CN104569212A - Method for measuring content of 4-(4-amino phenyl)-3-molindone by adopting high performance liquid chromatography - Google Patents
Method for measuring content of 4-(4-amino phenyl)-3-molindone by adopting high performance liquid chromatography Download PDFInfo
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- CN104569212A CN104569212A CN201510033416.8A CN201510033416A CN104569212A CN 104569212 A CN104569212 A CN 104569212A CN 201510033416 A CN201510033416 A CN 201510033416A CN 104569212 A CN104569212 A CN 104569212A
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Abstract
The invention discloses a method for measuring the content of a Rivaroxaban key midbody 4-(4-amino phenyl)-3-molindone by adopting high performance liquid chromatography. The method comprises the following steps: preparing a reference substance solution; measuring; by taking octadecyl silane bonded silica gel as a fixed phase of a high performance liquid chromatograph and taking a mixed solution of acetonitrile and 0.01mol/L monopotassium phosphate as a flowing phase, respectively sucking 20mu l of the reference substance solution and 10ul of a supplied sample solution at a column temperature of 30 to 40 DEG C, filling into the liquid chromatograph, and then reading data. By adopting the high performance liquid chromatography to measure the content of the (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide, the method disclosed by the invention is high in separation efficiency, high in analysis speed and high in detection sensitivity; the content of the 4-(4-amino phenyl)-3-molindone, the method disclosed by the invention is high in separation efficiency, high in analysis speed and high in detection sensitivity; the content of the 4-(4-amino phenyl)-3-molindone in a 4-(4-amino phenyl)-3-molindone raw material can be used for controlling the quality of Rivaroxaba, so that the stability of products can be controlled better and the cost can be lowered.
Description
Technical field
The present invention relates to high-efficient liquid phase chromatogram technology field, be specifically related to the method for 4-(4-aminophenyl)-3-morpholone content in a kind of high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material.
Background technology
Razaxaban is a kind of antithrombotic reagent, and it does not need antithrombin Ⅲ to participate in, can the direct antagonism Xa factor that dissociates and combine.4-(4-aminophenyl)-3-morpholone is razaxaban key intermediate, by measuring 4-(4-aminophenyl)-3-morpholone, can well control the quality of razaxaban.Therefore set up the method that measures 4-(4-aminophenyl)-3-morpholone content in 4-(4-aminophenyl)-3-morpholone raw material, better can control the quality of razaxaban, better control the stability of product.
Summary of the invention
The object of the invention is to set up the method that measures 4-(4-aminophenyl)-3-morpholone content in 4-(4-aminophenyl)-3-morpholone raw material, better can control the quality of razaxaban, better control the stability of product.
Technical scheme of the present invention is: the method for 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material, it comprises the steps:
(1) preparation of reference substance solution: 4-(4-the aminophenyl)-3-morpholone reference substance taking dry 24 ~ 48 hours in silica gel drier, adds acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg4-(4-aminophenyl)-3-morpholone;
(2) preparation of need testing solution: get 4-(4-aminophenyl)-3-morpholone raw material and add acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg 4-(4-aminophenyl)-3-morpholone raw material;
(3) measure: the Stationary liquid of efficient liquid phase chromatography is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of acetonitrile and water, and column temperature is 30 ~ 40 DEG C, draws reference substance solution and each 20 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
The detecting device of described high performance liquid chromatograph is ultraviolet absorption detector, and determined wavelength is 240nm.
Described acetonitrile and 0.01mol/L potassium dihydrogen phosphate volume ratio are 15:85 ~ 30:70.
The invention has the beneficial effects as follows: 4-(4-aminophenyl)-3-morpholone content in the present invention's application high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material, separation efficiency is high, analysis speed is fast, detection sensitivity is high, by detecting the content of 4-(4-aminophenyl)-3-morpholone in 4-(4-aminophenyl)-3-morpholone raw material, control 4-(4-aminophenyl)-3-morpholone material purity, thus the quality of razaxaban can be controlled, better control the stability of product.
Accompanying drawing illustrates: Fig. 1 is embodiment 1 reference substance solution chromatogram
Fig. 2 is embodiment 1 need testing solution chromatogram
Fig. 3 is embodiment 2 reference substance solution chromatogram
Fig. 4 is embodiment 2 need testing solution chromatogram
Fig. 5 is embodiment 3 reference substance solution chromatogram
Fig. 6 is embodiment 3 need testing solution chromatogram
Fig. 7 is embodiment 4 reference substance solution chromatogram
Fig. 8 is embodiment 4 need testing solution chromatogram.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and be only limitted to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement made according to ordinary skill knowledge and customary means or the amendment of change, include within the scope of the invention
.
Embodiment 1
The method of 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material, it comprises the steps:
(1) preparation of reference substance solution: 4-(4-the aminophenyl)-3-morpholone reference substance taking dry 24 hours in silica gel drier, adds acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg 4-(4-aminophenyl)-3-morpholone;
(2) preparation of need testing solution: get 4-(4-aminophenyl)-3-morpholone raw material and add acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg4-(4-aminophenyl)-3-morpholone raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of acetonitrile and 0.01mol/L potassium dihydrogen phosphate, column temperature is 30 DEG C, draw reference substance solution and each 20 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
(4) the chromatographic detecting device of high-efficient liquid phase color is ultraviolet absorption detector, and determined wavelength is 240nm.The volume ratio of mobile phase acetonitrile and 0.01mol/L potassium dihydrogen phosphate is 15:85.
Embodiment 2
The method of 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material, it comprises the steps:
(1) preparation of reference substance solution: 4-(4-the aminophenyl)-3-morpholone reference substance taking dry 48 hours in silica gel drier, adds acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg 4-(4-aminophenyl)-3-morpholone;
(2) preparation of need testing solution: get 4-(4-aminophenyl)-3-morpholone raw material and add acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg 4-(4-aminophenyl)-3-morpholone raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of acetonitrile and 0.01mol/L potassium dihydrogen phosphate, column temperature is 30 DEG C, draw reference substance solution and each 20 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
(4) the chromatographic detecting device of high-efficient liquid phase color is ultraviolet absorption detector, and determined wavelength is 240nm.The volume ratio of mobile phase acetonitrile and 0.01mol/L potassium dihydrogen phosphate is 20:80.
Embodiment 3
The method of 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material, it comprises the steps:
(1) preparation of reference substance solution: 4-(4-the aminophenyl)-3-morpholone reference substance taking dry 36 hours in silica gel drier, adds acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg 4-(4-aminophenyl)-3-morpholone;
(2) preparation of need testing solution: get 4-(4-aminophenyl)-3-morpholone raw material and add acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg 4-(4-aminophenyl)-3-morpholone raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of acetonitrile and 0.01mol/L potassium dihydrogen phosphate, column temperature is 30 DEG C, draw reference substance solution and each 20 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
(4) the chromatographic detecting device of high-efficient liquid phase color is ultraviolet absorption detector, and determined wavelength is 240nm.The volume ratio of mobile phase acetonitrile and 0.01mol/L potassium dihydrogen phosphate is 30:70.
Embodiment 4
The method of 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material, it comprises the steps:
(1) preparation of reference substance solution: 4-(4-the aminophenyl)-3-morpholone reference substance taking dry 48 hours in silica gel drier, adds acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg4-(4-aminophenyl)-3-morpholone;
(2) preparation of need testing solution: get 4-(4-aminophenyl)-3-morpholone raw material and add acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg4-(4-aminophenyl)-3-morpholone raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of acetonitrile and 0.01mol/L potassium dihydrogen phosphate, column temperature is 40 DEG C, draw reference substance solution and each 20 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
(4) the chromatographic detecting device of high-efficient liquid phase color is ultraviolet absorption detector, and determined wavelength is 240nm.The volume ratio of mobile phase acetonitrile and 0.01mol/L potassium dihydrogen phosphate is 30:70.
In above-described embodiment, 4-(4-aminophenyl)-3-morpholone reference substance is purchased from Nat'l Pharmaceutical & Biological Products Control Institute, and 4-(4-aminophenyl)-3-morpholone raw material is produced purchased from Wuhan Kai Lun New Chemical Material company limited.
Claims (3)
1. the method for 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-aminophenyl)-3-morpholone raw material, it is characterized in that, it comprises the steps:
(1) preparation of reference substance solution: 4-(4-the aminophenyl)-3-morpholone reference substance taking dry 24 ~ 48 hours in silica gel drier, adds acetonitrile: water (1:1) makes 4-(4-the aminophenyl)-3-morpholone solution of every 1ml containing 0.5mg;
(2) preparation of need testing solution: get 4-(4-aminophenyl)-3-morpholone raw material and add acetonitrile: water (1:1) makes the solution of every 1ml acetonitrile containing 0.5mg4-(4-aminophenyl)-3-morpholone raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of acetonitrile, 0.01mol/L potassium dihydrogen phosphate, column temperature is 30 ~ 40 DEG C, draw reference substance solution and each 20 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
2. according to the method for 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-the aminophenyl)-3-morpholone raw material described in claim 1, it is characterized in that: the detecting device of described high performance liquid chromatograph is ultraviolet absorption detector, and determined wavelength is 240nm.
3., according to the method for 4-(4-aminophenyl)-3-morpholone content in high effective liquid chromatography for measuring 4-(4-the aminophenyl)-3-morpholone raw material described in claim 1, it is characterized in that: the volume ratio of described acetonitrile, 0.01mol/L potassium dihydrogen phosphate is 15:85 ~ 30:70.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| WO2013152168A1 (en) * | 2012-04-06 | 2013-10-10 | Indiana University Research And Technology Corporation | Processes for preparing rivaroxaban |
| CN103980221A (en) * | 2014-05-26 | 2014-08-13 | 山东康美乐医药科技有限公司 | Preparation method of 4-(nitrobenzophenone)-3-morpholone and method for preparing rivaroxaban by using 4-(nitrobenzophenone)-3-morpholone |
| CN104193737A (en) * | 2014-08-19 | 2014-12-10 | 吉林省东盟制药有限公司 | Method for synthesizing rivaroxaban impurity |
-
2015
- 2015-01-23 CN CN201510033416.8A patent/CN104569212A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| WO2013152168A1 (en) * | 2012-04-06 | 2013-10-10 | Indiana University Research And Technology Corporation | Processes for preparing rivaroxaban |
| CN103980221A (en) * | 2014-05-26 | 2014-08-13 | 山东康美乐医药科技有限公司 | Preparation method of 4-(nitrobenzophenone)-3-morpholone and method for preparing rivaroxaban by using 4-(nitrobenzophenone)-3-morpholone |
| CN104193737A (en) * | 2014-08-19 | 2014-12-10 | 吉林省东盟制药有限公司 | Method for synthesizing rivaroxaban impurity |
Non-Patent Citations (3)
| Title |
|---|
| PERUMAL PANNEERSELVAM等: "Synthesis of Schiff bases of 4-(4-aminophenyl)-morpholine as potential antimicrobial agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 何洪光等: "4-(4-氨基苯基)-3-吗啉酮的制备", 《中国医药工业杂志》 * |
| 吴翔等: "利伐沙班中间体4－(4－氨基苯基)－3－吗啉酮的合成", 《天津理工大学学报》 * |
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