CN109839444B - Process for separating naphthol derivatives and their use - Google Patents
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- CN109839444B CN109839444B CN201711207368.5A CN201711207368A CN109839444B CN 109839444 B CN109839444 B CN 109839444B CN 201711207368 A CN201711207368 A CN 201711207368A CN 109839444 B CN109839444 B CN 109839444B
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Abstract
The invention discloses a separation method of naphthol derivatives and application thereof. The invention separates 1-isopropylamino-3- (2-naphthoxy) -2-propanol and propranolol hydrochloride by adopting a high performance liquid separation method; the method is simple to operate, has good separation degree, can separate other impurities in the propranolol hydrochloride at the same time, and is suitable for separating and detecting various known or unknown impurities generated under the synthesis condition.
Description
Technical Field
The invention relates to a separation method of naphthol derivatives and application thereof.
Background
Propranolol hydrochloride is shown in the following formula, has the chemical name of 1-isopropylamino-3- (l-naphthoxy) -2-propanol hydrochloride, is a non-selective beta-receptor blocker, blocks myocardial beta receptors, and has antagonism on both beta 1 and beta 2 receptors. The traditional Chinese medicine composition is clinically used for treating diseases such as hypertension, angina and arrhythmia, and has good drug effect.
At present, 1-naphthol and epoxy chloropropane are used as initial raw materials, and the propranolol hydrochloride is generated through reaction of an intermediate 1-naphthyl epoxy propyl ether, an intermediate 1-isopropylamino-3- (1-naphthoxy) -2-propanol and hydrochloric acid.
According to the 1-naphthol national standard (GBT 25782-. However, no document reporting the detection of 1-isopropylamino-3- (2-naphthoxy) -2-propanol in propranolol hydrochloride is reported at home, and the inventors found that the 2-naphthol derivative 1-isopropylamino-3- (2-naphthoxy) -2-propanol cannot be separated from propranolol hydrochloride regardless of the operation method of the detection by the method with reference to the relevant substances in propranolol hydrochloride (second part 1097 of chinese pharmacopoeia 2015) or the operation method of the detection by the method with reference to the content of propranolol hydrochloride in the us pharmacopoeia.
Therefore, in order to better control the quality of propranolol hydrochloride raw materials, a simple, reliable, stable and effective method needs to be established for detecting impurities or related substances in propranolol hydrochloride.
Disclosure of Invention
The invention aims to solve the technical problem that 1-isopropylamino-3- (2-naphthoxy) -2-propanol and propranolol hydrochloride cannot be well separated in the prior art, and provides a separation method of naphthol derivatives and application thereof. The method separates the 1-isopropylamino-3- (2-naphthoxy) -2-propanol from the propranolol hydrochloride by adopting a high-performance liquid phase separation method, has simple operation and good separation degree, can separate other impurities in the propranolol hydrochloride at the same time, and is suitable for separating and detecting various known or unknown impurities generated under the synthesis condition.
The invention solves the technical problems through the following technical scheme.
The invention provides a separation method of naphthol derivatives, which comprises the following steps: separating naphthol derivative by high performance liquid chromatography;
the chromatographic column in the high performance liquid chromatography is a C18 chromatographic column;
the mobile phase in the high performance liquid chromatography is a mixed solution with the pH value of 3.1-3.5, and the mixed solution contains an organic solvent (such as acetonitrile), water, sulfuric acid, sodium dodecyl sulfate and tetrabutylammonium phosphate;
the volume usage ratio of the organic solvent, the water and the sulfuric acid is (52-48): (48-52): 0.1;
the naphthol derivative comprises 1-isopropylamino-3- (2-naphthyloxy) -2-propanol and 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride; for example, the naphthol derivative is a mixture of 1-isopropylamino-3- (2-naphthyloxy) -2-propanol and 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride.
In the present invention, the naphthol derivative may comprise 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol and 3- (1-naphthyloxy) -1, 2-propanediol; for example, the naphthol derivative is a mixture of 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol and 3- (1-naphthyloxy) -1, 2-propanediol.
In the present invention, the naphthol derivative may comprise 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol and 1, 3-di- (1-naphthyloxy) propan-2-ol; for example, the naphthol derivative is a mixture of 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol and 1, 3-di- (1-naphthyloxy) propan-2-ol.
Preferably, the volume ratio of the organic solvent to the water to the sulfuric acid is (51-49): (49-51): 0.1; more preferably 50:50: 0.1.
In the invention, the concentration of the sodium dodecyl sulfate in the mixed solution can be 1.2 g/L-2.0 g/L; for example 1.6 g/L; the concentration of the tetrabutylammonium phosphate in the mixed solution can be 0.2-0.5 g/L; for example 0.31 g/L.
In the present invention, the pH can be adjusted by a sodium hydroxide solution, for example, a 2mol/L sodium hydroxide solution.
In the present invention, the C18 column may be an Agilent SB C18 column in the high performance liquid chromatography.
In the present invention, the temperature of the chromatographic column may be 20 to 50 ℃, for example 35 to 45 ℃, and further for example 40 ℃.
In the invention, the flow rate of the mobile phase can be 1-1.4 ml/min, such as 1.2 ml/min.
In the present invention, the filler particle size of the chromatography column may be 2.7 μm to 5 μm, for example 3 μm to 5 μm.
In the invention, the length of the chromatographic column can be 150-250 mm, such as 250 mm.
In the invention, the sample injection volume of the chromatographic column can be 1-50 muL, for example 10-20 muL.
In the present invention, the sample of the naphthol derivative is generally prepared in the form of a solution, the solvent in the solution may be the mobile phase, and the concentration of the naphthol derivative in the solution may be (1. mu.g to 1mg)/mL, for example, 2. mu.g/mL.
In the invention, the high performance liquid chromatograph can be an Agilent 1260 high performance liquid chromatograph.
The invention also provides a detection method of the naphthol derivative, which comprises the following steps: separating naphthol derivatives by adopting a high performance liquid chromatography, and detecting by using a high performance liquid chromatograph and a detector in the high performance liquid chromatography; then the method is finished;
the chromatographic column in the high performance liquid chromatography is a C18 chromatographic column;
the mobile phase in the high performance liquid chromatography is a mixed solution with the pH value of 3.1-3.5, and the mixed solution contains an organic solvent (such as acetonitrile), water, sulfuric acid, sodium dodecyl sulfate and tetrabutylammonium phosphate;
the volume usage ratio of the organic solvent, the water and the sulfuric acid is 52:48: 0.1-48: 52: 0.1.
Preferably, the volume usage ratio of the organic solvent, the water and the sulfuric acid is 51:49: 0.1-49: 51: 0.1; more preferably 50:50: 0.1.
In the present invention, the detector may be an ultraviolet detector, an ultraviolet-visible light detector, or a diode array detector; when an ultraviolet detector, an ultraviolet-visible light detector, or a diode array detector is employed, the detection wavelength may be 230nm to 290nm, for example 230 nm.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the invention separates 2-naphthol derivative 1-isopropylamino-3- (2-naphthoxy) -2-propanol and 1-isopropylamino-3- (l-naphthoxy) -2-propanol hydrochloride by adopting a high performance liquid phase separation method; the method is simple to operate, has good separation degree, can also simultaneously separate other impurities in the propranolol hydrochloride, such as 3- (1-naphthyloxy) -1, 2-propylene glycol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, 1, 3-di- (1-naphthyloxy) propan-2-ol), 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol and/or 1-naphthylepoxypropyl ether, and is suitable for separating and detecting various known or unknown impurities generated under the synthesis condition.
Drawings
FIG. 1 is an HPLC chromatogram of a 3- (1-naphthyloxy) -1, 2-propanediol positioning solution of example 1;
FIG. 2 is an HPLC chromatogram of a 1-isopropylamino-3- (2-naphthoxy) -2-propanol localisation solution from example 1;
FIG. 3 is an HPLC chromatogram of a 1-naphthyl epoxypropyl ether-localized solution of example 1;
FIG. 4 is an HPLC chromatogram of a 1, 2-di-isopropylamino-3- (1-naphthoxy) -2-propanol alignment solution from example 1;
FIG. 5 is an HPLC chromatogram of a 1, 3-bis- (1-naphthyloxy) propan-2-ol positioning solution in example 1;
FIG. 6 is an HPLC chromatogram of a 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol positioning solution of example 1;
FIG. 7 is an HPLC chromatogram of the resolution solution of example 1;
FIG. 8 is an HPLC chromatogram of the test solution in example 1;
FIG. 9 is an HPLC chromatogram of the resolution solution of example 2;
FIG. 10 is an HPLC chromatogram of the test solution in example 2;
FIG. 11 is an HPLC chromatogram of the resolution solution of example 3;
FIG. 12 is an HPLC chromatogram of the test solution in example 3;
FIG. 13 is an HPLC chromatogram of the resolution solution of example 4;
FIG. 14 is an HPLC chromatogram of the test solution in example 4;
FIG. 15 is an HPLC chromatogram of the resolution solution of example 5;
FIG. 16 is an HPLC chromatogram of the test solution in example 5;
FIG. 17 is an HPLC chromatogram of the resolution solution in comparative example 1;
FIG. 18 is an HPLC chromatogram of the test solution in comparative example 1;
FIG. 19 is an HPLC chromatogram of the resolution solution in comparative example 2;
FIG. 20 is an HPLC chromatogram of the test solution in comparative example 2;
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
The instrument comprises the following steps: agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter
The mobile phase is a mixed solution of acetonitrile-water-sulfuric acid (50:50:0.1) (1.6 g of sodium dodecyl sulfate and 0.31g of tetrabutylammonium dihydrogen phosphate are taken to be dissolved in 1000ml of the mixed solution, and the pH value is adjusted to 3.3 by 2mol/L of sodium hydroxide solution);
the column was Agilent SB C18(250 mm. times.4.6 mm. times.5 μm);
the flow rate is 1.2 ml/min;
the detection wavelength is 230 nm;
the column temperature is 40 ℃;
precisely weighing appropriate amounts of 3- (1-naphthyloxy) -1, 2-propanediol, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 1, 3-di- (1-naphthyloxy) propan-2-ol and 3, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, and diluting the mobile phase to 1ml of the appropriate amount of 3- (1-naphthyloxy) -1, 2-propanediol, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, and, 1-naphthyl epoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 1, 3-di- (1-naphthyloxy) propan-2-ol and 10. mu.g of 3, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol as a positioning solution;
precisely weighing propranolol hydrochloride, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol and a proper amount of 1, 3-di- (1-naphthyloxy) propan-2-ol, diluting the mobile phase to 1ml containing propranolol hydrochloride, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-naphthylepoxypropyl ether, 1-epoxypropyl ether, 1-naphthylepoxypropyl ether, 1-naphthylepoxypropyl ether, 3-1-naphthyloxy-2-propanediol, 3-propranol and 1, 3-naphthyloxy-2-propan-2-ol, A resolution solution of 2. mu.g each of 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol and 1, 3-di- (1-naphthyloxy) propan-2-ol;
precisely weighing a proper amount of propranolol hydrochloride, and diluting the mobile phase to 1ml of test solution containing 1mg of propranolol hydrochloride.
Precisely measuring 20 μ L of the positioning solution, 10 μ L of each of the resolution solution and the sample solution, injecting into a liquid chromatograph, and recording the chromatogram.
The chromatogram obtained by the method is shown in the attached figures 1-8.
The analytical and detection results of the positioning solution are shown in tables 1-6:
TABLE 1
Peak 1 is 3- (1-naphthyloxy) -1, 2-propanediol;
TABLE 2
Peak 1 is 1-isopropylamino-3- (2-naphthyloxy) -2-propanol;
TABLE 3
Peak number 1 is 1-naphthyl epoxypropyl ether;
TABLE 4
Peak 1 is 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol;
TABLE 5
Peak number 1 is 1, 3-bis- (1-naphthyloxy) propan-2-ol;
TABLE 6
The analytical results of the solution having the resolution of 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol as peak 1 are shown in Table 7:
TABLE 7
Wherein, the peak numbers are assigned as follows:
peak 1 is 3- (1-naphthyloxy) -1, 2-propanediol;
peak 2 is 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
peak 4 is 1-naphthyl epoxypropyl ether;
peak No. 5 is 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol;
peak No. 6 is 1, 3-bis- (1-naphthyloxy) propan-2-ol;
peak No. 7 is 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol.
The results of the assay of the test solutions are shown in table 8:
TABLE 8
Wherein, the peak number 4 is propranolol hydrochloride;
the peak numbers 1,2, 3, 5 and 6 are unknown impurities;
7 is 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol.
The result shows that in the method, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol and propranolol hydrochloride are better separated, and the detection of 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, 1, 3-di- (1-naphthyloxy) propan-2-ol, 1-naphthylepoxypropyl ether and 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol in propranolol hydrochloride can be realized at the same time, so that the method is suitable for separating and detecting various known or unknown related impurities generated under the synthesis condition.
Example 2
The procedure was as in example 1 except that the mobile phase was changed to a mixture of acetonitrile-water-sulfuric acid (51:49:0.1) (1.6 g of sodium dodecyl sulfate and 0.31g of tetrabutylammonium dihydrogen phosphate were dissolved in 1000ml of the mixture, and the pH was adjusted to 3.3 with 2mol/L sodium hydroxide solution), and the sample was sampled with the resolution solution and the sample solution.
The chromatogram is shown in detail in FIGS. 9 and 10.
The results of analytical measurements of the resolution solutions are shown in table 9:
TABLE 9
Wherein, the peak numbers are assigned as follows:
peak 1 is 3- (1-naphthyloxy) -1, 2-propanediol;
peak 2 is 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
peak 4 is 1-naphthyl epoxypropyl ether;
peak No. 5 is 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol;
peak No. 6 is 1, 3-bis- (1-naphthyloxy) propan-2-ol;
peak No. 7 is 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol.
The results of the assay of the test solutions are shown in table 10:
watch 10
The result shows that in the method, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol and propranolol hydrochloride are better separated, and the detection of 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, 1, 3-di- (1-naphthyloxy) propan-2-ol, 1-naphthylepoxypropyl ether and 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol in propranolol hydrochloride can be realized at the same time, so that the method is suitable for separating and detecting various known or unknown related impurities generated under the synthesis condition.
Example 3
The procedure was as in example 1 except that the mobile phase was changed to a mixture of acetonitrile-water-sulfuric acid (49:51:0.1) (1.6 g of sodium dodecyl sulfate and 0.31g of tetrabutylammonium dihydrogen phosphate were dissolved in 1000ml of the mixture, and the pH was adjusted to 3.3 with 2mol/L sodium hydroxide solution), and the sample was sampled with the resolution solution and the sample solution.
The chromatogram is shown in detail in FIGS. 11 and 12.
The results of analytical measurements of the resolution solutions are shown in table 11:
TABLE 11
Wherein, the peak numbers are assigned as follows:
peak 1 is 3- (1-naphthyloxy) -1, 2-propanediol;
peak 2 is 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
peak 4 is 1-naphthyl epoxypropyl ether;
peak No. 5 is 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol;
peak No. 6 is 1, 3-bis- (1-naphthyloxy) propan-2-ol;
peak No. 7 is 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol. The results of the assay of the test solutions are shown in table 12:
TABLE 12
The result shows that in the method, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol and propranolol hydrochloride are better separated, and the detection of 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, 1, 3-di- (1-naphthyloxy) propan-2-ol, 1-naphthylepoxypropyl ether and 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol in propranolol hydrochloride can be realized at the same time, so that the method is suitable for separating and detecting various known or unknown related impurities generated under the synthesis condition.
Example 4
The procedure was as in example 1 except that the mobile phase was changed to a mixture of acetonitrile-water-sulfur (52:48:0.1) (1.6 g of sodium dodecyl sulfate and 0.31g of tetrabutylammonium dihydrogen phosphate were dissolved in 1000ml of the mixture, and the pH was adjusted to 3.3 with 2mol/L sodium hydroxide solution). The sample adopts a resolution solution and a test solution.
The analytical test results of the resolution solutions are shown in table 13:
watch 13
Wherein, the peak numbers are assigned as follows:
peak 1 is 3- (1-naphthyloxy) -1, 2-propanediol;
peak 2 is 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
peak 4 is 1-naphthyl epoxypropyl ether;
peak No. 5 is 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol;
peak No. 6 is 1, 3-bis- (1-naphthyloxy) propan-2-ol;
peak No. 7 is 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol. The results of the assay of the test solutions are shown in table 14:
TABLE 14
Wherein, the peak number 6 is propranolol hydrochloride;
peak 9 is 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol;
the remaining peak numbers are unknown impurities.
The results show that the separation degree of 1-isopropylamino-3- (2-naphthoxy) -2-propanol from propranolol hydrochloride in this method is barely 1.5, but 1, 2-di-isopropylamino-3- (1-naphthoxy) -2-propanol and 3, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol cannot be separated effectively.
Example 5
The procedure was as in example 1 except that the mobile phase was changed to a mixture of acetonitrile-water-sulfuric acid (48:52:0.1) (1.6 g of sodium dodecyl sulfate and 0.31g of tetrabutylammonium dihydrogen phosphate were dissolved in 1000ml of the mixture, and the pH was adjusted to 3.3 with 2mol/L sodium hydroxide solution). Separating degree solution and sample solution are adopted.
The chromatograms of the resolution solution and the sample solution are shown in FIGS. 15 and 16.
The analytical test results of the resolution solutions are shown in table 15:
watch 15
The results of the assay of the test solutions are shown in table 16:
TABLE 16
The result shows that the method can achieve the separation effect of the 1-isopropylamino-3- (2-naphthoxy) -2-propanol and the propranolol hydrochloride in the separation degree solution, and meanwhile, the detection of 3- (1-naphthyloxy) -1, 2-propylene glycol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, 1, 3-di- (1-naphthyloxy) propan-2-ol, 1-naphthylepoxypropyl ether and 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol in propranolol hydrochloride can be realized, and the method is suitable for separating and detecting various known or unknown related impurities generated under the synthesis condition. But the main peak of the test solution is split.
Experiments show that the reduction of the proportion of acetonitrile is helpful for the separation of 1-isopropylamino-3- (2-naphthoxy) -2-propanol and propranolol hydrochloride, but the main peak solution of the test sample is split.
Comparative example 1
The instrument comprises the following steps: agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter
The method comprises the following steps: reference Chinese pharmacopoeia (2015 edition second part 1097) propranolol hydrochloride related substance detection method
Precisely weighing an appropriate amount of 1-isopropylamino-3- (2-naphthoxy) -2-propanol, and diluting the mobile phase to 1ml of a positioning solution containing 1mg of 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
precisely weighing a proper amount of propranolol hydrochloride, adding proper amounts of 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3 '- (isopropylamino) -di- (1-naphthyloxy) propan-2-ol and 1, 3-di- (1-naphthyloxy) propan-2-ol, and diluting the mobile phase to 1mg of propranolol hydrochloride, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, 1. mu.g each of 1, 3-bis- (1-naphthyloxy) propan-2-ol and 1, 2-bis-isopropylamino-3- (1-naphthyloxy) -2-propanol.
The mobile phase ratio is acetonitrile-water-sulfuric acid (55:45:0.1) mixture (taking sodium dodecyl sulfate 1.6g and ammonium dihydrogen phosphate 0.31g to dissolve in 1000ml mixture, using 2mol/L sodium hydroxide solution to adjust pH value to 3.3), the chromatographic column is Agilent SB C18(250mm x 4.6mm x 5 μm); the flow rate is 1.2 ml/min; the detection wavelength is 292 nm; the column temperature was 40 ℃.
Precisely measuring the positioning solution and the sample solution by 20 mu L respectively, injecting into a liquid chromatograph, and recording the chromatogram. The chromatograms obtained by the above method are shown in FIGS. 17 and 18.
Analytical test results for the localization solutions are shown in table 17:
TABLE 17
Peak number 1 is 1-isopropylamino-3- (2-naphthyloxy) -2-propanol.
The results of the assay of the test solutions are shown in table 18:
watch 18
Peak numbers were assigned as follows:
1 is 3- (1-naphthyloxy) -1, 2-propanediol; (ii) a
2 is propranolol hydrochloride and 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
3 is 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol;
4 is 3, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol;
5 is 1, 3-bis- (1-naphthyloxy) propan-2-ol;
the results show that 1-isopropylamino-3- (2-naphthoxy) -2-propanol cannot be separated from propranolol hydrochloride in the method.
Comparative example 2
The instrument comprises the following steps: agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter
Precisely weighing an appropriate amount of 1-isopropylamino-3- (2-naphthoxy) -2-propanol, and diluting the mobile phase to 1ml of a positioning solution containing 1mg of 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
precisely weighing a proper amount of propranolol hydrochloride, adding proper amounts of 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, 1, 3-di- (1-naphthyloxy) propan-2-ol and 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, diluting the mobile phase to 1ml containing 1mg of propranolol hydrochloride, 1-isopropylamino-3- (2-naphthyloxy) -2-propanol and 3- (1-naphthyloxy) -1, 1. mu.g each of 2-propanediol, 3' - (isopropylamino) -bis- (1-naphthyloxy) propan-2-ol, 1, 3-bis- (1-naphthyloxy) propan-2-ol, and 1, 2-bis-isopropylamino-3- (1-naphthyloxy) -2-propanol.
The column was Agilent SB C18(250 mm. times.4.6 mm. times.5 μm);
the flow rate is 1.2 ml/min;
the detection wavelength is 292 nm;
the column temperature is 40 ℃;
a mobile phase system, wherein phase A is 5.0g of sodium dodecyl sulfate, 180ml of 0.15mol/L phosphoric acid is added, water is added for dilution to 700ml, phase B is methanol, phase C is acetonitrile, the gradient elution mode is 0-20min, 34% of phase A, 33% of phase B and 33% of phase C; 20-30min, 34% A-20% A, 33% B-40% B, 33% C-40% C; 30-40min, 20% A, 40% B, 40% C; 40-45min, 20% A-34% A, 40% B-33% B, 44% C-33% C; 45-50min, 34% A, 33% B, 33% C.
Precisely measuring the positioning solution and the sample solution by 20 mu L respectively, injecting into a liquid chromatograph, and recording the chromatogram. The chromatogram of the sample solution obtained by the above method is shown in figures 19-20.
Analytical test results for the localization solutions are shown in table 19:
watch 19
Peak 1 is 1-isopropylamino-3- (2-naphthyloxy) -2-propanol;
the results of the assay of the test solutions are shown in table 20:
watch 20
Peak numbers were assigned as follows:
peak 1 is 3- (1-naphthyloxy) -1, 2-propanediol;
peak 2 is 1-isopropylamino-3- (2-naphthoxy) -2-propanol;
peak 4 is 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol;
The result shows that in the method, 1-isopropylamino-3- (2-naphthoxy) -2-propanol and propranolol hydrochloride can be separated relevantly (the separation degree is 1.3), but the system baseline is poor, the elution gradient is adjusted without great improvement, and the detection of related substances of the propranolol hydrochloride raw material cannot be met.
Claims (16)
1. A method for separating a naphthol derivative, comprising the steps of: separating naphthol derivative by high performance liquid chromatography;
the chromatographic column in the high performance liquid chromatography is a C18 chromatographic column;
the mobile phase in the high performance liquid chromatography is a mixed solution with the pH value of 3.1-3.5, and the mixed solution contains an organic solvent, water, sulfuric acid, sodium dodecyl sulfate and tetrabutylammonium phosphate;
the volume usage ratio of the organic solvent, the water and the sulfuric acid is (51-49): (49-51): 0.1;
the organic solvent is acetonitrile; the naphthol derivatives include 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol, and 1, 3-di- (1-naphthyloxy) propan-2-ol.
2. The separation process of claim 1, wherein the naphthol derivative is a mixture of 1-isopropylamino-3- (2-naphthyloxy) -2-propanol, 1-isopropylamino-3- (l-naphthyloxy) -2-propanol hydrochloride, 1-naphthylepoxypropyl ether, 1, 2-di-isopropylamino-3- (1-naphthyloxy) -2-propanol, 3- (1-naphthyloxy) -1, 2-propanediol, 3' - (isopropylamino) -di- (1-naphthyloxy) propan-2-ol and 1, 3-di- (1-naphthyloxy) propan-2-ol.
3. The separation method of claim 1, wherein the volume usage ratio of the organic solvent, the water, and the sulfuric acid is 50:50: 0.1.
4. The separation method of claim 1, wherein the pH is 3.3.
5. The separation process of claim 4, wherein the pH adjustment is performed by sodium hydroxide solution.
6. The separation method according to claim 5, wherein the sodium hydroxide solution is a 2mol/L sodium hydroxide solution.
7. The separation method according to claim 1, wherein the concentration of the sodium dodecyl sulfate in the mixed solution is 1.2g/L to 2.0 g/L; and/or the concentration of the tetrabutylammonium phosphate in the mixed solution is 0.2-0.5 g/L.
8. The separation method according to claim 7, wherein the concentration of the sodium lauryl sulfate in the mixed solution is 1.6 g/L; the concentration of the tetrabutylammonium phosphate in the mixed liquid is 0.31 g/L.
9. The separation method of claim 1, wherein the C18 chromatography column is an Agilent SB C18 column;
the temperature of the chromatographic column is 20-50 ℃;
the sample injection volume of the chromatographic column is 1-50 mu L;
the particle size of filler particles of the chromatographic column is 2.7-5 mu m;
the length of the chromatographic column is 150-250 mm;
the flow rate of the mobile phase is 1-1.4 ml/min.
10. The separation method of claim 9, wherein the temperature of the chromatographic column is 35 to 45 ℃;
the sample injection volume of the chromatographic column is 10-20 mu L;
the particle size of filler particles of the chromatographic column is 3-5 microns;
the length of the chromatographic column is 250 mm;
the flow rate of the mobile phase was 1.2 ml/min.
11. The separation method of claim 9, wherein the temperature of the chromatographic column is 40 ℃.
12. The separation method according to claim 1, wherein the sample of the naphthol derivative is prepared in the form of a solution, a solvent in the solution is the mobile phase, and the concentration of the naphthol derivative in the solution is (1 μ g-1 mg)/mL;
and/or the high performance liquid chromatograph is an Agilent 1260 high performance liquid chromatograph.
13. The separation method according to claim 12, wherein the concentration of the naphthol derivative in the solution is 2 μ g/mL.
14. A method for detecting a naphthol derivative, which comprises the steps of: separating naphthol derivatives by adopting a high performance liquid chromatography, and detecting by using a high performance liquid chromatograph and a detector in the high performance liquid chromatography; then the method is finished;
the naphthol derivative is as defined in claim 1 or 2;
the high performance liquid chromatography is as described in any one of the separation methods of claims 1-13.
15. The method for detecting a naphthol derivative according to claim 14, wherein the detector is an ultraviolet detector, an ultraviolet-visible light detector or a diode array detector; the detection wavelength is 230nm to 290 nm.
16. The method for detecting a naphthol derivative according to claim 15, wherein the detection wavelength is 230 nm.
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