CN110940759B - HPLC (high performance liquid chromatography) detection method of vildagliptin intermediate-5 - Google Patents
HPLC (high performance liquid chromatography) detection method of vildagliptin intermediate-5 Download PDFInfo
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Abstract
The invention relates to the technical field of drug detection, and particularly discloses an HPLC (high performance liquid chromatography) detection method of vildagliptin intermediate-5. Chromatographic conditions of the HPLC: and (3) chromatographic column: the filler is octadecylsilane chemically bonded silica; mobile phase: the mobile phase A is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 200:3-5: 3-5; the mobile phase B is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 80:90-100: 25-35; column temperature: 33-37 ℃; detection wavelength: 208-212 nm; flow rate: 1.6-1.8 ml/min; the elution mode is gradient elution. The chromatographic peaks in the chromatogram obtained by the method can be completely separated, the separation degree is good, the accuracy of the purity detection of the vildagliptin intermediate-5 in the sample can be ensured, and the reliable guarantee is provided for the quality and the curative effect of the subsequently synthesized vildagliptin.
Description
Technical Field
The invention relates to the technical field of drug detection, in particular to an HPLC (high performance liquid chromatography) detection method of vildagliptin intermediate-5.
Background
Vildagliptin (Vildagliptin) is a dipeptidyl peptidase iv inhibitor, which is a novel oral drug for the treatment of diabetes. The vildagliptin intermediate-5 is one of key intermediates in the vildagliptin synthesis process, and the chemical name of the vildagliptin intermediate is as follows: s-1- (2-chloroacetyl) pyrrolidine-2-carbonitrile having the molecular formula: C7H9ClN 2O; the molecular weight is: 172.61, respectively; the chemical structural formula of vildagliptin intermediate-5 is as follows:
in the process of synthesizing vildagliptin intermediate-5, paratoluenesulfonic acid is generated, if the paratoluenesulfonic acid is not completely removed, the purity and the quality of vildagliptin intermediate-5 are affected, and the residual paratoluenesulfonic acid may participate in subsequent reactions to generate genotoxic impurities, so that the product quality is greatly affected. In addition, hydrolysis may occur during the post-treatment of intermediate-5, producing the impurity intermediate-5 amide, while intermediate-5 also contains a small amount of unknown mono-hetero compound (WZ 5-1). Therefore, the detection and control of the purity of vildagliptin intermediate-5 and the content of p-toluenesulfonic acid and intermediate-5 amide are particularly important for the control of the quality and curative effect of vildagliptin.
Disclosure of Invention
Aiming at the problems that impurities such as p-toluenesulfonic acid, an intermediate-5 amide and the like are generated in the existing process of synthesizing vildagliptin intermediate-5, and the quality and curative effect of vildagliptin synthesized by using the impurities are difficult to guarantee, the invention provides an HPLC (high performance liquid chromatography) detection method of vildagliptin intermediate-5.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
an HPLC detection method of vildagliptin intermediate-5 comprises the following detection conditions:
a chromatographic column: the filler is octadecylsilane chemically bonded silica;
mobile phase: the mobile phase A is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 200:3-5: 3-5; the mobile phase B is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 80:90-100: 25-35; wherein the pH of the phosphate buffer solution is 2-3;
column temperature: 33-37 ℃;
detection wavelength: 208-212 nm;
flow rate: 1.6-1.8 ml/min;
elution conditions: 0-3min, phase A90 → 70 vol%, phase B10 → 30 vol%; 3-10min, phase A70 → 55 vol%, phase B30 → 45 vol%; 10-18min, 55 vol% of phase A and 45 vol% of phase B; 18-18.1min, 55 → 90 vol% of phase A, 45 → 10% of phase B; 18.1-22min, 90 vol% of phase A and 10 vol% of phase B.
Compared with the prior art, the HPLC detection method of the gliptin intermediate-5 provided by the invention can realize accurate detection of the contents of the vildagliptin intermediate-5, the p-toluenesulfonic acid and the intermediate-5 amide in the synthesized crude vildagliptin intermediate-5 product by selecting the HPLC chromatographic conditions, the separation degree of the p-toluenesulfonic acid and the intermediate-5 in a high performance liquid chromatogram obtained by detection is more than 2.5, each impurity peak has no interference with a main peak, each spectral peak can be completely separated, the separation degree is good, the accuracy of purity detection of the vildagliptin intermediate-5 in a sample can be ensured, and reliable guarantee is provided for the quality and curative effect of vildagliptin synthesized subsequently.
Preferably, the chromatographic column is an AgelaVenusal MP C18 column.
An AgelaVenusil MP C18 column is adopted, and a phosphate buffer solution-acetonitrile-methanol is matched as a mobile phase, so that the separation degree among all common peaks of a map can be further detected by HPLC, and a good peak shape is ensured.
Preferably, the phosphate buffer solution is obtained by adjusting the pH of 0.01-0.1mol/L phosphate solution to 2-3 by using 20-40 vt% of phosphoric acid solution.
Preferably, the phosphate is potassium dihydrogen phosphate.
Preferably, the mobile phase A is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 200:3: 3; the mobile phase B is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 80:90: 30.
Preferably, the column temperature is 35 ℃ and the flow rate is 1.7 ml/min.
Preferably, the detection wavelength is 210 nm.
Under the condition of the wavelength, the base line of each common peak is smooth and the response is good.
Preferably, the injection volume in the detection method is 8-12 muL.
The above-described preferable chromatographic conditions can further improve the degree of separation between the respective detection peaks in the chromatogram.
Preferably, the diluent of the reference solution and the test solution in the detection method consists of 0.1 vt% hydrochloric acid solution and acetonitrile in a volume ratio of 9-10: 1.
Preferably, the contents of the intermediate-5 amide, the p-toluenesulfonic acid and the vildagliptin intermediate-5 in the control solution in the detection method are 1.5-2 mu g/ml, 1.5-2 mu g/ml and 150-200 mu g/ml respectively; the content of the vildagliptin intermediate-5 crude product to be detected in the test solution is 0.4-0.6 mg/ml.
Drawings
FIG. 1 is an HPLC chromatogram of a control solution in example 1 of the present invention; wherein, the peak 1 is intermediate-5 amide, the peak 2 is p-toluenesulfonic acid, the peak 3 is vildagliptin intermediate-5, and the peak 4 is WZ 5-1;
FIG. 2 is an HPLC chromatogram of a test solution in example 1 of the present invention; wherein, the peak 1 is intermediate-5 amide, the peak 2 is p-toluenesulfonic acid, the peak 3 is vildagliptin intermediate-5, and the peak 4 is WZ 5-1;
FIG. 3 is an HPLC chromatogram of the dilution in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Instruments and conditions:
high performance liquid chromatograph: hitachi L-2000;
a chromatographic column: AgelaVenusl MP C18(2) column (4.6 mm. times.50 mm,3 μm);
mobile phase: taking phosphate buffer solution (taking 0.01mol/L potassium dihydrogen phosphate solution, adjusting pH to 2.4 with 20% (v/v) phosphoric acid solution), acetonitrile-methanol (200:3:3) as a mobile phase A, and taking phosphate buffer solution-acetonitrile-methanol (80:90:30) as a mobile phase B;
flow rate: 1.7 ml/min;
column temperature: 35 ℃;
detection wavelength: 210 nm;
sample introduction volume: 10 mu l of the mixture;
the elution mode is gradient elution, and the specific elution conditions are as follows: 0-3min, phase A90 → 70 vol%, phase B10 → 30 vol%; 3-10min, phase A70 → 55 vol%, phase B30 → 45 vol%; 10-18min, 55 vol% of phase A and 45 vol% of phase B; 18-18.1min, 55 → 90 vol% of phase A, 45 → 10% of phase B; 18.1-22min, 90 vol% of phase A and 10 vol% of phase B.
Test method
Preparing a diluent: uniformly mixing a 0.1 vt% hydrochloric acid solution and acetonitrile in a volume ratio of 9:1 to obtain the mixture;
control solution: respectively and precisely weighing appropriate amounts of an intermediate-5 amide, p-toluenesulfonic acid and vildagliptin intermediate-5 to respectively prepare an intermediate-5 amide mother liquor of 5 mu g/mL, a p-toluenesulfonic acid mother liquor of 5 mu g/mL and a vildagliptin intermediate-5 mother liquor of 500 mu g/mL, precisely weighing 1mL of each solution, and uniformly mixing to obtain a reference solution;
test solution: accurately weighing 12.5mg of vildagliptin intermediate-5 (batch number 1) to be detected, placing the vildagliptin intermediate-5 into a 25ml measuring flask, adding 15ml of the diluent, fully shaking to completely dissolve the vildagliptin intermediate-5, diluting the vildagliptin intermediate-5 to a scale with the diluent, and shaking uniformly to obtain a sample solution;
the detection method comprises the following steps: precisely measuring 10 μ L of each of the reference solution, the sample solution and the blank diluent, injecting into a liquid chromatograph, recording chromatogram, and detecting the chromatogram obtained from the reference solution as shown in FIG. 1, wherein the retention time of peak 1 is 1.013, the retention time of peak 2 is 1.953, the retention time of peak 3 is 2.453, and the retention time of peak 4 is 4.620; the chromatogram obtained by assaying the test solution is shown in FIG. 2, in which the retention time of peak 1 is 0.907, the retention time of peak 2 is 1.967, the retention time of peak 3 is 2.460, and the retention time of peak 4 is 4.633, and the chromatogram obtained by assaying the blank dilution is shown in FIG. 3. And calculating the content of each impurity and the purity of the main peak (except the solvent peak) in the vildagliptin intermediate-5 to be detected according to an area normalization method. As can be seen from fig. 1 and 2, in the chromatogram obtained by the detection of the method, the separation degree of the p-toluenesulfonic acid and the vildagliptin intermediate-5 is calculated to be more than 2.8, each impurity peak has no interference with the main peak, each chromatogram peak can be completely separated, the separation degree is good, and the accuracy of the purity determination of the vildagliptin intermediate-5 of the detection sample can be ensured.
Example 2
Instruments and conditions:
high performance liquid chromatograph: hitachi L-2000;
a chromatographic column: AgelaVenusl MP C18(2) column (4.6 mm. times.50 mm,3 μm);
mobile phase: taking phosphate buffer solution (0.05 mol/L potassium dihydrogen phosphate solution is taken, the pH value is adjusted to 2 by 30 percent (v/v) phosphoric acid solution), acetonitrile-methanol (200:4:4) is taken as a mobile phase A, and phosphate buffer solution-acetonitrile-methanol (80:95:25) is taken as a mobile phase B;
flow rate: 1.6 ml/min;
column temperature: 33 ℃;
detection wavelength: 208 nm;
sample introduction volume: 8 mu l of the solution;
the elution mode is gradient elution, and the specific elution conditions are as follows: 0-3min, phase A90 → 70 vol%, phase B10 → 30 vol%; 3-10min, phase A70 → 55 vol%, phase B30 → 45 vol%; 10-18min, 55 vol% of phase A and 45 vol% of phase B; 18-18.1min, 55 → 90 vol% of phase A, 45 → 10% of phase B; 18.1-22min, 90 vol% of phase A and 10 vol% of phase B.
Test method
Preparing a diluent: uniformly mixing a 0.1 vt% hydrochloric acid solution and acetonitrile in a volume ratio of 9.5:1 to obtain the compound;
control solution: respectively and precisely weighing appropriate amounts of an intermediate-5 amide, p-toluenesulfonic acid and vildagliptin intermediate-5 to respectively prepare an intermediate-5 amide mother liquor of 4.5 mu g/mL, a p-toluenesulfonic acid mother liquor of 4.5 mu g/mL and a vildagliptin intermediate-5 mother liquor of 450 mu g/mL, precisely weighing 1mL of each solution, and uniformly mixing to obtain a reference solution;
test solution: accurately weighing 10mg of vildagliptin intermediate-5 (batch number 2) to be detected, placing the vildagliptin intermediate-5 into a 25ml measuring flask, adding 15ml of the diluent, fully shaking to completely dissolve the vildagliptin intermediate-5, diluting the vildagliptin intermediate-5 to a scale with the diluent, and shaking uniformly to obtain a sample solution;
the detection method comprises the following steps: and precisely measuring 8 mu L of each of the reference solution, the test solution and the blank diluent, injecting into a liquid chromatograph, recording a chromatogram, and calculating the content of each impurity and the purity of a main peak in the vildagliptin intermediate-5 to be detected according to an area normalization method.
Example 3
Instruments and conditions:
high performance liquid chromatograph: hitachi L-2000;
a chromatographic column: AgelaVenusl MP C18(2) column (4.6 mm. times.50 mm,3 μm);
mobile phase: taking phosphate buffer solution (0.1 mol/L potassium dihydrogen phosphate solution is taken, the pH value is adjusted to 3 by 40 percent (v/v) phosphoric acid solution), acetonitrile-methanol (200:5:5) is taken as a mobile phase A, and phosphate buffer solution-acetonitrile-methanol (80:100:35) is taken as a mobile phase B;
flow rate: 1.8 ml/min;
column temperature: 37 ℃;
detection wavelength: 212 nm;
sample introduction volume: 12 mu l of the solution;
the elution mode is gradient elution, and the specific elution conditions are as follows: 0-3min, phase A90 → 70 vol%, phase B10 → 30 vol%; 3-10min, phase A70 → 55 vol%, phase B30 → 45 vol%; 10-18min, 55 vol% of phase A and 45 vol% of phase B; 18-18.1min, 55 → 90 vol% of phase A, 45 → 10% of phase B; 18.1-22min, 90 vol% of phase A and 10 vol% of phase B.
Test method
Preparing a diluent: uniformly mixing a 0.1 vt% hydrochloric acid solution and acetonitrile in a volume ratio of 10:1 to obtain the mixture;
control solution: respectively and precisely weighing appropriate amounts of an intermediate-5 amide, p-toluenesulfonic acid and vildagliptin intermediate-5 to respectively prepare an intermediate-5 amide mother liquor of 6 mu g/mL, a p-toluenesulfonic acid mother liquor of 6 mu g/mL and a vildagliptin intermediate-5 mother liquor of 600 mu g/mL, precisely weighing 1mL of each solution, and uniformly mixing to obtain a reference solution;
test solution: accurately weighing 15mg of vildagliptin intermediate-5 (batch 3) to be detected, placing the vildagliptin intermediate-5 into a 25ml measuring flask, adding 15ml of the diluent, fully shaking to completely dissolve the vildagliptin intermediate-5, diluting the vildagliptin intermediate-5 to a scale with the diluent, and shaking uniformly to obtain a sample solution;
the detection method comprises the following steps: and respectively and precisely measuring 12 mu L of reference solution, test solution and blank diluent, injecting into a liquid chromatograph, recording a chromatogram, and calculating the content of each impurity and the purity of a main peak in the vildagliptin intermediate-5 to be detected according to an area normalization method.
The calculated contents of vildagliptin intermediate-5 and impurities in 3 batches of vildagliptin intermediate-5 crude products to be detected in the embodiments 1-3 are shown in the following table:
| example 1 | Example 2 | Example 3 | |
| Intermediate-5 amide% | 0.01 | 0.02 | 0.01 |
| P-toluenesulfonic acid% | 0.03 | 0.02 | 0 |
| WZ5-1％ | 0.63 | 0.49 | 0.51 |
| Maximum unknown Single |
0 | 0 | 0.56 |
| Vildagliptin intermediate-5% | 99.33 | 99.47 | 99.44 |
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. An HPLC detection method of vildagliptin intermediate-5 is characterized in that: detection conditions of the HPLC:
a chromatographic column: the filler is octadecylsilane chemically bonded silica;
mobile phase: the mobile phase A is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 200:3-5: 3-5; the mobile phase B is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 80:90-100: 25-35; wherein the pH of the phosphate buffer solution is 2-3;
column temperature: 33-37 ℃;
detection wavelength: 208-212 nm;
flow rate: 1.6-1.8 ml/min;
elution conditions: 0-3min, phase A90 → 70 vol%, phase B10 → 30 vol%; 3-10min, phase A70 → 55 vol%, phase B30 → 45 vol%; 10-18min, 55 vol% of phase A and 45 vol% of phase B; 18-18.1min, 55 → 90 vol% of phase A, 45 → 10% of phase B; 18.1-22min, 90 vol% of phase A and 10 vol% of phase B;
the chemical structural formula of the vildagliptin intermediate-5 is as follows:
2. the HPLC detection method of vildagliptin intermediate-5 according to claim 1, characterized in that: the chromatographic column is an AgelaVenusil MP C18 column.
3. The HPLC detection method of vildagliptin intermediate-5 according to claim 1, characterized in that: the phosphate buffer solution is obtained by adjusting the pH value of 0.01-0.1mol/L phosphate solution to 2-3 by using 20-40 vt% of phosphoric acid solution.
4. The HPLC detection method of vildagliptin intermediate-5 according to claim 3, characterized in that: the phosphate is potassium dihydrogen phosphate.
5. The HPLC detection method of vildagliptin intermediate-5 according to claim 1, characterized in that: the mobile phase A is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 200:3: 3; the mobile phase B is phosphate buffer solution-acetonitrile-methanol with the volume ratio of 80:90: 30.
6. The HPLC detection method of vildagliptin intermediate-5 according to claim 1, characterized in that: the column temperature was 35 ℃ and the flow rate was 1.7 ml/min.
7. The HPLC detection method of vildagliptin intermediate-5 according to claim 1, characterized in that: the detection wavelength is 210 nm.
8. The HPLC detection method of vildagliptin intermediate-5 according to claim 1, characterized in that: the sample injection volume in the detection method is 8-12 mu L.
9. The HPLC detection method of vildagliptin intermediate-5 according to claim 1, characterized in that: the diluent of the reference solution and the test solution in the detection method consists of 0.1vt percent hydrochloric acid solution and acetonitrile with the volume ratio of 9-10: 1.
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| US20080167479A1 (en) * | 2007-01-10 | 2008-07-10 | Medichem, S.A. | Process for preparing vildagliptin |
| CZ2008512A3 (en) * | 2008-08-26 | 2010-03-10 | Zentiva, A. S | Process for preparing extremely pure vildagliptin |
| WO2014102815A1 (en) * | 2012-12-26 | 2014-07-03 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Improved process for preparation of vildagliptin |
| CN104030958B (en) * | 2014-06-06 | 2016-06-29 | 河北科技大学 | A kind of (S)-1-(2-chloracetyl) synthetic method of pyrrolidine-2-formonitrile HCN |
| CN104316606B (en) * | 2014-09-24 | 2020-07-07 | 万特制药(海南)有限公司 | Method for separating and measuring vildagliptin related substances by liquid chromatography |
| CN104326961A (en) * | 2014-11-20 | 2015-02-04 | 海南中和药业有限公司 | Synthetic process of vildagliptin |
| CN105193752B (en) * | 2015-10-27 | 2018-03-30 | 石家庄康贺威药业有限公司 | A kind of vildagliptin tablet and preparation method thereof |
| CN106568877A (en) * | 2016-11-09 | 2017-04-19 | 河北科技大学 | Analysis method for Vildagliptin intermediate-5 enantiomer detection |
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