CN1316245C - Method for testing tropine alcohol of residual intermediate product in synthesizing Troipisetron - Google Patents
Method for testing tropine alcohol of residual intermediate product in synthesizing Troipisetron Download PDFInfo
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- CN1316245C CN1316245C CNB2005100443176A CN200510044317A CN1316245C CN 1316245 C CN1316245 C CN 1316245C CN B2005100443176 A CNB2005100443176 A CN B2005100443176A CN 200510044317 A CN200510044317 A CN 200510044317A CN 1316245 C CN1316245 C CN 1316245C
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Abstract
The present invention discloses a method for detecting pseudotropanol as a residual intermediate compound in the synthesis of tropisetron. The present invention has the following steps: a test solution and a reference solution are prepared; the test solution and the reference solution are respectively dropped on the same silica gel G thin layer plate; acetone-ammonia water is used as a developing agent for carrying out thin layer chromatography measurement; a chromatographic container is expanded; a chromogenic agent of a potassium heptaiodobismuthate solution and a chromogenic agent of a sodium nitrite solution are used for developing color; a color development result is checked, etc. By using the detection method of the present invention, below 0.25 mug of residual pseudotropanol in the synthesis of tropisetron can be conveniently and quickly detected. The present invention provides a guarantee for strictly controlling a residual pseudotropanol content in a low limit during the synthesis preparation process for preparing tropisetron.
Description
Technical field
The present invention relates to the detection method of tropanol, relate in particular to Tropisetron synthetic in the detection method of residual intermediate tropanol.
Background technology
Tropisetron is potent, selectivity 5-HT3 receptor antagonist, is developed by Novartis Co.,Ltd, and 1992 in Britain's listing, and trade name: Navoban is used to prevent and treat that radiotherapy, chemotherapy causes feels sick, vomiting.Present this medicine is in the national listing of global dozens of, and its idicatio expands prevention to and treatment children chemicotherapy is nauseating, vomit prevention and treatment adult postoperative nausea and vomiting.
Because the curative effect that Tropisetron is definite, this medicine is used widely in big-and-middle-sized hospital.In the face of the whole nation ten thousand cancer patients that carry out chemicotherapy of whenever being close on sixty years of age, its market outlook very are wide.Therefore, synthesizing, produce, domesticizing of Tropisetron will bring huge business opportunity.
Yet, in the synthetic production run of preparation Tropisetron, tropanol is an important intermediate during Tropisetron synthesizes, after finishing Tropisetron synthetic, the content of remaining tropanol must be strict controlled in the very low limits, just can not influence the drug effect of Tropisetron, therefore, the detection of residual intermediate tropanol extremely was necessary during Tropisetron was synthetic, and had very high practical value.But in the synthetic production run of the preparation Tropisetron of reality, tropanol does not have uv absorption, and when using high performance liquid chromatogram to detect Tropisetron, tropanol does not show absorption peak, uncontrollable its residual quantity.Use evaporative light-scattering detector, precision is not enough, does not reach the requirement that detects its residual volume limit.And relevant sensitive, fast carry out Tropisetron synthetic in the detection of residual intermediate tropanol, by retrieval, yet there are no bibliographical information both at home and abroad.
Summary of the invention
At the deficiencies in the prior art, the problem to be solved in the present invention is, provide a kind of Tropisetron synthetic in the detection method of residual intermediate tropanol, utilize method of the present invention can detect tropanol and content thereof remaining in the synthetic production run of preparation Tropisetron easy, fast, delicately.
The detection method of residual intermediate tropanol during the bright Tropisetron that relates to of this law is synthetic, form by following step:
(1) takes by weighing sample, add dissolve with methanol and quantitative, make need testing solution;
(2) take by weighing pure tropanol, add dissolve with methanol and quantitative, make reference substance solution;
(3) getting each 15 μ l of above-mentioned need testing solution and reference substance solution, put respectively on same silica gel g thin-layer plate, is developping agent with acetone-ammoniacal liquor, carries out tlc determination; Wherein, described developping agent acetone: the volume ratio of ammoniacal liquor is 80-99: 20-1;
(4) treat above-mentioned specimen after chromatography cylinder launches, taking-up is to doing;
(5) with sprayer bismuth potassium iodide solution is sprayed on the thin layer equably, to doing;
(6) with sprayer sodium nitrite solution is sprayed on the thin layer equably again, to doing;
(7) with sprayer bismuth potassium iodide solution is sprayed on the thin layer equably again, to doing; Inspect the colour developing result;
(8) need testing solution can determine to contain in the sample tropanol as showing the tropanol spot; What of tropanol amount are the depth of its spot colors also can determine;
(9) utilizing tropanol spot colors and the apparent spot colors of reference substance solution to carry out power relatively, is the content that 0.2% amount of need testing solution concentration is determined tropanol with the concentration of reference substance solution; The tropanol content of medicinal Tropisetron remnants must not surpass 0.2% of its weight, and promptly the tropanol spot colors must not be darker than the color of standard reference material solution spot.
In above-mentioned detection method, the quantitative concentrations of described need testing solution is 25mg/ml preferably.
In above-mentioned detection method, the quantitative concentrations of described reference substance solution is 0.05mg/ml preferably.
In above-mentioned detection method, described developping agent acetone: the volume ratio of ammoniacal liquor is preferably 85-95: 15-5.
In above-mentioned detection method, described developping agent acetone: the volume ratio of ammoniacal liquor most preferably is 90: 10.
In above-mentioned detection method, the described bismuth potassium iodide solution of step (5) compound method is: get bismuth subnitrate and add glacial acetic acid and water-soluble separating, add liquor kalii iodide and mix, dilute promptly with glacial acetic acid and water.
Wherein, above-mentioned bismuth potassium iodide solution compound method preferably: get bismuth subnitrate 0.85g, add glacial acetic acid 10ml and water 40ml dissolving, get 5ml and add potassium iodide (4g/10ml) solution 5ml, shake up, add glacial acetic acid 20ml and water 100ml dilutes acquisition.
In above-mentioned detection method, the compound method of the described sodium nitrite solution of step (6) is: get sodium nitrite and add water and make, its preferred concentration is 1% (g/ml).
In above-mentioned detection method, the jet length of step (5), (6), (7) described sprayer and thin layer is 0.1～0.8 meter.
The detection method of residual intermediate tropanol had resolution height, highly sensitive, characteristics such as method is easy, speed is fast during the Tropisetron that the present invention relates to was synthetic; Through experimental test, utilize detection method of the present invention can detect Tropisetron synthetic in the residual following tropanol of 0.25 μ g amount, for in the synthetic production run of preparation Tropisetron, the content of the tropanol that strict control is remaining provides guarantee in a very low limit.
Embodiment
Embodiment 1:
The preparation of need testing solution: it is an amount of to get Tropisetron, adds dissolve with methanol and quantitatively dilutes the solution of making 25mg/ml; It is an amount of that precision takes by weighing pure tropanol, adds dissolve with methanol and quantitatively dilute the reference substance solution of making 0.05mg/ml; Get each 15 microlitres point of above-mentioned need testing solution, reference substance solution respectively on same silica gel g thin-layer plate, with acetone: the volume ratio of ammoniacal liquor is to be mixed and made into developping agent at 80: 20, and chromatography cylinder launches, and takes out, and dries; With sprayer bismuth potassium iodide solution is sprayed on the thin layer equably, dries up; With sprayer sodium nitrite solution (now joining) is sprayed on the thin layer equably again, dries up; With sprayer bismuth potassium iodide solution is sprayed on the thin layer equably again, dries up; Wherein, the jet length of described sprayer and thin layer is 0.1 meter; Described bismuth potassium iodide solution compound method is: get bismuth subnitrate 0.85g, add glacial acetic acid 10ml and water 40ml dissolving, get 5ml and add potassium iodide (4g/10ml) solution 5ml, shake up, add glacial acetic acid 20ml and water 100ml dilutes promptly.The concentration of described sodium nitrite solution is 1% (g/ml).Inspect the colour developing result; If need testing solution can determine to contain in the sample tropanol just like the spot of tropanol same position; Its spot colors is represented tropanol content height deeply, and shallow then content is few; Further utilizing tropanol spot colors and the apparent spot colors of reference substance solution to carry out power relatively, is the content that 0.2% amount of need testing solution concentration is determined tropanol with the concentration of reference substance solution; The tropanol content of medicinal Tropisetron remnants must not surpass 0.2% of its weight, and promptly the tropanol spot colors must not be darker than the color of standard reference material solution spot.
Embodiment 2:
It is an amount of to get Tropisetron, adds dissolve with methanol and quantitatively dilutes the need testing solution of making 25mg/ml; It is an amount of that precision takes by weighing pure tropanol, adds dissolve with methanol and quantitatively dilute the reference substance solution of making 0.05mg/ml; Get each 15 microlitres point of above-mentioned need testing solution, reference substance solution respectively on same silica gel g thin-layer plate, with acetone: the volume ratio of ammoniacal liquor is to be mixed and made into developping agent at 99: 1, and chromatography cylinder launches, and takes out, and dries; With sprayer bismuth potassium iodide solution is sprayed on the thin layer equably, dries up; With sprayer sodium nitrite solution (now joining) is sprayed on the thin layer equably again, dries up; With sprayer bismuth potassium iodide solution is sprayed on the thin layer equably again, dries up; Wherein, the jet length of described sprayer and thin layer is 0.4 meter; Described bismuth potassium iodide solution compound method is: get bismuth subnitrate 0.85g, add glacial acetic acid 10ml and water 40ml dissolving, get 5ml and add potassium iodide (4g/10ml) solution 5ml, shake up, add glacial acetic acid 20ml and water 100ml dilutes promptly.The concentration of described sodium nitrite solution is 1% (g/ml).Inspect the colour developing result; If need testing solution can determine to contain in the sample tropanol just like the spot of tropanol same position; Its spot colors is represented tropanol content height deeply, and shallow then content is few; Further utilize tropanol spot colors and the apparent spot colors of reference substance solution to carry out power relatively, determine the content of tropanol with the standard volume of reference substance solution; The tropanol content of medicinal Tropisetron remnants must not surpass 0.2% of its weight, and promptly the tropanol spot colors must not be darker than the color of standard reference material solution spot.
Embodiment 3:
It is an amount of to get Tropisetron, adds dissolve with methanol and quantitatively dilutes the need testing solution of making 25mg/ml; It is an amount of that precision takes by weighing pure tropanol, adds dissolve with methanol and quantitatively dilute the reference substance solution of making 0.05mg/ml; Get each 15 microlitres point of above-mentioned need testing solution, reference substance solution respectively on same silica gel g thin-layer plate, with acetone: the volume ratio of ammoniacal liquor is to be mixed and made into developping agent at 90: 10, and chromatography cylinder launches, and takes out, and dries; With sprayer bismuth potassium iodide solution is sprayed on the thin layer equably, dries up; With sprayer sodium nitrite solution (now joining) is sprayed on the thin layer equably again, dries up; With sprayer bismuth potassium iodide solution is sprayed on the thin layer equably again, dries up; Wherein, the jet length of described sprayer and thin layer is 0.8 meter; Described bismuth potassium iodide solution compound method is: get bismuth subnitrate 0.85g, add glacial acetic acid 10ml and water 40ml dissolving, get 5ml and add potassium iodide (4g/10ml) solution 5ml, shake up, add glacial acetic acid 20ml and water 100ml dilutes promptly.The concentration of described sodium nitrite solution is 1% (g/ml).Inspect the colour developing result; If need testing solution can determine to contain in the sample tropanol just like the spot of tropanol same position; Its spot colors is represented tropanol content height deeply, and shallow then content is few; Further utilize tropanol spot colors and the apparent spot colors of reference substance solution to carry out power relatively, determine the content of tropanol with the standard volume of reference substance solution; The tropanol content of medicinal Tropisetron remnants must not surpass 0.2% of its weight, and promptly the tropanol spot colors must not be darker than the color of standard reference material solution spot.
Embodiment 4:
It is an amount of to get Tropisetron, adds dissolve with methanol and quantitatively dilutes the need testing solution of making 25mg/ml; It is an amount of that precision takes by weighing tropanol, adds dissolve with methanol and quantitatively dilute the reference substance solution of making 0.05mg/ml; Get 15 microlitres point respectively on same silica gel g thin-layer plate, be mixed into developping agent with acetone-ammoniacal liquor (94: 6) parts by volume, chromatography cylinder launches, and is aided with the sodium nitrite solution chromogenic reagent with bismuth potassium iodide solution.Need testing solution can determine to contain in the sample tropanol as showing the tropanol spot; Its color is compared with the spot that reference substance solution is shown, must not darker (0.2%).
Claims (8)
1. the detection method of residual intermediate tropanol during a Tropisetron synthesizes, form by following step:
(1) takes by weighing sample, add dissolve with methanol and quantitative, make need testing solution;
(2) take by weighing pure tropanol, add dissolve with methanol and quantitative, make reference substance solution, the reference substance solution mass concentration is 0.2% of a need testing solution mass concentration;
(3) getting each 15 μ l of above-mentioned need testing solution and reference substance solution, put respectively on same silica gel g thin-layer plate, is developping agent with acetone-ammoniacal liquor, carries out tlc determination; Wherein, described developping agent acetone: the volume ratio of ammoniacal liquor is 80-99: 20-1;
(4) treat above-mentioned specimen after chromatography cylinder launches, taking-up is dried;
(5) with sprayer bismuth potassium iodide solution is sprayed on the thin layer equably, as for;
(6) with sprayer sodium nitrite solution is sprayed on the thin layer equably again, as for;
(7) with sprayer bismuth potassium iodide solution is sprayed on the thin layer equably again, as for; Inspect the colour developing result;
(8) need testing solution can determine to contain in the sample tropanol as showing the tropanol spot; What of tropanol amount are the depth of its spot colors also can determine;
(9) utilize tropanol spot colors and the apparent spot colors of reference substance solution to carry out power relatively, the tropanol spot colors must not be darker than the color of standard reference material solution spot.
2. the detection method of residual intermediate tropanol is characterized in that the quantitative concentrations of described need testing solution is 25mg/ml during Tropisetron as claimed in claim 1 was synthetic.
3. the detection method of residual intermediate tropanol is characterized in that the quantitative concentrations of described reference substance solution is 0.05mg/ml during Tropisetron as claimed in claim 1 was synthetic.
4. the detection method of residual intermediate tropanol during Tropisetron as claimed in claim 1 is synthetic, it is characterized in that described developping agent acetone: the volume ratio of ammoniacal liquor is 85-95: 15-5.
5. the detection method of residual intermediate tropanol during Tropisetron as claimed in claim 4 is synthetic, it is characterized in that described developping agent acetone: the volume ratio of ammoniacal liquor is 90: 10.
6. the detection method of residual intermediate tropanol during Tropisetron as claimed in claim 1 is synthetic, it is characterized in that, the described bismuth potassium iodide solution of step (5) compound method is: get bismuth subnitrate and add glacial acetic acid and water-soluble separating, add liquor kalii iodide and mix, dilute acquisition with glacial acetic acid and water.
7. the detection method of residual intermediate tropanol during Tropisetron as claimed in claim 1 is synthetic is characterized in that the compound method of the described sodium nitrite solution of step (6) is: get sodium nitrite and add water and make.
8. the detection method of residual intermediate tropanol is characterized in that the jet length of step (5), (6), (7) described sprayer and thin layer is 0.1～0.8 meter during Tropisetron as claimed in claim 1 was synthetic.
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| CNB2005100443176A CN1316245C (en) | 2005-07-28 | 2005-07-28 | Method for testing tropine alcohol of residual intermediate product in synthesizing Troipisetron |
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| CNB2005100443176A CN1316245C (en) | 2005-07-28 | 2005-07-28 | Method for testing tropine alcohol of residual intermediate product in synthesizing Troipisetron |
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| CN1316245C true CN1316245C (en) | 2007-05-16 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107328765A (en) * | 2017-06-28 | 2017-11-07 | 山东齐都药业有限公司 | A kind of relevant material of α tropanols and isomers inspection method |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102495170A (en) * | 2011-11-26 | 2012-06-13 | 山东齐都药业有限公司 | Method for detecting alpha-tropine in tropisetron hydrochloride injection |
| CN102565226B (en) * | 2011-12-30 | 2014-05-07 | 山东齐都药业有限公司 | Detection method for alpha-tropine as impurity in hydrochloric acid tropisetron |
| CN111141737A (en) * | 2019-12-31 | 2020-05-12 | 佛山市南海北沙制药有限公司 | Method for detecting 2-chloroquinoxaline related substances |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5571909A (en) * | 1993-06-09 | 1996-11-05 | Korea Institute Of Science And Technology | Cephalosporin compounds and processes for preparing thereof |
| CN1481383A (en) * | 2000-12-22 | 2004-03-10 | ���ָ��Ӣ��ķ�������Ϲ�˾ | Method for producing anticholinergic agent tiotropium bromide |
| CN1538172A (en) * | 2003-04-17 | 2004-10-20 | 江苏康缘药业股份有限公司 | Quality control method for Chinese medicinal preparation |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5571909A (en) * | 1993-06-09 | 1996-11-05 | Korea Institute Of Science And Technology | Cephalosporin compounds and processes for preparing thereof |
| CN1481383A (en) * | 2000-12-22 | 2004-03-10 | ���ָ��Ӣ��ķ�������Ϲ�˾ | Method for producing anticholinergic agent tiotropium bromide |
| CN1538172A (en) * | 2003-04-17 | 2004-10-20 | 江苏康缘药业股份有限公司 | Quality control method for Chinese medicinal preparation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107328765A (en) * | 2017-06-28 | 2017-11-07 | 山东齐都药业有限公司 | A kind of relevant material of α tropanols and isomers inspection method |
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Effective date of registration: 20160526 Address after: 129, room 1, building 266112, Qingdao blue bio Pharmaceutical Industrial Park, 368 Hedong Road, Hedong District, Qingdao, Shandong Patentee after: Qingdao Pu Ruisen Pharmaceutical Technology Co., Ltd Address before: 255400 Linzi, Shandong province people's road, No. 28 East Road, No. Patentee before: Qidu Pharmaceutical Co., Ltd., Shandong Prov. |