CN112986432A - Detection method and application of 2, 4-diamino-6-chloropyrimidine related substance - Google Patents
Detection method and application of 2, 4-diamino-6-chloropyrimidine related substance Download PDFInfo
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Abstract
The invention provides a method for detecting related substances of a minoxidil key starting material 2, 4-diamino-6-chloropyrimidine, which adopts liquid chromatography, takes octadecylsilane chemically bonded silica as a filler, takes a mixed solution of sodium heptanesulfonate and trifluoroacetic acid as a mobile phase A, and takes methanol as a mobile phase B, thereby quickly and accurately realizing the separation of the 2, 4-diamino-6-chloropyrimidine from an intermediate 3, an impurity B and an impurity C.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly provides a method for detecting related substances of a minoxidil key starting material 2, 4-diamino-6-chloropyrimidine.
Background
2, 4-Diamino-6-chloropyrimidine (English name: 2,4-Diamino-6-Chloro Pyridine) with molecular formula of C4H5ClN4The molecular weight is 144.56, CAS registry number is 156-83-2, and the structure is shown in formula I.
The synthesis process of 2, 4-diamino-6-chloropyrimidine takes ethyl cyanoacetate (1) and guanidine nitrate (2) as starting materials. Methyl cyanoacetate (1) and guanidine nitrate (2) react to obtain an intermediate 2, 4-diamino-6-hydroxypyrimidine (3). The intermediate 2, 4-diamino-6-hydroxypyrimidine (3) reacts with phosphorus oxychloride to obtain 2, 4-diamino-6-chloropyrimidine.
Methyl cyanoacetate and guanidine nitrate are starting materials for the synthesis of 2, 4-diamino-6-chloropyrimidine, and intermediate 3, impurity B and impurity C are process impurities for the synthesis of 2, 4-diamino-6-chloropyrimidine. Methyl cyanoacetate has no obvious ultraviolet absorption, the boiling point is 206 ℃, and the detection and control can be carried out by adopting a gas chromatography method. The guanidine nitrate has stronger activity, and is very easy to be removed in the synthesis process of the 2, 4-diamino-6-chloropyrimidine, so that the control in the 2, 4-diamino-6-chloropyrimidine is not needed. The intermediate 3, the impurity B and the impurity C can participate in subsequent reactions in the synthesis process of the minoxidil, have great influence on the quality of a minoxidil finished product, and are necessary to control related substances of the 2, 4-diamino-6-chloropyrimidine in order to ensure the medication safety.
Disclosure of Invention
The invention aims to provide a method for detecting 2, 4-diamino-6-chloropyrimidine-related substances as a key starting material of minoxidil by high performance liquid chromatography, and provides a new method for detecting and analyzing 2, 4-diamino-6-chloropyrimidine-related substances in the production process of minoxidil.
The purpose of the invention is realized by the following technical scheme:
separating 2, 4-diamino-6-chloropyrimidine and intermediate 3, impurity B and impurity C thereof by using high performance liquid chromatography, wherein the chromatographic conditions are as follows:
the chromatographic column is an octadecylsilane bonded silica chromatographic column selected from Kromasil C18, ODS-C18, Thermo Syncronis C18, Thermo Hypersil GOLD C18 and Agilent TC-C18, preferably Agilent TC-C18;
the mobile phase A is pure water or an aqueous solution of sodium dihydrogen phosphate, triethylamine, sodium heptanesulfonate, tetrabutylammonium hydroxide, trifluoroacetic acid, sodium acetate or a mixture thereof, preferably the mobile phase A is a mixed solution of sodium heptanesulfonate and trifluoroacetic acid, 1.0-3.0 g of sodium heptanesulfonate is contained in each 1000ml of the mobile phase A, and the volume fraction of the trifluoroacetic acid is 0.01-0.1%; more preferably, each 1000ml of the mobile phase A contains 1.5-2.5 g of sodium heptanesulfonate, and the volume fraction of trifluoroacetic acid is 0.05-0.1%; more preferably, the volume fraction of trifluoroacetic acid in mobile phase A per 1000ml contains 2g of sodium heptanesulfonate and 0.05 percent of trifluoroacetic acid;
the mobile phase B is one or a mixture of acetonitrile and methanol, preferably methanol;
the volume ratio of the mobile phase is mobile phase A: the mobile phase B is 80: 20-60: 40, preferably 75: 25-65: 35;
the diluent is a mobile phase;
the detector is one of an ultraviolet detector, a differential detector, an evaporative light scattering detector and a diode array detector, and is preferably an ultraviolet detector;
the flow rate of the mobile phase is 0.5-1.0ml/min, preferably 0.8 ml/min;
the temperature of the chromatographic column is 30-40 ℃, and preferably 33-37 ℃;
the detection wavelength is 220-265 nm, preferably 230 nm;
the sample concentration is 0.25-1.0 mg/ml, preferably 0.5 mg/ml;
and injecting a sample with a certain amount of sample concentration for analysis.
The method for detecting the 2, 4-diamino-6-chloropyrimidine related substances provided by the invention adopts the high performance liquid chromatography to realize the rapid and accurate determination of the intermediate 3, the impurity B and the impurity C, has higher sensitivity and specificity, is simple and convenient to operate, and has practical significance because the separation degree meets the standard (the separation degree between all impurity peaks is greater than 2.0, and the separation degree between the impurity peak and a main peak is greater than 2.0).
Drawings
FIG. 1 is a liquid chromatogram of a diluent-positioning solution.
FIG. 2 is a liquid chromatogram of the intermediate 3 positioning solution.
FIG. 3 is a liquid chromatogram of an impurity B localization solution.
FIG. 4 is a liquid chromatogram of an impurity C-localized solution.
FIG. 5 is a liquid chromatogram of a 2, 4-diamino-6-chloropyrimidine-positioning solution.
FIG. 6 is a liquid chromatogram of the mixed solution.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
Example 1
1) The experimental conditions are as follows:
agilent1260-VWD HPLC;
a chromatographic column: agilent TC-C184.6 is multiplied by 250mm and 5 mu m;
flow rate: 0.8 mL/min;
column temperature: 35 ℃;
sample introduction amount: 10 mu L of the solution;
sample concentration: 0.5 mg/ml;
diluent agent: a mobile phase;
detection wavelength: 230 nm;
mobile phase A: sodium heptanesulfonate solution (taking 2g of sodium heptanesulfonate, adding 1000ml of water for dissolution, adding 0.5ml of trifluoroacetic acid);
mobile phase B: methanol;
mobile phase a mobile phase B70: 30(V/V)
2) Preparation of solutions
Impurity control stock solution: respectively taking appropriate amount of intermediate 3 reference substance, impurity B reference substance and impurity C reference substance, precisely weighing, dissolving with diluent, and quantitatively diluting to obtain solution containing about 0.5mg of each impurity per 1 ml.
System applicability solution: precisely weighing 5mg of 2, 4-diamino-6-chloropyrimidine reference substance, placing the reference substance in a 10ml measuring flask, adding 0.1ml of impurity reference substance stock solution, dissolving by using a diluent and fixing the volume.
3) Assay method
And precisely measuring 10 mu l of system applicability solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
4) Results of the experiment
TABLE 1 results of the experiment
| Name (R) | Retention time min | Degree of separation |
| Intermediate 3 | 9.646 | — |
| Impurity B | 13.095 | 11.26 |
| 2, 4-diamino-6-chloropyrimidines | 18.567 | 12.61 |
| Impurity C | 22.159 | 6.55 |
As can be seen from the table above, the separation of each compound was good.
Example 2
1) The experimental conditions are as follows:
agilent1260-VWD HPLC;
a chromatographic column: agilent TC-C184.6 is multiplied by 250mm and 5 mu m;
flow rate: 0.8 mL/min;
column temperature: 33 ℃;
sample introduction amount: 10 mu L of the solution;
sample concentration: 0.5 mg/ml;
diluent agent: a mobile phase;
detection wavelength: 230 nm;
mobile phase A: sodium heptanesulfonate solution (taking 2g of sodium heptanesulfonate, adding 1000ml of water for dissolution, adding 0.5ml of trifluoroacetic acid);
mobile phase B: methanol;
mobile phase a mobile phase B70: 30(V/V)
2) Preparation of solutions
Impurity control stock solution: respectively taking appropriate amount of intermediate 3 reference substance, impurity B reference substance and impurity C reference substance, precisely weighing, dissolving with diluent, and quantitatively diluting to obtain solution containing about 0.5mg of each impurity per 1 ml.
System applicability solution: precisely weighing 5mg of 2, 4-diamino-6-chloropyrimidine reference substance, placing the reference substance in a 10ml measuring flask, adding 0.1ml of impurity reference substance stock solution, dissolving by using a diluent and fixing the volume.
3) Assay method
And precisely measuring 10 mu l of system applicability solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
4) Results of the experiment
TABLE 2 results of the experiment
| Name (R) | Retention time min | Degree of |
| Intermediate | ||
| 3 | 9.646 | — |
| Impurity B | 13.095 | 11.26 |
| 2, 4-diamino-6-chloropyrimidines | 18.567 | 12.61 |
| Impurity C | 22.159 | 6.55 |
As can be seen from the table above, the separation of each compound was good.
Example 3
1) The experimental conditions are as follows:
agilent1260-VWD HPLC;
a chromatographic column: agilent TC-C184.6 is multiplied by 250mm and 5 mu m;
flow rate: 0.8 mL/min;
column temperature: 37 ℃;
sample introduction amount: 10 mu L of the solution;
sample concentration: 0.5 mg/ml;
diluent agent: a mobile phase;
detection wavelength: 230 nm;
mobile phase A: sodium heptanesulfonate solution (taking 2g of sodium heptanesulfonate, adding 1000ml of water for dissolution, adding 0.5ml of trifluoroacetic acid);
mobile phase B: methanol;
mobile phase a mobile phase B70: 30(V/V)
2) Preparation of solutions
Impurity control stock solution: respectively taking appropriate amount of intermediate 3 reference substance, impurity B reference substance and impurity C reference substance, precisely weighing, dissolving with diluent, and quantitatively diluting to obtain solution containing about 0.5mg of each impurity per 1 ml.
System applicability solution: precisely weighing 5mg of 2, 4-diamino-6-chloropyrimidine reference substance, placing the reference substance in a 10ml measuring flask, adding 0.1ml of impurity reference substance stock solution, dissolving by using a diluent and fixing the volume.
3) Assay method
And precisely measuring 10 mu l of system applicability solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
4) Results of the experiment
TABLE 3 results of the experiment
| Name (R) | Retention time min | Degree of |
| Intermediate | ||
| 3 | 9.646 | — |
| Impurity B | 13.095 | 10.85 |
| 2, 4-diamino-6-chloropyrimidines | 18.567 | 12.30 |
| Impurity C | 22.159 | 6.38 |
As can be seen from the table above, the separation of each compound was good.
Example 4
1) The experimental conditions are as follows:
agilent1260-VWD HPLC;
a chromatographic column: agilent TC-C184.6 is multiplied by 250mm and 5 mu m;
flow rate: 0.8 mL/min;
column temperature: 35 ℃;
sample introduction amount: 10 mu L of the solution;
sample concentration: 0.5 mg/ml;
diluent agent: a mobile phase;
detection wavelength: 230 nm;
mobile phase A: sodium heptanesulfonate solution (taking 2g of sodium heptanesulfonate, adding 1000ml of water for dissolution, adding 0.5ml of trifluoroacetic acid);
mobile phase B: methanol;
mobile phase a mobile phase B68: 32(V/V)
2) Preparation of solutions
Impurity control stock solution: respectively taking appropriate amount of intermediate 3 reference substance, impurity B reference substance and impurity C reference substance, precisely weighing, dissolving with diluent, and quantitatively diluting to obtain solution containing about 0.5mg of each impurity per 1 ml.
System applicability solution: precisely weighing 5mg of 2, 4-diamino-6-chloropyrimidine reference substance, placing the reference substance in a 10ml measuring flask, adding 0.1ml of impurity reference substance stock solution, dissolving by using a diluent and fixing the volume.
3) Assay method
And precisely measuring 10 mu l of system applicability solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
4) Results of the experiment
TABLE 4 results of the experiment
| Name (R) | Retention time min | Degree of |
| Intermediate | ||
| 3 | 9.646 | — |
| Impurity B | 13.095 | 9.84 |
| 2, 4-diamino-6-chloropyrimidines | 18.567 | 11.41 |
| Impurity C | 22.159 | 6.26 |
As can be seen from the table above, the separation of each compound was good.
Example 5
1) The experimental conditions are as follows:
agilent1260-VWD HPLC;
a chromatographic column: agilent TC-C184.6 is multiplied by 250mm and 5 mu m;
flow rate: 0.8 mL/min;
column temperature: 35 ℃;
sample introduction amount: 10 mu L of the solution;
sample concentration: 0.5 mg/ml;
diluent agent: a mobile phase;
detection wavelength: 230 nm;
mobile phase A: sodium heptanesulfonate solution (taking 2g of sodium heptanesulfonate, adding 1000ml of water for dissolution, adding 0.5ml of trifluoroacetic acid);
mobile phase B: methanol;
mobile phase a mobile phase B72: 28(V/V)
2) Preparation of solutions
Impurity control stock solution: respectively taking appropriate amount of intermediate 3 reference substance, impurity B reference substance and impurity C reference substance, precisely weighing, dissolving with diluent, and quantitatively diluting to obtain solution containing about 0.5mg of each impurity per 1 ml.
System applicability solution: precisely weighing 5mg of 2, 4-diamino-6-chloropyrimidine reference substance, placing the reference substance in a 10ml measuring flask, adding 0.1ml of impurity reference substance stock solution, dissolving by using a diluent and fixing the volume.
3) Assay method
And precisely measuring 10 mu l of system applicability solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
4) Results of the experiment
TABLE 5 results of the experiment
| Name (R) | Retention time min | Degree of |
| Intermediate | ||
| 3 | 9.646 | — |
| Impurity B | 13.095 | 12.91 |
| 2, 4-diamino-6-chloropyrimidines | 18.567 | 13.71 |
| Impurity C | 22.159 | 6.80 |
As can be seen from the table above, the separation of each compound was good.
Example 6
1. Apparatus and conditions
An Agilent high performance liquid chromatograph; Milli-Q ultra-pure water machine; a mettler XS205DU electronic balance, ultrasonic cleaner; a vacuum filtration device; a chromatographic column: agilent TC-C184.6 is multiplied by 250mm and 5 mu m; mobile phase A: sodium heptanesulfonate solution (taking 2g of sodium heptanesulfonate, dissolving in 1000ml of water, adding 0.5ml of trifluoroacetic acid), mobile phase B: methanol, mobile phase a: mobile phase B70: 30; flow rate: 0.8 mL/min; detection wavelength: 230 nm; column temperature: 35 ℃; sample introduction amount: 10 mu L of the solution; sample concentration: 0.5 mg/ml; diluent agent: a mobile phase.
2. Experimental procedure
1) Preparing a solution:
intermediate 3 stock solution: an appropriate amount of the intermediate 3 control was precisely weighed, dissolved with a diluent and quantitatively diluted to a solution containing about 0.5mg of each impurity per 1 ml.
Impurity B stock solution: precisely weighing an appropriate amount of reference substance containing impurity B, precisely weighing, dissolving with diluent, and quantitatively diluting to obtain solution containing about 0.5mg of each impurity per 1 ml.
Impurity C stock solution: precisely weighing an appropriate amount of impurity C reference substance, precisely weighing, dissolving with diluent, and quantitatively diluting to obtain a solution containing about 0.5mg of each impurity per 1 ml.
Intermediate 3 positioning solution: precisely measuring 0.5ml of intermediate 3 stock solution, placing in a 50ml measuring flask, adding solvent to dilute to scale, and shaking up.
Impurity B localization solution: precisely measuring 0.5ml of impurity B stock solution, placing in a 50ml measuring flask, adding solvent to dilute to scale, and shaking up.
Impurity C localization solution: precisely measuring 0.5ml of impurity C stock solution, placing in a 50ml measuring flask, adding solvent to dilute to scale, and shaking up.
2, 4-diamino-6-chloropyrimidine-localizing solution: taking a proper amount of 2, 4-diamino-6-chloropyrimidine as a reference substance, precisely weighing, dissolving by using a diluent, and quantitatively diluting to prepare a solution containing 0.5mg per 1 ml.
System applicability solution: taking about 25mg of 2, 4-diamino-6-chloropyrimidine as a reference substance, precisely weighing, placing in a 50ml measuring flask, adding a proper amount of mobile phase for dissolution, respectively adding 0.5ml of the intermediate 3 stock solution, the impurity B stock solution and the impurity C stock solution, adding the mobile phase for dilution to a scale, and shaking up.
Test solution: weighing about 25mg of the product, accurately weighing, placing in a 50ml measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking.
0.2% control solution: precisely measuring 1ml of the test solution, diluting to 10ml with a solvent, precisely measuring 1ml, placing in a 50ml measuring flask, and diluting to scale with the solvent.
Linear solution: respectively preparing a 2, 4-diamino-6-chloropyrimidine reference substance, an intermediate 3 reference substance, an impurity B reference substance and an impurity C reference substance into mixed solutions with the LOQ concentration of 5 mu g/ml by using diluents.
Mixing the solution: the same applies to the solution.
2) Methodology validation
Specificity test:
and respectively taking 10 mu l of the diluent, the intermediate 3 positioning solution, the impurity B positioning solution, the impurity C positioning solution and the mixed solution, sequentially injecting into a liquid chromatograph, and recording the chromatogram. See table 6 and accompanying figures 1-5.
TABLE 6 results of the positioning experiment
Linear range: detection limit and quantification limit
TABLE 7 results of the linearity and sensitivity experiments
| Name (R) | Correlation coefficient | Detection limit (μ g/ml) | Limit of quantitation (ug/ml) |
| |
1.0000 | 0.006 | 0.02 |
| Impurity B | 1.0000 | 0.006 | 0.02 |
| Impurity C | 1.0000 | 0.006 | 0.02 |
| 2, 4-diamino-6-chloropyrimidines | 1.0000 | 0.006 | 0.02 |
And (3) sample determination: the intermediate 3, the impurity B and the impurity C are all measured by a self-contrast method with relative correction factors added.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (11)
1. The method for detecting the 2, 4-diamino-6-chloropyrimidine related substances is characterized by comprising the following steps of:
the chromatographic column is an octadecylsilane chemically bonded silica chromatographic column;
the mobile phase A is pure water or an aqueous solution of sodium dihydrogen phosphate, triethylamine, sodium heptanesulfonate, tetrabutylammonium hydroxide, trifluoroacetic acid, sodium acetate or a mixture thereof;
the mobile phase B is one or a mixture of acetonitrile, methanol and ethanol;
the volume ratio of the mobile phase is mobile phase A: the mobile phase B is 80: 20-60: 40;
the diluent is a mobile phase;
the column temperature is 20-50 ℃;
the flow rate is 0.2-1.2 ml/min;
the detector is an ultraviolet detector, a differential detector, an evaporative light scattering detector and a diode array detector;
the detection wavelength is 210-280 nm;
the sample concentration is 0.2-2 mg/ml.
2. The detection method according to claim 1, characterized in that: the volume ratio of the mobile phase is that the mobile phase A: and the mobile phase B is 75: 25-65: 35.
3. The detection method according to claim 1, characterized in that: the mobile phase A is a mixed solution of sodium heptanesulfonate and trifluoroacetic acid, wherein each 1000ml of the mobile phase A contains 1.0-3.0 g of sodium heptanesulfonate, and the volume fraction of the trifluoroacetic acid is 0.01-0.1%.
4. The detection method according to claim 1, characterized in that: the mobile phase A is characterized in that 1.5-2.5 g of sodium heptanesulfonate is contained in each 1000ml of the mobile phase A, and the volume fraction of trifluoroacetic acid is 0.05-0.1%.
5. The detection method according to claim 1, characterized in that: the mobile phase A contains 2g of sodium heptanesulfonate and 0.05 percent of trifluoroacetic acid by volume per 1000ml of the mobile phase A.
6. The detection method according to claim 1, characterized in that: the mobile phase B is methanol.
7. The detection method according to claim 1, characterized in that: the chromatographic column is selected from: kromasil C18, ODS-C18, Thermo Syncronis C18, Thermo Hypersil GOLD C18 and Agilent TC-C18, preferably Agilent TC-C18.
8. The detection method according to claim 1, characterized in that: the flow rate of the mobile phase is 0.5-1.0ml/min, and the flow rate of the mobile phase is preferably 0.8 ml/min.
9. The detection method according to claim 1, characterized in that: the temperature of the chromatographic column is 30-40 ℃, and preferably 33-37 ℃.
10. The detection method according to claim 1, characterized in that: the detection wavelength is 220-265 nm, and preferably 230 nm.
11. The detection method according to claim 1, characterized in that: the sample concentration is 0.25-1.0 mg/ml, preferably 0.5 mg/ml.
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