CN111039854A - Novel chlorpheniramine oxide impurity and preparation process thereof - Google Patents
Novel chlorpheniramine oxide impurity and preparation process thereof Download PDFInfo
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- CN111039854A CN111039854A CN201911413693.6A CN201911413693A CN111039854A CN 111039854 A CN111039854 A CN 111039854A CN 201911413693 A CN201911413693 A CN 201911413693A CN 111039854 A CN111039854 A CN 111039854A
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- chlorpheniramine
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- 239000012535 impurity Substances 0.000 title claims abstract description 46
- 229960003291 chlorphenamine Drugs 0.000 title claims abstract description 29
- 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 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 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 claims abstract description 56
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000013558 reference substance Substances 0.000 claims abstract description 13
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- 238000003908 quality control method Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 239000012071 phase Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000012085 test solution Substances 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 239000012088 reference solution Substances 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 229910017677 NH4H2 Inorganic materials 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 150000002978 peroxides Chemical group 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000007689 inspection Methods 0.000 claims 1
- 238000002474 experimental method Methods 0.000 abstract description 5
- 238000000926 separation method Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 17
- 239000000523 sample Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000010753 nasal discharge Diseases 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a chlorpheniramine oxide impurity, which has the following structure. The invention also provides a preparation process of the chlorpheniramine maleate oxidizing impurity. Experiments prove that the chlorpheniramine maleate oxidized impurities generally exist in the finished chlorpheniramine maleate product, and the separation difficulty is higher due to the fact that the chlorpheniramine maleate oxidized impurities are close to the structure of chlorpheniramine maleate. But the chlorpheniramine maleate oxidizing impurity is prepared by a simple process, can be used as a reference substance for quality control of chlorpheniramine maleate, and has a good application prospect.
Description
Technical Field
The invention belongs to the field of medicine purification, and particularly relates to a novel chlorpheniramine oxide impurity and a preparation process thereof.
Background
Chlorpheniramine maleate, malairamine maleate and chlorpheniramine maleate are also known as chlorpheniramine maleate and chlorpheniramine maleate. Is an antihistamine, and has antiallergic effect by antagonizing H1 receptor. It is mainly used for treating rhinitis, skin mucosa allergy, and relieving common cold symptoms such as lacrimation, sneeze, and watery nasal discharge. The structural formula is as follows:
the inventor finds that an impurity generally exists in a finished chlorpheniramine maleate product, the structure of the impurity is close to that of the chlorpheniramine maleate, and the separation purity is difficult. Therefore, if a simple method can be found for preparing the pure product of the impurity, the pure product can be used as a reference substance to carry out quality control on the finished chlorpheniramine maleate product, and the purity of the finished chlorpheniramine maleate product is further improved.
Disclosure of Invention
The invention aims to provide a new chlorpheniramine oxide impurity which can be used as a chlorpheniramine impurity reference substance and is convenient for controlling the impurity content in the processes of product production and finished product quality detection.
The invention provides a chlorpheniramine oxide impurity, which has the following structure:
the invention also provides a preparation method of the chlorpheniramine maleate oxidizing impurity, which comprises the following steps: reacting chlorphenamine and an oxidant serving as raw materials to obtain chlorphenamine
Oxidation into
Further, the oxidant is peroxide, preferably m-chloroperoxybenzoic acid or hydrogen peroxide;
and/or, the molar ratio of the chlorpheniramine to the oxidant is 1: (1.5 to 3.5), preferably 1: 2.4;
and/or, the reaction is carried out in the presence of a basic substance, preferably sodium bicarbonate; the mass ratio of the chlorpheniramine to the alkaline substance is 20: (12-17), preferably 20: 14.8.
further, the solvent for the reaction is an organic solvent, preferably a low-polarity organic solvent, more preferably dichloromethane.
Further, the reaction temperature is-20 ℃ to 0 ℃, preferably-10 ℃, and the reaction time is 1 to 4 hours, preferably 2 hours.
Further, the method further comprises a purification step, wherein the purification step comprises: and (3) adding water into the system after the reaction is finished for washing, taking an organic layer, then adding saturated saline solution into the organic layer for washing, taking the organic phase, concentrating and drying.
Further, the purification step further comprises purifying the dried product through a silica gel column, wherein the eluent is dichloromethane: methanol volume ratio of 10: 1.
The invention also provides the application of the chlorpheniramine maleate oxidized impurity serving as a reference substance in quality control of chlorpheniramine maleate.
The invention also provides a quality detection method of chlorpheniramine maleate, which adopts high performance liquid chromatography for detection and comprises the following specific steps:
a. preparing a test solution: dissolving chlorphenamine maleate in mobile phase to obtain the chlorphenamine maleate solution;
b. preparation of a reference solution: dissolving the chlorpheniramine oxide impurities in a mobile phase to obtain the chlorpheniramine maleate solid solution;
c. respectively sucking the test solution and the reference solution, injecting the solutions into a chromatograph, wherein the chromatographic conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent;
mobile phase: the volume ratio is 80: 20 NH4H2PO4The mixed solution of the solution and acetonitrile is a mobile phase, wherein NH is4H2PO4The pH of the solution was 3.0.
Furthermore, the detection wavelength of the step c is 225nm, the sample injection amount is 20ul, and the flow rate is 1.0 ml/min; the column temperature is 35 ℃;
the chromatographic column is Ultimate XDB-C18;
in the test solution, the mass-to-volume ratio of chlorpheniramine maleate to the mobile phase is 100: 10 mg/ml;
in the reference substance solution, the mass-to-volume ratio of the chlorpheniramine oxide impurities to the mobile phase is 0.01: 1 mg/ml.
Experiments prove that the chlorpheniramine maleate oxidized impurities generally exist in the finished chlorpheniramine maleate product, and the separation difficulty is higher due to the fact that the chlorpheniramine maleate oxidized impurities are close to the structure of chlorpheniramine maleate. But the chlorpheniramine maleate oxidizing impurity is prepared by a simple process, can be used as a reference substance for quality control of chlorpheniramine maleate, and has a good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a high performance liquid chromatogram of a sample 3.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1 preparation of the inventive oxidized impurity chlorpheniramine
Adding 20g of chlorpheniramine and 200ml of dichloromethane into a 500ml single-neck bottle, stirring for dissolving, cooling to-10 ℃, adding 14.8g of sodium bicarbonate, adding 30.4g of m-chloroperoxybenzoic acid (m-CPBA) in batches, reacting for 2 hours at-10 ℃, monitoring the reaction completion by TLC, adding 200ml of water, stirring for layering, taking an organic layer, adding 100ml of saturated saline solution for washing, taking the organic layer, adding anhydrous sodium sulfate and drying to obtain a crude product. And then, taking the crude product, and passing the crude product through a silica gel column (200-300 meshes of silica gel, the column length is 20cm, and an eluent is dichloromethane and methanol which are 10:1v/v), so as to obtain 15g of a target product (namely the chlorpheniramine oxide impurity). The yield was 72.37%, and the purity was 97%.
Structural characterization of the target product: MS (M/z):291[ M + H]+.1H-NMR(600MHz，CDC13):δ2.637～2.889(m，2H，-CH2CH2N(CH3)2)，3.131～3.183(s，6H，-N(CH3)2)，3.223～3.313(m，2H，-CH2N(CH3)2)，4.086～4.112(m，1H，-CHCH2CH2N(CH3)2) 7.128-7.157 (m, 2H, Ar-H), 7.254-7.285 (m, 4H, Py-H, Ar-H), 7.574-7.602 (m, 1H, Py-H), 8.556-8.564 (m, 1H, Py-H). (note: Ar/-H represents a proton on the benzene ring, Py-H represents a proton on the pyridine ring)
The beneficial effects of the present invention are demonstrated by the following experimental examples.
Experimental example 1, the effect of the oxidized impurity of chlorpheniramine of the invention as a positive reference substance in the quality detection of chlorpheniramine test sample
1. Experimental methods
The content of chlorpheniramine maleate oxidized impurities in the chlorpheniramine maleate test solution is measured according to a high performance liquid phase method (general rule 0512). Wherein chlorpheniramine maleate is a commercially available product or is prepared according to known methods (such as the method described in patent application 201910251936.4).
Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica gel as filler, and Ultimate XDB-C18(4.6 × 300mm, 5 μm) as chromatographic column; at 8.57g/L NH4H2PO4(pH3.0 adjusted with phosphoric acid) -acetonitrile (80: 20) as mobile phase; the detection wavelength is 225 nm; the flow rate is 1.0 ml/min; the column temperature was 35 ℃. 20ul of system applicability solution is taken for sample injection, and chlorphenamine and impurities are oxidizedThe degree of mass separation should meet the requirements.
Control solution: precisely weighing the oxidized impurities prepared in the embodiment 1 of the invention as a reference substance, and preparing 1mg/ml solution by using methanol as a reference substance stock solution; measuring appropriate amount of control stock solution, and making into 0.01mg/ml solution with mobile phase as control solution.
System applicability solution: 100mg of chlorpheniramine maleate is precisely weighed, placed in a 10ml volumetric flask, added with 0.1ml of reference substance stock solution, dissolved by using a mobile phase and fixed to the volume to be calibrated to be used as a system applicability solution.
Test solution: accurately weighing 100mg of chlorpheniramine maleate, placing in a 10ml volumetric flask, diluting with mobile phase to constant volume, shaking up to obtain test solution, and preparing 7 groups according to the same method. Measuring under the above chromatographic conditions, and injecting blank solution, system applicability solution, reference solution, and sample solution 20 μ l into liquid chromatograph. If the chlorpheniramine oxide impurity peak is displayed in the chromatogram of the test solution, the content of chlorpheniramine oxide impurities is calculated according to the peak area by an external standard method.
2. Results of the experiment
As shown in Table 1, chlorpheniramine oxide impurities were detected in all of samples 1-6 of 7 test solutions, and the content was 0.002%. Wherein, the chromatogram of sample 3 is shown in FIG. 1, wherein the peak corresponding to the outflow time of 32.614min is the peak of the chlorpheniramine oxide impurity of the invention.
Therefore, chlorpheniramine maleate does contain chlorpheniramine maleate oxidized impurities prepared by the invention. The chlorpheniramine maleate impurity prepared by the invention can be used as a positive reference substance, and the impurity content in the processes of chlorpheniramine maleate product production and finished product quality detection can be more accurately controlled.
TABLE 1 content of oxidized impurities of chlorpheniramine maleate in test solutions
| Test sample number | Batch number | Content (wt.) |
| 1 | LBNM-4-2019030801 | 0.002％ |
| 2 | LBNM-4-2019031301 | 0.002％ |
| 3 | LBNM-4-2019040201 | 0.002％ |
| 4 | 20190501 | 0.002％ |
| 5 | 20190502 | 0.002％ |
| 6 | 20190503 | 0.002％ |
| 7 | LBNM-2019102201 | Not detected out |
In conclusion, the invention provides a new chlorpheniramine oxide impurity and a preparation process thereof. Experiments prove that the chlorpheniramine maleate oxidized impurities generally exist in the finished chlorpheniramine maleate product, and the separation difficulty is higher due to the fact that the chlorpheniramine maleate oxidized impurities are close to the structure of chlorpheniramine maleate. But the chlorpheniramine maleate oxidizing impurity is prepared by a simple process, can be used as a reference substance for quality control of chlorpheniramine maleate, and has a good application prospect.
Claims (10)
1. A chlorpheniramine maleate oxidizing impurity, which is characterized in that: the structure of the chlorpheniramine oxide impurity is shown as follows:
2. a process for the preparation of the chlorpheniramine oxide impurity of claim 1, wherein: the method comprises the following steps: reacting chlorphenamine and an oxidant serving as raw materials to obtain chlorphenamine
Oxidation into
3. The method of claim 2, wherein: the oxidant is peroxide, preferably m-chloroperoxybenzoic acid or hydrogen peroxide;
and/or, the molar ratio of the chlorpheniramine to the oxidant is 1: (1.5 to 3.5), preferably 1: 2.4;
and/or, the reaction is carried out in the presence of a basic substance, preferably sodium bicarbonate; the mass ratio of the chlorpheniramine to the alkaline substance is 20: (12-17), preferably 20: 14.8.
4. the method of claim 2, wherein: the solvent for the reaction is an organic solvent, preferably a low polarity organic solvent, more preferably dichloromethane.
5. The method of claim 2, wherein: the reaction temperature is-20 ℃ to 0 ℃, preferably-10 ℃, and the reaction time is 1-4 h, preferably 2 h.
6. The method according to any one of claims 2 to 5, wherein: the method further comprises a purification step, wherein the purification step comprises the following steps: and (3) adding water into the system after the reaction is finished for washing, taking an organic layer, then adding saturated saline solution into the organic layer for washing, taking the organic phase, concentrating and drying.
7. The method of claim 6, wherein: the purification step further comprises purifying the dried product through a silica gel column, wherein the eluent is dichloromethane: methanol volume ratio of 10: 1.
8. Use of the oxidized impurity of chlorpheniramine maleate according to claim 1 as a control for quality control of chlorpheniramine maleate.
9. A quality detection method of chlorpheniramine maleate is characterized by comprising the following steps: the detection is carried out by adopting a high performance liquid chromatography, and the method comprises the following specific steps:
a. preparing a test solution: dissolving chlorphenamine maleate in mobile phase to obtain the chlorphenamine maleate solution;
b. preparation of a reference solution: dissolving chlorpheniramine maleate oxide impurities of claim 1 in mobile phase;
c. respectively sucking the test solution and the reference solution, injecting the solutions into a chromatograph, wherein the chromatographic conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent;
mobile phase: the volume ratio is 80: 20 NH4H2PO4The mixed solution of the solution and acetonitrile is a mobile phase, wherein NH is4H2PO4The pH of the solution was 3.0.
10. The quality inspection method according to claim 9, wherein: the detection wavelength of the step c is 225nm, the sample injection amount is 20ul, and the flow rate is 1.0 ml/min; the column temperature is 35 ℃;
the chromatographic column is Ultimate XDB-C18;
in the test solution, the mass-to-volume ratio of chlorpheniramine maleate to the mobile phase is 100: 10 mg/ml;
in the reference substance solution, the mass-to-volume ratio of the chlorpheniramine oxide impurities to the mobile phase is 0.01: 1 mg/ml.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| 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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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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