CN102786553A - Purification method for glucuronide compounds - Google Patents
Purification method for glucuronide compounds Download PDFInfo
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Abstract
The invention discloses a purification method for glucuronide compounds. The method comprises the following steps: dissolving a crude glucuronide compound containing both compounds respectively represented by formula 1 and formula 2 in a solvent, adding a lithium-containing compound under stirring at a temperature of 10 to 40 DEG C and adjusting a pH value of liquid to be 7 to 14 so as to form a glucuronide compound lithium salt complex insoluble in the solvent; separating the white glucuronide compound lithium salt complex precipitated from the liquid, adding a solvent, then adding acid into obtained mixed liquid to adjust the pH value of the mixed liquid until the glucuronide compound lithium salt complex is dissolved; and adding alkali into an obtained solution to adjust the pH value of the solution to 7 to 8 and separating the glucuronide compound represented by formula 1. The separation and purification methods provided by the invention has the advantages of a stable process, low cost, little pollution, low requirement on equipment, simple and convenient operation, cheap accessories, high yield, etc., and is suitable for large batch industrial production.
Description
Technical field
The invention belongs to medical compounds purifying field, be specifically related to a kind of purification process of glucuronic acid glycosides compound.
Background technology
The drug toxicity of glucuronic acid glycosides compound (formula 1) is low at present; In vivo smoothly metabolism discharge effective constituent, simultaneously can be in various degree in some histoorgan enrichment and have good characteristics such as target property, become the synthetic hot topic with the drug research field of medicine.
But the glucuronic acid glycosides compound is synthetic at present, also exists problems.
In the building-up process of glucuronic acid glycosides compound, the selection of the blocking group of hydroxyl is very crucial on the glucuronic acid structure.Suc as formula 3 structures; When forming ether or ester group protection for 3, under the reaction conditions of deprotection, inevitably can produce two key impurity (formula 4); This contaminant characteristics is very similar with the glucuronic acid glycosides compound; In the process of preparation, produce a large amount of pigments simultaneously, 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 adopt directly from methyl alcohol or other solvents the crystalline method to carry out purifying, but can't obtain purer title product.Therefore, can't realize the purification of glucuronic acid glycosides compound through the method for direct recrystallization.
The purification process of other these compounds of bibliographical information is generally chromatography column purifying or chromatographic column preparation.For example: One-Step Stereocontrolled Synthesis of α-Anomeric Carboxylic Acid Esters from Unprotected Glycosyl Donors:A Water-Soluble Aspirin Pro-Drug Analogue (Synthesis2002; NO.14:1959-1968) report in; In the building-up process of the compound that contains the glucuronide group; All adopt the separation method of chromatography column or chromatographic column to carry out purifying, this method cost is high, is difficult to industriallization.
In Industrial processes, with reference to above-mentioned document, when the separation method of employing chromatography column or chromatographic column carries out purifying, find to be difficult to separate the pigment that produces when removing pair key impurity with reaction, obtain purer glucuronide class targets product.
In view of the difficulty of glucuronide compounds purifying, both domestic and external have a Many researchers, begins to study from the structure of reaction substrate, hopes to search out to solve the glucuronic acid glycosides compound and prepare difficult method.
Article Protecting Groups for Glucuronic Acid:Application to the Synthesis of New Paclitaxel (Taxol) Derivatives (J.Org.Chem.2006; Author 71:9628-9636) proposes in article; Change the blocking group of hydroxyl on the glucuronic acid structure; Use allyl group oxygen acyl group (CH2=CHCH2OCO-) is used as the blocking group of hydroxyl on the glucuronic acid structure, passes through the mode deprotection base of shortening then.Though changing the protection base, this method avoided production of by-products suc as formula 4 structures; But, the hydroxyl of glucuronic acid and carboxylic acid group's protective reaction complex steps, yield is not high; The supplementary material that uses simultaneously is more expensive; Industrial production cost is higher, and when deprotection reaction, needs the precious metal palladium shortening, and not only contaminate environment also further increases production cost.
If in synthetic process, adopt common and cheap blocking group to carry out protective reaction, though the by product of a certain amount of formula 2 compounds inevitably can occur suc as formula 1 glucuronic acid glycosides compound.If but can explore an effective isolating method that can realize these two compounds, and will significantly reduce reactions step, reduce production costs significantly simultaneously, to promoting the development of glucuronic acid glycoside medicine, with playing very important effect.
In the heuristic process of purification process, the by product (formula 2) and the pigment that produce when how to remove reaction are the keys of preparation high purity glucuronic acid glycosides compound (formula 1).
Summary of the invention
The purpose of this invention is to provide a kind of purification process suc as formula bullion in the compound process of the glycoside of glucuronic acid shown in 1.The compound purity that contains glucose group class through the preparation of this method can reach common medicinal standard up to more than 99.9%.
The object of the invention can reach through following measure:
A kind of purification process of glucuronic acid glycosides compound, it comprises the steps:
(1), the glucuronic acid glycosides compound bullion that contains formula 1 and formula 2 compounds simultaneously is dissolved in the solvent; In 10～40 ℃ and the following lithium-containing compound that adds of stirring; Regulate the pH value and reach 7～14, form the lithium salt complex of the glucuronic acid glycoside compound that is insoluble to solvent;
(2), isolate the lithium salt complex of the glucuronic acid glycoside compound of from liquid, separating out, join in the solvent, in the mixed solution that obtains, add the lithium salt complex dissolving of acid for adjusting pH value to glucuronic acid glycoside compound again;
(3) in the solution that step (2) obtains, add alkali, pH value to 7～8 of regulator solution, the glucuronic acid glycoside compound shown in the formula 1 that separating dissociates from solution.
The present invention does not have particular requirement to formula 1 and each group in the formula 2, so long as the various groups that this purification mechanisms is not had an influence all can be used.Concrete, can adopt following radicals in formula 1 and the formula 2:
X is selected from N, O or S, and wherein n is 2 when X is N, and n is 1 when X is selected from O or S;
R
1, R
2Independently be selected from hydrogen or replacement or non-substituted following radicals: C respectively
1-10Alkyl, C
1-10Acyl group, C
1-10Acyloxy, C
3-10Cyclic hydrocarbon radical, C
5-20Heterocyclic radical, C
6-19Aryl, C
7-15Aralkyl; Said substituted radical is selected from: hydroxyl, halogen, amino, nitro, alkyl, alkoxyl group, ether, aryl, cyanic acid, carboxyl, ester group, carboxamido-group, urea groups, alkylsulfonyl;
R
3Be selected from hydrogen or replacement 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; Said 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
1-6Alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl, the substituted piperazine carbonyl phenyl of pyrimidine, the substituted piperazine carbonyl halogenophenyl of pyrimidine, C
3-10Naphthenic base, C
1-10The substituted piperidyl of alkyl, C
3-10The piperidyl of cycloalkyl substituted, C
1-10The substituted pyrrolidyl of alkyl, C
3-10The pyrrolidyl of cycloalkyl substituted, ether, cyanic acid, carboxyl, ester group, carboxamido-group, urea groups, alkylsulfonyl.
In present method; In crude product solution, add lithium-containing compound; In alkaline condition following formula 1 compound and lithium ion generation complex reaction; Form the complex compound of water insoluble or other solvents, and formula 2 compounds are dissolved in the solvent because of complex reaction can not take place for the reason of self structure, through filtering or other separation methods can be realized the separation of two compounds.The lithium salt compound of formula 1 is regulated pH through adding acidic cpd again, obtains high purity glucal glycosides compound (formula 1).
Lithium-containing compound adds the lithium salt complex that affiliation forms the glucuronic acid glycoside compound of water insoluble and other solvents in the step 1; And after lithium salt complex fully separates out; Generally filter and get final product; In filtrating, the solid purity that suction filtration goes out significantly improves mostly for two key impurity and pigment, and pigment obviously reduces.Repeat to add acid for adjusting pH value and make dissolving and add the operation that lithium-containing compound forms lithium salt complex, can obtain more highly purified glucuronide lithium salt compound.
In a kind of preferred version; In order to obtain more highly purified glucuronic acid glycoside compound; In step 2, add after the lithium salt complex dissolving of acid for adjusting pH value to glucuronic acid glycoside compound; The step of the lithium salt complex of the adding lithium-containing compound formation glucuronic acid glycoside compound in the repeating step 1 and the lithium salt complex dissolved step that adds acid for adjusting pH value to glucuronic acid glycoside compound in the step 2; Lithium salt complex until the glucuronic acid glycoside compound that obtains reaches target purity, just proceeds step 2 and 3.Repetitive process wherein can (comprise once) more than once.In above-mentioned repetitive process; Can constantly detect the purity of the lithium salt complex of glucuronic acid glycoside compound; Generally can interrupt repetitive process 99% when above when the purity of the lithium salt complex of glucuronic acid glycoside compound; Proceed the operation of step 2 and 3, this repetitive process can farthest reduce the content of formula 2 compounds and pigment, and the purity that further guarantees the glucuronic acid glycoside compound is more than 99.9%.
In step (1); In the said glucuronic acid glycosides compound bullion that contains formula 1 and formula 2 compounds simultaneously; The content of formula 2 compounds is (comprising 50%) below 50%, and according to the generalized case in the building-up process, the content of formula 2 compounds is further between 2%～15%.
Add pH value to 7～14 that lithium-containing compound need be regulated liquid in the step 1, when lithium-containing compound is alkalescence, can directly adopt alkaline lithium-containing compound to regulate.When lithium-containing compound is not alkalescence, can directly use alkali to regulate.When the pH of solution value during, also can no longer carry out extra adjusting directly in this scope or better scope.Alkali alkali described here (non-alkaline lithium-containing compound) can be selected from metal hydroxides, alkali metal bicarbonate salt, metal carbonic acid thing; Further be selected from sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood, further be selected from sodium hydroxide.
Solvent in the step 1 is organic solvent and/or water, and wherein organic solvent is V with the volume mass ratio of bullion compound
Organic solvent: M
Bullion=0～150:1mL/g is preferably V
Organic solvent: M
Bullion=0～15:1mL/g; Water is V with the volume mass ratio of bullion compound
Water: M
Bullion=0～150:1mL/g, preferred V
Water: M
Bullion=20～40:1mL/g.Aforementioned organic solvent and water are 0mL/g with the volume mass of bullion compound than not simultaneously.
Lithium-containing compound in the step 1 comprises but is not limited to the oxyhydroxide that contains lithium, for example: Lithium Hydroxide MonoHydrate, lithium hydroxide monohydrate; The carbonic acid or the carbonic acid hydrogenate that contain lithium, for example: Quilonum Retard, lithium bicarbonate; Organic lithiumation thing, for example: lithium methoxide, lithium ethoxide, Virahol lithium, trimethyl carbinol lithium, butyllithium, phenyl lithium, tert-butyl lithium; The halogeno salt that contains lithium, lithiumbromide for example, lithium chloride perhaps can become the compound of lithium salts with formula 1 compound complexing through the mode of exchange.Lithium-containing compound is the lithium-containing compound of alkalescence preferably, comprises the hydrate and the Quilonum Retard of Lithium Hydroxide MonoHydrate, Lithium Hydroxide MonoHydrate.After the adding of lithium-containing compound, the PH scope that forms the lithium salt complex of formula 1 compound is 7-14, and preferred pH value reaches 9～13, further preferred 11～13.
In step 1, lithium-containing compound need under agitation add solution, and adding the continued stirring, is stirred in more than 1 minute, preferably at 5～30 minutes.
In step 2, said solvent is organic solvent and/or water, and the volume mass of formula 1 compound that wherein contains in the lithium salt complex of solvent and glucuronic acid glycoside compound is than being V
Organic solvent: M
Formula 1 lithium salt complex=1～150:1mL/g further is preferably V
Organic solvent: M
Formula 1 lithium salt complex=5～15:1mL/g.
Acid described in the step 2 is selected from mineral acid or organic acid, further is selected from hydrochloric acid, nitric acid, Hydrogen bromide, sulfuric acid, acetic acid, formic acid or propionic acid; Be preferably acetic acid or hydrochloric acid; Usable acid is regulated pH value to 1～6.5 of mixed solution in the step 2, preferably to 2～5, to impel the dissolving fully of lithium salt complex.
Alkali in the step 3 can adopt the form of the solid or the aqueous solution to use; This alkali is but is not limited to metal hydroxides, alkali metal bicarbonate salt, metal carbonic acid thing, further can be selected from sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood etc.; The preferred sodium hydroxide that adopts.The pH value that adds the alkali regulator solution in the step 3 is near neutrality, preferably to 7.0～7.5, further preferably to 7.1～7.2.In order to prevent the interference of impurity, in solution, adding before the alkali to be filtering with microporous membrane with solution with water earlier.
Solvent in the 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, ETHYLE ACETATE, ether, benzene, toluene, THF, methyl alcohol, ethanol, the Virahol.Solvent among the present invention is preferably water.
Each group in formula 1 and the formula 2:
In a kind of scheme, X is selected from O or S, and n is 1.
Preferably, X is O, and n is 1.
In a kind of scheme, R
1, R
2Independently be selected from hydrogen, replacement or non-substituted C respectively
1-6Alkyl, replacement or non-substituted C
3-6Cyclic hydrocarbon radical, replacement or non-substituted C
6-19Aryl; Said substituted radical is selected from hydroxyl, halogen, amino, nitro, C
1-6Alkyl, C
1-6In the alkoxyl group one or more.
Preferably, R
1, R
2Independently be selected from hydrogen, replacement or non-substituted C respectively
1-6Alkyl; Said substituted radical is selected from one or more in hydroxyl, halogen, amino, the nitro.
Preferably, R
1, R
2Independently be selected from hydrogen respectively.
In a kind of scheme, R
3Be selected from hydrogen or replacement or non-substituted following radicals: pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane and 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 replacement or non-substituted following radicals: pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane and Pyrazolopyridine base.
Preferably, R
3In substituting group be selected from halogen, C
1-6Alkyl, C
3-6Naphthenic base, C
1-6Haloalkyl, phenyl, C
1-6Alkyl-substituted phenyl, C
1-6Alkoxy substituted phenyl, halogenophenyl, C
1-6Alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl, the substituted piperazine carbonyl phenyl of pyrimidine, the substituted piperazine carbonyl halogenophenyl of pyrimidine, C
1-6The substituted piperidyl of alkyl, C
3-6The piperidyl of cycloalkyl substituted, C
1-6The substituted pyrrolidyl of alkyl, C
3-6In the pyrrolidyl of cycloalkyl substituted one or more.
In a kind of scheme, R
3In substituting group be selected from halogen, C
1-6Alkyl, C
3-6Naphthenic base, C
1-6Haloalkyl, phenyl, C
1-6Alkyl-substituted phenyl, C
1-6Alkoxy substituted phenyl, halogenophenyl, the substituted piperazine carbonyl halogenophenyl of pyrimidine, C
1-6The substituted piperidyl of alkyl, C
1-6The substituted pyrrolidyl of alkyl, C
3-6In the pyrrolidyl of cycloalkyl substituted one or more.
Preferably, R
3In substituting group be selected from halogen, methyl, ethyl, n-propyl, sec.-propyl, 4-fluoro-3-(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, sec.-propyl pyrrolidyl, the cyclopentyl pyrrolidyl one or more.
In a kind of scheme, R
3Be selected from substituted pyrazolo Tetrahydronaphthyridderivates base, its substituting group is selected from one or more in methyl, ethyl, n-propyl, the sec.-propyl.
In a kind of scheme, R
3Be selected from substituted tetrahydrochysene phthalazinyl, its substituting group is selected from the substituted piperazine carbonyl phenyl of pyrimidine, the substituted piperazine carbonyl halogenophenyl of pyrimidine, phenyl, C
1-6Alkyl-substituted phenyl, C
1-6Alkoxy substituted phenyl, halogenophenyl, C
1-6In alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, the piperazine carbonyl phenyl one or more further are 4-fluoro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) phenyl.
In a kind of scheme, R
3Be selected from substituted pyrazolo tetrahydro isoquinolyl, its substituting group is selected from phenyl, C
1-6Alkyl-substituted phenyl, C
1-6Alkoxy substituted phenyl, halogenophenyl, C
1-6Alkyl, C
3-6Naphthenic base, C
1-6Haloalkyl, C
1-6The substituted piperidyl of alkyl, C
3-6The piperidyl of cycloalkyl substituted, C
1-6The substituted pyrrolidyl of alkyl, C
3-6In the pyrrolidyl of cycloalkyl substituted one or more further are selected from methyl, sec.-propyl, trifluoro n-propyl, phenyl, methyl piperidine base, ethyl piperidine base, n-propyl piperidyl, N-ethyl pyrrole N-alkyl, n-propyl pyrrolidyl, sec.-propyl pyrrolidyl, the cyclopentyl pyrrolidyl one or more.
In a kind of scheme, R
3Be selected from substituted Pyrazoloisoquinolinederivatives base, its substituting group is selected from C
1-6Alkyl, C
1-6In the substituted pyrrolidyl of alkyl one or more further are selected from methyl, the n-propyl pyrrolidyl one or more.
In a kind of scheme, R
3Be selected from substituted tetrahydro cyclopentyl alkane and Pyrazolopyridine base, its substituting group is selected from C
1-6Alkyl, C
1-6In the substituted pyrrolidyl of alkyl one or more further are selected from methyl, the n-propyl pyrrolidyl one or more.
" C among the present invention
1-10Alkyl " be meant the straight or branched alkyl that contains 1～10 carbon atom.The carbonatoms of " alkyl " among the present invention is generally 1～10, is preferably 1～6, further is preferably 1～4.
" alkoxyl group " among the present invention is meant the alkyl oxy of straight or branched, and wherein the carbonatoms of alkyl is generally 1～10, is preferably 1～6, further is preferably 1～4.
" haloalkyl " among the present invention is meant the alkyl that has a halogenic substituent at least.
" C among the present invention
1-10Acyl group " be meant the straight or branched acyl group that contains 1～10 carbon atom, it is " HC (=O)-" group when carbonatoms is 1, when carbonatoms greater than 1 the time, it is " alkyl-C (=O)-" group.
" carbonyl " among the present invention is meant " C (=O)-" group.
" C among the present invention
1-10Acyloxy " be meant " C
1-10Acyl group-O-" group.
" C among the present invention
3-10Cyclic hydrocarbon radical " be meant by the saturated cyclic group of 3～10 carbon atoms, include but not limited to cyclopropyl, cyclopentyl, cyclohexyl etc.
" C among the present invention
5-20Heterocyclic radical " be meant the cyclic group that contains at least one heteroatoms (N, O, S) that constitutes by 5～20 annular atomses; be monocycle, dicyclo, three ring or Fourth Ring systems; it further can be divided into fused heterocycle base and single heterocyclic radical, comprises the member ring systems of condensed 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 and Pyrazolopyridine base, quinolyl, isoquinolyl, indyl, benzofuryl, purine radicals, acridyl, pyridyl, pyrimidyl, imidazolyl, pyrryl, thienyl.
" C among the present invention
6-19Aryl " be meant that it includes but not limited to phenyl, naphthyl, xenyl, anthryl etc. by the aromatic series monocycle that is made up of 6～19 carbon atoms or many cyclic groups.The carbon raw coal subnumber of " aryl " among the present invention is generally 6～19, is preferably 6～14, further is preferably 6～12.
" C among the present invention
7-15Aralkyl " be meant the group that contains aryl and alkyl that constitutes by by 7～15 carbon atoms.Include but not limited to benzyl, styroyl, diphenyl methyl etc.
" halogen " among the present invention is meant fluorine, chlorine, bromine or iodine.
" halogenophenyl " among the present invention is meant the phenyl that has a halogenic substituent at least.
" alkyl-substituted phenyl " among the present invention is meant the phenyl that has an alkyl substituent at least.
" alkoxy substituted phenyl " among the present invention is meant the phenyl that has an alkoxy substituent at least.
" ether " among the present invention is meant " R
2-O-R
1-" group, the R here
1, R
2Can be groups such as alkyl, naphthenic base, heterocyclic radical or aryl independently.
" carboxyl " among the present invention is meant " COOH " group.
" ester group " among the present invention is meant " COO-R " group, and the R here can be groups such as alkyl, naphthenic base, heterocyclic radical or aryl.
" carboxamido-group " among the present invention is meant " R
2-CONR
1-" group, the R here
1, R
2Can be groups such as hydrogen, alkyl, naphthenic base, heterocyclic radical or aryl independently.
" urea groups " among the present invention is meant " H2N-C (=O) NH-" group.
" alkylsulfonyl " among the present invention is meant " R-S (O)
2-" group, the R here can be groups such as alkyl, naphthenic base, heterocyclic radical or aryl.
Present method can be removed two key impurity and the pigment in the glucuronic acid glycosides compound bullion effectively, behind this law place, can obtain purity up to 99.9% above glucuronic acid glycosides compound.
The contriver finds; There is a general character in the glucuronic acid glycosides compound: it is under alkaline condition; Glucuronic acid glycosides compound suc as formula 1 structure can form the complex compound of water insoluble or other solvents with lithium ion, and does not have above-mentioned character suc as formula the double bond compound of 2 structures, through the difference of this character; Can realize effectively separating of formula 1 compound and formula 2 compounds, and the pigment that produces can remove reaction in this isolating while the time.
On the basis of above-mentioned research, the contriver further discovers suc as formula 3 structure glucuronic acid glycoside compounds, to have only the R of working as
3And R
4In the time of for hydrogen promptly 2 exist under the situation that there are hydroxyl in carboxylic acid group and 3, can in basic soln, form the complex compound of water insoluble or other solvents with lithium ion.Remove the glucuronic acid glycosides compound of this structure, do not have above-mentioned characteristic.In the process of synthesis type 1 compound, produce suc as formula two key by products of 2, do not have such characteristic too.
The contriver adopts ethanoyl, benzyloxy etc. as the protection base, synthetic multiple glucuronic acid glycoside compound, and through measuring, in building-up process, the content of formula 2 impurity is generally between the 2%-15%.Simultaneously, adopt the synthetic method, synthesized formula 2 impurity respectively, and formula 2 impurity are added in formula 1 compound; Form the formula 1 of different content and the mixture of formula 2 compounds, adopt method of the present invention to purify respectively, when the content of formula 2 compounds is equal to or less than 50%; All successfully realize separating, formula 1 compound after the separation, HPLC purity all can reach more than 99.9%; Simultaneously, the pigment that produces in the reaction process is also removed fully.
Separation purification method of the present invention has process stabilizing, cost is low, pollution is little, low for equipment requirements, simple to operation, auxiliary material is cheap, the yield advantages of higher; Be fit to very much large batch of suitability for industrialized production, with the fast development that greatly promotes glucuronic acid glycoside medicine.
Embodiment
Below through embodiment the present invention is further specified, but scope of the present invention is not limit the content of following embodiment.
Embodiment 1
The compound that contains the glucose group of processing to be purified is: 3,4, and 5-trihydroxy--6-(3-methyl isophthalic acid-(1-n-propyl tetramethyleneimine-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 bullion: compound 3,4,5-trihydroxy--6-(3-methyl-(1-propyl pyrrole alkane-3-yl)-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%, two key impurity (promptly identical with the substituting group of target compound formula 2 compounds, down with) content is 7.5%; Other foreign matter contents are 0.1%, and bullion is Vandyke brown.
The adding pure water is diluted to 25mL in the bullion of 1.83g formula 5 compounds, under stirring fast, adds the lithium hydroxide monohydrate solid and transfers pH to 11.70, and suction filtration is to dripless behind the stirring 5min, and filter cake is beige.
In filter cake, add 30mL water, stir adding Glacial acetic acid min. 99.5 down, regulate about PH to 3, be stirred to dissolve clear after, transfer pH to 11.70～12.20 with lithium hydroxide monohydrate, stir suction filtration to dripless behind the 5min, it is light grey that filter cake is.
After the repetition epimere operation 4 times, lithium salts is pure white.The lithium salts solid that takes a morsel adds an amount of dilute acetic acid and transfers to neutral back HPLC and analyze, and purity is 99.38%.。
Lithium salts is stirred with 5mL water, drip concentrated hydrochloric acid and regulate pH to 3.3～3.4, be stirred to and dissolve clearly; With water system millipore filtration suction filtration, filtrating is transferred pH to 7.10～7.20, stirring and crystallizing with 40% aqueous sodium hydroxide solution; After waiting to separate out a large amount of white solids, place refrigerator (5 ℃) refrigeration 16h, suction filtration is to dripless; Obtain pure white solid product 1.36 grams after the oven dry, purification yield 74.3%, purity are 99.93%.
Embodiment 2
The compound structure that contains the glucose group of processing to be purified is: 3,4, and 5-trihydroxy--6-(3-methyl isophthalic acid-(1-n-propyl tetramethyleneimine-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 bullion: compound 3,4,5-trihydroxy--6-(3-methyl-(1-propyl pyrrole alkane-3-yl)-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%; Two key foreign matter contents are 51.72%, and other foreign matter contents are 0.01%, and bullion is Vandyke brown.
The adding pure water is diluted to 50mL in the bullion of 2.8g formula 5 compounds, under stirring fast, adds the lithium hydroxide monohydrate solid and transfers pH to 11.70, and suction filtration is to dripless behind the stirring 5min, and filter cake is beige.
In filter cake, add 25mL water, stir adding Glacial acetic acid min. 99.5 down, regulate about PH to 3, be stirred to dissolve clear after, transfer pH to 11.70～12.20 with lithium hydroxide monohydrate, stir suction filtration to dripless behind the 5min, it is light grey that filter cake is.
After the repetition epimere operation 6 times, lithium salts is pure white.The lithium salts solid that takes a morsel adds an amount of dilute acetic acid and transfers to neutral back HPLC and analyze, and purity is 99.48%.。
Lithium salts is stirred with 5mL water, drip concentrated hydrochloric acid and regulate pH to 3.3～3.4, be stirred to and dissolve clearly; With water system millipore filtration suction filtration, filtrating is transferred pH to 7.10～7.20, stirring and crystallizing with 40% aqueous sodium hydroxide solution; After waiting to separate out a large amount of white solids, place refrigerator (5 ℃) refrigeration 16h.Suction filtration obtains pure white solid product 1.03 grams to dripless after the oven dry, purification yield 36.8%, purity are 99.95%.
Embodiment 3
The compound that contains the glucose group of processing to be purified is: 6-(4-(4-fluoro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) phenyl)-5,6,7,8-tetrahydrochysene phthalazines-1-oxygen base)-3,4,5-three hydrogen-2H-pyrans-2-formic acid.
HPLC measures bullion: compound 6-(4-(4-fluoro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) phenyl)-5,6,7; 8-tetrahydrochysene phthalazines-1-oxygen base)-3,4,5-three hydrogen-2H-pyrans-2-formic acid content is 83.71%; Two key foreign matter contents are 16.25%, and bullion is Vandyke brown.
In the bullion of 1.73g formula 6 compounds, add pure water and be diluted to 30mL, under quick mechanical stirring, add the lithium hydroxide monohydrate solid and transfer pH to 10.62, suction filtration is to dripless behind the stirring 5min, and filter cake is beige.
In filter cake, add 35mL water, stir adding Glacial acetic acid min. 99.5 down, be stirred to mixed solution dissolve clear after, transfer pH to 11.73 with lithium hydroxide monohydrate, stir suction filtration to dripless behind the 5min, it is light grey that filter cake is.
After the repetition epimere operation 3 times, lithium salts is off-white color.The lithium salts solid that takes a morsel adds an amount of dilute acetic acid and transfers to neutral back HPLC and analyze, and purity is 99.46%.。
Lithium salts is stirred with the 10mL pure water, drip concentrated hydrochloric acid and regulate pH to 3.3～3.4, be stirred to and dissolve clearly; With water system millipore filtration suction filtration, filtrating is transferred pH to 7.10～7.20, stirring and crystallizing with 40% aqueous sodium hydroxide solution; After waiting to separate out a large amount of white solids, place refrigerator (5 ℃) refrigeration 16h.Suction filtration obtains pure white solid product 1.16 grams, purification yield 67.1% to dripless after the oven dry.Purity is 99.92%.
Embodiment 4
The compound that contains the glucose group of processing to be purified is: 3,4, and 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 bullion: 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%, and two key foreign matter contents are 13.55%, and bullion is Vandyke brown.
In the bullion that quantitatively contains 1.14g formula 7 compounds, the adding pure water is diluted to 20mL, under stirring fast, adds the lithium hydroxide monohydrate solid and transfers pH to 12.53, and suction filtration is to dripless behind the stirring 5min, and filter cake is beige.
In filter cake, add 25mL water, stir adding Glacial acetic acid min. 99.5 down, be stirred to mixed solution dissolve clear after, transfer pH to 12.73 with the lithium hydroxide monohydrate solid, stir suction filtration to dripless behind the 5min, filter cake is light gray.
After the repetition epimere operation 3 times, lithium salts is off-white color.The lithium salts solid that takes a morsel adds an amount of dilute acetic acid and transfers to neutral back HPLC and analyze, and purity is 99.49%.。
Lithium salts is stirred with the 5mL pure water, drip concentrated hydrochloric acid and regulate pH to 3.3～3.4, be stirred to and dissolve clearly; With water system millipore filtration suction filtration, filtrating is transferred pH to 7.10～7.20, stirring and crystallizing with 40% aqueous sodium hydroxide solution; After waiting to separate out a large amount of white solids, place refrigerator (5 ℃) refrigeration 4h.Take out, suction filtration obtains pure white solid product 0.78 gram, purification yield 68.42% to dripless after the oven dry.Purity is 99.90%.
Embodiment 5
The compound that contains the glucose group of processing to be purified is: 3,4, and 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 the bullion: 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)-and tetrahydrochysene-2H-pyrans-2-formic acid content is 71.26%, and two key foreign matter contents are 28.74%, and bullion is Vandyke brown.
In the bullion that quantitatively contains 1.86g formula 8 compounds, add pure water and be diluted to 30mL, under quick mechanical stirring, add the lithium hydroxide monohydrate solid and transfer pH to 12.70, suction filtration is to dripless behind the stirring 5min, and filter cake is beige.
In filter cake, add 35mL water, stir adding Glacial acetic acid min. 99.5 down, be stirred to mixed solution dissolve clear after, transfer pH to 12.70 with lithium hydroxide monohydrate, stir suction filtration to dripless behind the 5min, it is light grey that filter cake is.
After the repetition epimere operation 4 times, lithium salts is off-white color.The lithium salts solid that takes a morsel adds an amount of dilute acetic acid and transfers to neutral back HPLC and analyze, and purity is 99.33%.
Lithium salts is stirred with 5mL water, drip concentrated hydrochloric acid and regulate pH to 3.3～3.4, be stirred to and dissolve clearly; With water system millipore filtration suction filtration, filtrating is transferred pH to 7.10～7.20, stirring and crystallizing with 40% aqueous sodium hydroxide solution; After waiting to separate out a large amount of white solids, place refrigerator (5 ℃) refrigeration 7h.Suction filtration obtains pure white solid product 1.07 grams to dripless after the oven dry, purification yield 57.5%, purity are 99.91%.
Claims (12)
1. the purification process of a glucuronic acid glycosides compound is characterized in that comprising the steps:
(1), the glucuronic acid glycosides compound bullion that contains formula 1 and formula 2 compounds simultaneously is dissolved in the solvent; In 10～40 ℃ and the following lithium-containing compound that adds of stirring; The pH value of regulating liquid reaches 7～14, forms the lithium salt complex of the glucuronic acid glycoside compound that is insoluble to solvent;
(2), isolate the lithium salt complex of the glucuronic acid glycoside compound of from liquid, separating out, join in the solvent, in the mixed solution that obtains, add the lithium salt complex dissolving of acid for adjusting pH value to glucuronic acid glycoside compound again;
(3) in the solution that step (2) obtains, add alkali, pH value to 7～8 of regulator solution, the glucuronic acid glycoside compound shown in the formula 1 that separating dissociates from solution;
In the formula,
X is selected from N, O or S, and wherein n is 2 when X is N, and n is 1 when X is selected from O or S;
R
1, R
2Independently be selected from hydrogen or replacement or non-substituted following radicals: C respectively
1-10Alkyl, C
1-10Acyl group, C
1-10Acyloxy, C
3-10Cyclic hydrocarbon radical, C
5-20Heterocyclic radical, C
6-19Aryl, C
7-15Aralkyl; Said substituted radical is selected from: hydroxyl, halogen, amino, nitro, alkyl, alkoxyl group, ether, aryl, cyanic acid, carboxyl, ester group, carboxamido-group, urea groups, alkylsulfonyl;
R
3Be selected from hydrogen or replacement 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; Said 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
1-6Alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl, the substituted piperazine carbonyl phenyl of pyrimidine, the substituted piperazine carbonyl halogenophenyl of pyrimidine, C
3-10Naphthenic base, C
1-10The substituted piperidyl of alkyl, C
3-10The piperidyl of cycloalkyl substituted, C
1-10The substituted pyrrolidyl of alkyl, C
3-10The pyrrolidyl of cycloalkyl substituted, ether, cyanic acid, carboxyl, ester group, carboxamido-group, urea groups, alkylsulfonyl.
2. method according to claim 1 is characterized in that in formula 1 and the formula 2,
X is selected from O or S, and n is 1;
R
1, R
2Independently be selected from hydrogen, replacement or non-substituted C respectively
1-6Alkyl, replacement or non-substituted C
3-6Cyclic hydrocarbon radical, replacement or non-substituted C
6-19Aryl; Said substituted radical is selected from hydroxyl, halogen, amino, nitro, C
1-6Alkyl, C
1-6In the alkoxyl group one or more;
R
3Be selected from hydrogen or replacement or non-substituted following radicals: pyrazolo Tetrahydronaphthyridderivates base, pyrazolo naphthyridinyl, tetrahydrochysene phthalazinyl, pyrazolo tetrahydro isoquinolyl, Pyrazoloisoquinolinederivatives base, tetrahydro cyclopentyl alkane and 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; Said substituting group is selected from halogen, C
1-6Alkyl, C
3-6Naphthenic base, C
1-6Haloalkyl, phenyl, C
1-6Alkyl-substituted phenyl, C
1-6Alkoxy substituted phenyl, halogenophenyl, C
1-6Alkyl substituted carbonyl phenyl, piperazine carbonyl halogenophenyl, piperazine carbonyl phenyl, the substituted piperazine carbonyl phenyl of pyrimidine, the substituted piperazine carbonyl halogenophenyl of pyrimidine, C
1-6The substituted piperidyl of alkyl, C
3-6The piperidyl of cycloalkyl substituted, C
1-6The substituted pyrrolidyl of alkyl, C
3-6In the pyrrolidyl of cycloalkyl substituted one or more; Said substituting group further is selected from one or more in halogen methyl, ethyl, n-propyl, sec.-propyl, 4-fluoro-3-(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, sec.-propyl pyrrolidyl, the cyclopentyl pyrrolidyl.
3. method according to claim 1; It is characterized in that in step (2), adding after the lithium salt complex dissolving of acid for adjusting pH value to glucuronic acid glycoside compound; The step of the lithium salt complex of the adding lithium-containing compound formation glucuronic acid glycoside compound in the repeating step (1) and the lithium salt complex dissolved step that adds acid for adjusting pH value to glucuronic acid glycoside compound in the step (2); Lithium salt complex until the glucuronic acid glycoside compound that obtains reaches target purity, just proceeds step (2) and (3).
4. method according to claim 3, the target purity of lithium salt complex that it is characterized in that described glucuronic acid glycoside compound is more than 99%.
5. method according to claim 1 is characterized in that the solvent in the step (1) is organic solvent and/or water, and wherein organic solvent is V with the volume mass ratio of bullion
Organic solvent: M
Bullion=0～150:1mL/g, water is V with the volume mass ratio of bullion
Water: M
Bullion=0～150:1mL/g, and the volume mass of organic solvent and water and bullion is 0mL/g than not simultaneously; Further, organic solvent is V with the volume mass ratio of bullion
Organic solvent: M
Bullion=0～15:1mL/g, water is V with the volume mass ratio of bullion
Water: M
Bullion=20～40:1mL/g.
6. method according to claim 1 is characterized in that in the step (1), said lithium-containing compound be selected from contain lithium oxyhydroxide, contain the lithium carbonated, contain lithium carbonic acid hydrogenate, organic lithiumation thing or contain the lithium halogeno salt; Preferred alkaline lithium-containing compound; Further be selected from Lithium Hydroxide MonoHydrate, Quilonum Retard, lithium bicarbonate, lithium methoxide, lithium ethoxide, Virahol lithium, trimethyl carbinol lithium, butyllithium, phenyl lithium, tert-butyl lithium, lithiumbromide, lithium chloride, or its hydrate.
7. method according to claim 1 is characterized in that lithium-containing compound under agitation adds solution in the step (1), and adding the continued stirring, is stirred in more than 1 minute, further at 5～30 minutes.
8. method according to claim 1 is characterized in that in the step (2), said solvent is organic solvent and/or water, and the volume mass of formula 1 compound that wherein contains in the lithium salt complex of solvent and glucuronic acid glycoside compound is than being V
Organic solvent: M
Lithium salt complex=1～150:1mL/g further is V
Organic solvent: M
Lithium salt complex=5～15:1mL/g.
9. method according to claim 1 is characterized in that said acid is selected from mineral acid or organic acid in the step (2), further is selected from hydrochloric acid, nitric acid, Hydrogen bromide, sulfuric acid, acetic acid, formic acid or propionic acid; With pH value to 1～6.5 of acid adjusting mixed solution, further to 2～5.
10. method according to claim 1 is characterized in that in the step (3), and said alkali adopts the form of the solid or the aqueous solution to use; Alkali is selected from metal hydroxides, alkali metal bicarbonate salt, metal carbonic acid thing, further is selected from sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood, further is selected from sodium hydroxide; In solution, adding before the alkali is filtering with microporous membrane with solution with water earlier; PH value to 7.0～7.5 with the alkali regulator solution.
11., it is characterized in that said organic solvent is selected from one or more in chloroform, methylene dichloride, ETHYLE ACETATE, ether, benzene, toluene, THF, methyl alcohol, ethanol, the Virahol according to claim 1,5 or 8 described methods.
12. method according to claim 1 is characterized in that the content of formula 2 compounds is below 50%, further between 2%～15% in the said glucuronic acid glycosides compound bullion that contains formula 1 and formula 2 compounds simultaneously; The purity of the glucuronic acid glycoside compound shown in the isolated formula 1 reaches more than 99.9% in the step (3).
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