CN114773176A - Chlorpheniramine maleate impurity, and preparation method and application thereof - Google Patents
Chlorpheniramine maleate impurity, and preparation method and application thereof Download PDFInfo
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- CN114773176A CN114773176A CN202210513181.2A CN202210513181A CN114773176A CN 114773176 A CN114773176 A CN 114773176A CN 202210513181 A CN202210513181 A CN 202210513181A CN 114773176 A CN114773176 A CN 114773176A
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- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
- C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
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- C07C45/44—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reduction and hydrolysis of nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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Abstract
The invention relates to the technical field of medicines, and particularly relates to a chlorpheniramine maleate impurity as well as a preparation method and application thereof. The method comprises the following specific steps: dissolving 4-chloro-phenylacetonitrile and sodium amide in an organic solvent, dropwise adding a small amount of water, adding water after the reaction is finished, quenching, extracting the water phase with the organic solvent, washing with a saturated ammonium chloride aqueous solution, drying with an organic phase, performing suction filtration, and concentrating to obtain a brown liquid; adding concentrated hydrochloric acid for acidification reaction, heating until the reaction is finished and cooling, then adjusting the pH value with a sodium hydroxide solution, extracting with an organic solvent, drying with an organic phase, performing suction filtration, and concentrating to obtain a residue as a crude product; and purifying the crude product by column chromatography, and then obtaining the refined product with the final structural formula 2 by using a recrystallization method. The invention discloses a new impurity discovered for the first time in the process of preparing chlorpheniramine maleate, which is used as a technical impurity standard or reference substance of chlorpheniramine maleate raw material medicines and can help to improve the quality control system of the chlorpheniramine maleate raw material medicines.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a chlorpheniramine maleate impurity and a preparation method and application thereof.
Background
Chlorphenamine maleate is N, N-dimethyl-gamma- (4-chlorphenyl) -2-pyridylpropylamine maleate and has a molecular formula of C20H23ClN2O4Molecular weight: 390.87, CAS number 113-92-8, and its structural formula is shown in the specification
Chlorpheniramine maleate, also called chlorpheniramine, is a histamine H1 receptor antagonist, belongs to the most classical and representative antiallergic drugs, is mainly clinically used for treating allergic urticaria of skin, drug eruption caused by drug allergy, and symptoms such as rhinorrhea, sneeze and the like caused by allergic rhinitis, skin mucosa allergy and influenza virus, can be relieved by using chlorpheniramine maleate, and has great market demand.
In the production process of medicines, the research on impurity spectra is very important, and the existence of medicine impurities not only influences the efficacy of the medicines, but also can cause adverse reactions. Therefore, the analysis and research on the medicine impurities can ensure the safety, effectiveness and stability of the medicine, and provide a basis for the quality assurance in the production and circulation processes.
Therefore, in the production and quality control processes of the chlorpheniramine maleate bulk drug, the research on impurities is carried out in a standard way, the impurities are controlled within a safe and reasonable limit range, and the impurity mass spectrum is continuously perfected; the impurity standard substance is researched and prepared, and can be used for qualitative and quantitative analysis of impurities in chlorphenamine maleate production, so that the quality standard of chlorphenamine maleate is improved, and necessary work is provided.
The examination of the literature shows that the maleic chlorpheniramine maleate compound is synthesized by the literature 1(From Synlett, (9), 1293-1295; 2011) by taking p-chlorobenzyl bromide as a raw material with the yield of 43 percent; document 2(Angewandte Chemie, International Edition,58(22), 7454-7458; 2019) synthesizes chlorpheniramine maleate compound with 60% yield by using p-chlorobenzyl chloride and ethyl chloroformate as raw materials; meanwhile, chlorpheniramine maleate compounds are synthesized from p-chlorophenylacetic acid in the references 3(Organic Chemistry Frontiers,6(24), 3973-. However, the yield reported in the literature is not very high, and the operation is relatively complicated. Therefore, it is very significant to develop a new synthesis route of new impurities of chlorpheniramine maleate and prepare high-purity new impurities of chlorpheniramine maleate as a reference substance for quality research.
Disclosure of Invention
The present invention is designed to solve at least one of the technical problems of the prior art, and therefore an aspect of the present invention is to provide a chlorpheniramine maleate impurity compound having the following chemical formula 2:
the structure confirmation data is as follows:1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.4Hz,4H),7.06(d,J＝8.4Hz,4H),3.69(s,4H).13C NMR(100MHz,CDCl3)δ204.49,133.18,133.18,132.15,132.15,130.85,130.85,130.85,130.85,128.90,128.90,128.90,128.90,48.39,48.39.HRMS(ESI,m/z)calcd for C15H11Cl2O[M-H]-277.0187.Found:277.0161。
another aspect of the present invention aims to provide a method for preparing chlorpheniramine maleate impurities, which comprises the following specific steps:
s1, dissolving 4-chloro-phenylacetonitrile and sodium amide in an organic solvent, slowly dropwise adding a small amount of water under a stirring state, heating to react, adding water to quench after the reaction is finished, extracting the water phase with the organic solvent, combining organic phases, washing with a saturated ammonium chloride aqueous solution, drying with an organic phase, performing suction filtration, and concentrating to obtain a brown liquid;
s2, adding concentrated hydrochloric acid into the brown liquid prepared in the step S1 to perform an acidification reaction, heating until the reaction is finished and cooling, then adjusting the pH value with a sodium hydroxide solution, extracting with an organic solvent, drying with an organic phase, performing suction filtration, and concentrating to obtain a residue which is a crude product of a compound structural formula 2;
s3, purifying the crude product of the compound structural formula 2 obtained in the S2 in a column chromatography mode, and then preparing a refined product of the compound structural formula 2 by using a recrystallization method;
the reaction formula is as follows:
preferably, the mass ratio of the total volume of the 4-chloro-phenylacetonitrile and the sodium amide in the S1 to the mass volume ratio of the organic solvent is 1-2:1, and the mass volume ratio of the total volume of the 4-chloro-phenylacetonitrile and the sodium amide to the organic solvent is 1: 15g is mL; the organic solvent is any one or mixture of toluene, benzene and dioxane.
Preferably, the aqueous phase in S1 is extracted 2 times with an organic solvent, and the organic solvent of the aqueous phase is ethyl acetate; the washing was performed 2 times with a saturated aqueous ammonium chloride solution; the organic phase was dried over anhydrous magnesium sulfate.
Preferably, the S2 is heated to 70-80 ℃ for acidification reaction, and the acidification reaction time is 5-8 hours; cooling to 40-50 ℃ after the reaction is finished; and adjusting the pH value of the sodium hydroxide solution to be 8-10.
Preferably, the organic solvent in S2 is extracted for 2 times, and the organic solvent is ethyl acetate; the organic phase was dried over anhydrous magnesium sulfate.
Preferably, the column chromatography in S3 is silica gel column chromatography, wherein the eluent ratio is: petroleum ether: ethyl acetate 100: 1.
preferably, the recrystallization method in S3 is to dissolve the purified crude compound of formula 2 in an organic solvent, heat reflux, cool crystallization, filter, and dry to obtain the refined compound of formula 2.
Preferably, the organic solvent of the recrystallization method is petroleum ether; the volume ratio of the crude product of the purified compound structural formula 2 to the petroleum ether is 1: 50-90; the temperature for heat preservation and crystallization is 20-25 ℃, and the time is 2 hours.
In another aspect, the invention provides a use of chlorpheniramine maleate impurities.
The compound with the structural formula 2 is used as an impurity reference substance in the chlorphenamine maleate raw material process, and can be used for improving a chlorphenamine maleate quality control system.
The invention has the following beneficial effects:
(1) the invention is a new impurity discovered for the first time in the process of preparing chlorpheniramine maleate;
(2) provides a brand new preparation method and a recrystallization method thereof;
(3) the chlorphenamine maleate salt can be used as an impurity standard substance or a reference substance in the chlorphenamine maleate raw material process, and can help improve the quality control system of the chlorphenamine maleate raw material.
Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of compound formula 2 of the present invention;
FIG. 2 is a nuclear magnetic carbon spectrum of compound formula 2 of the present invention;
FIG. 3 is a high resolution mass spectrum of the compound of formula 2 of the present invention.
Detailed Description
In order that the above objects, features and advantages of the present invention can be more clearly understood, the present invention will be described in further detail with reference to the accompanying drawings and specific embodiments. It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as specifically described and thus the scope of the present invention is not limited by the specific embodiments disclosed below.
The invention discovers an impurity which is not reported in related researches on chlorpheniramine maleate in quality researches on chlorpheniramine maleate, and is characterized in that the impurity has a structural formula 2, the impurity is prepared and separated in order to realize better quality researches on chlorpheniramine maleate, the structure of the impurity is confirmed by technologies such as nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry and the like, the generation process of the compound is tracked, and the route chart of the raw material medicine for producing the chlorpheniramine maleate is as follows:
a chlorpheniramine maleate impurity compound having the chemical structural formula 2 as follows:
the invention determines the structure of the compound through nuclear magnetic resonance spectrum and high resolution mass spectrum, the structure is correct, the nuclear magnetic resonance hydrogen spectrum is shown as figure 1, the nuclear magnetic resonance carbon spectrum is shown as figure 2, and the high resolution mass spectrum is analyzed as figure 3, the structure confirmation data is as follows:1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.4Hz,4H),7.06(d,J＝8.4Hz,4H),3.69(s,4H).13C NMR(100MHz,CDCl3)δ204.49,133.18,133.18,132.15,132.15,130.85,130.85,130.85,130.85,128.90,128.90,128.90,128.90,48.39,48.39.HRMS(ESI,m/z)calcd for C15H11Cl2O[M-H]-277.0187.Found:277.0161。
examples
Adding 16 g of sodium amide and 250mL of toluene into a 500mL reaction bottle, slowly dropwise adding 5mL of water under the stirring state, then adding 26 g of p-chlorobenzonitrile, heating to 50 ℃ for reaction for about 7 hours, adding 200mL of water for quenching, extracting the water phase for 2 times by 200mL of ethyl acetate, combining the organic phases, washing for 2 times by 200mL of saturated ammonium chloride aqueous solution, drying the organic phases by anhydrous magnesium sulfate, filtering by suction, and concentrating to obtain 37 g of brown liquid. And adding the brown liquid into another 500mL reaction bottle, adding 74 g of concentrated hydrochloric acid for acidification reaction, heating to 70 ℃ for reaction for 4 hours, cooling to 40 ℃, then adjusting the pH to 8 by using a sodium hydroxide aqueous solution, extracting for 2 times by using 20mL of ethyl acetate, drying an organic phase by using anhydrous magnesium sulfate, performing suction filtration and concentrating to obtain a residue which is a crude product of the compound structural formula 2. The crude product of the compound with the structural formula 2 is purified by column chromatography, and an eluent is: petroleum ether: ethyl acetate 100: 1. and adding the crude product of the compound structural formula 2 into another 500mL reaction bottle, adding 90 times of petroleum ether, heating and refluxing, cooling to 25 ℃, keeping the temperature for two hours, crystallizing, performing suction filtration, and drying to obtain a refined product of the compound structural formula 2, wherein the yield is 82%, and the purity is 98.9% through detection.
The compound of the invention with the structural formula 2 can be used as an impurity reference substance for the raw material process of chlorphenamine maleate, and can be used for improving the quality control system of chlorphenamine maleate.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes may be made to the present invention by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The chlorpheniramine maleate impurity is characterized in that: the chlorpheniramine maleate impurity compound has the following chemical structural formula 2:
the structure confirmation data is as follows:1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.4Hz,4H),7.06(d,J＝8.4Hz,4H),3.69(s,4H).13C NMR(100MHz,CDCl3)δ204.49,133.18,133.18,132.15,132.15,130.85,130.85,130.85,130.85,128.90,128.90,128.90,128.90,48.39,48.39.HRMS(ESI,m/z)calcd for C15H11Cl2O[M-H]-277.0187.Found:277.0161。
2. a preparation method of chlorpheniramine maleate impurities is characterized by comprising the following steps: the method comprises the following specific steps:
s1, dissolving 4-chloro-benzyl cyanide and sodium amide in an organic solvent, slowly dropwise adding a small amount of water under a stirring state, heating to react, adding water to quench after the reaction is finished, extracting the water phase with the organic solvent, combining organic phases, washing with a saturated ammonium chloride aqueous solution, drying with an organic phase, performing suction filtration, and concentrating to obtain a brown liquid;
s2, adding concentrated hydrochloric acid into the brown liquid prepared in the step S1 to carry out an acidification reaction, heating until the reaction is finished, cooling, then adjusting the pH value with a sodium hydroxide solution, extracting with an organic solvent, drying with an organic phase, carrying out suction filtration, and concentrating to obtain a residue which is a crude product of a compound structural formula 2;
s3, purifying the crude product of the compound structural formula 2 obtained in the S2 in a column chromatography manner, and then preparing a refined product of the compound structural formula 2 by using a recrystallization method;
the reaction formula is as follows:
3. the method for preparing chlorpheniramine maleate impurity according to claim 2, wherein: the mass ratio of the total volume of the 4-chloro-phenylacetonitrile and the sodium amide in the S1 to the mass volume ratio of the organic solvent is 1-2:1, and the mass volume ratio of the total volume of the 4-chloro-phenylacetonitrile and the sodium amide to the organic solvent is 1: 15 g/mL; the organic solvent is any one or mixture of toluene, benzene and dioxane.
4. The method for preparing chlorpheniramine maleate impurity according to claim 2, wherein: extracting the water phase in the S1 with an organic solvent for 2 times, wherein the organic solvent for the water phase is ethyl acetate; the washing was performed 2 times with a saturated aqueous ammonium chloride solution; the organic phase was dried over anhydrous magnesium sulfate.
5. The method for preparing chlorpheniramine maleate impurity according to claim 2, wherein: heating the S2 to 70-80 ℃ for acidification reaction, wherein the acidification reaction time is 5-8 hours; cooling to 40-50 ℃ after the reaction is finished; and adjusting the pH value of the sodium hydroxide solution to be 8-10.
6. The method for preparing chlorpheniramine maleate impurity according to claim 2, wherein: extracting the organic solvent in the S2 for 2 times, wherein the organic solvent is ethyl acetate; the organic phase was dried over anhydrous magnesium sulfate.
7. The method for preparing the chlorpheniramine maleate impurity according to claim 2, wherein the method comprises the following steps: the column chromatography in S3 is silica gel column chromatography, wherein the eluent ratio is as follows: petroleum ether: ethyl acetate 100: 1.
8. the method for preparing chlorpheniramine maleate impurity according to claim 2, wherein: and the recrystallization method in the S3 is to dissolve the purified crude product of the compound structural formula 2 in an organic solvent, heat and reflux, cool and crystallize, filter and dry to obtain the refined product of the compound structural formula 2.
9. The method for preparing chlorpheniramine maleate impurity according to claim 8, wherein: the organic solvent of the recrystallization method is petroleum ether; the volume ratio of the crude product of the purified compound structural formula 2 to the petroleum ether is 1: 50-90; the temperature for heat preservation and crystallization is 20-25 ℃, and the time is 2 hours.
10. The application of chlorpheniramine maleate impurities is characterized in that: the compound with the structural formula 2 can be used as an impurity reference substance for the raw material process of chlorphenamine maleate, and can be used for improving a quality control system of chlorphenamine maleate.
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| CN115160215A (en) * | 2022-08-10 | 2022-10-11 | 南京联智医药科技有限公司 | Method for synthesizing chlorpheniramine maleate oxidation degradation product |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112694437A (en) * | 2020-12-30 | 2021-04-23 | 北京悦康科创医药科技股份有限公司 | Preparation method of chlorpheniramine maleate impurity |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112694437A (en) * | 2020-12-30 | 2021-04-23 | 北京悦康科创医药科技股份有限公司 | Preparation method of chlorpheniramine maleate impurity |
| 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 |
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| Title |
|---|
| HU, CHUNQI 等，: "Design, Synthesis, and Biological Evaluation of Pyrazole Derivatives", 《CHEMICAL BIOLOGY & DRUG DESIGN》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115160215A (en) * | 2022-08-10 | 2022-10-11 | 南京联智医药科技有限公司 | Method for synthesizing chlorpheniramine maleate oxidation degradation product |
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