CN114773176B - 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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- CN114773176B CN114773176B CN202210513181.2A CN202210513181A CN114773176B CN 114773176 B CN114773176 B CN 114773176B CN 202210513181 A CN202210513181 A CN 202210513181A CN 114773176 B CN114773176 B CN 114773176B
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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-benzyl cyanide 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; purifying the crude product by column chromatography, and recrystallizing to obtain the final refined product with structural formula 2. The invention discloses a new impurity discovered for the first time in the process of preparing chlorphenamine maleate, which is used as a standard substance or a reference substance of raw material process impurities of the chlorphenamine maleate, and can help to improve the quality control system of the raw material medicine of the chlorphenamine maleate.
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
The chlorphenamine maleate has the chemical name of N, N-dimethyl-gamma- (4-chlorphenyl) -2-pyridylpropylamine maleateDiacid salt of formula C 20 H 23 ClN 2 O 4 Molecular weight: 390.87, CAS No. 113-92-8, the structural formula is as follows
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 urticaria allergic to skin, drug rash 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 application and provide a basis for the quality assurance of 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 the method is very necessary work.
Through examination of the literature, the maleic chlorpheniramine compound is synthesized in 43% yield by taking p-chlorobenzyl bromide as a raw material in literature 1 (From Synlett, (9), 1293-1295; reference 2 (angelandante Chemie, international Edition,58 (22), 7454-7458, 2019) synthesizes chlorpheniramine maleate compound with 60% yield from p-chlorobenzyl chloride and ethyl chloroformate; meanwhile, the chlorpheniramine maleate compound is synthesized by using p-chlorophenylacetic acid as a raw material in the literatures 3 (Organic Chemistry Frontiers,6 (24), 3973-3977. 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 directed to solving at least one of the 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: 1 H NMR(400MHz,CDCl 3 )δ7.28(d,J＝8.4Hz,4H),7.06(d,J＝8.4Hz,4H),3.69(s,4H). 13 C NMR(100MHz,CDCl 3 )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 C 15 H 11 Cl 2 O[M-H] - 277.0187.Found:277.0161。
another aspect of the present invention is to provide a method for preparing chlorpheniramine maleate impurities, which comprises the following 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 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 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 organic solvent is 1-2: 15g; the organic solvent is any one or mixture of toluene, benzene and dioxane.
Preferably, the aqueous phase in the S1 is extracted for 2 times by using 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 the 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 structural formula 2 in an organic solvent, heat reflux, cool crystallization, filter, and dry to obtain the refined compound of structural 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 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.
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 of 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, therefore, 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 is a compound 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 diagram of a raw material medicine for producing the chlorpheniramine maleate is as follows:
a chlorpheniramine maleate impurity compound of formula 2 below:
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: 1 H NMR(400MHz,CDCl 3 )δ7.28(d,J＝8.4Hz,4H),7.06(d,J＝8.4Hz,4H),3.69(s,4H). 13 C NMR(100MHz,CDCl 3 )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 C 15 H 11 Cl 2 O[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 reacting for about 7 hours, adding 200mL of water for quenching, extracting an aqueous phase for 2 times by using 200mL of ethyl acetate, combining organic phases, washing for 2 times by using 200mL of saturated ammonium chloride aqueous solution, drying an organic phase by using anhydrous magnesium sulfate, carrying out suction filtration, 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 of the 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 drug process of chlorphenamine maleate, and can be used for improving the quality control system of the 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 (4)
1. A process for preparing a compound of formula 2, characterized in that: the compound of formula 2 has the following structural formula:
the structure confirmation data is as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (d, J = 8.4 Hz, 4H), 7.06 (d, J = 8.4 Hz, 4H), 3.69 (s, 4H). 13 C NMR (100 MHz, CDCl 3 ) 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 C 15 H 11 Cl 2 O [M-H] - 277.0187. Found: 277.0161；
the preparation method 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 the organic phase with anhydrous magnesium sulfate, performing suction filtration, and concentrating to obtain a brown liquid;
s2, adding concentrated hydrochloric acid into the brown liquid prepared in the S1 to carry out 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 the organic phase with anhydrous magnesium sulfate, 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 mode, and then preparing a refined product of the final compound structural formula 2 by using a recrystallization method;
the reaction formula is as follows:
the mass ratio of the total volume of the 4-chloro-phenylacetonitrile and the sodium amide in the S1 to the mass volume of the organic solvent is 1-2: 15g/mL; the organic solvent is any one or a mixture of more of toluene, benzene and dioxane;
extracting the water phase in the S1 for 2 times by using an organic solvent, wherein the organic solvent is ethyl acetate; the washing was performed 2 times with a saturated aqueous ammonium chloride solution;
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; adjusting the pH value of the sodium hydroxide solution to 8-10;
and extracting the organic solvent in the S2 for 2 times, wherein the organic solvent is ethyl acetate.
2. A process for the preparation of a compound of formula 2 according to claim 1, characterized in that: the column chromatography in S3 is silica gel column chromatography, wherein the eluent ratio is as follows: petroleum ether: ethyl acetate =100:1.
3. a process for the preparation of a compound of formula 2 according to claim 1, characterized in that: 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.
4. A process for the preparation of a compound of formula 2 according to claim 3, characterized in that: 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.
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