CN113866318B - Detection method of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride - Google Patents
Detection method of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride Download PDFInfo
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- HOWMFJAGZXHDHP-UHFFFAOYSA-N (6-aminopyridin-2-yl)-(1-methylpiperidin-4-yl)methanone;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCC1C(=O)C1=CC=CC(N)=N1 HOWMFJAGZXHDHP-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 238000001514 detection method Methods 0.000 title claims abstract description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 72
- 238000004811 liquid chromatography Methods 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims description 70
- 238000012360 testing method Methods 0.000 claims description 58
- 239000013558 reference substance Substances 0.000 claims description 34
- 239000012535 impurity Substances 0.000 claims description 30
- 239000012488 sample solution Substances 0.000 claims description 21
- VNXBMAJAOYPLGV-UHFFFAOYSA-N (1-methylpiperidin-4-yl)-pyrrolidin-1-ylmethanone Chemical compound C1CN(C)CCC1C(=O)N1CCCC1 VNXBMAJAOYPLGV-UHFFFAOYSA-N 0.000 claims description 20
- XIFPGOFGUAEGAC-UHFFFAOYSA-N (6-bromopyridin-2-yl)-(1-methylpiperidin-4-yl)methanone Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(Br)=N1 XIFPGOFGUAEGAC-UHFFFAOYSA-N 0.000 claims description 16
- 239000000523 sample Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 13
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 13
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- 239000003085 diluting agent Substances 0.000 claims description 12
- 239000008055 phosphate buffer solution Substances 0.000 claims description 9
- 239000012085 test solution Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims 1
- 238000010790 dilution Methods 0.000 claims 1
- 238000010828 elution Methods 0.000 abstract description 19
- 239000008363 phosphate buffer Substances 0.000 abstract description 10
- 238000004458 analytical method Methods 0.000 abstract description 3
- 239000005416 organic matter Substances 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 82
- 239000007788 liquid Substances 0.000 description 27
- 230000010354 integration Effects 0.000 description 26
- 230000000052 comparative effect Effects 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002835 absorbance Methods 0.000 description 10
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010606 normalization Methods 0.000 description 6
- YLTJVIIEHKBRPA-UHFFFAOYSA-N (6-aminopyridin-2-yl)-(1-methylpiperidin-4-yl)methanone Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(N)=N1 YLTJVIIEHKBRPA-UHFFFAOYSA-N 0.000 description 4
- -1 (6-aminopyridin-4-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride Chemical compound 0.000 description 4
- OVFCBLGFGOVCJD-UHFFFAOYSA-N bis(1-methylpiperidin-4-yl)methanone Chemical compound C1CN(C)CCC1C(=O)C1CCN(C)CC1 OVFCBLGFGOVCJD-UHFFFAOYSA-N 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010829 isocratic elution Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
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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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- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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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 belongs to the technical field of organic matter detection and analysis, and discloses a detection method of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride. The detection method comprises the following steps: detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride by liquid chromatography; the conditions of the liquid chromatography include: the adopted mobile phase comprises a mobile phase A and a mobile phase B; mobile phase a is phosphate buffer; mobile phase B is acetonitrile; the mobile phase is subjected to gradient elution according to certain conditions. The detection method can accurately detect the purity of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) ketone dihydrochloride in the sample.
Description
Technical Field
The invention belongs to the technical field of organic matter detection and analysis, and particularly relates to a detection method of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride.
Background
(6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, CAS number: 613678-10-7, which is an important intermediate for producing the drug of lasmidbody, the purity and impurity of which directly influence the purity and the size of the impurity of the drug, thereby directly influencing the curative effect of the drug.
At present, no relevant literature and report on a method for detecting the purity of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride are found, and in order to enhance the quality control of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride and further control the quality of lasmidbody, the method for detecting the purity and impurity content of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride is particularly important.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a detection method of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) ketone dihydrochloride, which has the advantages of simplicity, convenience, accuracy, good repeatability, rapidness, reliability and the like.
The invention provides a detection method of (6-aminopyridine-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride, which comprises the following steps:
detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride by liquid chromatography;
the conditions of the liquid chromatography include: the adopted mobile phase comprises a mobile phase A and a mobile phase B; the mobile phase A is phosphate buffer solution; the mobile phase B is acetonitrile;
the mobile phase eluted according to the following gradient:
0 minutes, 65-75% of mobile phase A and 25-35% of mobile phase B;
5 minutes, the mobile phase A is 65-75%, and the mobile phase B is 25-35%;
25 minutes, 15-25% of mobile phase A and 75-85% of mobile phase B;
30 minutes, 15-25% of mobile phase A and 75-85% of mobile phase B;
35 minutes, mobile phase A is 65-75%, mobile phase B is 25-35%;
40 minutes, mobile phase A is 65-75% and mobile phase B is 25-35%.
Preferably, the detection method comprises the steps of:
dissolving (6-aminopyridine-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride in a diluent to obtain a reference substance solution;
dissolving a test sample containing (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride in a diluent to obtain a test sample solution;
taking the reference substance solution, detecting by liquid chromatography, and recording a chromatogram A;
taking the sample solution, detecting by liquid chromatography, and recording a chromatogram B;
calculating the purity of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride from the chromatogram a and the chromatogram B;
the conditions of the liquid chromatography include: the adopted mobile phase comprises a mobile phase A and a mobile phase B; the mobile phase A is phosphate buffer solution; the mobile phase B is acetonitrile;
the mobile phase eluted according to the following gradient:
0 minutes, 65-75% mobile phase A, 25-35% mobile phase B, preferably 70% mobile phase A, 20% mobile phase B;
5 minutes, mobile phase A is 65-75%, mobile phase B is 25-35%, preferably mobile phase A is 70%, mobile phase B is 20%;
25 minutes, 15-25% mobile phase A, 75-85% mobile phase B, preferably 20% mobile phase A, 70% mobile phase B;
30 minutes, 15-25% mobile phase A, 75-85% mobile phase B, preferably 20% mobile phase A and 70% mobile phase B;
35 minutes, 65-75% mobile phase A, 25-35% mobile phase B, preferably 70% mobile phase A, 20% mobile phase B;
40 minutes, mobile phase A is 65-75%, mobile phase B is 25-35%, preferably mobile phase A is 70% and mobile phase B is 20%.
Preferably, the diluent is a mixture of water and acetonitrile, and the volume ratio of water to acetonitrile in the diluent is (1-2): (1-2), more preferably the volume ratio is 1:1; in the reference substance solution, the concentration of the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride is 0.25-1mg/mL, more preferably 0.5mg/mL; in the test solution, the concentration of the test is 0.25-1mg/mL, more preferably 0.5mg/mL.
Preferably, the detection method further comprises the step of a system applicability test, wherein the system applicability test is as follows: dissolving (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, (6-bromo-2-pyridyl) (1-methyl-4-piperidinyl) methanone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone in a diluent to obtain a system applicability solution; and detecting the system applicability solution by adopting liquid chromatography, and recording a chromatogram C. The purpose of the system suitability test is primarily to determine that the chromatographic system used for analysis is effective and suitable.
Preferably, the concentration of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride in the system applicability solution is 0.25-1mg/mL, more preferably 0.5mg/mL; the concentration of the (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) methanone is 0.15-0.5mg/mL, more preferably 0.25mg/mL; the concentration of (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone is from 0.15 to 0.5mg/mL, more preferably 0.25mg/mL.
Preferably, the result of said detection: the theoretical plate number is not less than 2000 calculated by (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, and the separation degree of the main peak and the adjacent impurities is more than 1.5.
Preferably, the detection method further includes the step of a blank test, wherein the blank test is: detecting the diluent by liquid chromatography, recording a chromatogram D, subtracting a chromatographic peak in the chromatogram D from the chromatogram B, and calculating according to an area normalization method. The blank test aims to eliminate the influence caused by the diluent and can further improve the detection accuracy.
Preferably, the phosphate buffer is a potassium dihydrogen phosphate buffer; the concentration of the potassium dihydrogen phosphate buffer is 0.01-0.03mol/L, more preferably 0.01mol/L; the pH of the potassium dihydrogen phosphate buffer is 5.0 to 8.0, more preferably 7.0. The pH of the phosphate buffer is selected to help improve the peak profile, especially when the pH is 7.0, which is optimal.
Preferably, the conditions of the liquid chromatography further include:
chromatographic column: wondaSil C18 Superb (5 um, 4.6X250 mm) (W) and its equivalent C18 column;
sample injection amount: 5-30. Mu.L, more preferably 10. Mu.L;
mobile phase flow rate: 0.5-0.7mL/min, more preferably 0.6mL/min;
column temperature: 20-30 ℃, more preferably 26 ℃;
detection wavelength: 210-220nm, more preferably 215nm;
a detector: an ultraviolet detector.
Another aspect of the present invention is to provide the use of the above detection method for the preparation of masculine.
In particular to an application of the detection method of the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride in preparing the lasmidbody.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, phosphate buffer solution is adopted as a mobile phase A and acetonitrile is adopted as a mobile phase B, and gradient elution is carried out according to a certain proportion, so that (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) ketone dihydrochloride, known impurities and unknown impurities of the (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) ketone dihydrochloride can be effectively separated, the separation effect is improved, and the detection accuracy, the detection speed and the sensitivity are improved.
2. The detection method has the advantages of simplicity, convenience, accuracy, good repeatability, rapidness, reliability and the like, is beneficial to strengthening the quality control of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride, and further controls the quality of the lasmidbody.
Drawings
FIG. 1 is a liquid chromatogram of a system applicability solution of example 1 of the present invention;
FIG. 2 is a first liquid chromatogram of a control solution of example 1 of the present invention;
FIG. 3 is a second liquid-phase chromatogram of the control solution of example 1 of the present invention;
FIG. 4 is a liquid chromatogram of a sample solution of example 1 of the present invention;
FIG. 5 is a liquid chromatogram of a sample solution of example 2 of the present invention;
FIG. 6 is a liquid chromatogram of a sample solution of example 3 of the present invention;
FIG. 7 is a liquid chromatogram of a sample solution of example 4 of the present invention;
FIG. 8 is a liquid chromatogram of a system applicability solution of example 5 of the invention;
FIG. 9 is a liquid chromatogram of a system applicability solution of example 6 of the invention;
FIG. 10 is a liquid chromatogram of a solution of comparative example 1 of the present invention;
FIG. 11 is a liquid chromatogram of a system applicability solution of comparative example 2 of the present invention;
FIG. 12 is a liquid chromatogram of a solution of comparative example 3 of the present invention.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following examples do not limit the scope of the invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
Four batches of (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride products produced by the same production specification instruction are taken as test products 1-4, the test products are respectively detected according to the detection methods of the examples 1-4, and the purity and the impurity of the products are calculated by adopting an area normalization method. Known impurities in the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride product are: (6-bromo-2-pyridinyl) (1-methyl-4-piperidinyl) methanone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone.
Example 1
A method for detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, comprising the following steps:
1) Preparing a reference substance solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, and dissolving the reference substance by using an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
2) Preparing a test solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride test sample, and dissolving the test sample in an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
3) Preparing a system applicability solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone, placing the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone and the (1-methylpiperidin-4-yl) ketone into the same volumetric flask, and dissolving the (6-aminopyridin-4-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, 0.25mg/mL of (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and 0.25mg/mL of (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone into a 50% acetonitrile aqueous solution by volume percentage concentration to prepare a system applicability solution;
4) Blank test, precisely measuring 10 mu L of acetonitrile aqueous solution with the volume percentage concentration of 50%, injecting into a liquid chromatograph, and recording a chromatogram; the blank must not have interference;
5) System applicability test: precisely measuring 10 mu L of system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, wherein the theoretical plate number is not lower than 2000 according to (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride, and the separation degree of a main peak and adjacent impurities is larger than 1.5;
6) Test article solution test: precisely measuring 10 mu L of the sample solution, injecting into a liquid chromatograph, recording a chromatogram, deducting a chromatographic peak of a blank test from the chromatogram of the sample solution, and calculating the concentration of the sample according to an area normalization method.
The test conditions of the liquid chromatograph of the present embodiment were set as follows: the chromatographic column is an island fluid Wondasil C18 Superb chromatographic column with the specification of 4.6X250 mm and 5 μm, and the column temperature is 26 ℃; gradient elution is carried out by adopting a double mobile phase, wherein the mobile phase A is potassium dihydrogen phosphate buffer solution with the concentration of 0.01mol/L (the pH value is adjusted to 7.0 by sodium hydroxide solution), the mobile phase B is acetonitrile, and the flow rate of the mobile phase is 0.6mL/min; the detector is an ultraviolet detector, and the detection wavelength is 215nm; the gradient elution conditions are shown in table 1, and the volume ratio of mobile phase a to mobile phase B is uniform and gradually changed.
TABLE 1 gradient elution conditions
| Time (%) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 5 | 70 | 30 |
| 25 | 20 | 80 |
| 30 | 20 | 80 |
| 35 | 70 | 30 |
| 40 | 70 | 30 |
The chromatogram of the system applicability solution of this example is shown in FIG. 1, in which "1" in FIG. 1 represents the peak corresponding to (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone, "2" represents the peak corresponding to (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, "3" represents the peak corresponding to (6-bromo-2-pyridinyl) (1-methyl-4-piperidinyl) methanone, and "4, 5, 6, 7" represents the peaks corresponding to other impurities (ordinate "Absorbance" in FIG. 1 represents Absorbance in mAU). As can be seen from FIG. 1, the degree of separation between the 3 main peaks is greater than 1.5, and the number of trays is high. The integration results and detection results are shown in tables 2 and 3.
TABLE 2 integration results of chromatograms
TABLE 3 detection results of System applicability solutions
In this example, the reference solution was detected twice, and the two chromatograms of the reference solution are shown in fig. 2 and 3, respectively, "2" in fig. 2 and 3 represents the peak corresponding to (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, and "1, 3, 4" represents the peak corresponding to other impurities (the ordinate "absorpance" in fig. 2 and 3 represents Absorbance in mAU). The results of integration of the two times and the detection results are shown in tables 4, 5, 6 and 7.
TABLE 4 integration results of first chromatograms
TABLE 5 first detection results of control solutions
TABLE 6 integration results of the second chromatogram
TABLE 7 results of second detection of control solutions
The peak areas of the two determinations were analyzed and their Relative Standard Deviation (RSD) was calculated as: 0.02% and good repeatability. The purity (relative peak area) of the two determinations was analyzed and the Relative Standard Deviation (RSD) was calculated as: 0.01%, and good repeatability.
The chromatogram of the sample solution of this example is shown in FIG. 4, in which "2" in FIG. 4 represents the peak corresponding to (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone, "3" represents the peak corresponding to (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, "4" represents the peak corresponding to the largest single impurity, and "1, 5, 6" represents the peaks corresponding to other impurities (ordinate "Absorbance" in FIG. 4 represents Absorbance in mAU). The integration results and detection results are shown in tables 8 and 9.
Table 8 integration results of chromatograms
TABLE 9 test results of test solutions
Example 2
A method for detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, comprising the following steps:
1) Preparing a reference substance solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, and dissolving the reference substance by using an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
2) Preparing a test solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride test sample, and dissolving the test sample in an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
3) Preparing a system applicability solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone, placing the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone and the (1-methylpiperidin-4-yl) ketone into the same volumetric flask, and dissolving the (6-aminopyridin-4-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, 0.25mg/mL of (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and 0.25mg/mL of (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone into a 50% acetonitrile aqueous solution by volume percentage concentration to prepare a system applicability solution;
4) Blank test, precisely measuring 10 mu L of acetonitrile aqueous solution with the volume percentage concentration of 50%, injecting into a liquid chromatograph, and recording a chromatogram; the blank must not have interference;
5) System applicability test: precisely measuring 10 mu L of system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, wherein the theoretical plate number is not lower than 2000 according to (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride, and the separation degree of a main peak and adjacent impurities is larger than 1.5;
6) Test article solution test: precisely measuring 10 mu L of the sample solution, injecting into a liquid chromatograph, recording a chromatogram, deducting a chromatographic peak of a blank test from the chromatogram of the sample solution, and calculating the concentration of the sample according to an area normalization method.
The test conditions of the liquid chromatograph of the present embodiment were set as follows: the chromatographic column is an island fluid Wondasil C18 Superb chromatographic column with the specification of 4.6X250 mm and 5 μm, and the column temperature is 26 ℃; gradient elution is carried out by adopting a double mobile phase, wherein the mobile phase A is potassium dihydrogen phosphate buffer solution with the concentration of 0.01mol/L (the pH value is adjusted to 7.0 by sodium hydroxide solution), the mobile phase B is acetonitrile, and the flow rate of the mobile phase is 0.6mL/min; the detector is an ultraviolet detector, and the detection wavelength is 215nm; the conditions for gradient elution are shown in Table 10.
TABLE 10 gradient elution conditions
| Time (%) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 5 | 70 | 30 |
| 25 | 20 | 80 |
| 30 | 20 | 80 |
| 35 | 70 | 30 |
| 40 | 70 | 30 |
The chromatogram and the integration result of the sample solution in this example are shown in FIG. 5, in which "2" in FIG. 5 represents the peak corresponding to (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone, "3" represents the peak corresponding to (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, "4" represents the peak corresponding to the largest single impurity, and "1, 5" represents the peak corresponding to other impurities (ordinate "Absorbance" in FIG. 5 represents Absorbance in mAU). The integration results and detection results are shown in tables 11 and 12.
Table 11 integration results of chromatograms
TABLE 12 test results of test solutions
Example 3
A method for detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, comprising the following steps:
1) Preparing a reference substance solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, and dissolving the reference substance by using an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
2) Preparing a test solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride test sample, and dissolving the test sample in an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
3) Preparing a system applicability solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone, placing the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone and the (1-methylpiperidin-4-yl) ketone into the same volumetric flask, and dissolving the (6-aminopyridin-4-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, 0.25mg/mL of (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and 0.25mg/mL of (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone into a 50% acetonitrile aqueous solution by volume percentage concentration to prepare a system applicability solution;
4) Blank test, precisely measuring 10 mu L of acetonitrile aqueous solution with the volume percentage concentration of 50%, injecting into a liquid chromatograph, and recording a chromatogram; the blank must not have interference;
5) System applicability test: precisely measuring 10 mu L of system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, wherein the theoretical plate number is not lower than 2000 according to (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride, and the separation degree of a main peak and adjacent impurities is larger than 1.5;
6) Test article solution test: precisely measuring 10 mu L of the sample solution, injecting into a liquid chromatograph, recording a chromatogram, deducting a chromatographic peak of a blank test from the chromatogram of the sample solution, and calculating the concentration of the sample according to an area normalization method.
The test conditions of the liquid chromatograph of the present embodiment were set as follows: the chromatographic column is an island fluid Wondasil C18 Superb chromatographic column with the specification of 4.6X250 mm and 5 μm, and the column temperature is 26 ℃; gradient elution is carried out by adopting a double mobile phase, wherein the mobile phase A is potassium dihydrogen phosphate buffer solution with the concentration of 0.01mol/L (the pH value is adjusted to 7.0 by sodium hydroxide solution), the mobile phase B is acetonitrile, and the flow rate of the mobile phase is 0.6mL/min; the detector is an ultraviolet detector, and the detection wavelength is 215nm; the conditions for gradient elution are shown in Table 13.
TABLE 13 gradient elution conditions
| Time (%) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 5 | 70 | 30 |
| 25 | 20 | 80 |
| 30 | 20 | 80 |
| 35 | 70 | 30 |
| 40 | 70 | 30 |
The chromatogram and the integration result of the sample solution in this example are shown in FIG. 6, in which "2" in FIG. 6 represents the peak corresponding to (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone, "3" represents the peak corresponding to (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, "4" represents the peak corresponding to the largest single impurity, and "1, 5, 6, 7" represents the peak corresponding to other impurities (ordinate "Absorbance" in FIG. 6 represents Absorbance in mAU). The integration results and detection results are shown in tables 14 and 15.
TABLE 14 integration results of chromatograms
TABLE 15 test results of test solutions
Example 4
A method for detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, comprising the following steps:
1) Preparing a reference substance solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, and dissolving the reference substance by using an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
2) Preparing a test solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride test sample, and dissolving the test sample in an acetonitrile water solution with the volume percentage concentration of 50% to obtain a reference substance solution with the concentration of 0.5mg/mL;
3) Preparing a system applicability solution: taking a proper amount of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone, placing the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone and the (1-methylpiperidin-4-yl) ketone into the same volumetric flask, and dissolving the (6-aminopyridin-4-yl) (1-methylpiperidin-4-yl) ketone dihydrochloride reference substance, 0.25mg/mL of (6-bromo-2-pyridyl) (1-methyl-4-piperidyl) ketone and 0.25mg/mL of (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) ketone into a 50% acetonitrile aqueous solution by volume percentage concentration to prepare a system applicability solution;
4) Blank test, precisely measuring 10 mu L of acetonitrile aqueous solution with the volume percentage concentration of 50%, injecting into a liquid chromatograph, and recording a chromatogram; the blank must not have interference;
5) System applicability test: precisely measuring 10 mu L of system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, wherein the theoretical plate number is not lower than 2000 according to (6-aminopyridine-2-yl) (1-methylpiperidine-4-yl) methanone dihydrochloride, and the separation degree of a main peak and adjacent impurities is larger than 1.5;
6) Test article solution test: precisely measuring 10 mu L of the sample solution, injecting into a liquid chromatograph, recording a chromatogram, deducting a chromatographic peak of a blank test from the chromatogram of the sample solution, and calculating the concentration of the sample according to an area normalization method.
The test conditions of the liquid chromatograph of the present embodiment were set as follows: the chromatographic column is an island fluid Wondasil C18 Superb chromatographic column with the specification of 4.6X250 mm and 5 μm, and the column temperature is 26 ℃; gradient elution is carried out by adopting a double mobile phase, wherein the mobile phase A is potassium dihydrogen phosphate buffer solution with the concentration of 0.01mol/L (the pH value is adjusted to 7.0 by sodium hydroxide solution), the mobile phase B is acetonitrile, and the flow rate of the mobile phase is 0.6mL/min; the detector is an ultraviolet detector, and the detection wavelength is 215nm; the conditions for gradient elution are shown in Table 16.
TABLE 16 gradient elution conditions
The chromatogram and the integration result of the sample solution in this example are shown in fig. 7, in which "1" in fig. 7 represents the peak corresponding to the maximum single impurity, "2" represents the peak corresponding to (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, and "3, 4" represent the peaks corresponding to other impurities (ordinate "absorpance" in fig. 7 represents Absorbance in mAU). The integration results and detection results are shown in tables 17 and 18.
Table 17 integration results of chromatograms
TABLE 18 test results of sample solutions
As can be seen from the detection results of examples 1 to 4, different purities, known impurities and unknown impurities of different batches of samples can be detected.
Example 5
Example 5 differs from example 1 in that the pH of the mobile phase A potassium dihydrogen phosphate buffer was 8.5, with the other conditions being the same as in example 1. The system applicability solution of example 5 was subjected to a system applicability test, and the chromatogram thereof is shown in FIG. 8. As can be seen from FIG. 8, when the pH of the potassium dihydrogen phosphate buffer is not within the limit of the present invention, the peak of the known impurity (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone diverges, the peak form is poor, and the judgment of the unknown impurity and the known impurity is affected. The integration results are shown in Table 19.
Table 19 integration results of chromatograms
Example 6
Example 6 differs from example 1 in that the pH of the mobile phase A potassium dihydrogen phosphate buffer was 4.5, with the other conditions being the same as in example 1. The system applicability test was performed on the system applicability solution of example 6, and the chromatogram thereof is shown in fig. 9. As can be seen from FIG. 9, when the pH of the potassium dihydrogen phosphate buffer is not within the range defined in the present invention, the separation of the substances is not made, the degree of separation is extremely poor, and the peak pattern is also poor. The integration results are shown in Table 20.
Integration results of Table 20 chromatograms
Comparative example 1
Comparative example 1 differs from example 1 in that comparative example 1 employs isocratic elution, the elution conditions of which are shown in table 21.
Table 21 isocratic elution conditions
| Time (%) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 50 | 50 |
| 30 | 50 | 50 |
The system applicability test was performed on the system applicability solution of the present comparative example, and the chromatogram thereof is shown in fig. 10. As can be seen from fig. 10, comparative example 1 resulted in a difference in separation degree between substances, a difference in peak type, and the chromatographic system was not applicable due to the use of isocratic elution. The integration results are shown in Table 22.
Integration results of Table 22 chromatograms
Comparative example 2
Comparative example 2 is different from example 1 in that the gradient elution of comparative example 2 is not within the scope of the present invention, and the gradient elution conditions are shown in table 23.
TABLE 23 gradient elution conditions
| Time (%) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 60 | 40 |
| 5 | 60 | 40 |
| 25 | 30 | 70 |
| 30 | 30 | 70 |
| 35 | 60 | 40 |
| 40 | 60 | 40 |
The system applicability test was performed on the system applicability solution of the present comparative example, and the chromatogram thereof is shown in fig. 11. As can be seen from fig. 11, comparative example 2 was unsuitable for the chromatographic system because the gradient elution condition was not within the range defined by the present invention, resulting in a difference in separation degree between substances, a difference in peak type. The integration results are shown in Table 24.
Integration results of Table 24 chromatograms
Comparative example 3
Comparative example 3 differs from example 1 in that comparative example 3 mobile phase B uses methanol instead of acetonitrile, and other conditions and detection methods are the same as example 1. The system applicability test was performed on the system applicability solution of the present comparative example, and the chromatogram thereof is shown in fig. 12. As can be seen from FIG. 12, comparative example 3 has good separation degree but poor peak type and base line due to the use of methanol instead of acetonitrile. The integration results are shown in Table 25.
Integration results of Table 25 chromatogram
While the preferred embodiments of the present invention have been illustrated and described, the present invention is not limited to the embodiments, and various equivalent modifications and substitutions can be made by one skilled in the art without departing from the spirit of the present invention, and these are intended to be included in the scope of the present invention as defined in the appended claims.
Claims (9)
1. A method for detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, which is characterized by comprising the following steps:
detecting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride by liquid chromatography;
the conditions of the liquid chromatography include: using a C18 chromatographic column, and using mobile phases including mobile phase a and mobile phase B; the mobile phase A is potassium dihydrogen phosphate buffer solution with the pH value of 7.0; the mobile phase B is acetonitrile;
the mobile phase eluted according to the following gradient:
0 minutes, 70% mobile phase A, 30% mobile phase B;
5 minutes, 70% mobile phase A and 30% mobile phase B;
25 minutes, mobile phase A20%, mobile phase B80%;
30 minutes, 20% mobile phase A and 80% mobile phase B;
35 minutes, 70% mobile phase A and 30% mobile phase B;
40 minutes, 70% mobile phase A and 30% mobile phase B;
known impurities in the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride are: (6-bromo-2-pyridinyl) (1-methyl-4-piperidinyl) methanone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone.
2. The method of detection according to claim 1, comprising the steps of:
dissolving (6-aminopyridine-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride in a diluent to obtain a reference substance solution;
dissolving a test sample containing (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride in a diluent to obtain a test sample solution;
taking the reference substance solution, detecting by liquid chromatography, and recording a chromatogram A;
taking the sample solution, detecting by liquid chromatography, and recording a chromatogram B;
calculating the purity of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride from the chromatogram a and the chromatogram B;
the conditions of the liquid chromatography include: using a C18 chromatographic column, and using mobile phases including mobile phase a and mobile phase B; the mobile phase A is potassium dihydrogen phosphate buffer solution with the pH value of 7.0; the mobile phase B is acetonitrile;
the mobile phase eluted according to the following gradient:
0 minutes, 70% mobile phase A, 30% mobile phase B;
5 minutes, 70% mobile phase A and 30% mobile phase B;
25 minutes, mobile phase A20%, mobile phase B80%;
30 minutes, 20% mobile phase A and 80% mobile phase B;
35 minutes, 70% mobile phase A and 30% mobile phase B;
40 minutes, 70% mobile phase A and 30% mobile phase B;
known impurities in the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride are: (6-bromo-2-pyridinyl) (1-methyl-4-piperidinyl) methanone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone.
3. The method according to claim 2, wherein the diluent is a mixture of water and acetonitrile, and the volume ratio of water to acetonitrile in the diluent is (1-2): 1-2; in the reference substance solution, the concentration of the (6-aminopyridine-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride is 0.25-1mg/mL; in the test solution, the concentration of the test is 0.25-1mg/mL.
4. The method of claim 2, further comprising the step of testing for system suitability as: dissolving (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, (6-bromo-2-pyridyl) (1-methyl-4-piperidinyl) methanone and (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone in a diluent to obtain a system applicability solution; and detecting the system applicability solution by adopting liquid chromatography, and recording a chromatogram C.
5. The method according to claim 4, wherein the concentration of (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride in the system applicability solution is 0.25 to 1mg/mL, the concentration of (6-bromo-2-pyridinyl) (1-methyl-4-piperidinyl) methanone is 0.15 to 0.5mg/mL, and the concentration of (1-methylpiperidin-4-yl) (pyrrolidin-1-yl) methanone is 0.15 to 0.5mg/mL.
6. The method according to claim 4, wherein the result of the detection: the theoretical plate number is not less than 2000 calculated by (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone dihydrochloride, and the separation degree of the main peak and the adjacent impurities is more than 1.5.
7. The method of claim 2, further comprising the step of testing for a blank test, the blank test being: the dilutions were detected by liquid chromatography and chromatogram D was recorded.
8. The method according to claim 1, wherein the conditions of the liquid chromatography further comprise:
sample injection amount: 5-30 mu L;
mobile phase flow rate: 0.5-0.7mL/min;
column temperature: 20-30 ℃;
detection wavelength: 210-220nm.
9. Use of the detection method according to any one of claims 1-8 for the preparation of masmiphene.
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