows: precision takes 10mg compound in different bottles respectively, add artificial simulation gastric juices, on an empty stomach lower artificial simulation intestinal juice, the artificial simulation intestinal juice (seeing Chinese Pharmacopoeia or American Pharmacopeia) after feed, balance to solubleness no longer changes, HPLC measures drug level, and detected result is shown in Fig. 5.As seen from Figure 5: ursolic acid is at artificial simulation gastric juices, on an empty stomach lower artificial simulation intestinal juice, in the artificial simulation intestinal juice after feed, solubleness is respectively 0.034,0.130 and 0.159mg/mL; Ursolic acid piperazine salt is at artificial simulation gastric juices, and empty stomach is artificial simulation intestinal juice down, and in the artificial simulation intestinal juice after feed, solubleness is respectively 0.0001,0.108,0.712mg/mL; Known, in the artificial simulation intestinal juice after on the feed, ursolic acid piperazine salt solubleness has clear improvement than ursolic acid.
Test example 6 gegenion assay methods
Ursolic acid piperazine salt crystallization high performance liquid phase method prepared by embodiment 1 is carried out quantitatively, experimental technique is: Waters high performance liquid phase instrument (2695-2998), detector is evaporat light scattering, generating tube temperature is 50 DEG C, atomization gas pressure is 3.4bar, liquid phase post is the cyano group post (5 μ m, 4.6 × 250mm) of YMC, No. SN: 042578321; Moving phase is the water of 3% (v/v) nitric acid: acetonitrile (5: 95); Sampling volume is 5 μ L, and column temperature is 30 DEG C; Flow rate of mobile phase 1mL/min; The single needle time: 10min.Quantitative that to contain piperazine in ursolic acid piperazine salt be 8.626% (wt) by external standard method; Its theoretical content is 8.633% (wt).The ursolic acid that this experiment confirmation ursolic acid piperazine salt contains 1 molecule and the piperazine of 0.5 molecule.
Comparative example
According to the condition same with test example 4, water absorbability to other a few class ursolic acid salts is measured, find sodium salt, sylvite (75% relative humidity moisture absorption 10-15%), choline salt (75% relative humidity moisture absorption 6-10%), calcium salt (75% relative humidity moisture absorption 2-5%), magnesium salts (75% relative humidity moisture absorption 2-5%), easily moisture absorption; And tert-butylamine salt (75% relative humidity moisture absorption 0.6% left and right), although non-hygroscopic, solubleness do not have clear improvement (in manual simulation's gastrointestinal fluid, solubleness is between 0.007-0.095mg/mL).
Claims (7)
1. a crystal for ursolic acid piperazine salt, is characterized in that, in the X-ray powder diffraction pattern of this crystal, source of radiation is CuK α
1, in angle of diffraction 2 θ=5.095, there is main peak at 5.649,10.582,10.987,11.881,14.380,15.383 degree places; And in 2 θ=13.019, there is weak peak at 16.426,17.422,19.519,20.471,21.061,22.265,22.925,26.005 degree places; Wherein 2 θ value limit of error are ± 0.3;
Described ursolic acid piperazine salt, has following chemical structural formula:
2. the preparation method of the crystal of ursolic acid piperazine salt as claimed in claim 1, is characterized in that, comprises the following steps: in polar solvent, ursolic acid and piperazine are carried out to neutralization reaction; After described neutralization reaction finishes, reaction soln can obtain the ursolic acid piperazine salt of crystal shape through crystallization, and wherein the method for crystallization is solvent evaporation method, anti-solvent method, method of cooling, anti-solvent-method of cooling, anti-solvent-crystal seed method, cooling-crystal seed method or anti-solvent-cooling-crystal seed method;
Described ursolic acid piperazine salt, has following chemical structural formula:
3. the preparation method of the crystal of ursolic acid piperazine salt as claimed in claim 2, is characterized in that, described polar solvent is medium polar solvent.
4. the preparation method of the crystal of ursolic acid piperazine salt as claimed in claim 2 or claim 3, it is characterized in that, the anti-solvent using in described anti-solvent method is selected from one or more in water, acetonitrile, acetone, Virahol, ethyl acetate, methyl ethyl ketone, methyl tertiary butyl ether, isopropyl acetate, hexanaphthene, normal hexane, heptane and pentane, and the add-on of anti-solvent is 1～10 times of solvent volume amount.
5. the preparation method of the crystal of ursolic acid piperazine salt as claimed in claim 2 or claim 3, is characterized in that, in described method of cooling, the cooling speed of reaction soln is 2～10 DEG C/h.
6. the preparation method of the crystal of ursolic acid piperazine salt as claimed in claim 5, is characterized in that, in described method of cooling, the cooling speed of reaction soln is 5 DEG C/h.
7. the preparation method of the crystal of ursolic acid piperazine salt as claimed in claim 2 or claim 3, is characterized in that, in described crystal seed method, the temperature that adds crystal seed is 30～120 DEG C; The amount that adds crystal seed is 0.1～1%, and described per-cent is the per-cent that crystal seed amount accounts for ursolic acid piperazine salt theoretical yield; The particle diameter that adds crystal seed is 10～500 μ m.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3903089A (en) * | 1973-03-15 | 1975-09-02 | Biorex Laboratories Ltd | Ursolic acid derivatives |
| CN1449372A (en) * | 2000-08-08 | 2003-10-15 | 日清奥利友株式会社 | Process for producing oleanolic acid and/or maslinic acid |
| CN101987863A (en) * | 2009-07-31 | 2011-03-23 | 上海开拓者医药发展有限公司 | Oleanolic acid piperazine salt and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3903089A (en) * | 1973-03-15 | 1975-09-02 | Biorex Laboratories Ltd | Ursolic acid derivatives |
| CN1449372A (en) * | 2000-08-08 | 2003-10-15 | 日清奥利友株式会社 | Process for producing oleanolic acid and/or maslinic acid |
| CN101987863A (en) * | 2009-07-31 | 2011-03-23 | 上海开拓者医药发展有限公司 | Oleanolic acid piperazine salt and preparation method thereof |
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