CN104569213A - Method for measuring content of (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide by adopting high performance liquid chromatography - Google Patents
Method for measuring content of (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide by adopting high performance liquid chromatography Download PDFInfo
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- CN104569213A CN104569213A CN201510033449.2A CN201510033449A CN104569213A CN 104569213 A CN104569213 A CN 104569213A CN 201510033449 A CN201510033449 A CN 201510033449A CN 104569213 A CN104569213 A CN 104569213A
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Abstract
The invention discloses a method for measuring the content of a Rivaroxaban key midbody (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide by adopting high performance liquid chromatography. The method comprises the following steps: preparing a reference substance solution; measuring, wherein a fixed phase of a high performance liquid chromatograph is octadecyl silane bonded silica gel; a flowing phase is a mixed solution of methanol and 0.01mol/L ammonium acetate; the column temperature is 30 to 50 DEG C; 10mu l of the reference substance solution and 10ul of a supplied sample solution are respectively sucked and filled into the liquid chromatograph, and then data is read. 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 (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide in a (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide raw material can be used for controlling the quality of Rivaroxaban, 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 a kind of high effective liquid chromatography for measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) method of (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide content in phthalimide 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.(S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide is razaxaban key intermediate, by measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide, the quality of razaxaban can well be controlled.Therefore mensuration (S)-(+)-N-(2 is set up, 3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, 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 mensuration (S)-(+)-N-(2,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, better can control the quality of razaxaban, better control the stability of product.
Technical scheme of the present invention is: high effective liquid chromatography for measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it comprises the steps:
(1) preparation of reference substance solution: (S)-(+)-N-(2 of 24 ~ 48 hours taking dry 24 ~ 48 hours in silica gel drier, 3-ethoxycarbonyl propyl) phthalimide reference substance, add water and make the solution of every 1ml water containing 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide;
(2) preparation of need testing solution: get (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material adds water and makes every 1ml water containing the solution of 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material;
(3) measure: the Stationary liquid of efficient liquid phase chromatography is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of first alcohol and water, and column temperature is 30 ~ 50 DEG C, draws reference substance solution and each 10 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 230nm.
The volume ratio of described methyl alcohol and 0.01mol/L ammonium acetate is 1:1.
The invention has the beneficial effects as follows: the present invention's application high effective liquid chromatography for measuring (S)-(+)-N-(2, 3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) phthalimide content, separation efficiency is high, analysis speed is fast, detection sensitivity is high, by detecting (S)-(+)-N-(2, 3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) content of phthalimide, control (S)-(+)-N-(2, 3-ethoxycarbonyl propyl) phthalimide material purity, thus the quality of razaxaban can be controlled, the stability of better control product.
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
High effective liquid chromatography for measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it comprises the steps:
(1) preparation of reference substance solution: (S)-(+)-N-(2 taking dry 24 hours in silica gel drier, 3-ethoxycarbonyl propyl) phthalimide reference substance, add water and make the solution of every 1ml water containing 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide;
(2) preparation of need testing solution: get (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material adds water and makes every 1ml water containing the solution of 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of methyl alcohol and 0.01mol/L ammonium acetate, and column temperature is 30 DEG C, draws reference substance solution and each 10 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
Embodiment 2
High effective liquid chromatography for measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it comprises the steps:
(1) preparation of reference substance solution: (S)-(+)-N-(2 taking dry 48 hours in silica gel drier, 3-ethoxycarbonyl propyl) phthalimide reference substance, add water and make the solution of every 1ml water containing 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide;
(2) preparation of need testing solution: get (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material adds water and makes every 1ml water containing the solution of 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of methyl alcohol and 0.01mol/L ammonium acetate, and column temperature is 35 DEG C, draws reference substance solution and each 10 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
Embodiment 3
High effective liquid chromatography for measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it comprises the steps:
(1) preparation of reference substance solution: (S)-(+)-N-(2 taking dry 36 hours in silica gel drier, 3-ethoxycarbonyl propyl) phthalimide reference substance, add water and make the solution of every 1ml water containing 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide;
(2) preparation of need testing solution: get (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material adds water and makes every 1ml water containing the solution of 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of methyl alcohol and 0.01mol/L ammonium acetate, and column temperature is 40 DEG C, draws reference substance solution and each 10 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
Embodiment 4
High effective liquid chromatography for measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it comprises the steps:
(1) preparation of reference substance solution: (S)-(+)-N-(2 taking dry 48 hours in silica gel drier, 3-ethoxycarbonyl propyl) phthalimide reference substance, add water and make the solution of every 1ml water containing 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide;
(2) preparation of need testing solution: get (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material adds water and makes every 1ml water containing the solution of 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of methyl alcohol and 0.01mol/L ammonium acetate, and column temperature is 50 DEG C, draws reference substance solution and each 10 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
In above-described embodiment, the chromatographic detecting device of high-efficient liquid phase color is ultraviolet absorption detector, and determined wavelength is 230nm.The volume ratio of mobile phase methanol and 0.01mol/L ammonium acetate is 1:1.
In above-described embodiment, (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide reference substance is purchased from Nat'l Pharmaceutical & Biological Products Control Institute, (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material is produced purchased from Tianfeng Biological Science & Technology Co., Ltd., Xi'an.
Claims (3)
1. high effective liquid chromatography for measuring (S)-(+)-N-(2,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it is characterized in that, it comprises the steps:
(1) preparation of reference substance solution: (S)-(+)-N-(2 taking dry 24 ~ 48 hours in silica gel drier, 3-ethoxycarbonyl propyl) phthalimide reference substance, add water and make (S)-(+)-N-(2,3-ethoxycarbonyl propyl) the phthalimide solution of every 1ml water containing 0.25mg;
(2) preparation of need testing solution: get (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material adds water and makes every 1ml water containing the solution of 0.25mg (S)-(+)-N-(2,3-ethoxycarbonyl propyl) phthalimide raw material;
(3) measure: the Stationary liquid of high performance liquid chromatograph is octadecylsilane chemically bonded silica, mobile phase is the mixed solution of methyl alcohol, 0.01mol/L ammonium acetate, column temperature is 30 ~ 50 DEG C, draw reference substance solution and each 10 μ l of need testing solution respectively, inject high performance liquid chromatograph, read data.
2. according to high effective liquid chromatography for measuring (S)-(+)-N-(2 described in claim 1,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it is characterized in that: the detecting device of described high performance liquid chromatograph is ultraviolet absorption detector, and determined wavelength is 230nm.
3. according to high effective liquid chromatography for measuring (S)-(+)-N-(2 described in claim 1,3-ethoxycarbonyl propyl) (S)-(+)-N-(2 in phthalimide raw material, 3-ethoxycarbonyl propyl) method of phthalimide content, it is characterized in that: the volume ratio of described methyl alcohol, 0.01mol/L ammonium acetate is 1:1.
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Citations (5)
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|---|---|---|---|---|
| WO2006031179A1 (en) * | 2004-09-13 | 2006-03-23 | Astrazeneca Ab | Process for preparation of phtalimide |
| TW201011005A (en) * | 2008-09-10 | 2010-03-16 | Shyang Jen Biotech Co Ltd | A novel mothod for preparation of glycidyl phthalimide |
| WO2012051692A1 (en) * | 2010-10-18 | 2012-04-26 | Apotex Pharmachem Inc. | Processes for the preparation of rivaroxaban and intermediates thereof |
| CN103382200A (en) * | 2012-05-02 | 2013-11-06 | 成都国弘医药有限公司 | Preparation method of S-glycidylphthalimide |
| CN104193737A (en) * | 2014-08-19 | 2014-12-10 | 吉林省东盟制药有限公司 | Method for synthesizing rivaroxaban impurity |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006031179A1 (en) * | 2004-09-13 | 2006-03-23 | Astrazeneca Ab | Process for preparation of phtalimide |
| TW201011005A (en) * | 2008-09-10 | 2010-03-16 | Shyang Jen Biotech Co Ltd | A novel mothod for preparation of glycidyl phthalimide |
| WO2012051692A1 (en) * | 2010-10-18 | 2012-04-26 | Apotex Pharmachem Inc. | Processes for the preparation of rivaroxaban and intermediates thereof |
| CN103382200A (en) * | 2012-05-02 | 2013-11-06 | 成都国弘医药有限公司 | Preparation method of S-glycidylphthalimide |
| 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 (2)
| Title |
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| HELOISE BRICE等: "Stereocontrolled access to optically-enriched oxabispidines", 《CHEM. COMMUN.》, vol. 48, 31 December 2012 (2012-12-31), pages 4836 - 4838 * |
| 杨银萍等: "利伐沙班的合成工艺改进", 《中国药物化学杂志》, vol. 23, no. 1, 28 February 2013 (2013-02-28), pages 26 - 29 * |
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