CN112362778B - Detection method of neratedlol intermediate related substances - Google Patents
Detection method of neratedlol intermediate related substances Download PDFInfo
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- 239000000126 substance Substances 0.000 title claims abstract description 103
- 238000001514 detection method Methods 0.000 title claims abstract description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 72
- 239000000243 solution Substances 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000012085 test solution Substances 0.000 claims abstract description 26
- 238000012360 testing method Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 239000013558 reference substance Substances 0.000 claims abstract description 15
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 3
- -1 (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl Chemical group 0.000 claims description 58
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- 238000010828 elution Methods 0.000 claims description 9
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 claims description 4
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- 239000000377 silicon dioxide Substances 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
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- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- ZADSZNPGFHTHPB-UHFFFAOYSA-N benzyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=CC=C1 ZADSZNPGFHTHPB-UHFFFAOYSA-N 0.000 description 22
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- QQDRLKRHJOAQDC-FBHGDYMESA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 QQDRLKRHJOAQDC-FBHGDYMESA-N 0.000 description 1
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- 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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- 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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- G01N30/06—Preparation
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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
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
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Abstract
The invention discloses a detection method of a neratedlar intermediate related substance, which comprises the following steps: a. preparing a test solution: dissolving the intermediate of the natal in acetonitrile water to obtain a sample solution; b. preparation of system suitability solution: respectively taking the intermediate of the natal and a reference substance A of the related substance, adding acetonitrile aqueous solution for dissolving, and mixing to obtain a system applicability solution; c. the following chromatographic conditions are adopted to detect the test sample and the system applicability solution respectively. The quality of the intermediate of the neratidel can be effectively controlled, the quality of the bulk drug of the neratidel is improved, and the synthesis process of the intermediate of the neratidel and the synthesis process of the bulk drug of the neratidel can be effectively monitored.
Description
Technical Field
The invention relates to a detection method of a nertadol intermediate related substance, in particular to detection of a (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxylidenopropane-2-yl) benzyl 2, 4-dimethylbenzoate related substance, and belongs to the field of medicines.
Background
Glaucoma is a disease that damages the optic nerve and is characterized by progressive degeneration of retinal cells, resulting in irreversible loss of vision. It is reported that at least 6000 million people worldwide are affected by glaucoma. The national eye institute estimates that over 270 million people in the united states have glaucoma, with an estimated 430 million by 2030. In addition, the ophthalmic disease epidemiological research group estimates that only half of americans with glaucoma know that they are suffering from glaucoma. Thus, glaucoma remains a leading cause of blindness in adults, but is also one of the most preventable diseases through diagnosis and effective treatment. Netarsubulil dimesylate was developed by america Pharmaceuticals. The Food and Drug Administration (FDA) approval was obtained for marketing on 18.12 months in 2017. Under the trade name Rhopressa, a Rho kinase inhibitor used to lower intraocular pressure in patients with open angle glaucoma or ocular hypertension. The chemical name of natadil is benzoic acid 2, 4-dimethyl-, [4- [ ((1S) -1- (aminomethyl) -2- (6-isoquinolinylamino) -2-oxoethyl]Phenyl radical]Methyl radical]Ester, mesylate (1: 2), formula C 30 H 35 N 3 O 9 S 2 The structural formula is as follows:
the substance with the chemical name of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate is a key intermediate for synthesizing a nertadol bulk drug, and in order to ensure the quality of a nertadol API, the related substance of the intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate needs to be controlled, so as to avoid the excessive content of related substances and the formation of byproducts in the next reaction, which causes the overproof of related substances of the Netadalal API.
The chemical structure of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate is as follows:
the chemical structure of the Netadalal intermediate and the synthesis process thereof are analyzed, and the following findings are obtained: the intermediate contains a substance A, which is chemically named as (S) -3- ((tert-butoxycarbonyl) amino) -2- (4- (((2, 4-xylyl) oxy) methyl) phenyl) propionic acid, and is difficult to separate from a nemadel intermediate, so that the quality can be unstable. The quality of the intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate can be strictly controlled by developing an analytical detection method of the related substances and carrying out qualitative and quantitative analysis, so that the quality of the final product, namely the nertadol API is ensured to meet the requirements.
The prior art does not report about a detection method of a substance A of the natadel API, and does not report about the importance of the substance A in controlling the natadel API or a raw material medicine. Therefore, the development of a content analysis method of the related substance A is very important for effectively controlling the quality of the Netadalal API or the bulk drug, and has guiding significance for the synthesis process of the Netadalal API or the bulk drug.
Disclosure of Invention
In order to effectively control the quality of the neratide intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropane-2-yl) benzyl 2, 4-dimethyl benzoate and further control the quality of the neratide, the invention provides a detection method of a neratide intermediate related substance, which comprises the following steps:
a. preparation of a test solution: adding acetonitrile aqueous solution into a to-be-detected Nentadil intermediate to be dissolved to obtain a test solution;
b. preparation of system applicability solution: respectively taking the intermediate of the natal and a reference substance A of the related substance, adding acetonitrile aqueous solution for dissolving, and mixing to obtain a system applicability solution;
the neratide intermediate is (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate;
the related substance A is: (S) -3- ((tert-butoxycarbonyl) amino) -2- (4- (((2, 4-xyleneformyl) oxy) methyl) phenyl) propanoic acid;
c. the following chromatographic conditions are adopted to respectively detect the test sample and the system applicability solution:
stationary phase: octadecylsilane chemically bonded silica is used as a filling agent;
mobile phase: using 0.01-0.1% trifluoroacetic acid water solution as a mobile phase A and acetonitrile as a mobile phase B;
the gradient elution procedure was as follows:
further, the mass-to-volume ratio of the netatedil intermediate in the step a to the acetonitrile aqueous solution is 0.25-1 mg: 1ml, preferably 0.5 mg: 1 ml.
Furthermore, the concentration of the Netedlar intermediate in the system applicable solution in the step b is 0.3-0.8 mg/ml, the concentration of the related substance A control is 30-80 mug/ml, preferably, the concentration of the Netedlar intermediate is 0.5mg/ml, and the concentration of the related substance control is 50 mug/ml.
Still further, the nettadol intermediate is (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate.
Further, the volume ratio of acetonitrile to water in the acetonitrile aqueous solution is 60: 40.
Further, the mobile phase A in the step c is 0.05% trifluoroacetic acid aqueous solution; the detection wavelength in the chromatographic condition is 240-260 nm, and 254nm is preferred; the flow rate is 0.5-1.5 ml/min, preferably 0.8 ml/min; the column temperature is 30-40 ℃, and preferably 30 ℃; the sample amount is 10-20 μ l, preferably 10 μ l.
Further, the gradient elution procedure of step c is:
further, the chromatogram of the test solution shows a chromatographic peak corresponding to the retention time of the chromatographic peak of the related substance A in the chromatogram of the system applicability solution, i.e. the test solution contains the related substance A.
The invention also provides a content determination method of the neratide intermediate related substances, which comprises the following specific steps:
1) detecting according to the method;
2) the content of the related substances is calculated according to the following formula:
wherein, X i Percent: the content of the relevant substance in the sample, A i : peak area of the relevant substance in the test sample, A: sum of all peak areas in the test solution.
The detection method can effectively separate the peaks of the intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinoline-6-ylamino) -1-oxyylidenepropane-2-yl) benzyl 2, 4-dimethylbenzoate of the nertadol from the peaks of the related substances, accurately determine the content of the related substances, and has stable and reliable determination results and strong specificity.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 HPLC chart of sample solution in example 1
FIG. 2 example 2 HPLC chart of test solution
FIG. 3 HPLC chart of sample solution in example 3
Detailed Description
(1) Material
(S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl
2, 4-Dimethylbenzoate samples (supplied by Chengdu bang pharmaceutical Co., Ltd., lots VB50010501, VB50010502, VB50010601)
Reference substance A (provided by Chengdu bang pharmaceutical industry Co., Ltd., batch No. VBZ005A)
(2) Main instrument
A high performance liquid chromatograph: shimadzu LC-20AT, column: synergi RP-80A, 4.6X 250mm, 4 μm
Example 1
Content determination of related substance A of neratide intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxylidenopropane-2-yl) benzyl 2, 4-dimethyl benzoate
(1) Preparation of a test solution: (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate (batch No. WB50010501) was precisely weighed, and dissolved in an aqueous acetonitrile solution to prepare a test solution of 0.5 mg/ml.
(2) Preparation of system suitability solution: precisely weighing a related substance A reference substance, dissolving the related substance A in acetonitrile water solution to prepare a solution with the concentration of 500 mu g/ml, and taking the solution as a related substance A reference substance stock solution. Accurately weighing 25.00mg of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropane-2-yl) benzyl 2, 4-dimethylbenzoate, accurately weighing 5ml of a related substance A stock solution, placing the stock solution into a50 ml volumetric flask, dissolving the stock solution in acetonitrile aqueous solution, shaking up, and fixing the volume, wherein the solution is a system applicability solution.
(3) Chromatographic condition settings
And (3) chromatographic column: synergi RP-80A, specification 4.6X 250mm, 4 μm;
detection wavelength: 254 nm;
the flow rate is: 0.8 ml/min;
the column temperature was: at 30 ℃.
Mobile phase: taking a 0.05% trifluoroacetic acid aqueous solution as a mobile phase A, and acetonitrile as a mobile phase B;
the ratio of mobile phases a: B in the gradient elution procedure was as follows:
| time (min) | Mobile phase B (%) | Mobile phase A (%) |
| 0.01 | 15 | 85 |
| 8 | 50 | 50 |
| 10 | 75 | 25 |
| 25 | 75 | 25 |
| 27 | 50 | 50 |
| 31 | 15 | 85 |
| 35 | 15 | 85 |
(4) Measurement of
Respectively sucking 10 μ l of sample solution of the test sample and system applicability solution, injecting into chromatograph, recording chromatogram, and respectively recording related substance peak area A in the test sample i And the sum A of all peak areas in the test sample solution, and calculating the content of the related substance A in the test sample by using an area normalization method. The calculation formula is as follows:
wherein, X i Percent: the content of the relevant substances in the test sample,
A i : the peak area of the related substance in the test sample is 16758,
a: the sum of all peak areas in the test solution is 40107459, and the HPLC chromatogram of the test solution is shown in FIG. 1.
And (3) calculating the result: the contents of the relevant substances in (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate sample batch VB50010501 are respectively: related substance a ═ 0.042%.
Example 2
Content determination of related substance A of neratide intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxylidenopropane-2-yl) benzyl 2, 4-dimethyl benzoate
(1) Preparation of a test solution: (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate (batch No. WB50010502) was precisely weighed, and dissolved in an aqueous acetonitrile solution to prepare a test solution of 0.5 mg/ml.
(2) Preparation of system suitability solution: precisely weighing the reference substance A, dissolving the reference substance A in acetonitrile water solution to prepare solution with the concentration of 500 mu g/ml, and taking the solution as the stock solution of the reference substance A. Precisely weighing 25.00mg of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxylidenepropan-2-yl) benzyl 2, 4-dimethyl benzoate, precisely weighing 5ml of related substance A stock solution, placing the stock solution in a50 ml volumetric flask, dissolving the stock solution in acetonitrile aqueous solution, shaking the solution uniformly, and fixing the volume to obtain the system applicability solution.
(3) Chromatographic condition settings
A chromatographic column: synergi RP-80A, specification 4.6X 250mm, 4 μm;
detection wavelength: 254 nm.
The flow rate is: 0.8 ml/min;
the column temperature was: at 30 ℃.
Mobile phase: using 0.05% trifluoroacetic acid water solution as a mobile phase A and acetonitrile as a mobile phase B;
the ratio of mobile phases a: B in the gradient elution procedure was as follows:
| time (min) | Mobile phase B (%) | Mobile phase A (%) |
| 0.01 | 10 | 90 |
| 8 | 50 | 50 |
| 10 | 75 | 25 |
| 25 | 75 | 25 |
| 27 | 50 | 50 |
| 31 | 10 | 90 |
| 35 | 10 | 90 |
(4) Measurement of
Sucking 10. mu.l of each of the test solution and the system suitability solutionInjecting the sample into chromatograph, recording chromatogram, and respectively recording peak area A of related substances in the sample i And the sum A of all peak areas in the test sample solution, and calculating the content of the related substance A in the test sample by using an area normalization method. The calculation formula is as follows:
wherein, X i Percent: the content of the relevant substances in the test sample,
A i : the peak area 16978 of the related substance in the sample,
a: the sum of all peak areas in the test solution is 40173605, and the HPLC chromatogram of the test solution is shown in FIG. 2.
And (3) calculating the result: the contents of the relevant substances in (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate sample batch VB50010502 are respectively: related substance a ═ 0.042%.
Example 3
Determination of Netadalal intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxylidenopropan-2-yl) benzyl 2, 4-dimethylbenzoate related substance A
(1) Preparation of a test solution: accurately weighing (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxylidenepropan-2-yl) benzyl
2, 4-Dimethylbenzoate (lot VB50010601) was dissolved in an aqueous acetonitrile solution to prepare a test sample solution of 0.5 mg/ml.
(2) Preparation of system suitability solution: precisely weighing the reference substance A, dissolving the reference substance A in acetonitrile water solution to prepare solution with the concentration of 500 mu g/ml, and taking the solution as the stock solution of the reference substance A. Accurately weighing 25.00mg of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropane-2-yl) benzyl 2, 4-dimethylbenzoate, accurately weighing 5ml of a related substance A stock solution, placing the stock solution into a50 ml volumetric flask, dissolving the stock solution in acetonitrile aqueous solution, shaking up, and fixing the volume, wherein the solution is a system applicability solution.
(3) Chromatographic condition settings
A chromatographic column: synergi RP-80A, specification 4.6X 250mm, 4 μm;
detection wavelength: 254 nm.
The flow rate is: 0.8 ml/min;
the column temperature was: at 30 ℃.
Mobile phase: using 0.05% trifluoroacetic acid water solution as a mobile phase A and acetonitrile as a mobile phase B;
the ratio of mobile phases a: B in the gradient elution procedure was as follows:
| time (min) | Mobile phase B (%) | Mobile phase A (%) |
| 0.01 | 20 | 80 |
| 8 | 50 | 50 |
| 10 | 75 | 25 |
| 25 | 75 | 25 |
| 27 | 50 | 50 |
| 31 | 20 | 80 |
| 35 | 20 | 80 |
(4) Measurement of
Respectively sucking 10 μ l of sample solution of the sample and the system applicability solution, injecting into chromatograph, recording chromatogram, and respectively recording peak area A of related substances in the sample i And the sum A of all peak areas in the test sample solution, and calculating the content of the related substance A in the test sample by using an area normalization method. The calculation formula is as follows:
wherein, X i Percent: the content of the relevant substances in the test sample,
A i : the peak area 17456 of the relevant substance in the test sample,
a: the sum of all peak areas in the test solution is 47038180, and the HPLC chromatogram of the test solution is shown in FIG. 3.
And (3) calculating the result: the contents of the relevant substances in (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate sample batch VB50010601 were: related substance a ═ 0.037%.
Comparative example 1 assay of Netadalal intermediate (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate related substance A
(1) Blank solution (following dilutions): acetonitrile: water 60:40(v/v)
(2) Control stock solutions for related substance a: accurately weighing 10mg of the related substance A as a reference substance in a 20ml measuring flask, diluting the solution and fixing the volume (the related substance A: 500 ug/ml).
(3) System applicability solution: precisely weighing 25mg of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate (batch number VB50010601) in a50 ml measuring flask, precisely adding 5ml of related substance stock solution, and adding a diluent to dilute to constant volume. (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate 0.5mg/ml, reference substance A50ug/ml)
d. Respectively sucking blank solution and system applicability solution to inject into a chromatograph, wherein the chromatographic conditions are as follows:
a chromatographic column: synergi RP-80A, specification 4.6X 250mm, 4 μm;
mobile phase: a mobile phase A: 0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile, detection wavelength: 254nm
Column oven: 30 ℃, column flow: 0.8ml/min, the sample size is 10 mul
The gradient elution conditions were:
| time (min) | Mobile phase B (%) | Mobile phase A (%) |
| 0.01 | 15 | 85 |
| 8 | 55 | 45 |
| 10 | 80 | 20 |
| 25 | 85 | 15 |
| 27 | 50 | 50 |
| 31 | 15 | 85 |
| 35 | 15 | 85 |
As a result: and (3) detecting the unknown impurity interference impurity A in the chromatogram, wherein the gradient elution procedure comprises the following steps: eluting the mixture for 0-8 min, 90-80% → 45-55% A, 8-10 min, 45-55% → 25-15% A, 10-25 min, 25-15% A, 25-27 min, 25-15% → 45-55% A, 27-32 min, 45-55% → 90-80%, 31-35 min and 90-80% A, wherein the separation degree is as follows: 1.903 is less than 2, (in examples 1 to 3, the separation degrees are respectively 6.513, 6.374 and 8.95 which are all more than 2, and meet the standard requirements of national and international pharmacopoeia), so the separation effect is not good, and the detection accuracy is influenced.
The beneficial effects of the invention are further illustrated by way of test examples as follows:
experimental example 1 System applicability
The instrument comprises the following steps: a high performance liquid chromatograph: shimadzu LC-20AT, column: synergi RP-80A, 4.6X 250mm, 4 μm, flow rate: 0.8ml/min, column temperature: 30 ℃, sample size 10ul, detector wavelength: 254nm, mobile phase A: 0.05% aqueous trifluoroacetic acid mobile phase B: acetonitrile, gradient elution conditions were as follows:
| time (min) | Mobile phase B (%) | Mobile phase A (%) |
| 0.01 | 15 | 85 |
| 8 | 50 | 50 |
| 10 | 75 | 25 |
| 25 | 75 | 25 |
| 27 | 50 | 50 |
| 31 | 15 | 85 |
| 35 | 15 | 85 |
(1) Blank solution (following dilutions): acetonitrile: water 60:40(v/v)
(2) Related substance stock solution: 10mg of the related substance A is precisely weighed in a 20ml measuring flask, and the solution of the diluent is diluted and fixed to the constant volume (the related substance A: 500 ug/ml).
(3) System applicability solution: precisely weighing 25mg of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate into a50 ml measuring flask, precisely adding 5ml of related substance stock solution, adding a diluent, diluting and fixing the volume. (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate 0.5mg/ml, related substance A50ug/ml)
(4) Relevant substance positioning solution: weighing related substances A5mg respectively, placing in 100ml measuring bottles respectively, and adding the diluent to dissolve to a constant volume. (related substance A: 50ug/ml)
(5) Test solution: accurately weighing 25mg of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropan-2-yl) benzyl 2, 4-dimethylbenzoate into a50 ml measuring flask, and adding a diluent solution to a constant volume.
Blank solution, system applicability solution and sample solution are injected according to chromatographic conditions, and the chromatographic process is recorded, and the results are shown in table 1.
TABLE 1 System applicability
Experimental example 2 specificity
Experimental conditions, liquid chromatography method and solution preparation As in Experimental example 1
The method specifically inspects peak identification and selectivity, samples blank solution and related substance positioning solution respectively, records chromatogram, and the result is shown in Table 2.
TABLE 2 specialization
| Name of solution | Name of substance | Concentration of solution | Retention time |
| Positioning solution of related substance A | Related substance A | 498.2ug/ml | 20.512 |
Experimental example 3 detection and quantitation limits
Experimental conditions, liquid chromatography method and solution preparation As in Experimental example 1
For known related substances, the limit of detection (LOD) and limit of quantitation (LOQ) are determined from the signal-to-noise ratio. Diluting the relevant substance stock solution with known concentration to low concentration for sample injection, determining the detection signal-to-noise ratio S/N (signal-to-noise ratio) to be more than or equal to 10 as a quantitative limit, and determining the S/N to be 2-4 as a detection limit. For unknown related substances, (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate was used instead of examining the detection and quantification limits for individual unknown related substances. The test results are shown in Table 3.
TABLE 3 quantitation and detection limits
Experimental example 4 linearity and Range
Experimental conditions, liquid chromatography method and solution formulation were as in experimental example 1.
For known related substances, 6 points were selected from the range from the LOQ concentration to the index concentration of not less than 150% for investigation,
the linear relationship is plotted as a function of the measured response signal (peak area) versus analyte concentration, and a linear regression is performed using a least squares method, with at least the correlation coefficient R being reported 2 To confirm a good linear relationship, the linear regression coefficient R is required 2 Should not be less than 0.990.
For unknown related substances, (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate was used instead of linearity and range of unknown related substances, and the results are shown in Table 4.
TABLE 4 linearity and range
EXAMPLE 5 precision
Experimental conditions, liquid chromatography method and solution preparation As in Experimental example 1
Taking the resolution solution as a test solution, preparing 6 parts in parallel, and sequentially injecting samples, wherein the repeatability results are shown in a table 5.
TABLE 5 repeatability
| Sequence of | Related substance A | Max unknown |
| 1 | 0.042 | 0.16 |
| 2 | 0.042 | 0.16 |
| 3 | 0.040 | 0.16 |
| 4 | 0.041 | 0.15 |
| 5 | 0.040 | 0.16 |
| 6 | 0.041 | 0.15 |
| RSD％ | 2.18 | 3.30 |
Intermediate precision was performed by the same operating method and by different personnel on different instruments, and the results are shown in Table 6 and Table 6 for intermediate precision
Experimental example 6 accuracy
Experimental conditions, liquid chromatography method and solution preparation As in Experimental example 1
The accuracy is obtained by adding three related substances with different concentrations of 80%, 100% and 120% of the index into a test sample and measuring the recovery rate of the related substances. The accuracy of the known substance is determined by adding a known amount of the substance and measuring the ratio (recovery) between the amount of the known substance in the sample to the theoretical value, expressed as a percentage%. The unknown related substance was replaced by (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate. The results are shown in Table 7.
TABLE 7 accuracy
Experimental examples 1-6 show that the method for measuring the related substances of (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyylidenepropane-2-yl) benzyl 2, 4-dimethylbenzoate has good specificity, good precision, high accuracy and high sensitivity, and can be suitable for quality control of related substances in the synthesis of raw material medicines.
In conclusion, the method meets the requirement of 'Chinese pharmacopoeia' 2015 edition on analysis methodology, so that the quality of the neratidel intermediate can be effectively controlled, the quality of the neratidel bulk drug can be improved, and the synthesis process of the neratidel intermediate and the synthesis process of the neratidel bulk drug can be effectively monitored.
Claims (8)
1. A detection method of a substance related to a nemadel intermediate is characterized by comprising the following steps: it comprises the following steps:
a. preparation of a test solution: adding acetonitrile aqueous solution into a to-be-detected Nentadil intermediate to be dissolved to obtain a test solution;
b. preparation of system suitability solution: respectively taking the intermediate of the natal and a reference substance A of the related substance, adding acetonitrile aqueous solution for dissolving, and mixing to obtain a system applicability solution;
the nettadil intermediate is (S) -4- (3- ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxyiminopropan-2-yl) benzyl 2, 4-dimethylbenzoate;
the related substance A is: (S) -3- ((tert-butoxycarbonyl) amino) -2- (4- (((2, 4-ditoluoyloxy) methyl) phenyl) propanoic acid;
c. the following chromatographic conditions are adopted to respectively detect the sample and the system applicability solution:
stationary phase: octadecylsilane chemically bonded silica is used as a filling agent;
mobile phase: using 0.01-0.1% trifluoroacetic acid water solution as a mobile phase A and acetonitrile as a mobile phase B;
the gradient elution procedure was as follows:
2. the detection method according to claim 1, wherein: the mass-to-volume ratio of the nemadel intermediate in the step a to the acetonitrile water solution is 0.25-1 mg: 1 ml.
3. The detection method according to claim 1, wherein: the concentration of the Netedioler intermediate in the system applicability solution in the step b is 0.3-0.8 mg/ml, and the concentration of the related substance A reference substance is 30-80 mu g/ml.
4. The detection method according to claim 1 or 2, characterized by: the volume ratio of acetonitrile to water in the acetonitrile water solution is 60: 40.
5. The detection method according to claim 1, wherein: step c, the mobile phase A is 0.05 percent of trifluoroacetic acid aqueous solution; the detection wavelength in the chromatographic condition is 240-260 nm; the flow rate is 0.5-1.5 ml/min; the column temperature is 30-40 ℃; the sample injection amount is 10-20 mul.
6. The detection method as claimed in claim 5, wherein: c, detecting the wavelength of 254nm in the chromatographic condition; the flow rate is 0.8 ml/min; the column temperature is 30 ℃; the sample volume was 10. mu.l.
7. The detection method according to claim 1, wherein: and a chromatographic peak corresponding to the retention time of the chromatographic peak of the related substance A in the chromatogram of the system applicability solution is presented in the chromatogram of the test solution, namely the test solution contains the related substance A.
8. A content determination method of a neratedlar intermediate related substance is characterized by comprising the following steps: the method comprises the following specific steps:
1) detected according to the method of any one of claims 1 to 6;
2) the content of the related substances is calculated according to the following formula:
wherein the content of the first and second substances,X i %: the content of the relevant substances in the test sample,A i : the peak area of the related substance in the test sample,A: the sum of all peak areas in the test solution.
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| Asymmetric Synthesis of Netarsudil: A New Therapeutic for Open-Angle Glaucoma;Mitchell A. deLong et al;《Synthesis》;20191231;953-959 * |
| Development and validation of a stability-indicating reverse-phase ultra-performance liquid chromatography method for the simultaneous determination of netarsudil and latanoprost in bulk and pharmaceutical formulation;G. Dharmamoorthy et al;《International Journal of Green Pharmacy》;20200731;第14卷(第2期);179 * |
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Application publication date: 20210212 Assignee: Sichuan meiyugao Biomedical Technology Co.,Ltd. Assignor: CHENGDU MIRACLE PHARMACEUTICAL CO.,LTD. Contract record no.: X2023980054100 Denomination of invention: A detection method for substances related to the intermediate of natalidomide Granted publication date: 20220826 License type: Common License Record date: 20231227 |