CN101580528A - Method for purifying cytidine (deoxidation) and derivatives thereof - Google Patents
Method for purifying cytidine (deoxidation) and derivatives thereof Download PDFInfo
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Abstract
The invention provides a method for purifying cytidine (deoxidation)and derivatives thereof, including the steps: (1) aqueous solution containing compound shown as formula I is fed onto an alkaline resin; (2) water is used for eluting to obtain high purity compound shown as formula I; wherein, R1 is hydrogen, halogen, alkyl or alkoxyl, R2 is hydrogen, hydroxide radical or halogen, R3 is hydrogen, hydroxide radical, halogen, alkoxyl or nitrine, and R4 is hydroxide radical, halogen, alkoxyl or nitrine.
Description
Technical field
The present invention relates to the refining of deoxynucleoside, especially by uridine (deoxidation) and the cytidine (deoxidation) of derivative conversion and the purification process of derivative thereof.
Background technology
In recent years, along with gene is formed the development of medicine, antisense DNA medicine etc. is developed rapidly.Thereupon, constituting the DNA oligopolymer of raw material and the nucleosides of formation oligopolymer raw material and the needs of derivative thereof increases day by day.On the other hand, in the purposes of pharmaceuticals,, be necessary to use very highly purified nucleosides and derivative thereof for the secondary resultant of doing one's utmost to suppress to generate by the impurity that contains.
The cytidine (deoxidation) that is transformed by uridine (deoxidation) and derivative thereof and the process for purification of derivative thereof have following several up to now:
1.EP0204264 in the cytidine (deoxidation) that will obtain and derivative thereof disclosed reaction solution concentrate after, obtain product by crystallization.Can not remove uridine (deoxidation) and derivative thereof effectively in this method.For example, the unreacted that contains in cytidine (deoxidation) and the derivatives reaction liquid thereof is the by product (uridylic and the derivative thereof that generate of uridine (deoxidation) and derivative thereof and reaction process completely, cytosine(Cyt) and derivative thereof etc.), be difficult to especially remove by crystallization method, in addition these impurity in the pharmaceuticals manufacturing can under go on foot operation and produce a very large impact.
2.FRG Patent NO.2122991 discloses the reaction solution of the cytidine (deoxidation) that will obtain and derivative thereof concentrate after, by refining cytidine (deoxidation) of silica gel column chromatography chromatography and derivative thereof.EP0204264 and CAN.J.CHEM.VOL.68, in 1990 also relevant for the description of similar approach.This method needs huge purification apparatus in industrialization, and from a large amount of solvents of needs, for mass production in the future, supplies with in a large number and production safety, and environment protection waits and has very big problem.
3.EP0204264 disclose by acidic ion exchange resin refining, earlier with the aqueous solution of cytidine reactant acidic ion exchange resin by different model.Cytidine is adsorbed like this, and uridine flows out, and reaches the purified purpose thereby with ammoniacal liquor cytidine is washed then.But this method has following problem: all can produce cytosine(Cyt) and derivative thereof inevitably in the reaction process of all cytidines (deoxidation) that transformed by uridine (deoxidation) and derivative thereof and derivative thereof, and these materials can be adsorbed also and washed by ammoniacal liquor and be present in the product by acidic ion exchange resin.
Therefore, this area press for provide a kind of effectively and need not the method that obtains highly purified cytidine (deoxidation) and derivative thereof of special equipment.
Summary of the invention
The present invention aims to provide the purification process of a kind of cytidine (deoxidation) and derivative thereof.
In the present invention, provide a kind of purification process of the compound suc as formula I, described method comprises step:
(1) will contain on the aqueous solution of formula I compound sample to basic resin; With
(2) water wash-out obtains highly purified formula I compound;
In the formula, R1 represents hydrogen, halogen, alkyl, alkoxyl group;
R2 represents hydrogen, hydroxyl, halogen;
R3 represents hydrogen, hydroxyl, halogen, alkoxyl group, nitrine;
R4 represents hydroxyl, halogen, alkoxyl group, nitrine.
In another preference, foreign matter content is counted 3-10w/w% with the gross weight of solute in the described aqueous solution that contains formula I compound.
In another preference, the described content that contains the aqueous solution Chinese style I compound of formula I compound is counted 90-97w/w% with the gross weight of solute.
In another preference, described impurity is selected from following one or more: suc as formula the compound shown in the II, cytosine(Cyt), uridylic, thymus pyrimidine;
In the formula, R1 represents hydrogen, halogen, alkyl, alkoxyl group;
R2 represents hydrogen, hydroxyl, halogen;
R3 represents hydrogen, hydroxyl, halogen, alkoxyl group, nitrine;
R4 represents hydroxyl, halogen, alkoxyl group, nitrine.
Uridylic
In another preference, described basic resin is a basic resin; More preferably, be selected from acetic acid type basic resin, formic acid type basic resin, chlorine type basic resin or hydrogen-oxygen type basic resin.
In another preference, the described pH5.5-14 that contains the aqueous solution of formula I compound.
In another preference, the described pH8.0-14 that contains the aqueous solution of formula I compound.
In another preference, the volume of described basic resin (L) be contain the formula I compound in the aqueous solution of formula I compound weight (Kg) 10-50 doubly.
In another preference, the volume of described basic resin (L) be contain the formula I compound in the aqueous solution of formula I compound weight (Kg) 20-40 doubly.
In another preference, the temperature of the wash-out water in the step (2) is 10-20 ℃.
In view of the above, the invention provides a kind of effectively and need not the method that obtains highly purified cytidine (deoxidation) and derivative thereof of special equipment.
Embodiment
The contriver is through extensive and deep research, discovery can be by the chromatography purification cytidine (deoxidation) and the derivative thereof of basic resin, especially at the cytidine (deoxidation) that obtains by uridine (deoxidation) and derivative conversion thereof and the purifying of derivative thereof, can obtain very highly purified cytidine (deoxidation) and derivative thereof, thereby finish the present invention.
Definition
" basic resin " as used herein and " anionite-exchange resin " can exchange use, all are meant the solid phase of positively charged (as have the part of one or more positively chargeds attached to it, for example quaternary ammonium group).The commercial anionite-exchange resin of buying comprises DEAE-Mierocrystalline cellulose, QAE SEPHADEX
TMWith FAST Q SEPHAROSE
TM(Pharmacia).
" solid phase " refers to that one or more charged parts can adherent non-aqueous matrix.Solid phase can be discontinuous phase, film or the filter membrane etc. of purification column, a kind of disperse particles.The examples of material that can form solid phase comprises polysaccharide (as agarose and Mierocrystalline cellulose); And other mechanically stable matrix such as silicon (as controllable bore diameter glass), poly-(vinylbenzene divinyl) benzene, polyacrylamide, ceramic particle and above-mentioned arbitrary derivative.
" aqueous solution that contains formula I compound " be meant be used for will contain the composition of interested formula I compound and one or more impurity be added to solution on the ion exchange resin.The pH that it has can make interested formula I compound (with common one or more impurity) combine with ion exchange resin.
" purifying " formula I compound from the composition that contains formula I compound and one or more impurity, refer to by from composition (wholly or in part) remove the purity that at least a impurity improves composition Chinese style I compound." purification step " can be a part that obtains in total purge process of " homogeneous " composition (" homogeneous " weight of referring to contain formula I compound interested at least about 90%, preferred weight is at least about 95% composition with respect to the gross weight of composition) in this article.
With certain molecule " combination " to ion-exchange material, finger (pH) under appropriate condition makes this molecule contact with ion-exchange material, and this molecule is fixed in the ion-exchange material by the ionic interaction reversible between one or more charged groups on molecule and the ion-exchange material or on the material under this condition.
Molecule " wash-out " from ion-exchange material is got off, refer to remove this molecule down by changing ion-exchange material liquid ions intensity on every side from ion-exchange material, this ionic strength can make the charged site on solution and the molecule competitive ion exchange material.
" solute " is meant the material that is scattered in the aqueous solution that contains formula I compound in the water, comprises formula I compound and one or more impurity.Described impurity comes from the synthesis step of formula I compound, such as but not limited to, suc as formula the compound shown in the II, cytosine(Cyt) and derivative thereof, uridylic and derivative thereof, thymus pyrimidine and derivative thereof.
The invention provides a kind of purification process of the compound suc as formula I, described method comprises step:
(1) will contain on the aqueous solution of formula I compound sample to basic resin; With
(2) water wash-out obtains highly purified formula I compound;
In the formula, R1 represents hydrogen, halogen, alkyl, alkoxyl group;
R2 represents hydrogen, hydroxyl, halogen;
R3 represents hydrogen, hydroxyl, halogen, alkoxyl group, nitrine;
R4 represents hydroxyl, halogen, alkoxyl group, nitrine.
Preferably, will remove by the aqueous solution behind chromatography decompression and obtain behind the moisture or reduce pressure to remove behind the moisture suspending and obtaining, then drying under the pressure below the normal atmosphere with containing alcoholic solvent.
The chromatography temperature of basic resin of the present invention preferably is 10-20 ℃ at 10-30 ℃, more preferably is 12-17 ℃.
Content (purity) measuring method of formula I compound of the present invention and impurity uses high performance liquid phase to measure (HPLC), and their content is represented with the per-cent of its peak area and each composition peak area sum.
Formula I compound of the present invention can obtain by method well known in the art, is preferably to obtain by the compound bio-transformation suc as formula II.Described bioconversion method is well known in the art, such as but not limited to, comprise step: with formula II compound, acetonitrile, trolamine and triazole etc. mix, after the reaction and ammoniacal liquor mix, obtain formula I compound.
Contain one or more impurity in the formula I compound of the raw material of the purification process that conduct provides among the present invention, the content of described impurity is 3-10w/w%, preferably is 5-7w/w%.
The basic resin that the present invention uses is a strongly basic anion exchange resin, has the univalent positive charge, includes but not limited to chlorine type basic resin, acetic acid type basic resin, formic acid type basic resin, hydrogen-oxygen type basic resin.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets is disclosed can with any composition forms and usefulness, each feature that is disclosed in the specification sheets can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore removing has special instruction, and the feature that is disclosed only is the general example of equalization or similar features.
Major advantage of the present invention is:
1, the purification process that provides is easy, need not specific installation, and is with low cost.
2, the purification process effect that provides is remarkable, the content of uridine (deoxidation) and impurity such as derivative cytosine(Cyt) and derivative thereof thereof all detect less than.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in the percent weight in volume among the present invention is well-known to those skilled in the art, for example is meant the weight of solute in 100 milliliters solution.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
HPLC (high performance liquid chromatography) condition (2 '-dCR, 5-Me-dCR, the analysis condition of 2 '-OMe-CR) among the following embodiment of the present invention
Post: YMC-AQ 250*4.6mm
Flow velocity: 0.8ml/min
Column temperature: 25 ℃
Detect wavelength: 260nm
Mobile phase: gradient condition
Time (min) A liquid (%) B liquid (%)
0 100 0
2 100 0
12 70 30
42 70 30
48 100 0
58 100 0
A liquid: with Na
2HPO
4(1.323g), NaH
2PO
4(0.0938g) be dissolved in the distilled water and be settled to 1L, use the 0.22um water film filtering then.
B liquid: hplc grade methanol
A liquid in the analytic process, the online degassing of B liquid, helium flow velocity 50ml/min.
Reference example 1
(2 '-dCR) the preparation of 2 '-Deoxyribose cytidine
3 ', 5 '-di-O-acetyl-2 '-dUR 50g joins 800ml acetonitrile, 220ml TEA, 106g1, and 2,4-Triazole and 120ml POCl
3Mixed solution in, controlled temperature 8-15 ℃, reaction is evaporated to after spending the night dried, obtain a kind of flaxen oily matter and be 4-Triazine-1-(3 ', 5 '-di-O-acetyl-2 '-uracil of Deoxy-β-D-ribofuranosyl).
Add 40 ℃ of vigorous stirring of ammoniacal liquor 2000ml temperature control and be evaporated to driedly after 5 hours in this oily matter, add water 500ml dissolving back HPLC and analyze: 2 '-dUR and as the cytosine(Cyt) of by product, uridylic contains 2.3%, 1.2% respectively, 2.1%.
Reference example 2
The preparation of 5-methyl-2 '-Deoxyribose cytidine (5-Me-dCR)
3 ', 5 '-di-O-acetyl-2 '-dTR 10g joins 160ml acetonitrile, 40ml TEA (three trolamines), 20g 1,2,4-Triazole (triazole) and 25ml POCl
3Mixed solution in, controlled temperature 8--15 ℃, reaction is evaporated to after spending the night dried, obtain a kind of flaxen oily matter and be 4-Triazine-1-(3 ', 5 '-di-O-acetyl-2 '-thymine of Deoxy-β-D-ribofuranosyl).
Add 40 ℃ of vigorous stirring of ammoniacal liquor 400ml temperature control and be evaporated to driedly after 5 hours in this oily matter, add water 100ml dissolving back HPLC and analyze: 2 '-dTR and as the thymus pyrimidine of by product, 5-methylcytosine contains 1.8%, 1.9% respectively, 2.1%.
Reference example 3
(2 '-OMe-CR) the preparation of 2 '-methoxyl group-cytidine
3 ', 5 '-di-O-acetyl-2 '-OMe-UR 10g joins 160ml acetonitrile, 38ml TEA, 17.5g 1,2,4-Triazole and 23ml POCl
3Mixed solution in, controlled temperature 8--15 ℃, reaction is evaporated to after spending the night dried, obtain a kind of flaxen oily matter and be 4-Triazine-1-(3 ', 5 '-di-O-acetyl-2 '-cytosine of OMe-β-D-ribofuranosyl).
Add 40 ℃ of vigorous stirring of ammoniacal liquor 400ml temperature control and be evaporated to driedly after 5 hours in this oily matter, add water 100ml dissolving back HPLC and analyze: 2 '-OMe-UR and as the uridylic of by product, cytosine(Cyt) contains 1.3%, 2.2% respectively, 2.5%.
Embodiment 1
The purifying of 2 '-Deoxyribose cytidine
Synthetic 2 ' in the reference example 1-Deoxyribose cytidine aqueous solution 100ml is transferred PH to 10.0 with 10N NaOH, and last sample is to 200ml acetic acid type basic resin.With 15 ℃ washing and collection effluent liquid, there is not uv-absorbing then until effluent liquid.Merge and collect liquid, obtain white solid at 55 ℃ of following concentrating under reduced pressure removal moisture.This solid to constant weight, gets 6.78g. at 60 ℃ of following drying under reduced pressure
HPLC analyzes: contain 2 '-dCR (99.99%), and 2 '-dUR and as the cytosine(Cyt) of by product, uridylic is undetected.Detect below the boundary (0.01%).
Ultimate analysis (C
9H
13N
3O
4): sample detection C:47.51%; H:5.82%; N:18.43%.
(theoretical value: C:47.57%; H:5.77%; N:18.49%)
Rotational analysis: [α]
D 20+ 54 ° of (C=2, H
2O)
Embodiment 2
The purifying of 5-Me-dCR
Synthetic 5-Me-dCR aqueous solution 100ml in the reference example 2 is transferred PH to 9.0 with 10N NaOH, and last sample is to 200ml formic acid type basic resin.With 15 ℃ washing and collection effluent liquid, there is not uv-absorbing then until effluent liquid.Merge and collect liquid, obtain white solid at 55 ℃ of following concentrating under reduced pressure removal moisture.This solid to constant weight, gets 6.22g. at 60 ℃ of following drying under reduced pressure
HPLC analyzes: contain 5-Me-dCR (99.99%), and 2 '-dTR and as the thymus pyrimidine of by product, 5-methylcytosine is undetected.Detect below the boundary (0.01%).
Ultimate analysis (C
10H
15N
3O
4): sample detection C:49.72%; H:6.26%; N:17.38%.
(theoretical value: C:49.79%; H:6.27%; N:17.42%)
Embodiment 3
The purifying of 2 '-OMe-CR
Synthetic 2 ' in the reference example 3-OMe-CR aqueous solution 100ml is transferred PH to 13.5 with 10N NaOH, and last sample is to 400ml chlorine type basic resin.With 2--5 ℃ washing and collection effluent liquid, there is not uv-absorbing then until effluent liquid.Merge and collect liquid, obtain white solid at 55 ℃ of following concentrating under reduced pressure removal moisture.This solid to constant weight, gets 6.6g. at 60 ℃ of following drying under reduced pressure
HPLC analyzes: contain 5-Me-dCR (99.99%), and 2 '-OMe-UR and as the uridylic of by product, cytosine(Cyt) is undetected.Detect below the boundary (0.01%).
Ultimate analysis (C
10H
15N
3O
4): sample detection C:46.62%; H:5.87%; N:16.25%.
(theoretical value: C:46.69%; H:5.88%; N:16.33%)
The above only is preferred embodiment of the present invention, be not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is broadly to be defined in the claim scope of application, any technology entity or method that other people finish, if it is defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.
Claims (10)
1. the purification process suc as formula the compound of I is characterized in that, described method comprises step:
(1) will contain on the aqueous solution of formula I compound sample to basic resin; With
(2) water wash-out obtains highly purified formula I compound;
In the formula, R1 represents hydrogen, halogen, alkyl, alkoxyl group;
R2 represents hydrogen, hydroxyl, halogen;
R3 represents hydrogen, hydroxyl, halogen, alkoxyl group, nitrine;
R4 represents hydroxyl, halogen, alkoxyl group, nitrine.
2. purification process as claimed in claim 1 is characterized in that, foreign matter content is counted 3-10w/w% with the gross weight of solute in the described aqueous solution that contains formula I compound.
3. purification process as claimed in claim 1 is characterized in that, the described content that contains the aqueous solution Chinese style I compound of formula I compound is counted 90-97w/w% with the gross weight of solute.
4. purification process as claimed in claim 2 is characterized in that, described impurity is selected from following one or more: suc as formula the compound shown in the II, cytosine(Cyt), uridylic, thymus pyrimidine;
In the formula, R1 represents hydrogen, halogen, alkyl, alkoxyl group;
R2 represents hydrogen, hydroxyl, halogen;
R3 represents hydrogen, hydroxyl, halogen, alkoxyl group, nitrine;
R4 represents hydroxyl, halogen, alkoxyl group, nitrine.
5. purification process as claimed in claim 1 is characterized in that described basic resin is a basic resin; Preferably from acetic acid type basic resin, formic acid type basic resin, chlorine type basic resin or hydrogen-oxygen type basic resin.
6. purification process as claimed in claim 1 is characterized in that, the described pH5.5-14 that contains the aqueous solution of formula I compound.
7. purification process as claimed in claim 6 is characterized in that, the described pH8.0-14 that contains the aqueous solution of formula I compound.
8. purification process as claimed in claim 1 is characterized in that, the volume of described basic resin (L) be contain the formula I compound in the aqueous solution of formula I compound weight (Kg) 10-50 doubly.
9. purification process as claimed in claim 8 is characterized in that, the volume of described basic resin (L) be contain the formula I compound in the aqueous solution of formula I compound weight (Kg) 20-40 doubly.
10. purification process as claimed in claim 1 is characterized in that, the temperature of the wash-out water in the step (2) is 10-20 ℃.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910053053 CN101580528B (en) | 2009-06-15 | 2009-06-15 | Method for purifying cytidine (deoxidation) and derivatives thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910053053 CN101580528B (en) | 2009-06-15 | 2009-06-15 | Method for purifying cytidine (deoxidation) and derivatives thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101580528A true CN101580528A (en) | 2009-11-18 |
| CN101580528B CN101580528B (en) | 2013-05-22 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993255A (en) * | 2011-09-19 | 2013-03-27 | 上海兆维科技发展有限公司 | Preparation of 2'-O-(2-methyl ethyl)-5-methyl uridine and 2'-O-(2-methyl ethyl)-5-methyl cytidine and derivative and purifying method thereof |
| CN105859809B (en) * | 2016-04-09 | 2018-12-04 | 南昌大学 | A method of extracting beta-thymidine from fermentation liquid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1331615A (en) * | 1961-08-29 | 1963-07-05 | Schwarz Biores | Advanced process for enzymatic digestion of nucleic acids |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4754026A (en) * | 1985-06-04 | 1988-06-28 | Takeda Chemical Industries, Ltd. | Conversion of uracil derivatives to cytosine derivatives |
-
2009
- 2009-06-15 CN CN 200910053053 patent/CN101580528B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1331615A (en) * | 1961-08-29 | 1963-07-05 | Schwarz Biores | Advanced process for enzymatic digestion of nucleic acids |
Non-Patent Citations (1)
| Title |
|---|
| BYRNE, P. V.等: ""Separation of deoxycytidine from urine by ion-exchange chromatography"", 《JOURNAL OF CHROMATOGRAPHY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993255A (en) * | 2011-09-19 | 2013-03-27 | 上海兆维科技发展有限公司 | Preparation of 2'-O-(2-methyl ethyl)-5-methyl uridine and 2'-O-(2-methyl ethyl)-5-methyl cytidine and derivative and purifying method thereof |
| CN102993255B (en) * | 2011-09-19 | 2016-02-10 | 上海兆维科技发展有限公司 | The preparation of 2 '-O-(2-methoxyethyl)-5-methyl-uridin and 2 '-O-(2-methoxyethyl)-5-methylcytidine and derivative thereof and purification process thereof |
| CN105859809B (en) * | 2016-04-09 | 2018-12-04 | 南昌大学 | A method of extracting beta-thymidine from fermentation liquid |
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| Publication number | Publication date |
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| CN101580528B (en) | 2013-05-22 |
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