CN106442806A - Method for analyzing purity and related substances of intermediate cyanide of febuxostat - Google Patents
Method for analyzing purity and related substances of intermediate cyanide of febuxostat Download PDFInfo
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- CN106442806A CN106442806A CN201611066097.1A CN201611066097A CN106442806A CN 106442806 A CN106442806 A CN 106442806A CN 201611066097 A CN201611066097 A CN 201611066097A CN 106442806 A CN106442806 A CN 106442806A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
The invention discloses a method for analyzing purity and related substances of intermediate cyanide of febuxostat. The method refers to a high-efficiency liquid chromatography method which includes the steps of 1) reference substance solution preparation; 2) test solution preparation; 3) test sample measuring; 4) computation: computing product content and content of the related substances by a peak area according to an area normalization method. According to a high performance liquid chromatography of the purity and related substances of intermediate cyanide of febuxostat, the chromatography conditions are shown as follows: chromatographic column: a C18 chromatographic column; detecting wavelength: 322nm; mobile phase ratio of acetonitrile to 0.1mol/L ammonium acetate solution (pH4.0): 60:40 (in volume); flow speed: 1.5mL/min; column temperature: 30 DEG C. The method for analyzing the purity and the related substances of the intermediate cyanide of the febuxostat controls the intermediate quality intermediate in a febuxostat cyaniding process, so as to improve the reaction degree of subsequent reaction and quality of final product.
Description
Technical field
The invention belongs to chemical analysis method field, and in particular to a kind of purity of Febustat intermediate cyano thing and phase
Close the analysis method of material.
Background technology
Febustat Main Ingredients and Appearance is Fei Buzuosita, its chemical entitled 2- [(3- cyano-4-isobutoxy) phenyl] -4-
Methyl-5-thiazole carboxylic acid, is xanthine oxidase (XO) inhibitor, it is adaptable to the hyperuricemia with gout symptom long-term
Treatment.The common method for preparing Febustat be using 2- [3- formoxyl -4- hydroxy phenyl] -4- methylthiazol-5-formic acid second
Ester becomes ether with isobutane bromide after rectification, then obtains Febustat crude product through cyaniding, hydrolysis, obtains high-purity after recrystallization
Febustat.
At present, Febustat important intermediate cyano group thing（Chemical name is 2-（3- cyano group -4- hydroxy phenyl）- 4- methyl-
5- thiazole ethyl formate, structural formula is as follows：
The intermediate is obtained through cyaniding operation by isobutyl substratess, reaction need to be controlled, be made product content in cyano group produce product
97.0% is not less than, related substanceses content is not more than 0.5%, and total impurities content is not more than 2.0%, to improve final products Fei Busi
His quality.In existing analysis, the purity of Febustat intermediate cyano thing and the analysis method of related substanceses have no.
Content of the invention
The technical problem to be solved in the present invention is to fill up the purity of Febustat intermediate cyano thing and dividing for related substanceses
Analysis method, provides a kind of the accurate, reliable of analysis result, the purity of the simple Febustat intermediate cyano thing of operating process and
The analysis method of related substanceses.
The purpose of the present invention is by the following technical programs implementing：
A kind of purity of Febustat intermediate cyano thing and the analysis method of related substanceses, comprise the steps：
1）. reference substance solution is prepared
Precision weighs 25mg reference substance in the volumetric flask of 25mL, dissolves and be diluted to scale with diluent, mixes；Accurately pipette
Solution 1.0mL with diluted to scale, is mixed in the volumetric flask of 10mL（Reference substance concentration：0.1mg/mL）；
2）. need testing solution is prepared
Precision weighs 25mg sample in the volumetric flask of 25mL, dissolves and be diluted to scale with diluent, mixes；This is accurately pipetted
1.0mL with diluted to scale, is mixed in the volumetric flask of 10mL（Test sample concentration：0.1mg/mL）；
3）. Specimen Determination
Under above-mentioned chromatographic condition, after Chromatogram Baseline is stable, difference sample introduction, 1 pin of blank solution, standard solution, test sample are molten
Each 1 pin of liquid, records chromatographic process；Confirm noiseless between all the components.
4）. calculate
Area normalization method, under purity testing item, the retention time of need testing solution main peak should be with reference substance solution main peak
Retention time is consistent, in the chromatogram of need testing solution gained, it is desirable to which the peak area of the single impurity of related substanceses must not be big
In the 0.5% of total peak area, the peak area sum of all impurity cannot be greater than the 2.0% of total peak area, and the peak area of main peak must not
Less than total peak area 98.0%；
The step 3）In, operation condition of chromatogram is as follows：
| Instrument | High performance liquid chromatograph is equipped with UV-detector |
| Chromatographic column | 200 × 4.6mm of Diamosil C18,5 m or equivalent post |
| Mobile phase A | 0.1mol/L Spirit of Mindererus., pH 4.0 |
| Mobile phase B | Acetonitrile |
| Mobile phase | Mobile phase A：Mobile phase B=60：40（% V/V） |
| Detection wavelength, nm | 22 |
| Flow velocity, mL/min | 1.5 |
| Column temperature, DEG C | 30 |
| Sample size, μ l | 20 |
| Run time, min | 30 |
Collection of illustrative plates is checked after the completion of analysis, integrate component peak；After process, record analyses result, after analysis, injector is clear with mobile phase
Wash, then cleaned with toluene, dry.
Beneficial effects of the present invention：
A kind of purity of Febustat intermediate cyano thing of the present invention and the analysis method of related substanceses, analysis method uses liquid phase
Chromatograph, it is ensured that accurate, the reliability of analysis result, operating process is simple, and which can be to the pure of Febustat intermediate cyano thing
The content of degree and related substanceses is measured.The present invention has that scope of application width, step be simple, analysis method takes short, analysis
Low cost；The advantages of analysis method is stable to analysis result accuracy height, range of linearity width, favorable reproducibility, analysis condition, can be wide
The general on-line analyses being applied in production.
Specific embodiment
Below by way of specific embodiment, technical scheme is described in further detail, but the protection model of the present invention
Enclose and be not limited thereto.
Embodiment 1
A kind of purity of Febustat intermediate cyano thing and the analysis method of related substanceses
1st, operation condition of chromatogram is set
Chromatograph carries out necessary regulation after starting, and to reach the typical operation conditions that table 1 gives, or can obtain detached on an equal basis
Other suitable conditions.After instrument stabilizer, you can be measured.
Chromatographic column and typical operation conditions that table 1 is recommended
| Instrument | High performance liquid chromatograph is equipped with UV-detector |
| Chromatographic column | Diamosil C18 200×4.6mm 5µm |
| Mobile phase A | 0.1mol/L Spirit of Mindererus., pH 4.0 |
| Mobile phase B | Acetonitrile |
| Mobile phase | Mobile phase A：Mobile phase B=60：40（% V/V） |
| Detection wavelength, nm | 322 |
| Flow velocity, mL/min | 1.5 |
| Column temperature, DEG C | 30 |
| Sample size, μ l | 20 |
| Run time, min | 30 |
2nd, reference substance solution and need testing solution are prepared（Weighing method）
Reference substance solution is prepared：Precision weighs 25mg reference substance in the volumetric flask of 25mL, dissolves and be diluted to quarter with diluent
Degree, mixes；Solution 1.0mL is accurately pipetted in the volumetric flask of 10mL, with diluted to scale, mix（Reference substance is dense
Degree：0.1mg/mL）；
Need testing solution is prepared：Precision weighs 25mg sample in the volumetric flask of 25mL, is dissolved with diluent and is diluted to scale,
Mix；The 1.0mL is accurately pipetted in the volumetric flask of 10mL, with diluted to scale, mix（Test sample concentration：
0.1mg/mL）；
3rd, Specimen Determination
Under above-mentioned chromatographic condition, after Chromatogram Baseline is stable, difference sample introduction, 1 pin of blank solution, standard solution, test sample are molten
Each 1 pin of liquid, records chromatographic process；Confirm noiseless between all the components.
Spectrogram is checked after the completion of analysis, integrate each component peak.After process, record analyses result.
After analysis, injector mobile phase is cleaned and then is cleaned with toluene and dries.
4th, calculate
Area normalization method, under purity testing item, the retention time of need testing solution main peak should be with reference substance solution main peak
Retention time is consistent, in the chromatogram of need testing solution gained, it is desirable to which the peak area of the single impurity of related substanceses must not be big
In the 0.5% of total peak area, the peak area sum of all impurity cannot be greater than the 2.0% of total peak area, and the peak area of main peak must not
Less than total peak area 98.0%；
5th, the statement of analysis result
5.1 after the completion of analysis, it is stipulated that after the value of result should retain arithmetic point, three bit digital, i.e. result are taken to 0.001%.
5.2 it is repeated
Same operator use same instrument, under the same operating conditions, with normal and correct operational approach to same
Sample carries out determining twice in succession.
As a result it is not more than the 20% of arithmetic mean of instantaneous value in its difference of 0.001%-0.1% concentration range.
As a result 0.1%-0.2% concentration range be difference be not more than arithmetic mean of instantaneous value 5%.
As a result it is being that difference is not more than the 2% of arithmetic mean of instantaneous value more than 0.2% concentration range.
The preferred embodiments of the present invention are the foregoing is only, the present invention is not limited to, although with reference to aforementioned reality
Apply example to be described in detail the present invention, for a person skilled in the art, which still can be to aforementioned each enforcement
Technical scheme described in example is modified, or carries out equivalent to which part technical characteristic.All essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement that is made etc., should be included within the scope of the present invention.
Claims (3)
1. the analysis method of a kind of purity of Febustat intermediate cyano thing and related substanceses, it is characterised in that including as follows
Step：
1）. reference substance solution is prepared
Precision weighs 25mg reference substance in the volumetric flask of 25mL, dissolves and be diluted to scale with diluent, mixes；Accurately pipette
Solution 1.0mL with diluted to scale, is mixed in the volumetric flask of 10mL（Reference substance concentration：0.1mg/mL）；
2）. need testing solution is prepared
Precision weighs 25mg sample in the volumetric flask of 25mL, dissolves and be diluted to scale with diluent, mixes；This is accurately pipetted
1.0mL with diluted to scale, is mixed in the volumetric flask of 10mL（Test sample concentration：0.1mg/mL）；
3）. Specimen Determination
Under above-mentioned chromatographic condition, after Chromatogram Baseline is stable, difference sample introduction, 1 pin of blank solution, standard solution, test sample are molten
Each 1 pin of liquid, records chromatographic process；Confirm noiseless between all the components；
4）. calculate
Area normalization method, under purity testing item, the retention time of need testing solution main peak should be with reference substance solution main peak
Retention time is consistent, in the chromatogram of need testing solution gained, it is desirable to which the main peak area of product is cannot be less than in total peak area
98.0%, the peak area of other single impurity cannot be greater than the 0.5% of total peak area, and the peak area sum of all impurity must not be big
In total peak area 2.0%.
2. the analysis method of a kind of purity of Febustat intermediate cyano thing according to claim 1 and related substanceses,
It is characterized in that：The step 3）In, the operation condition of chromatogram is as follows：
.
3. the analysis method of a kind of purity of Febustat intermediate cyano thing according to claim 1 and related substanceses,
Characterized in that, collection of illustrative plates is checked after the completion of analysis, integrate component peak；After process, record analyses result, injector stream after analysis
Move and mutually clean, then cleaned with toluene, dry.
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| CN201611066097.1A CN106442806A (en) | 2016-11-28 | 2016-11-28 | Method for analyzing purity and related substances of intermediate cyanide of febuxostat |
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| CN201611066097.1A CN106442806A (en) | 2016-11-28 | 2016-11-28 | Method for analyzing purity and related substances of intermediate cyanide of febuxostat |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107202848A (en) * | 2017-07-24 | 2017-09-26 | 浙江华海药业股份有限公司 | A kind of liquid phase chromatography analytical method of Clofazimine |
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| WO2011022757A1 (en) * | 2009-08-24 | 2011-03-03 | Queensland University Of Technology | Purine-targeted diagnosis and therapy of wounds |
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| CN107202848A (en) * | 2017-07-24 | 2017-09-26 | 浙江华海药业股份有限公司 | A kind of liquid phase chromatography analytical method of Clofazimine |
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