CN115160215A - Method for synthesizing chlorpheniramine maleate oxidation degradation product - Google Patents
Method for synthesizing chlorpheniramine maleate oxidation degradation product Download PDFInfo
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- CN115160215A CN115160215A CN202210954386.4A CN202210954386A CN115160215A CN 115160215 A CN115160215 A CN 115160215A CN 202210954386 A CN202210954386 A CN 202210954386A CN 115160215 A CN115160215 A CN 115160215A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
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Abstract
The invention provides a synthesis method of a chlorpheniramine maleate oxidation degradation product, which is characterized in that the structure of the chlorpheniramine maleate oxidation degradation product is as follows: in the synthesis process of the chlorpheniramine maleate oxidative degradation product, 5.0g of chlorpheniramine maleate is dissolved in 50mL of dichloromethane, and ozone is introduced into the mixture at the temperature of 0-10 ℃ to complete the reaction process; the analysis and detection method for confirming the structure of the chlorpheniramine maleate oxidation degradation product comprises the following steps: high resolution mass spectrometry; one-dimensional nuclear magnetic hydrogen spectrum; one-dimensional nuclear magnetic carbon spectrum; two-dimensional nuclear magnetic 1H-1H COSY spectrogram, HMQC spectrogram and HSQC spectrogram. The method carries out clear structural identification on the chlorpheniramine maleate by using a high-resolution mass spectrum, a one-dimensional nuclear magnetic hydrogen spectrum carbon spectrum, a two-dimensional nuclear magnetic 1H-1H COSY spectrogram, an HMQC spectrogram and an HSQC spectrogram, and plays an effective supporting role in the quality research of the chlorpheniramine maleate.
Description
Technical Field
The invention relates to the technical field of chemistry, in particular to a synthesis method of a chlorpheniramine maleate oxidation degradation product.
Background
CN111039854 describes a chlorpheniramine maleate impurity oxidation and preparation process, peroxide is used as an oxidant for oxidation, and mass spectrum and one-dimensional nuclear magnetism are used for structural characterization. In the study on the stability of chlorpheniramine maleate, the chlorpheniramine does have oxidative degradation impurities, and because fatty amine and aromatic amine structural fragments exist in the chemical structure of the chlorpheniramine, the fatty amine and aromatic amine structural fragments are potential oxidative degradation occurrence sites, the corresponding oxidative degradation products are of two structures of a formula I and a formula II, and the two structures of the formula I and the formula II cannot be clearly distinguished only through a one-dimensional nuclear magnetic hydrogen spectrum and a carbon spectrum.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides a method for synthesizing chlorpheniramine maleate oxidative degradation products, so as to solve the technical problems related to the background technology.
In order to solve the technical problems, the invention adopts the technical scheme that: a method for synthesizing chlorpheniramine maleate oxidative degradation products has the following structure:
in the synthesis process of the chlorpheniramine maleate oxidative degradation product, 1.0g of chlorpheniramine maleate is dissolved in 20mL of acetone, and ozone is introduced into the mixture under the alkaline environment of 0-10 ℃ to complete the reaction process;
the analysis and detection method for confirming the structure of the chlorpheniramine maleate oxidation degradation product comprises the following steps: high resolution mass spectrometry; one-dimensional nuclear magnetic hydrogen spectrum; one-dimensional nuclear magnetic carbon spectrum; two-dimensional nuclear magnetism 1 H- 1 HCOSY spectra, HMQC spectra, and HSQC spectra.
Furthermore, in the oxidation process of chlorpheniramine maleate, the used oxidant is ozone, and the amount of the ozone is detected by TLC until the raw materials are completely reacted. .
Further, the synthesis process also comprises purification, and the purification process specifically comprises the following steps: and concentrating the reaction solution obtained after the reaction is finished to be dry, and purifying by a silica gel column layer.
Further, during the purification process, the mobile phase comprises 0.1% trifluoroacetic acid-water solution and acetonitrile, and gradient elution is carried out by using the mobile phase at 10-90%.
Further, the product was concentrated to dryness at 60 ℃ under reduced pressure, with a yield of 86%.
Compared with the prior art, the invention has the beneficial effects that: by high resolution mass spectrometry, one-dimensional nuclear magnetic hydrogen spectrum carbon spectrum and two-dimensional nuclear magnetism 1 H- 1 The HCOSY spectrogram, the HMQC spectrogram and the HSQC spectrogram are used for carrying out definite structural identification on the chlorphenamine maleate, and the quality research of chlorphenamine maleate is effectively supported.
Drawings
The disclosure of the present invention is illustrated with reference to the accompanying drawings. It is to be understood that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention. In the drawings, like reference numerals are used to refer to like parts. Wherein:
FIG. 1 is an HPLC chromatogram of the oxidative degradation product of chlorpheniramine maleate (formula I);
FIG. 2 of the oxidative degradation product of chlorpheniramine maleate (formula I) 1 An H-NMR spectrum;
FIG. 3 of the product of the oxidative degradation of chlorpheniramine maleate (formula I) 13 A C-NMR spectrum;
FIG. 4 of the product of oxidative degradation of chlorpheniramine maleate (formula I) 1 H- 1 HCOSY spectra;
FIG. 5 HMQC spectrum of the oxidative degradation product of chlorpheniramine maleate (formula I);
FIG. 6 HMBC spectra of the chlorpheniramine maleate oxidative degradation product (formula I);
FIG. 7 is a high resolution mass spectrum of the oxidative degradation product of chlorpheniramine maleate (formula I).
Detailed Description
It is easily understood that according to the technical solution of the present invention, a person skilled in the art can propose various alternative structures and implementation ways without changing the spirit of the present invention. Therefore, the following detailed description and the accompanying drawings are merely illustrative of the technical aspects of the present invention, and should not be construed as all of the present invention or as limitations or limitations on the technical aspects of the present invention.
A method for synthesizing chlorpheniramine maleate oxidation degradation products, wherein in the synthesis process, the used oxidant is ozone, the used alkali is sodium hydroxide, the used reaction solvent is acetone, and the reaction temperature is 0-10 ℃; after the reaction is finished, gradient elution is carried out by a Waters XTERAPR18, 250X 4.6mm X5 μm or equivalent performance chromatographic column, in the process, the adopted mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is 0.1% trifluoroacetic acid-water solution, the mobile phase B is acetonitrile, and the elution mode is gradient elution of 10-90%. Concentrating the product obtained by elution at 60 deg.C under reduced pressure to dryness to obtain chlorphenamine maleate oxidative degradation product, and performing high resolution mass spectrometry, one-dimensional nuclear magnetic hydrogen spectrum carbon spectrum and two-dimensional nuclear magnetic spectrum 1 H- 1 And performing structural identification on the obtained product by using an HCOSY spectrogram, an HMQC spectrogram and an HSQC spectrogram.
The present application will be described in detail with reference to examples.
Example (b): preparation of chlorpheniramine oxidative degradation product (formula I)
Adding chlorpheniramine 1.0g and acetone 20mL into a 100mL three-neck flask, controlling the temperature to be 0-10 ℃, adding sodium hydroxide 112mg (1.1 eq), stirring for 15 minutes, introducing ozone, slowly stirring, filtering reaction liquid after TLC detection reaction is finished, concentrating filtrate under reduced pressure to dryness to obtain a crude product, purifying the crude product by a preparation liquid phase (Waters XTERAPRR 18, 250X 4.6mm X5 mu m; mobile phases: A is a 0.1% trifluoroacetic acid-water solution, B is acetonitrile, and gradient elution is carried out by 10% -90%), collecting a product, concentrating the product under reduced pressure at 60 ℃ to dryness to obtain a light yellow oily substance 640mg, wherein the yield is 86%.
The products obtained in the above examples were analyzed and their HPLC profiles are shown in FIG. 1, which shows 1 The H-NMR spectrum is shown in FIG. 2Show, it 13 The C-NMR spectrum is shown in FIG. 3, which is 1 H- 1 The HCOSY spectrum is shown in figure 4, the HMQC spectrum is shown in figure 5, the HMBC spectrum is shown in figure 6, and the high-resolution mass spectrum is shown in figure 7.
By high resolution mass spectrometry, one-dimensional nuclear magnetic hydrogen spectroscopy, carbon spectroscopy and two-dimensional nuclear magnetism 1 H- 1 The HCOSY spectrogram, the HMQC spectrogram and the HSQC spectrogram are used for carrying out definite structural identification on the chlorpheniramine maleate, and an effective supporting effect is achieved on the quality research of the chlorpheniramine maleate; therefore, the synthesis method of the chlorpheniramine maleate oxidative degradation product provided by the invention can stably prepare the chlorpheniramine maleate oxidative degradation product in the formula I.
The technical scope of the present invention is not limited to the above description, and those skilled in the art can make various changes and modifications to the above embodiments without departing from the technical spirit of the present invention, and such changes and modifications should fall within the protective scope of the present invention.
Claims (5)
1. A synthetic method of a chlorpheniramine maleate oxidative degradation product is characterized in that the structure of the chlorpheniramine maleate oxidative degradation product is as follows:
in the synthesis process of the chlorpheniramine maleate oxidation degradation product, 1.0g of chlorpheniramine maleate is dissolved in 20mL of acetone, and ozone is introduced into the mixture under the alkaline environment of 0-10 ℃ to complete the reaction process;
the analysis and detection method for confirming the structure of the chlorpheniramine maleate oxidation degradation product comprises the following steps: high resolution mass spectrometry; one-dimensional nuclear magnetic hydrogen spectrum; one-dimensional nuclear magnetic carbon spectrum; two-dimensional nuclear magnetism 1 H- 1 H COSY spectrogram, HMQC spectrogram and HSQC spectrogram.
2. The method for synthesizing an oxidative degradation product of chlorpheniramine maleate according to claim 1, wherein the oxidizing agent used in the oxidization process of chlorpheniramine maleate is ozone, and the amount of ozone is detected by TLC until the reaction of the raw materials is completed.
3. The method for synthesizing an oxidative degradation product of chlorpheniramine maleate according to claim 1, wherein the synthesis process further comprises purification, and the purification process is as follows: and concentrating the reaction solution obtained after the reaction is finished to be dry, and purifying by a silica gel column layer.
4. The method for synthesizing an oxidative degradation product of chlorpheniramine maleate according to claim 3, wherein the mobile phase comprises 0.1% trifluoroacetic acid-water solution and acetonitrile, and the gradient elution is performed by using 10-90% mobile phase in the purification process.
5. The method for synthesizing an oxidative degradation product of chlorpheniramine maleate according to claim 4, wherein the product is concentrated to dryness under reduced pressure at 60 ℃ with a yield of 86%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111039854A (en) * | 2019-12-31 | 2020-04-21 | 四川迪菲特药业有限公司 | Novel chlorpheniramine oxide impurity and preparation process thereof |
| CN111100067A (en) * | 2019-12-31 | 2020-05-05 | 四川迪菲特药业有限公司 | New chlorpheniramine maleate impurity and preparation process thereof |
| CN113956197A (en) * | 2021-09-29 | 2022-01-21 | 艾希尔（深圳）药物研发有限公司 | Preparation method of chlorpheniramine maleate impurity |
| CN114062530A (en) * | 2021-09-30 | 2022-02-18 | 浙江美诺华药物化学有限公司 | Determination and analysis method for isomer impurities in crude chlorpheniramine maleate product |
| CN114773176A (en) * | 2022-05-12 | 2022-07-22 | 山西辅仁恒峰药业有限公司 | Chlorpheniramine maleate impurity, and preparation method and application thereof |
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- 2022-08-10 CN CN202210954386.4A patent/CN115160215A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111039854A (en) * | 2019-12-31 | 2020-04-21 | 四川迪菲特药业有限公司 | Novel chlorpheniramine oxide impurity and preparation process thereof |
| CN111100067A (en) * | 2019-12-31 | 2020-05-05 | 四川迪菲特药业有限公司 | New chlorpheniramine maleate impurity and preparation process thereof |
| CN113956197A (en) * | 2021-09-29 | 2022-01-21 | 艾希尔（深圳）药物研发有限公司 | Preparation method of chlorpheniramine maleate impurity |
| CN114062530A (en) * | 2021-09-30 | 2022-02-18 | 浙江美诺华药物化学有限公司 | Determination and analysis method for isomer impurities in crude chlorpheniramine maleate product |
| CN114773176A (en) * | 2022-05-12 | 2022-07-22 | 山西辅仁恒峰药业有限公司 | Chlorpheniramine maleate impurity, and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| HANSEN, E. B. 等: "Fungal transformations of antihistamines: metabolism of brompheniramine, chlorpheniramine, and pheniramine to N-oxide and N-demethylated metabolites by the fungus Cunninghamella elegans", 《XENOBIOTICA》, vol. 25, no. 10, pages 1081 - 1092 * |
| KAREN M. FRIED，等: "The enantioselective determination of chlorpheniramine and its major metabolites in human plasma using chiral chromatography on a β-cyclodextrin chiral stationary phase and mass spectrometric detection", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》《》, vol. 27, pages 479 - 488 * |
| ZHANG, ZHI-YI，等: "Chlorpheniramine", 《HANDBOOK OF METABOLIC PATHWAYS OF XENOBIOTICS 》, vol. 3, pages 1098 - 1100 * |
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