CN115785095A - Preparation and purification method of moxifloxacin impurity RC-4 - Google Patents
Preparation and purification method of moxifloxacin impurity RC-4 Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 54
- 229960003702 moxifloxacin Drugs 0.000 title claims abstract description 40
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 238000000746 purification Methods 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 24
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 claims abstract description 17
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 claims abstract description 17
- 230000003647 oxidation Effects 0.000 claims abstract description 5
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000012071 phase Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000010828 elution Methods 0.000 claims description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000002414 normal-phase solid-phase extraction Methods 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- OQVYMXCRDHDTTH-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)-2-[4-(diethoxyphosphorylmethyl)pyridin-2-yl]pyridine Chemical compound CCOP(=O)(OCC)CC1=CC=NC(C=2N=CC=C(CP(=O)(OCC)OCC)C=2)=C1 OQVYMXCRDHDTTH-UHFFFAOYSA-N 0.000 claims description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000004005 microsphere Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000012856 packing Methods 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 238000004262 preparative liquid chromatography Methods 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000013558 reference substance Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- 238000005562 fading Methods 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
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- 238000003756 stirring Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
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- 238000001647 drug administration Methods 0.000 description 1
- 238000005108 dry cleaning Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method and a purification method of moxifloxacin impurity RC-4 and application of the moxifloxacin impurity RC-4 serving as an impurity reference substance. The moxifloxacin hydrochloride is used as a raw material, a target product can be obtained through one-step oxidation, the process is simple, the operation is convenient, and the yield is high; the purification method of the impurity RC-4 ensures that the purity of the impurity reference substance is more than 95 percent, can be used for researching related substances of moxifloxacin hydrochloride, and has important significance for improving the quality control of products.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method, a purification method and application of moxifloxacin impurities.
Background
Moxifloxacin hydrochloride (moxifloxacin hydrochloride, 1-cyclopropyl-7- { S, S-2, 8-diazo-bicyclo [4.3.0] nonan-8-yl } -6-fluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride) is a fourth-generation quinolone antibiotic marketed in 1999, developed by the german bayer company. The strain has strong antibacterial activity on streptococcus pneumoniae, haemophilus influenzae and staphylococcus aureus, is mainly used for treating community-acquired pneumonia, acute attack of chronic bronchitis and various skin infections, has the advantages of low toxicity, high efficiency, broad spectrum and low drug resistance, is called as a nearly ideal drug for treating respiratory tract infection, and has the following structure:
the research on the impurities of the medicine is an important content of the research and development of the medicine, and has great influence on the pharmacological activity and adverse reaction of the medicine, so that the impurities are controlled within a safe and reasonable range, and the quality and the safety of the medicine on the market are directly influenced.
Sources of impurities typically include process impurities, degradation products, impurities that are incorporated from reactants and reagents, and the like. The invention provides a preparation method and a purification method from moxifloxacin hydrochloride raw material medicine to oxidation impurity RC-4. RC-4 has the chemical name of 1-cyclopropyl-2-hydroxy-7- (S, S-2, 8-diazabicyclo [4.3.0] nonan-3-oxo-8-yl) -6-fluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid, has a molecular weight of 431.4, is an oxidation product of moxifloxacin and a potential oxidative degradation impurity containing two oxidation sites, namely a pyrrole epoxidation site and a quinoline epoxidation site. The moxifloxacin RC-4 impurity is recorded in United states pharmacopoeia USP38-NF 33S 2-moxifloxacin eye drops monograph and the drug registration standard imported by the State drug administration (moxifloxacin hydrochloride eye drops) (RRT 0.3, correction factor 1.0), and is a common impurity in the moxifloxacin eye drops.
The acquisition of the impurities has important significance for product quality monitoring, especially stability research.
Disclosure of Invention
The invention aims to provide a preparation method and a purification method of moxifloxacin impurity RC-4, which can quickly and efficiently obtain an impurity reference substance and are more beneficial to quality control of moxifloxacin hydrochloride.
The technical scheme for solving the technical problems is as follows:
a preparation method of moxifloxacin impurity RC-4 is characterized in that a compound of formula I, moxifloxacin hydrochloride is dissolved in a solvent, alkali and an oxidant are added for reaction, and the compound of formula II, moxifloxacin impurity RC-4, is prepared;
further, the alkaline reagent is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; the molar ratio of the alkali to the moxifloxacin hydrochloride is (10);
further, the oxidant is one or more of manganese dioxide, potassium persulfate, hydrogen peroxide, potassium permanganate, potassium manganate and m-chloroperoxybenzoic acid, and potassium permanganate, potassium persulfate and hydrogen peroxide are preferred. The concentration of the oxidant solution is 3 mg/mL-8 mg/mL, preferably 4 mg/mL-6 mg/mL, more preferably 5mg/mL; the molar ratio of the oxidant to the moxifloxacin hydrochloride is (1-10);
further, the solvent is a mixed solvent of an organic solvent such as methanol, ethanol, isopropanol, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, dioxane and the like and water, or pure water, preferably methanol, acetonitrile, a mixed solvent of ethanol and water or pure water, and the mixing ratio is 1 to 1;
further, the preparation method also comprises one or more steps of solid phase extraction purification and medium-pressure preparation purification;
wherein, the solid phase extraction and purification specifically comprises the following steps: taking monodisperse microspheres as chromatographic column packing; washing the residue with purified water and eluting the product with methanol; also comprises the steps of collecting eluent and spin-drying;
the medium-pressure preparation and purification specifically comprises: (1) sample preparation: dissolving the sample by adding a solvent, wherein the solvent is selected from disodium hydrogen phosphate aqueous solution, purified water or methanol; (2) chromatographic conditions: c18 chromatographic column is adopted; taking 0.1% formic acid water as a mobile phase A and methanol as a mobile phase B; the flow rate is 25mL/min; the collection wavelength is 262nm; gradient elution is adopted; also comprises the steps of collecting eluent and spin-drying;
the invention also provides a purification method of the moxifloxacin impurity RC-4 crude isolate prepared by the method, which is characterized by adopting a preparative liquid chromatography for purification, and specifically comprises the following steps: (1) sample preparation: adding a diluent to dissolve a sample, wherein the diluent is selected from a formic acid aqueous solution, and the ratio of the two is 50; (2) chromatographic conditions: c18 chromatographic column is adopted; taking ammonium carbonate solution as a mobile phase A and acetonitrile as a mobile phase B; the flow rate is 20mL/min; the sample injection amount is 4mL; the detection wavelength is 262nm; gradient elution is adopted; also comprises the steps of eluent collection and spin drying;
further, the pH value of the mobile phase A is 7.5-8.5, preferably 7.8.
Further, the parameters of the gradient elution are as follows:
| time (min) | Mobile phase A (% V/V) | Mobile phase B (% V/V) |
| 0.0 | 95 | 5 |
| 30 | 85 | 15 |
| 34 | 40 | 60 |
| 40 | 40 | 60 |
| 40.1 | 95 | 5 |
| 50 | 95 | 5 |
The invention also provides application of the moxifloxacin impurity RC-4 obtained by the preparation method or the purification method in preparation of moxifloxacin raw materials or preparations as an impurity reference substance.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for a significant error in the formula.
The invention has the beneficial effects that:
the preparation method of the moxifloxacin impurity RC-4 disclosed by the invention takes moxifloxacin hydrochloride as a raw material, and a target product can be obtained by oxidizing the moxifloxacin hydrochloride in one step by using an oxidizing agent, so that the synthesis process is simple, the operation is convenient, and the yield is high; the purification method of moxifloxacin impurity RC-4 provided ensures that the purity of the impurity reference substance is more than 95%, can be used for researching related substances of moxifloxacin hydrochloride, and has important significance for improving the quality control of products.
Drawings
FIG. 1: a preparative chromatographic content map of moxifloxacin impurity RC-4 in example 1;
FIG. 2 is a drawing: a high resolution mass spectrogram of moxifloxacin impurity RC-4 in example 1;
FIG. 3: an infrared spectrum of moxifloxacin impurity RC-4 in example 1;
FIG. 4 is a drawing: method for preparing moxifloxacin impurity RC-4 in example 1 1 An H-NMR spectrum;
FIG. 5: method for preparing moxifloxacin impurity RC-4 in example 1 13 C-NMR spectrum.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
and (3) crude product preparation and separation: dissolving 11g moxifloxacin hydrochloride in 2L NaOH solution (10 mg/mL), stirring, dissolving, and adding 3L KMnO in portions 4 And (3) adding the solution (5 mg/mL) for the next time after fading, continuously stirring after adding, completely fading the blue-green color of the solution, precipitating completely, filtering, collecting a reaction solution containing moxifloxacin impurity RC-4, and monitoring the reaction solution by HPLC, wherein the content of the impurity RC-4 is 80%.
Adding the reaction solution to the activated SPE column, adding a proper amount of purified water for washing, and discarding the filtrate; the product was eluted with additional methanol, the methanol eluate was collected and spin dried on a rotary evaporator to an oil.
Dissolving the oily substance in appropriate amount of Na 2 HPO 4 Loading the solution (60 mmol) onto a medium-pressure preparation column, performing gradient elution according to parameters in Table 1, collecting eluate with wavelength of 262nm, determining the purity of liquid phase in the test tube before and after, and mixing and collecting; and (4) rotating methanol in the dry cleaning stripping solution, and repeatedly performing SPE purification under the same conditions to obtain crude moxifloxacin RC-4 impurity.
Table 1: medium pressure preparative chromatography parameters
Purifying an impurity RC-4: weighing 60mg of crude product into a 15ml centrifuge tube, adding 4ml of 50% formic acid aqueous solution to prepare a sample solution, carrying out gradient elution according to parameters in a table 2, adjusting the pH value of a mobile phase A to 7.8, collecting and spin-drying a stripping solution to obtain a moxifloxacin RC-4 impurity pure product with the purity of 98.68%.
Table 2: preparative chromatography gradient elution parameters
Example 2:
the concentration of the potassium persulfate solution used was 2mg/mL, and the other conditions and procedures were the same as in example 1.
The content of moxifloxacin impurity RC-4 in the reaction liquid is 57% by HPLC monitoring.
The purity of moxifloxacin impurity RC-4 obtained by purification is 96.23%.
Example 3:
the concentration of the aqueous hydrogen peroxide solution used was 10mg/mL, and the conditions and procedure were the same as in example 1.
The content of moxifloxacin impurity RC-4 in the reaction liquid is 36% by HPLC monitoring.
The purity of the moxifloxacin impurity RC-4 obtained by purification is 92.57%.
Example 4:
the KMnO used 4 The concentration of the solution was 3mg/mL, and the other conditions and procedures were the same as in example 1.
The content of moxifloxacin impurity RC-4 in the reaction liquid is 75% by HPLC monitoring.
The purity of moxifloxacin impurity RC-4 obtained by purification is 96.23%.
Example 5:
the KMnO used 4 The concentration of the solution was 8mg/mL, and the other conditions and procedures were the same as in example 1.
The content of moxifloxacin impurity RC-4 in the reaction liquid is 76% by HPLC monitoring.
The purity of the moxifloxacin impurity RC-4 obtained by purification is 96.10%.
Example 6:
the conditions and steps for crude preparation and separation were the same as in example 1, and the content of moxifloxacin impurity RC-4 in the reaction solution was monitored by HPLC to be 81%.
Purifying an impurity RC-4: weighing 60mg of crude product into a 15ml centrifuge tube, adding 4ml of methanol to prepare a sample solution, carrying out gradient elution according to the parameters in the table 2, adjusting the pH value of the mobile phase A to 7, collecting and spin-drying the eluent to obtain a pure moxifloxacin impurity RC-4 product with the purity of 92.25%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A preparation method of moxifloxacin impurity RC-4 is characterized in that moxifloxacin hydrochloride of a compound shown in a formula I is dissolved in a solvent, inorganic base and an oxidant are added for reaction, a crude product is obtained, and the crude product is subjected to preparation separation to obtain moxifloxacin oxidation impurity RC-4 of a compound shown in a formula II;
2. the production method according to claim 1, wherein the solvent is a mixed solvent of an organic solvent such as methanol, ethanol, isopropanol, acetonitrile, dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran, dioxane, or the like and water, or pure water, preferably methanol, acetonitrile, a mixed solvent of ethanol and water, or pure water, and the mixing ratio is 1 to 1; the inorganic alkali reagent can be one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; the inorganic base is preferably sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the molar ratio of the alkali to the moxifloxacin hydrochloride is 10.
3. The preparation method according to claim 1, wherein the oxidant is one or more of manganese dioxide, potassium persulfate, hydrogen peroxide, potassium permanganate, potassium manganate and m-chloroperoxybenzoic acid, preferably potassium permanganate, potassium persulfate and hydrogen peroxide. The concentration of the oxidant solution is 3 mg/mL-8 mg/mL; the molar ratio of the oxidant to the moxifloxacin hydrochloride is 2-1.
4. The method of claim 1, further comprising one or more steps of solid phase extraction purification and medium pressure preparative purification.
5. The method according to claim 4, wherein the solid phase extraction and purification specifically comprises: taking monodisperse microspheres as chromatographic column packing; washing the residue with purified water and eluting the product with methanol; also comprises the steps of collecting eluent and spin-drying.
6. The preparation method according to claim 4, wherein the medium-pressure preparation purification specifically comprises: (1) sample preparation: dissolving the sample by adding a solvent, wherein the solvent is selected from disodium hydrogen phosphate aqueous solution, purified water or methanol; (2) chromatographic conditions: by C 18 A chromatographic column; 0.1% formic acid water is used as a mobile phase A, and methanol is used as a mobile phase B; the flow rate is 25mL/min; the collection wavelength is 262nm; gradient elution is adopted; also comprises the steps of eluent collection and spin drying.
7. A purification method of moxifloxacin impurity RC-4 obtained by the preparation method according to any one of claims 1 to 6, which is characterized by adopting preparative liquid chromatography for purification, and specifically comprises the following steps: (1) sample preparation: adding a diluent to dissolve a sample, wherein the diluent is selected from aqueous formic acid solution, and the ratio of the two is 50; (2) chromatographic conditions: c18 chromatographic column is adopted; taking ammonium carbonate solution as a mobile phase A, and taking acetonitrile as a mobile phase B; the flow rate is 20mL/min; the sample injection amount is 4mL; the detection wavelength is 262nm; gradient elution is adopted; also comprises the steps of collecting eluent and spin-drying.
8. The purification process according to claim 7, wherein the pH of the mobile phase A is 7.0 to 11.5.
9. Purification method according to any one of claims 7 to 8, characterized in that the gradient elution parameters are as follows:
10. Use of moxifloxacin impurity RC-4 according to any one of claims 1 to 9 as an impurity control in the preparation of moxifloxacin raw material or formulation.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396416A (en) * | 2013-07-17 | 2013-11-20 | 南京优科生物医药研究有限公司 | Preparation method of moxifloxacin impurity F |
| CN104945398A (en) * | 2014-03-26 | 2015-09-30 | 南京优科生物医药研究有限公司 | Method for preparing Moxifloxacin impurity E |
| CN104945399A (en) * | 2014-03-26 | 2015-09-30 | 南京优科生物医药研究有限公司 | Method for preparing Moxifloxacin impurity C |
| CN105566322A (en) * | 2015-11-18 | 2016-05-11 | 广东众生药业股份有限公司 | Preparation method of moxifloxacin impurity G compound |
| CN111514125A (en) * | 2020-05-26 | 2020-08-11 | 中山万汉制药有限公司 | Composition containing quinolone compound and edetic acid compound |
| CN112961153A (en) * | 2020-07-06 | 2021-06-15 | 北京新康哌森医药科技有限公司 | Preparation method of moxifloxacin impurity |
| CN113820409A (en) * | 2021-09-01 | 2021-12-21 | 河北国龙制药有限公司 | Method for detecting related substances in mother nucleus of moxifloxacin |
-
2022
- 2022-12-20 CN CN202211644335.8A patent/CN115785095B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396416A (en) * | 2013-07-17 | 2013-11-20 | 南京优科生物医药研究有限公司 | Preparation method of moxifloxacin impurity F |
| CN104945398A (en) * | 2014-03-26 | 2015-09-30 | 南京优科生物医药研究有限公司 | Method for preparing Moxifloxacin impurity E |
| CN104945399A (en) * | 2014-03-26 | 2015-09-30 | 南京优科生物医药研究有限公司 | Method for preparing Moxifloxacin impurity C |
| CN105566322A (en) * | 2015-11-18 | 2016-05-11 | 广东众生药业股份有限公司 | Preparation method of moxifloxacin impurity G compound |
| CN111514125A (en) * | 2020-05-26 | 2020-08-11 | 中山万汉制药有限公司 | Composition containing quinolone compound and edetic acid compound |
| CN112961153A (en) * | 2020-07-06 | 2021-06-15 | 北京新康哌森医药科技有限公司 | Preparation method of moxifloxacin impurity |
| CN113820409A (en) * | 2021-09-01 | 2021-12-21 | 河北国龙制药有限公司 | Method for detecting related substances in mother nucleus of moxifloxacin |
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