CN101566610B - Analysis and detection method for voglibose intermediate - Google Patents
Analysis and detection method for voglibose intermediate Download PDFInfo
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- CN101566610B CN101566610B CN2008100936711A CN200810093671A CN101566610B CN 101566610 B CN101566610 B CN 101566610B CN 2008100936711 A CN2008100936711 A CN 2008100936711A CN 200810093671 A CN200810093671 A CN 200810093671A CN 101566610 B CN101566610 B CN 101566610B
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Abstract
The invention relates to an analysis and detection method for a voglibose intermediate, which is used for the analysis and detection of (1S)-(1 (hydroxide radical), 2, 4/1, 3)-2, 3, 4-three-O-phenmethyl-1-C-[(benzyloxy)-methyl]-6, 6-methyl disulfide-5-oxygen-1, 2, 3, 4-cyclohexanetetraol and a diastereoisomer thereof. The method is characterized in that a chromatographic column using octadecyl silane linking silica gel as a filler is adopted, an acetonitrile-ammonium acetate solution system or an acetonitrile-phosphate solution system is used as a mobile phase, the detection wavelength is 200-300nm, and reversed phase high-efficiency liquid chromatography detection is performed. The method has good separation effect and high detection sensitivity.
Description
Technical field
The present invention relates to medical technical field, in particular, relate to voglibose intermedium (1S)-(1 (hydroxyl); 2,4/1,3)-2; 3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1; 2,3, the separation of 4-cyclohexanetetraol and diastereo-isomerism thereof and analyzing detecting method.
Background technology
Voglibose intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6; 6-two sulfidomethyls-5-oxygen-1,2,3,4-cyclohexanetetraol are as the important intermediate of voglibose, and there is optical isomer in configuration in it; I.e. (1R)-(1 (hydroxyl), 2,4/1,3)-2,3; 4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3,4-cyclohexanetetraol.Therefore, to (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the quality control effect of 4-cyclohexanetetraol directly has influence on the quality of final finished.
Document US 5004838 and Synthesis of a Branched-Chain InososeDerivative, J.Org.Chem.Vol 57, No.13,1992 have reported voglibose intermedium (1S)-(1 (hydroxyl); 2,4/1,3)-2; 3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1; 2,3, document parameters such as the preparation method of 4-cyclohexanetetraol and isomeride thereof and fusing point, optical activity.Not enough below this quality control exists: 1, optical activity is comparatively rough to the quality control of chiral intermediate, can not accurately reflect the absolute optical purity of product.2, this method can not accurately be controlled limiting the quantity of of isomeride, and is very big to follow-up synthetic product quality influence.
Summary of the invention
The object of the invention purpose is to provide a kind of analyzing detecting method of voglibose intermedium, is that a kind of application reversed-phased high performace liquid chromatographic is analyzed (1S)-(1 (hydroxyl), 2; 4/1,3)-2,3; 4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2; 3, the method for 4-cyclohexanetetraol and diastereo-isomerism thereof.This method can accurately analyze (1S)-(1 (hydroxyl), 2,4/1,3)-2,3; 4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3; The optical purity of 4-cyclohexanetetraol also can detect diastereo-isomerism (1R)-(1 (hydroxyl), 2,4/1 accurately; 3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1; 2,3, the limit of 4-cyclohexanetetraol, and this method have highly sensitive, precision good, advantage such as quick, stable and easy.
The present invention adopts following technical scheme: a kind of detection method of voglibose intermedium is used for (1S)-(1 (hydroxyl), 2; 4/1,3)-2,3; 4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2; 3, the detection of 4-cyclohexanetetraol and diastereo-isomerism thereof, adopting with the octadecylsilane chemically bonded silica is the chromatographic column of filler; As moving phase, is 200nm～300nm to detect wavelength with acetonitrile-ammonium acetate solution system or acetonitrile-phosphate solution system, carries out reversed-phased high performace liquid chromatographic and detects.
Described detection ripple is preferably 210nm ± 2nm.
Described acetonitrile-ammonium acetate solution system is the moving phase that is formed by 80: 20 by volume ratios of the ammonium acetate solution of acetonitrile and 0.1mol/l.
This analyzing detecting method of the present invention, ability enough common C18 post separated in synchronization (1S)-(1 (hydroxyl), 2,4/1; 3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6; 6-two sulfidomethyls-5-oxygen-1,2,3; 4-cyclohexanetetraol and diastereo-isomerism thereof, degree of separation can complete baseline separation up to 3.7.Utilize reversed-phased high performace liquid chromatographic to carry out check and analysis, highly sensitive, R type isomeride detects and is limited to 10ng.Can accurately examine, measure delicately (1S)-(1 (hydroxyl), 2,4/1; 3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6; 6-two sulfidomethyls-5-oxygen-1,2,3; The optical purity of 4-cyclohexanetetraol and R type isomeride thereof is effectively controlled the limit of R type isomeride, for the final finished quality provides effective assurance.The chromatographic column that reversed-phased high performace liquid chromatographic according to the invention is used can be the chromatographic column of different manufacturers octadecylsilane chemically bonded silica that produce, different model as filler.
Description of drawings
Fig. 1 S type isomeride high-efficient liquid phase chromatogram.
Fig. 2 R type isomeride high-efficient liquid phase chromatogram.
Fig. 3 S type+R type isomeride high-efficient liquid phase chromatogram.
Fig. 4 baseline noise high-efficient liquid phase chromatogram.
Fig. 5 R type isomeride detection limit high-efficient liquid phase chromatogram.
Embodiment
Below embodiment be in order to help better to understand the present invention, rather than as limit.With regard to those skilled in the art, under instruction of the present invention, it is made amendment or the alternative protection scope of the present invention that still belongs to.
Embodiment 1:
Instrument and condition
Day island proper Tianjin high performance liquid chromatograph; The N2000 of Zhejiang University chromatographic work station; Chromatographic column adopting octadecylsilane chemically bonded silica post; Ultraviolet detection wavelength 210nm; Ammonium acetate solution (80: 20) with acetonitrile-0.1mol/l is a moving phase.
Experimental procedure
Get intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the 4-cyclohexanetetraol is an amount of, with moving phase dissolving and be diluted to the solution that every 1ml contains 1mg approximately.Get this solution 20 μ l and inject liquid chromatograph, the record chromatogram can be known intermedium (1S)-(1 (hydroxyl), 2 by Fig. 1; 4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6; 6-two sulfidomethyls-5-oxygen-1,2,3, the retention time of 4-cyclohexanetetraol main peak is 21.5min.Get intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the R type isomeride of 4-cyclohexanetetraol is an amount of, with moving phase dissolving and be diluted to the solution that 1ml contains 1mg approximately.Get this solution 20 μ l and inject liquid chromatograph, the record chromatogram can be known intermedium (1S)-(1 (hydroxyl) by Fig. 2; 2,4/1,3)-2; 3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1; 2,3, the retention time of the R type isomeride main peak of 4-cyclohexanetetraol is 18.3min.Other gets intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6; 6-two sulfidomethyls-5-oxygen-1,2,3, the R type isomeride of 4-cyclohexanetetraol is an amount of, with moving phase dissolving and an amount of dilution back and intermedium (1S)-(1 (hydroxyl), 2; 4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1; 2,3,4-cyclohexanetetraol solution mixes, and gets this solution 20 μ l and injects liquid chromatograph, the record chromatogram.Can know by Fig. 3, intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the degree of separation of 4-cyclohexanetetraol and its R type isomeride is good.
This shows that this chromatographic condition can be used for voglibose intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the R type isomer separation and the inspection of 4-cyclohexanetetraol.
Embodiment 2:
By above-mentioned chromatographic condition, record baseline noise: 0.22mv, 0.20mv, 0.15mv, 0.14mv, 0.15mv, mean value are 0.17mv.3 times of peak heights of baseline noise are 0.17mv * 3=0.51mv.
Precision takes by weighing voglibose intermedium (1S)-(1 (hydroxyl), 2,4/1; 3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6; 6-two sulfidomethyls-5-oxygen-1,2,3; The R type isomeride 0.0123g of 4-cyclohexanetetraol puts in the 25ml measuring bottle, adds to flow mutual-assistance dissolving and be diluted to scale, shakes up.Precision is measured above-mentioned solution 1ml and is put respectively in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up; Precision is measured 1ml and is put respectively in the 10ml measuring bottle, adds moving phase and is diluted to scale, shakes up; Getting concentration is the solution of 0.49 μ g/ml, gets 20 μ l and injects liquid chromatograph, and it is 0.41mv that the record chromatogram gets peak height, with 3 times of baseline noise basically identicals.
Intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the R type isomeride of 4-cyclohexanetetraol detect and are limited to 0.49 μ g/ml * 20 μ l * 10
3* 10
-3=9.8ng.
So intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the minimum detectability amount of the R type isomeride of 4-cyclohexanetetraol is: 10ng.Explain that this instrument can satisfy the sensitivity requirement of detection.See Fig. 4～5.
Embodiment 3:
Get intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2; 3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2; 3,4-cyclohexanetetraol sample is an amount of, adds the moving phase dissolving and is diluted to the solution that every 1ml contains 1mg approximately, as need testing solution.Other gets intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2; 3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2; 3, the R type isomeride of 4-cyclohexanetetraol is an amount of, adds the moving phase dissolving and is diluted to the solution that every 1ml contains 5 μ g, as reference substance solution.By above-mentioned chromatographic condition, to get each 20 μ l of need testing solution and reference substance solution and inject liquid chromatograph, the record chromatogram is returned-calculating of change method by area, promptly gets the content of these article; If have and the identical chromatographic peak of R type isomeride retention time, its peak area must not be greater than the main peak area (0.5%) of reference substance solution in the need testing solution chromatogram.See table 1.
Table 1 intermedium (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the 4-cyclohexanetetraol is measured the result
Table
This shows, this analytical approach can be accurately quantitative (1S)-(1 (hydroxyl), 2,4/1,3)-2,3,4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2,3, the purity of 4-cyclohexanetetraol and R type isomeride thereof.
Claims (3)
1. the analyzing detecting method of a voglibose intermedium is used for (1S)-(1 (hydroxyl), 2; 4/1,3)-2,3; 4-three-O-benzyl-1-C-[(benzyloxy)-methyl]-6,6-two sulfidomethyls-5-oxygen-1,2; 3, the analyzing and testing of 4-cyclohexanetetraol and diastereo-isomerism thereof is characterized in that: adopting with the octadecylsilane chemically bonded silica is the chromatographic column of filler; As moving phase, the detection wavelength is 200nm～300nm with 80: 20 by volume the ratio of ammonium acetate solution of acetonitrile and 0.1mol/l, carries out reversed-phased high performace liquid chromatographic and detects.
2. the analyzing detecting method of voglibose intermedium as claimed in claim 1 is characterized in that: described detection wavelength is 210nm ± 2nm.
3. according to claim 1 or claim 2 the analyzing detecting method of voglibose intermedium, it is characterized in that: said chromatographic column is the C18 post.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5004838A (en) * | 1986-09-09 | 1991-04-02 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5004838A (en) * | 1986-09-09 | 1991-04-02 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
Non-Patent Citations (3)
| Title |
|---|
| JP特开2001-2567A 2001.01.09 |
| 张秀玲.HPLC法柱后衍生荧光测定伏格列波糖片有关物质及含量.《中国药品标准》.2004,第5卷(第5期),第41-43页. * |
| 曾洁.RID-HPLC法测定伏格列波糖口腔崩解片中伏格列波糖的含量.《中国药事》.2008,第22卷(第12期),第1093-1130. * |
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