CN114773176B - Chlorpheniramine maleate impurity and preparation method and application thereof - Google Patents
Chlorpheniramine maleate impurity and preparation method and application thereof Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- organic solvent
- compound
- reaction
- structural formula
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 title abstract description 32
- 239000012535 impurity Substances 0.000 title abstract description 28
- 229940046978 chlorpheniramine maleate Drugs 0.000 title abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- 239000012074 organic phase Substances 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000000967 suction filtration Methods 0.000 claims abstract description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000020477 pH reduction Effects 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims abstract description 7
- 238000004440 column chromatography Methods 0.000 claims abstract description 6
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims abstract description 5
- 239000012071 phase Substances 0.000 claims abstract description 4
- 238000010791 quenching Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000012790 confirmation Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000003908 quality control method Methods 0.000 abstract description 5
- 239000013558 reference substance Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 230000000171 quenching effect Effects 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- -1 chlorpheniramine compound Chemical class 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 2
- 229960003291 chlorphenamine Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 1
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 1
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 description 1
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000019872 Drug Eruptions Diseases 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000005311 drug allergy Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- 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
-
- 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
-
- 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
- C07C45/44—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
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210513181.2A CN114773176B (en) | 2022-05-12 | 2022-05-12 | Chlorpheniramine maleate impurity and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210513181.2A CN114773176B (en) | 2022-05-12 | 2022-05-12 | Chlorpheniramine maleate impurity and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114773176A CN114773176A (en) | 2022-07-22 |
| CN114773176B true CN114773176B (en) | 2023-04-14 |
Family
ID=82436232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210513181.2A Active CN114773176B (en) | 2022-05-12 | 2022-05-12 | Chlorpheniramine maleate impurity and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114773176B (en) |
Families Citing this family (1)
| 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 |
Family Cites Families (3)
| 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 |
-
2022
- 2022-05-12 CN CN202210513181.2A patent/CN114773176B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114773176A (en) | 2022-07-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109020881B (en) | Preparation method of apatinib | |
| CN108699068B (en) | Preparation method of trifluoromethyl substituted pyran derivative | |
| CN114437031B (en) | Synthesis method of 6-methyl nicotine | |
| CN114773176B (en) | Chlorpheniramine maleate impurity and preparation method and application thereof | |
| US11566000B2 (en) | Crystalline form of sofpironium bromide and preparation method thereof | |
| CN106905319B (en) | The preparation method of substituted benzenesulfonyl matrine or its hydrochloride | |
| CN109456253B (en) | Method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salt thereof through chiral induction | |
| CN111217791A (en) | Ibrustat intermediate and preparation method thereof | |
| CN113620868A (en) | Torasemide new impurity and preparation method thereof | |
| CN115872906A (en) | Levatinib impurity and preparation method thereof | |
| CN111362935B (en) | Synthesis method of N-hydroxy tropisetron | |
| CN110818678A (en) | Method for preparing cyclohexane derivative | |
| CN115286548A (en) | Preparation method of vortioxetine hydrobromide impurity standard substance | |
| CN102786489A (en) | Preparation method of 5-methyl isoxazole-4-ethyl formate | |
| CN111269211B (en) | Preparation method of benzothiophene derivative | |
| WO2021259051A1 (en) | Method for improving synthesis process of hypidone free base | |
| US4851420A (en) | 2,6-diamino-3-halobenzylpyridines and processes for their manufacture as well as their use in pharmaceuticals | |
| CN113024472A (en) | Preparation method of lung cancer targeted drug dacomitinib | |
| CN105111217B (en) | A kind of synthetic method of iso-indoles dihydroquinazoline derivatives | |
| CN109836411A (en) | A kind of preparation method of cardiovascular drugs Ketanserine tartaric acid | |
| CN118239940A (en) | Preparation method of azilsartan medoxomil dimer derivative | |
| CN114057707A (en) | Preparation method of N-4-indolyl-2-furancarboxamide compound | |
| CN115057810A (en) | Preparation method of ropivacaine hydrochloride intermediate | |
| CN119912375A (en) | Paricalcitol 24-ene degradation impurity and synthesis method thereof | |
| CN120117960A (en) | Impurity compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |