CN102786553B - A kind of purification process of glucuronic acid glycosides compound - Google Patents
A kind of purification process of glucuronic acid glycosides compound Download PDFInfo
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Abstract
The invention discloses a kind of purification process of glucuronic acid glycosides compound, it comprises: be dissolved in solvent by the glucuronic acid glycosides compound crude product simultaneously containing formula 1 and formula 2 compound, lithium-containing compound is added under 10 ~ 40 DEG C and stirring, the pH value of regulates liquid reaches 7 ~ 14, forms the lithium salt complex being insoluble to the glucuronic acid glycoside compound of solvent; Isolate the lithium salt complex of the glucuronic acid glycoside compound of the white separated out from liquid, add solvent, then in the mixed solution obtained, add acid for adjusting pH value to the lithium salt complex of glucuronic acid glycoside compound dissolve; Alkali is added, pH value to 7 ~ 8 of regulator solution, the glucuronic acid glycoside compound shown in separate type 1 in the solution obtained; Separation purification method of the present invention have process stabilizing, cost low, pollute little, low for equipment requirements, simple to operation, auxiliary material is cheap, yield advantages of higher, is very applicable to large batch of suitability for industrialized production.
Description
Technical field
The invention belongs to medical compounds purification art, be specifically related to a kind of purification process of glucuronic acid glycosides compound.
Background technology
The drug toxicity of current glucuronic acid glycosides compound (formula 1) is low, in vivo can smoothly metabolism release effective constituent, simultaneously can enrichment in various degree and there is the features such as excellent targeting in some histoorgan, become the hot topic in pharmaceutical synthesis and drug research field.
But the synthesis of current glucuronic acid glycosides compound, also also exists problems.
In the building-up process of glucuronic acid glycosides compound, in glucuronic acid structure, the selection of the blocking group of hydroxyl is very crucial.Such as formula 3 structures; when forming ether or ester group protection for 3; under the reaction conditions of deprotection; inevitably produce double bond impurity (formula 4); this contaminant characteristics is very similar to glucuronic acid glycosides compound; simultaneously in the process of preparation, produce a large amount of pigments, adopt common purification process to be difficult to obtain purer glucuronic acid glycosides compound.
Document Synthesis of Morphine-3,6-di-β-D-glucuronide (Synthesis, October1997:1165-1168) propose in, morphine-3,6-β-D-diglucuronide adopts the method for directly crystallization from methyl alcohol or other solvents to carry out purifying, but cannot obtain purer target product.Therefore, the purification of glucuronic acid glycosides compound cannot be realized by the method for direct recrystallization.
The purification process of other these compounds of bibliographical information is generally column chromatography or chromatographic column preparation.Such as: One-Step Stereocontrolled Synthesis of α-Anomeric Carboxylic Acid Esters from UnprotectedGlycosyl Donors:A Water-Soluble Aspirin Pro-Drug Analogue(Synthesis2002, NO.14:1959-1968) report in, in the building-up process of the compound containing glucuronide group, the separation method of chromatography column or chromatographic column is all adopted to carry out purifying, the method cost is high, is difficult to industrialization.
In Industrial processes, with reference to above-mentioned document, when adopting the separation method of chromatography column or chromatographic column to carry out purifying, find to be difficult to be separated the pigment produced when removing double bond impurity and reaction, obtain purer glucuronide class target product.
In view of the difficulty of glucuronide compounds purifying, both domestic and external have Many researchers, starts to study from the structure of reaction substrate, ites is desirable to search out the method solving glucuronic acid glycosides compound and prepare difficulty.
Article Protecting Groups for Glucuronic Acid:Application to the Synthesis of NewPaclitaxel (Taxol) Derivatives (J.Org.Chem.2006; author 71:9628-9636) proposes in article; change the blocking group of hydroxyl in glucuronic acid structure; allyl group oxygen acyl group (CH2=CHCH2OCO-) is used to be used as the blocking group of hydroxyl in glucuronic acid structure, then by the mode Deprotection of shortening.Although the method changes the generation that protecting group avoids the by product such as formula 4 structures; but; the hydroxyl of glucuronic acid and the protective reaction complex steps of carboxylic acid group; yield is not high; the supplementary material simultaneously used is more expensive; industrial production cost is higher, and needs precious metal palladium shortening when deprotection reaction, and not only contaminate environment also increases production cost further.
If synthesizing in the process such as formula 1 glucuronic acid glycosides compound, adopt common and the blocking group of cheapness carries out protective reaction, although inevitably there will be the by product of a certain amount of formula 2 compound.But if the method that can realize effective separation of these two compounds could be explored, will reactions steps would be greatly reduced, reduce production cost significantly simultaneously, to the development promoting glucuronic acid glycoside medicine, will very important effect be played.
In the heuristic process of purification process, the by product (formula 2) produced when how to remove reaction and pigment are the keys of preparation high purity glucuronic acid glycosides compound (formula 1).
Summary of the invention
The object of this invention is to provide the purification process of crude product in a kind of preparation of compounds of the glycoside of glucuronic acid as shown in Equation 1.The compound purity containing glucose group class prepared by the method, up to more than 99.9%, can reach usual medicinal standard.
Object of the present invention can be reached by following measures:
A purification process for glucuronic acid glycosides compound, it comprises the steps:
(1), the glucuronic acid glycosides compound crude product simultaneously containing formula 1 and formula 2 compound is dissolved in solvent, lithium-containing compound is added under 10 ~ 40 DEG C and stirring, adjust ph reaches 7 ~ 14, forms the lithium salt complex being insoluble to the glucuronic acid glycoside compound of solvent;
(2), isolate the lithium salt complex of the glucuronic acid glycoside compound of separating out from liquid, join in solvent, then in the mixed solution obtained, add acid for adjusting pH value to the lithium salt complex of glucuronic acid glycoside compound dissolve;
(3) add alkali, pH value to 7 ~ 8 of regulator solution in the solution obtained to step (2), be separated the glucuronic acid glycoside compound shown in formula 1 that to dissociate from solution.
The present invention there is no particular requirement to each group in formula 1 and formula 2, as long as all can apply the various groups of this purification mechanisms without impact.Concrete, can following radicals be adopted in formula 1 and formula 2:
X is selected from N, O or S, and wherein when X is N, n is 2, and when X is selected from O or S, n is 1;
R
1, R
2independently be selected from hydrogen or substituted or non-substituted following radicals: C
1-10alkyl, C
1-10acyl group, C
1-10acyloxy, C
3-10cyclic hydrocarbon radical, C
5-20heterocyclic radical, C
6-19aryl, C
7-15aralkyl; Described substituted radical is selected from: hydroxyl, halogen, amino, nitro, alkyl, alkoxyl group, ether, aryl, cyano group, carboxyl, ester group, amide group, urea groups, alkylsulfonyl;
R
3be selected from hydrogen or substituted or non-substituted following radicals: C
1-10alkyl, C
1-10haloalkyl, C
1-10acyl group, C
1-10acyloxy, C
3-10cyclic hydrocarbon radical, C
5-20fused heterocycle base, C
5-20single heterocyclic radical, C
6-19aryl, C
7-15aralkyl; Described substituted radical is selected from: hydroxyl, halogen, amino, nitro, C
1-10alkyl, C
1-10haloalkyl, C
1-10alkoxyl group, phenyl, C
1-6alkyl-substituted phenyl, C
1-6alkoxy substituted phenyl, halogenophenyl, C
1-6piperazine carbonyl halogenophenyl, C that the piperazine carbonyl phenyl that alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl, pyrimidine replace, pyrimidine replace
3-10cycloalkyl, C
1-10piperidyl, C that alkyl replaces
3-10the piperidyl of cycloalkyl substituted, C
1-10pyrrolidyl, C that alkyl replaces
3-10the pyrrolidyl of cycloalkyl substituted, ether, cyano group, carboxyl, ester group, amide group, urea groups, alkylsulfonyl.
In present method, lithium-containing compound is added in crude product solution, formula 1 compound and lithium ion generation complex reaction in the basic conditions, form complex compound that is water insoluble or other solvents, and formula 2 compound dissolves in a solvent because the reason of self structure complex reaction can not occur, by filter or other separation methods can realize the separation of two compounds.The lithium salt compound of formula 1 regulates pH through adding acidic cpd again, obtains high purity glucal glycosides compound (formula 1).
In step 1, the membership that adds of lithium-containing compound forms lithium salt complex that is water insoluble and the glucuronic acid glycoside compound of other solvents, and after lithium salt complex fully separates out, generally carry out filtering, double bond impurity and pigment are mostly in filtrate, the solid purity that suction filtration goes out significantly improves, and pigment obviously reduces.Repeat to add acid for adjusting pH value to make dissolving and add the operation that lithium-containing compound forms lithium salt complex, more highly purified glucuronide lithium salt compound can be obtained.
In a kind of preferred version, in order to obtain more highly purified glucuronic acid glycoside compound, add in step 2 acid for adjusting pH value to glucuronic acid glycoside compound lithium salt complex dissolve after, the lithium-containing compound that adds in repeating step 1 is formed and adds the step that acid for adjusting pH value to the lithium salt complex of glucuronic acid glycoside compound dissolves in the step of the lithium salt complex of glucuronic acid glycoside compound and step 2, until the lithium salt complex of the glucuronic acid glycoside compound obtained reaches aimed purity, just proceed step 2 and 3.Repetitive process wherein (can comprise once) more than once.In above-mentioned repetitive process, constantly can detect the purity of the lithium salt complex of glucuronic acid glycoside compound, general when the purity of the lithium salt complex of glucuronic acid glycoside compound is more than 99% and interruptible price repetitive process, proceed the operation of step 2 and 3, this repetitive process farthest can reduce the content of formula 2 compound and pigment, ensures that the purity of glucuronic acid glycoside compound is more than 99.9% further.
In step (1), described simultaneously containing in the glucuronic acid glycosides compound crude product of formula 1 and formula 2 compound, the content of formula 2 compound (comprises 50%) below 50%, and according to the generalized case in building-up process, the content of formula 2 compound is further between 2% ~ 15%.
PH value to 7 ~ 14 that lithium-containing compound needs regulates liquid are added, when lithium-containing compound can directly adopt alkaline lithium-containing compound to regulate for during alkalescence in step 1.When lithium-containing compound is not alkalescence, can alkali be directly used to regulate.When the pH value of solution is directly in this scope or better scope, also no longer extra adjustment can be carried out.Alkali alkali (non-alkaline lithium-containing compound) described here can be selected from metal hydroxides, alkali metal bicarbonate salt, metal carbonate thing, be selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus, sodium carbonate or salt of wormwood further, be further selected from sodium hydroxide.
Solvent in step 1 is organic solvent and/or water, and wherein organic solvent and the volume mass of crude Compound are than being V
organic solvent: M
crude product=0 ~ 150:1mL/g, is preferably V
organic solvent: M
crude product=0 ~ 15:1mL/g; Water is V with the volume mass ratio of crude Compound
water: M
crude product=0 ~ 150:1mL/g, preferred V
water: M
crude product=20 ~ 40:1mL/g.The volume mass of aforementioned organic solvents and water and crude Compound is than being 0mL/g time different.
Lithium-containing compound in step 1 including but not limited to containing the oxyhydroxide of lithium, such as: lithium hydroxide, lithium hydroxide monohydrate; Containing carbonic acid or the hydrogen-carbonate compound of lithium, such as: Quilonum Retard, lithium bicarbonate; Organolithium compound, such as: lithium methoxide, lithium ethoxide, isopropyl lithium alkoxide, trimethyl carbinol lithium, butyllithium, phenyl lithium, tert-butyl lithium; Such as, containing the halogeno salt of lithium, lithiumbromide, lithium chloride, or by the mode exchanged, can become the compound of lithium salts with the complexing of formula 1 compound.The lithium-containing compound of the preferred alkalescence of lithium-containing compound, comprises lithium hydroxide, the hydrate of lithium hydroxide and Quilonum Retard.After the adding of lithium-containing compound, the PH scope forming the lithium salt complex of formula 1 compound is 7-14, and preferable ph reaches 9 ~ 13, further preferably 11 ~ 13.
In step 1, lithium-containing compound under agitation need add solution, and continues after the addition to stir, and is stirred in more than 1 minute, preferably at 5 ~ 30 minutes.
In step 2, described solvent is organic solvent and/or water, and the volume mass of formula 1 compound wherein contained in solvent and the lithium salt complex of glucuronic acid glycoside compound is than being V
organic solvent: M
formula 1 lithium salt complex=1 ~ 150:1mL/g, more preferably V
organic solvent: M
formula 1 lithium salt complex=5 ~ 15:1mL/g.
Acid described in step 2 is selected from mineral acid or organic acid, is selected from hydrochloric acid, nitric acid, Hydrogen bromide, sulfuric acid, acetic acid, formic acid or propionic acid further; Be preferably acetic acid or hydrochloric acid; In step 2, usable acid regulates pH value to 1 ~ 6.5 of mixed solution, and preferably to 2 ~ 5, to impel the dissolving completely of lithium salt complex.
Alkali in step 3 can adopt the form of solid or the aqueous solution to use; This alkali is but is not limited to metal hydroxides, alkali metal bicarbonate salt, metal carbonate thing, further selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus, sodium carbonate or salt of wormwood etc.; Preferred employing sodium hydroxide.The pH value of alkali regulator solution is added near neutral, preferably to 7.0 ~ 7.5 in step 3, preferred to 7.1 ~ 7.2 further.In order to prevent the interference of impurity, can first by solution with water system filtering with microporous membrane add alkali in solution before.
Solvent in step 1 of the present invention and 2 is organic solvent and/or water, and wherein organic solvent is selected from one or more in chloroform, methylene dichloride, ethyl acetate, ether, benzene, toluene, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol.Solvent in the present invention is preferably water.
Each group in formula 1 and formula 2:
In a kind of scheme, X is selected from O or S, and n is 1.
Preferably, X is O, n is 1.
In a kind of scheme, R
1, R
2independently be selected from hydrogen, substituted or non-substituted C
1-6alkyl, substituted or non-substituted C
3-6cyclic hydrocarbon radical, substituted or non-substituted C
6-19aryl; Described substituted radical is selected from hydroxyl, halogen, amino, nitro, C
1-6alkyl, C
1-6one or more in alkoxyl group.
Preferably, R
1, R
2independently be selected from hydrogen, substituted or non-substituted C
1-6alkyl; Described substituted radical is selected from one or more in hydroxyl, halogen, amino, nitro.
Preferably, R
1, R
2independently be selected from hydrogen.
In a kind of scheme, R
3be selected from hydrogen or substituted or non-substituted following radicals: pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane Pyrazolopyridine base, quinolyl, isoquinolyl, indyl, benzofuryl, purine radicals, acridyl, pyridyl, pyrimidyl, imidazolyl, pyrryl, thienyl, C
1-6alkyl, C
3-10cyclic hydrocarbon radical, C
6-19aryl.
Preferably, R
3be selected from hydrogen or substituted or non-substituted following radicals: pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane Pyrazolopyridine base.
Preferably, R
3in substituting group be selected from halogen, C
1-6alkyl, C
3-6cycloalkyl, C
1-6haloalkyl, phenyl, C
1-6alkyl-substituted phenyl, C
1-6alkoxy substituted phenyl, halogenophenyl, C
1-6piperazine carbonyl halogenophenyl, C that the piperazine carbonyl phenyl that alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl, pyrimidine replace, pyrimidine replace
1-6piperidyl, C that alkyl replaces
3-6the piperidyl of cycloalkyl substituted, C
1-6pyrrolidyl, C that alkyl replaces
3-6one or more in the pyrrolidyl of cycloalkyl substituted.
In a kind of scheme, R
3in substituting group be selected from halogen, C
1-6alkyl, C
3-6cycloalkyl, C
1-6haloalkyl, phenyl, C
1-6alkyl-substituted phenyl, C
1-6piperazine carbonyl halogenophenyl, C that alkoxy substituted phenyl, halogenophenyl, pyrimidine replace
1-6piperidyl, C that alkyl replaces
1-6pyrrolidyl, C that alkyl replaces
3-6one or more in the pyrrolidyl of cycloalkyl substituted.
Preferably, R
3in substituting group be selected from halogen, methyl, ethyl, n-propyl, sec.-propyl, the fluoro-3-(4-(pyrimidine-2-base of 4-) piperazine-1-carbonyl) phenyl, trifluoro n-propyl, phenyl, methyl piperidine base, ethyl piperidine base, n-propyl piperidyl, N-ethyl pyrrole N-alkyl, n-propyl pyrrolidyl, isopropylpyrrolidine base, one or more in cyclopentyl pyrrolidyl.
In a kind of scheme, R
3be selected from the pyrazolo Tetrahydronaphthyridderivates base of replacement, its substituting group is selected from one or more in methyl, ethyl, n-propyl, sec.-propyl.
In a kind of scheme, R
3be selected from the tetrahydrochysene phthalazinyl of replacement, its substituting group is selected from the piperazine carbonyl phenyl of pyrimidine replacement, piperazine carbonyl halogenophenyl, phenyl, the C of pyrimidine replacement
1-6alkyl-substituted phenyl, C
1-6alkoxy substituted phenyl, halogenophenyl, C
1-6one or more in alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl are the fluoro-3-(4-(pyrimidine-2-base of 4-further) piperazine-1-carbonyl) phenyl.
In a kind of scheme, R
3be selected from the pyrazolo tetrahydro isoquinolyl of replacement, its substituting group is selected from phenyl, C
1-6alkyl-substituted phenyl, C
1-6alkoxy substituted phenyl, halogenophenyl, C
1-6alkyl, C
3-6cycloalkyl, C
1-6haloalkyl, C
1-6piperidyl, C that alkyl replaces
3-6the piperidyl of cycloalkyl substituted, C
1-6pyrrolidyl, C that alkyl replaces
3-6one or more in the pyrrolidyl of cycloalkyl substituted, are selected from one or more in methyl, sec.-propyl, trifluoro n-propyl, phenyl, methyl piperidine base, ethyl piperidine base, n-propyl piperidyl, N-ethyl pyrrole N-alkyl, n-propyl pyrrolidyl, isopropylpyrrolidine base, cyclopentyl pyrrolidyl further.
In a kind of scheme, R
3be selected from the Pyrazoloisoquinolinederivatives base of replacement, its substituting group is selected from C
1-6alkyl, C
1-6alkyl replace pyrrolidyl in one or more, be selected from one or more in methyl, n-propyl pyrrolidyl further.
In a kind of scheme, R
3be selected from the tetrahydro cyclopentyl alkane of replacement and Pyrazolopyridine base, its substituting group is selected from C
1-6alkyl, C
1-6alkyl replace pyrrolidyl in one or more, be selected from one or more in methyl, n-propyl pyrrolidyl further.
" C in the present invention
1-10alkyl " refer to straight or branched alkyl containing 1 ~ 10 carbon atom.The carbonatoms of " alkyl " in the present invention is generally 1 ~ 10, is preferably 1 ~ 6, more preferably 1 ~ 4.
" alkoxyl group " in the present invention refers to the alkyl oxy of straight or branched, and wherein the carbonatoms of alkyl is generally 1 ~ 10, is preferably 1 ~ 6, more preferably 1 ~ 4.
" haloalkyl " in the present invention refers to the alkyl having a halogenic substituent at least.
" C in the present invention
1-10acyl group " refer to straight or branched acyl group containing 1 ~ 10 carbon atom, when carbonatoms is 1, it is " HC (=O)-" group, and when carbonatoms is greater than 1, it is " alkyl-C (=O)-" group.
" carbonyl " in the present invention refers to "-C (=O)-" group.
" C in the present invention
1-10acyloxy " refer to " C
1-10acyl group-O-" group.
" C in the present invention
3-10cyclic hydrocarbon radical " refer to by the saturated cyclic group of 3 ~ 10 carbon atoms, include but not limited to cyclopropyl, cyclopentyl, cyclohexyl etc.
" C in the present invention
5-20heterocyclic radical " refer to by 5 ~ 20 annular atomses form containing the cyclic group of at least one heteroatoms (N, O, S); be monocycle, dicyclo, three rings or tetracyclic ring system; it can be divided into fused heterocycle base and single heterocyclic radical further, comprise member ring systems that is that condense or bridging.Such heterocyclic radical includes but not limited to pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane Pyrazolopyridine base, quinolyl, isoquinolyl, indyl, benzofuryl, purine radicals, acridyl, pyridyl, pyrimidyl, imidazolyl, pyrryl, thienyl.
" C in the present invention
6-19aryl " refer to that, by the aromatic monocyclic be made up of 6 ~ 19 carbon atoms or polycyclic moiety, it includes but not limited to phenyl, naphthyl, xenyl, anthryl etc.The carbon raw coal subnumber of " aryl " in the present invention is generally 6 ~ 19, is preferably 6 ~ 14, more preferably 6 ~ 12.
" C in the present invention
7-15aralkyl " refer to by the group containing aryl and alkyl be made up of 7 ~ 15 carbon atoms.Include but not limited to benzyl, styroyl, diphenyl methyl etc.
" halogen " in the present invention refers to fluorine, chlorine, bromine or iodine.
" halogenophenyl " in the present invention refers to the phenyl at least with a halogenic substituent.
" alkyl-substituted phenyl " in the present invention refers to the phenyl at least with an alkyl substituent.
" alkoxy substituted phenyl " in the present invention refers to the phenyl at least with an alkoxy substituent.
" ether " in the present invention refers to " R
2-O-R
1-" group, R here
1, R
2can be the groups such as alkyl, cycloalkyl, heterocyclic radical or aryl independently.
" carboxyl " in the present invention refers to "-COOH " group.
" ester group " in the present invention refers to "-COO-R " group, and R here can be the groups such as alkyl, cycloalkyl, heterocyclic radical or aryl.
" amide group " in the present invention refers to " R
2-CONR
1-" group, R here
1, R
2can be the groups such as hydrogen, alkyl, cycloalkyl, heterocyclic radical or aryl independently.
" urea groups " in the present invention refers to " H2N-C (=O) NH-" group.
" alkylsulfonyl " in the present invention refers to " R-S (O)
2-" group, R here can be the groups such as alkyl, cycloalkyl, heterocyclic radical or aryl.
Present method can remove double bond impurity in glucuronic acid glycosides compound crude product and pigment effectively, can obtain high purity more than 99.9% glucuronic acid glycosides compound behind this law place.
Contriver finds, there is a general character in glucuronic acid glycosides compound: it in the basic conditions, glucuronic acid glycosides compound such as formula 1 structure can form complex compound that is water insoluble or other solvents with lithium ion, and such as formula the double bond compound of 2 structures, not there is above-mentioned character, by this property qualitative difference, effectively being separated of formula 1 compound and formula 2 compound can be realized, and the pigment produced when can remove reaction while this is separated.
On the basis of above-mentioned research, contriver studies discovery further, such as formula 3 structure glucuronic acid glycoside compounds, only has and works as R
3and R
4for when hydrogen that is 2 exist carboxylic acid group and 3 there is hydroxyl when, complex compound that is water insoluble or other solvents can be formed with lithium ion in basic solution.Except the glucuronic acid glycosides compound of this structure, not there is above-mentioned characteristic.Produce in the process of synthesis type 1 compound such as formula 2 double bond by product, too not there is such characteristic.
Contriver adopts ethanoyl, benzyloxy etc. as protecting group, synthesizes multiple glucuronic acid glycoside compound, and after measured, in building-up process, the content of formula 2 impurity is generally between 2%-15%.Meanwhile, adopt the method for synthesis, synthesized formula 2 impurity respectively, and formula 2 impurity is added in formula 1 compound, form the formula 1 of different content and the mixture of formula 2 compound, adopt method of the present invention to purify respectively, when the content of formula 2 compound is equal to or less than 50%, all successfully realize being separated, formula 1 compound after separation, HPLC purity all can reach more than 99.9%, simultaneously, the pigment produced in reaction process, is also completely removed.
Separation purification method of the present invention have process stabilizing, cost low, pollute little, low for equipment requirements, simple to operation, auxiliary material is cheap, yield advantages of higher, very be applicable to large batch of suitability for industrialized production, will greatly promote the fast development of glucuronic acid glycoside medicine.
Embodiment
The present invention will be further described by the following examples, but scope of the present invention does not limit the content of following embodiment.
Embodiment 1
The compound containing glucose group of process to be purified is: 3,4,5-trihydroxy--6-(3-methyl isophthalic acid-(1-n-propyl pyrrolidin-3-yl)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5-oxygen base)-tetrahydrochysene-2H-pyrans-2-formic acid
HPLC measures crude product: compound 3,4,5-trihydroxy--6-(3-methyl-(1-propyl pyrrole alkane-3-base)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5-oxygen base) content of-tetrahydrochysene-2H-pyrans-2-formic acid is 92.4%, double bond impurity (namely identical with the substituting group of target compound formula 2 compound, lower with) content is 7.5%, other foreign matter contents are 0.1%, and crude product is Vandyke brown.
In the crude product of 1.83g formula 5 compound, add pure water be diluted to 25mL, under fast stirring, add lithium hydroxide monohydrate solid and adjust pH to 11.70, after stirring 5min, suction filtration is to dripless, and filter cake is beige.
In filter cake, add 30mL water, under stirring, add Glacial acetic acid, regulate about PH to 3, be stirred to molten clear after, adjust pH to 11.70 ~ 12.20 with lithium hydroxide monohydrate, after stirring 5min, suction filtration is to dripless, and filter cake is in light grey.
After repetition epimere operates 4 times, lithium salts is pure white.Take a morsel lithium salts solid, and add appropriate dilute acetic acid and be adjusted to neutral rear HPLC analysis, purity is 99.38%.。
Lithium salts 5mL water is stirred, drip concentrated hydrochloric acid and regulate pH to 3.3 ~ 3.4, be stirred to clearly molten, with water system millipore filtration suction filtration, filtrate adjusts pH to 7.10 ~ 7.20 with 40% aqueous sodium hydroxide solution, stirring and crystallizing, after separating out a large amount of white solid, places refrigerator (5 DEG C) refrigeration 16h, suction filtration is to dripless, obtain pure white solid product 1.36 grams after oven dry, purification yield 74.3%, purity is 99.93%.
Embodiment 2
The compound structure containing glucose group of process to be purified is: 3,4,5-trihydroxy--6-(3-methyl isophthalic acid-(1-n-propyl pyrrolidin-3-yl)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5-oxygen base)-tetrahydrochysene-2H-pyrans-2-formic acid
HPLC measures crude product: compound 3,4,5-trihydroxy--6-(3-methyl-(1-propyl pyrrole alkane-3-base)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5-oxygen base) content of-tetrahydrochysene-2H-pyrans-2-formic acid is 48.27%, double bond foreign matter content is 51.72%, and other foreign matter contents are 0.01%, and crude product is Vandyke brown.
In the crude product of 2.8g formula 5 compound, add pure water be diluted to 50mL, under fast stirring, add lithium hydroxide monohydrate solid and adjust pH to 11.70, after stirring 5min, suction filtration is to dripless, and filter cake is beige.
In filter cake, add 25mL water, under stirring, add Glacial acetic acid, regulate about PH to 3, be stirred to molten clear after, adjust pH to 11.70 ~ 12.20 with lithium hydroxide monohydrate, after stirring 5min, suction filtration is to dripless, and filter cake is in light grey.
After repetition epimere operates 6 times, lithium salts is pure white.Take a morsel lithium salts solid, and add appropriate dilute acetic acid and be adjusted to neutral rear HPLC analysis, purity is 99.48%.。
Lithium salts 5mL water is stirred, drips concentrated hydrochloric acid and regulate pH to 3.3 ~ 3.4, be stirred to clearly molten, with water system millipore filtration suction filtration, filtrate adjusts pH to 7.10 ~ 7.20 with 40% aqueous sodium hydroxide solution, stirring and crystallizing, after separating out a large amount of white solid, place refrigerator (5 DEG C) refrigeration 16h.Suction filtration, to dripless, obtains pure white solid product 1.03 grams, purification yield 36.8% after oven dry, purity is 99.95%.
Embodiment 3
The compound containing glucose group of process to be purified is: the fluoro-3-(4-(pyrimidine-2-base of 6-(4-(4-) piperazine-1-carbonyl) phenyl)-5,6,7,8-tetrahydrochysene phthalazines-1-oxygen bases)-3,4,5-tri-hydrogen-2H-pyrans-2-formic acid.
HPLC measures crude product: the fluoro-3-(4-(pyrimidine-2-base of compound 6-(4-(4-) piperazine-1-carbonyl) phenyl)-5,6,7,8-tetrahydrochysene phthalazines-1-oxygen base)-3,4,5-tri-hydrogen-2H-pyrans-2-formic acid contents are 83.71%, double bond foreign matter content is 16.25%, and crude product is Vandyke brown.
To in the crude product of 1.73g formula 6 compound, add pure water and be diluted to 30mL, under Quick mechanical stirs, add lithium hydroxide monohydrate solid and adjust pH to 10.62, after stirring 5min, suction filtration is to dripless, and filter cake is beige.
In filter cake, add 35mL water, under stirring, add Glacial acetic acid, be stirred to mixed solution molten clear after, adjust pH to 11.73 with lithium hydroxide monohydrate, after stirring 5min, suction filtration is to dripless, and filter cake is in light grey.
After repetition epimere operates 3 times, lithium salts is off-white color.Take a morsel lithium salts solid, and add appropriate dilute acetic acid and be adjusted to neutral rear HPLC analysis, purity is 99.46%.。
Lithium salts 10mL pure water is stirred, drips concentrated hydrochloric acid and regulate pH to 3.3 ~ 3.4, be stirred to clearly molten, with water system millipore filtration suction filtration, filtrate adjusts pH to 7.10 ~ 7.20 with 40% aqueous sodium hydroxide solution, stirring and crystallizing, after separating out a large amount of white solid, place refrigerator (5 DEG C) refrigeration 16h.Suction filtration, to dripless, obtains pure white solid product 1.16 grams, purification yield 67.1% after oven dry.Purity is 99.92%.
Embodiment 4
The compound containing glucose group of process to be purified is: 3,4,5-trihydroxy--6-(3-methyl isophthalic acid-phenyl-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5-oxygen base)-tetrahydrochysene-2H-pyrans-2-formic acid.
HPLC measures crude product: compound 3,4,5-trihydroxy--6-(3-methyl isophthalic acid-phenyl-6,7,8,9-tetrahydrochysene-3H-pyrazoline [3,4-c] isoquinoline 99.9-5-oxygen base)-tetrahydrochysene-2H-pyrans-2-formic acid content is 86.42%, double bond foreign matter content is 13.55%, and crude product is Vandyke brown.
To quantitatively containing in the crude product of 1.14g formula 7 compound, add pure water and be diluted to 20mL, under fast stirring, add lithium hydroxide monohydrate solid and adjust pH to 12.53, after stirring 5min, suction filtration is to dripless, and filter cake is beige.
In filter cake, add 25mL water, under stirring, add Glacial acetic acid, be stirred to mixed solution molten clear after, adjust pH to 12.73 with lithium hydroxide monohydrate solid, after stirring 5min, suction filtration is to dripless, and filter cake is in light grey.
After repetition epimere operates 3 times, lithium salts is off-white color.Take a morsel lithium salts solid, and add appropriate dilute acetic acid and be adjusted to neutral rear HPLC analysis, purity is 99.49%.。
Lithium salts 5mL pure water is stirred, drips concentrated hydrochloric acid and regulate pH to 3.3 ~ 3.4, be stirred to clearly molten, with water system millipore filtration suction filtration, filtrate adjusts pH to 7.10 ~ 7.20 with 40% aqueous sodium hydroxide solution, stirring and crystallizing, after separating out a large amount of white solid, place refrigerator (5 DEG C) refrigeration 4h.Take out, suction filtration, to dripless, obtains pure white solid product 0.78 gram, purification yield 68.42% after oven dry.Purity is 99.90%.
Embodiment 5
The compound containing glucose group of process to be purified is: 3,4,5-trihydroxy--6-(9-sec.-propyl-7-methyl-2,3,4,7-tetrahydrochysene-1-H-pyrazolo [3,4-h] [1,6] naphthyridines-5-oxygen base)-tetrahydrochysene-2H-pyrans-2-formic acid.
HPLC measures in crude product: compound 3,4,5-trihydroxy--6-(9-sec.-propyl-7-methyl-2,3,4,7-tetrahydrochysene-1-H-pyrazolo [3,4-h] [1,6] naphthyridines-5-oxygen base)-tetrahydrochysene-2H-pyrans-2-formic acid content is 71.26%, double bond foreign matter content is 28.74%, and crude product is Vandyke brown.
To being quantitatively diluted to 30mL containing adding pure water in the crude product of 1.86g formula 8 compound, under Quick mechanical stirs, add lithium hydroxide monohydrate solid and adjust pH to 12.70, after stirring 5min, suction filtration is to dripless, and filter cake is beige.
In filter cake, add 35mL water, under stirring, add Glacial acetic acid, be stirred to mixed solution molten clear after, adjust pH to 12.70 with lithium hydroxide monohydrate, after stirring 5min, suction filtration is to dripless, and filter cake is in light grey.
After repetition epimere operates 4 times, lithium salts is off-white color.Take a morsel lithium salts solid, and add appropriate dilute acetic acid and be adjusted to neutral rear HPLC analysis, purity is 99.33%.
Lithium salts 5mL water is stirred, drips concentrated hydrochloric acid and regulate pH to 3.3 ~ 3.4, be stirred to clearly molten, with water system millipore filtration suction filtration, filtrate adjusts pH to 7.10 ~ 7.20 with 40% aqueous sodium hydroxide solution, stirring and crystallizing, after separating out a large amount of white solid, place refrigerator (5 DEG C) refrigeration 7h.Suction filtration, to dripless, obtains pure white solid product 1.07 grams, purification yield 57.5% after oven dry, purity is 99.91%.
Claims (20)
1. a purification process for glucuronic acid glycosides compound, is characterized in that comprising the steps:
(1), the glucuronic acid glycosides compound crude product simultaneously containing formula 1 and formula 2 compound is dissolved in solvent, lithium-containing compound is added under 10 ~ 40 DEG C and stirring, the pH value of regulates liquid reaches 9 ~ 13, forms the lithium salt complex being insoluble to the glucuronic acid glycoside compound of solvent;
(2), isolate the lithium salt complex of the glucuronic acid glycoside compound of separating out from liquid, join in solvent, then in the mixed solution obtained, add acid for adjusting pH value to the lithium salt complex of glucuronic acid glycoside compound dissolve;
(3) add alkali, pH value to 7 ~ 8 of regulator solution in the solution obtained to step (2), be separated the glucuronic acid glycoside compound shown in formula 1 that to dissociate from solution;
In formula,
X is selected from O or S, and n is 1;
R
1, R
2independently be selected from hydrogen, substituted or non-substituted C
1-6alkyl or substituted or non-substituted C
3-6cyclic hydrocarbon radical; Described substituted radical is selected from hydroxyl, halogen, amino, nitro, C
1-6alkyl, C
1-6one or more in alkoxyl group;
R
3be selected from hydrogen or substituted or non-substituted following radicals: pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane Pyrazolopyridine base, quinolyl, isoquinolyl, indyl, benzofuryl, purine radicals, acridyl, pyridyl, pyrimidyl, imidazolyl, pyrryl, thienyl, C
1-6alkyl, C
3-10cyclic hydrocarbon radical, C
6-19aryl; Described substituting group is selected from halogen, C
1-6alkyl, C
3-6cycloalkyl, C
1-6haloalkyl, phenyl, C
1-6alkyl-substituted phenyl, C
1-6alkoxy substituted phenyl, halogenophenyl, C
1-6piperazine carbonyl halogenophenyl, C that the piperazine carbonyl phenyl that alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl, pyrimidine replace, pyrimidine replace
1-6piperidyl, C that alkyl replaces
3-6the piperidyl of cycloalkyl substituted, C
1-6pyrrolidyl, C that alkyl replaces
3-6one or more in the pyrrolidyl of cycloalkyl substituted;
In step (1) and (2), described solvent is organic solvent and/or water, and wherein said organic solvent is tetrahydrofuran (THF), methyl alcohol, ethanol or Virahol.
2. method according to claim 1, is characterized in that in formula 1 and formula 2,
X is selected from O or S, and n is 1;
R
1, R
2independently be selected from hydrogen, substituted or non-substituted C
1-6alkyl or substituted or non-substituted C
3-6cyclic hydrocarbon radical; Described substituted radical is selected from hydroxyl, halogen, amino, nitro, C
1-6alkyl, C
1-6one or more in alkoxyl group;
R
3be selected from hydrogen or substituted or non-substituted following radicals: pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane Pyrazolopyridine base, quinolyl, isoquinolyl, indyl, benzofuryl, purine radicals, acridyl, pyridyl, pyrimidyl, imidazolyl, pyrryl, thienyl, C
1-6alkyl, C
3-10cyclic hydrocarbon radical, C
6-19aryl; Described substituting group is selected from one or more in halogen, methyl, ethyl, n-propyl, sec.-propyl, the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) phenyl, trifluoro n-propyl, phenyl, methyl piperidine base, ethyl piperidine base, n-propyl piperidyl, N-ethyl pyrrole N-alkyl, n-propyl pyrrolidyl, isopropylpyrrolidine base, cyclopentyl pyrrolidyl.
3. method according to claim 1, it is characterized in that adding in step (2) after acid for adjusting pH value to the lithium salt complex of glucuronic acid glycoside compound dissolves, the lithium-containing compound that adds in repeating step (1) is formed and adds the step that acid for adjusting pH value to the lithium salt complex of glucuronic acid glycoside compound dissolves in the step of the lithium salt complex of glucuronic acid glycoside compound and step (2), until the lithium salt complex of the glucuronic acid glycoside compound obtained reaches aimed purity, just proceed step (2) and (3).
4. method according to claim 3, is characterized in that the aimed purity of the lithium salt complex of described glucuronic acid glycoside compound is more than 99%.
5. method according to claim 1, is characterized in that in step (1), organic solvent is V with the volume mass ratio of crude product
organic solvent: M
crude product=0 ~ 150:1mL/g, water is V with the volume mass ratio of crude product
water: M
crude product=0 ~ 150:1mL/g, and the volume mass of organic solvent and water and crude product is than being 0mL/g time different.
6. method according to claim 5, is characterized in that the solvent in step (1) is organic solvent and/or water, and wherein organic solvent and the volume mass of crude product are than being V
organic solvent: M
crude product=0 ~ 15:1mL/g, water is V with the volume mass ratio of crude product
water: M
crude product=20 ~ 40:1mL/g.
7. method according to claim 1, is characterized in that in step (1), and described lithium-containing compound is selected from containing lithium oxyhydroxide, containing lithium carbonated, containing lithium hydrogen-carbonate compound, organolithium compound or containing lithium halogeno salt.
8. method according to claim 7, is characterized in that in step (1), described lithium-containing compound is selected from alkaline lithium-containing compound.
9. method according to claim 8, it is characterized in that in step (1), described lithium-containing compound is selected from lithium hydroxide, Quilonum Retard, lithium bicarbonate, lithium methoxide, lithium ethoxide, isopropyl lithium alkoxide, trimethyl carbinol lithium, butyllithium, phenyl lithium, tert-butyl lithium, lithiumbromide, lithium chloride, or its hydrate.
10. method according to claim 1, is characterized in that in step (1), lithium-containing compound under agitation adds solution, and continues after the addition to stir, and is stirred in more than 1 minute.
11. methods according to claim 10, is characterized in that in step (1), lithium-containing compound under agitation adds solution, and continue after the addition to stir, and churning time is 5 ~ 30 minutes.
12. methods according to claim 1, is characterized in that in step (2), and solvent is V with the volume mass ratio of the lithium salt complex of glucuronic acid glycoside compound
organic solvent: M
lithium salt complex=1 ~ 150:1mL/g.
13. methods according to claim 12, is characterized in that in step (2), and solvent is V with the volume mass ratio of the lithium salt complex of glucuronic acid glycoside compound
organic solvent: M
lithium salt complex=5 ~ 15:1mL/g.
14. methods according to claim 1, is characterized in that in step (2), described acid is selected from mineral acid or organic acid; PH value to 1 ~ 6.5 of mixed solution are regulated with acid.
15. methods according to claim 14, is characterized in that in step (2), described acid is selected from hydrochloric acid, nitric acid, Hydrogen bromide, sulfuric acid, acetic acid, formic acid or propionic acid; PH value to 2 ~ 5 of mixed solution are regulated with acid.
16. method according to claim 1, it is characterized in that in step (3), described alkali adopts the form of solid or the aqueous solution to use; Alkali is selected from metal hydroxides, alkali metal bicarbonate salt, metal carbonate thing; Add in solution before alkali first by solution with water system filtering with microporous membrane; With pH value to 7.0 ~ 7.5 of alkali regulator solution.
17. methods according to claim 16, is characterized in that in step (3), described alkali is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus, sodium carbonate or salt of wormwood.
18. methods according to claim 17, is characterized in that in step (3), described alkali is selected from sodium hydroxide.
19. methods according to claim 1, it is characterized in that described simultaneously containing in the glucuronic acid glycosides compound crude product of formula 1 and formula 2 compound, the content of formula 2 compound is below 50%; In step (3), the purity of the glucuronic acid glycoside compound shown in isolated formula 1 reaches more than 99.9%.
20. methods according to claim 19, it is characterized in that described simultaneously containing in the glucuronic acid glycosides compound crude product of formula 1 and formula 2 compound, the content of formula 2 compound is between 2% ~ 15%.
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| US20020128209A1 (en) * | 2000-10-24 | 2002-09-12 | Ralf Anderskewitz | Pyranoside derivatives |
| CN101817862A (en) * | 2009-02-26 | 2010-09-01 | 中国药科大学 | Ursolic acid-3-O-beta-D-pyranglucuronide and derivatives thereof, and preparation method and medicinal application thereof |
| WO2011147296A1 (en) * | 2010-05-24 | 2011-12-01 | 苏州汉德森星湖生物制药有限公司 | Pyrazole derivatives |
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| US20020128209A1 (en) * | 2000-10-24 | 2002-09-12 | Ralf Anderskewitz | Pyranoside derivatives |
| CN101817862A (en) * | 2009-02-26 | 2010-09-01 | 中国药科大学 | Ursolic acid-3-O-beta-D-pyranglucuronide and derivatives thereof, and preparation method and medicinal application thereof |
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