CN114716391B - Methanazole impurity and preparation method and application thereof - Google Patents
Methanazole impurity and preparation method and application thereof Download PDFInfo
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- CN114716391B CN114716391B CN202210450074.XA CN202210450074A CN114716391B CN 114716391 B CN114716391 B CN 114716391B CN 202210450074 A CN202210450074 A CN 202210450074A CN 114716391 B CN114716391 B CN 114716391B
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- 239000012535 impurity Substances 0.000 title claims abstract description 90
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 claims abstract description 51
- 229960004083 methazolamide Drugs 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 21
- 238000000926 separation method Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 11
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 239000000523 sample Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000012488 sample solution Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000003908 quality control method Methods 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- 238000005576 amination reaction Methods 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- GDGIVSREGUOIJZ-UHFFFAOYSA-N 5-amino-3h-1,3,4-thiadiazole-2-thione Chemical compound NC1=NN=C(S)S1 GDGIVSREGUOIJZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims 1
- 238000004458 analytical method Methods 0.000 abstract description 5
- 239000013558 reference substance Substances 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000005728 strengthening Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 1
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- FLOSMHQXBMRNHR-UHFFFAOYSA-N N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2-ylidene)acetamide Chemical compound CC(=O)N=C1SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-UHFFFAOYSA-N 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 201000001326 acute closed-angle glaucoma Diseases 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
Abstract
The application provides an acemetazolamide unknown impurity, and a preparation method, an analysis method and application thereof, belonging to the field of organic synthetic medicinal chemistry. The application discloses two new impurity compounds in methazolamide for the first time, and preparation and analysis methods thereof, wherein an impurity sample prepared by the preparation method is high in purity, simple and efficient in operation, moderate in reaction condition, high in safety, easy to control, and suitable for preparing impurities as a reference substance so as to monitor product quality.
Description
Technical Field
The application relates to the field of organic synthetic pharmaceutical chemistry, in particular to an methazolamide impurity, a preparation method and application thereof.
Background
Methazolamide, a synonym for formamide, trade name abroad: naptazane, english name: methazolamide, U.S. pharmacopoeia, has already been documented. The product is an anti-glaucoma drug of carbonic anhydrase inhibitor, and is mainly used for treating chronic open angle glaucoma, acute angle closure glaucoma, secondary glaucoma, ocular operation ocular tension reduction and the like clinically.
For example, chinese patent application 200510050599.0 discloses a method for preparing methazolamide, which uses 5-amino-2-mercapto-1, 3, 4-thiadiazole as a raw material, and obtains a crude methazolamide product through condensation, acetylation, methylation, oxidation and amination reactions, and then obtains a refined methazolamide product through refining, wherein sodium hypochlorite raw material is added in the oxidation and amination reaction process, and the reaction is performed in the presence of ferric chloride as a catalyst, and the intermediate obtained through the reaction is subjected to amination reaction to obtain the crude methazolamide product; adding 5% NaOH solution into the crude methazolamide, adjusting pH=4-5 to obtain precipitate, washing and drying to obtain a finished product; wherein the reaction temperature is controlled to be 35-50 ℃ during the oxidation reaction. The reaction formula is as follows:
impurities are inevitably generated during synthesis, processing and storage of methazolamide and may be potentially toxic during use. Therefore, it is necessary to investigate impurities in the methazolamide product and limit its content in the final product. In each big pharmacopoeia, the content of a single impurity is required to be controlled below 0.10%, so that the content of part of impurities is tiny and difficult to separate and confirm, and the quality control of the impurities cannot be performed by obtaining a standard substance. The quality control level of the methazolamide needs to be improved further by perfecting the methazolamide impurity spectrum.
Disclosure of Invention
As described above, the structural identification of impurities is a basic requirement for drug registration, and the impurity content in the drug methazolamide is controlled in order to further improve the quality of methazolamide.
It is an object of the present application to provide an methazolamide impurity compound represented by the following formula (I),
the compound of the formula (I) can be used as a standard product in finished product detection analysis of methazolamide, and is beneficial to strengthening safety control of medicines.
The inventors have found that the compound of formula (I) is an unknown impurity which has not been found at present in the production of methazolamide, and is formed by the reaction of a sulfonyl chloride intermediate with the impurity benzylamine.
Accordingly, another object of the present application is to provide a process for preparing an impurity compound of formula (I), comprising the steps of:
(1) Mixing sulfonyl chloride intermediate, benzylamine, alkali and solvent, and reacting to obtain a reaction solution;
(2) Concentrating the reaction liquid obtained in the step (1) under reduced pressure until the reaction liquid is dry, and eluting the reaction liquid through a column to obtain the impurity compound in the formula (I).
According to one embodiment of the application, in step (1), the reaction conditions are: stirring at room temperature for 2-5 hr, heating to 40-70deg.C, and stirring for 0.5-3 hr. Preferably, the reaction conditions are: stirring at room temperature for 3.5 hours, then heating to 50 ℃ and stirring for 1.5 hours.
According to a specific embodiment of the present application, in step (1), the base includes, but is not limited to, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, etc., preferably sodium carbonate. The solvent may be a solvent conventional in the art, such as water, an alcohol-based solvent, an ester-based solvent, an ether-based solvent, etc., preferably a solvent having no hydroxyl group, such as tetrahydrofuran, methylene chloride, etc.
According to one embodiment of the application, in step (2), the column used is a C18 chromatographic column.
According to one embodiment of the application, in step (2), the eluent is a mixture of n-hexane and ethyl acetate, preferably a mixture of n-hexane and ethyl acetate in a volume ratio of 1:1.
The structural formula of the sulfonyl chloride intermediate is as follows:
the structural formula of the benzylamine is as follows:
it is still another object of the present application to provide an methazolamide impurity compound represented by the following formula (II),
the compound of the formula (II) can be used as a standard product in finished product detection analysis of methazolamide, and is beneficial to strengthening safety control of medicines.
The inventors have found that the compound of formula (II) is an unknown impurity which has not been found in the production of methazolamide, and is formed by the reaction of methazolamide with a sulfonyl chloride intermediate.
Accordingly, it is still another object of the present application to provide a process for preparing an impurity compound of formula (II), which comprises the steps of:
methanolamine is dissolved in a solvent and separated by DAC50 system to obtain impurity compound (II).
According to a specific embodiment of the present application, the solvent is selected from at least one of methanol, acetonitrile, water, preferably methanol, further preferably 80% methanol.
According to one embodiment of the application, the specific steps of the separation are: and (3) carrying out first separation, collecting a part containing the impurity compound (II), concentrating under reduced pressure to obtain a crude product, and then carrying out second separation, and collecting the impurity compound (II).
Further, according to a specific embodiment of the present application, the conditions of the first separation are:
chromatographic column: an inverted C18 column;
flow rate: 45.0-55.0mL/min;
ultraviolet wavelength: 285-295nm;
mobile phase: a mixed mobile phase of sodium sulfate and acetonitrile.
Preferably, it is:
chromatographic column: an inverted C18 column;
flow rate: 50.0mL/min;
ultraviolet wavelength: 290nm;
mobile phase: the volume ratio is 75:25 of 20mM sodium sulfate and acetonitrile.
Further, according to a specific embodiment of the present application, the conditions of the second separation are:
chromatographic column: an inverted C18 column;
flow rate: 45.0-55.0mL/min;
ultraviolet wavelength: 285-295nm;
mobile phase: formic acid-water and acetonitrile.
Preferably, it is:
chromatographic column: an inverted C18 column;
flow rate: 50.0mL/min;
ultraviolet wavelength: 290nm;
mobile phase: the volume ratio is 75: 25.1% formic acid-water and acetonitrile.
Another preparation method of the impurity compound shown in the structure of the formula (II) comprises the following steps: mixing methazolamide, triethylamine and a solvent, stirring, adding a sulfonyl chloride intermediate for reaction, adding water and dichloromethane for extraction, concentrating an organic layer, performing silica gel column chromatography on the obtained organic layer, eluting ethyl acetate and ethanol with a volume ratio of 5-15:1, and collecting an impurity compound (II).
Preferably, the eluting solvent is ethyl acetate and ethanol in a volume ratio of 10:1.
It is a further object of the present application to provide the use of the impurity compounds of formula (I) and the impurity compounds of formula (II) for quality control of methazolamide.
The final object of the application is to provide a method for detecting methazolamide impurity, which is characterized in that the impurity compound of formula (I) and/or the impurity compound of formula (II) are used as standard substances, and the method comprises the following steps:
sample solution preparation: the solution with the ratio of mobile phase A to mobile phase B of 18:82 is taken as a solvent to dissolve the sample, and the concentration is 0.1-10mg/ml, preferably 5mg/ml
Standard substance solution preparation: solvent sample solutions at a concentration of 0.1-10. Mu.g/ml, preferably 5. Mu.g/ml
Chromatographic column: phenyl column
Mobile phase A acetonitrile
Mobile phase B monopotassium phosphate (6.8 g/L)
Gradient elution:
| Time | B(％) |
| 0 | 80-85 |
| 10 | 80-85 |
| 30 | 38-42 |
| 35 | 38-42 |
| 35.1 | 80-85 |
| 45 | 80-85 |
wavelength: 290/250
Flow rate: 0.8-1.2mL/min
Sample injection amount: 5. Mu.L.
The application has the following beneficial effects:
1) The application discloses the structures of compounds of the formula (I) and the formula (II) of the unknown impurities of the methazolamide for the first time, and has important significance on the quality research of the methazolamide;
2) The application discloses a preparation method of compounds with unknown impurities of methazolamide in formulas (I) and (II), which has the advantages of high purity of an impurity sample prepared by the preparation method, simple and efficient operation, moderate reaction conditions, high safety and easy control, and is suitable for preparing impurities as a reference substance to monitor the quality of products.
Drawings
FIG. 1 is a mass spectrum of impurity (I);
FIG. 2 hydrogen profile of impurity (I);
FIG. 3 impurity (I) C 13 A spectrogram;
FIG. 4 IR spectrum of impurity (I);
FIG. 5 ultraviolet spectrum of impurity (I);
FIG. 6 is a diagram of the impurity (II) liquid phase;
FIG. 7 mass spectrum of impurity (II) (positive ions);
FIG. 8 impurity (II) mass spectrum (negative ions);
FIG. 9 IR spectrum of impurity (II);
FIG. 10 ultraviolet spectrum of impurity (II);
FIG. 11 impurity (II) hydrogen profile;
FIG. 12 impurity (II) C 13 A spectrogram;
FIG. 13 impurity (II) DEPT-135 carbon spectrum;
FIG. 14 is a two-dimensional hydrogen spectrum (H-H COSY) diagram of impurity (II);
FIG. 15 impurity (II) two-dimensional hydrocarbon correlation (HSQC) diagram;
fig. 16 two-dimensional hydrocarbon correlation (HMBC) map of impurity (II).
Detailed Description
The following typical reactions are used to illustrate the application. Simple substitutions and modifications of the application will occur to those skilled in the art, and are within the scope of the application as defined by the appended claims. The reagents used in the present application are all commercially available or can be prepared by the methods described herein.
EXAMPLE 1 preparation of impurity Compounds of formula (I)
(1) To the reaction flask, 2.05g of sulfonyl chloride intermediate, 0.87g of benzylamine, 0.86g of sodium carbonate and 20mL of tetrahydrofuran were added, and the mixture was stirred at room temperature for 3.5 hours, then heated to 50℃and stirred for 1.5 hours.
(2) Concentrating the dry reaction solution under reduced pressure, purifying with silica gel column, eluting with n-hexane and ethyl acetate (1:1), concentrating the dry eluent to obtain white solid impurity compound (I) 0.8g, purity 98%, yield 70%.
EXAMPLE 2 structural characterization of impurity Compound (I)
2.1 wave data:
UV-Visλ(CH 3 OH)nm:258,295(λ max )；IR(KBr)ν max cm -1 :3070(s,br),2865(m),2801(m,sh),1590(s),1490(s),1455(s,sh),1400(s),1359(s),1323(s)； 1 H NMR(500MHz；DMSO-d6；TMS)ppm:δ H 2.96(3H,s,H-7),3.84(3H,s,H-8),4.24(2H,d,H-10),7.218-7.302(5H,m,H-12/12’/13/13’/14),9.30(1H,t,9-NH)； 13 C NMR(125MHz；DMSO-d6；TMS)ppm:δ C 26.38(C-7),38.23(C-8),46.33(C-11),127.37(C-14),127.80and 128.19(C-12/12’/13/13’),155.33(C-5),164.28(C-2),179.74(C-6)；ms([M+H] + )m/z:327.0590(Calc.327.0580).
2.2 Mass Spectrometry, hydrogen Spectrometry, carbon Spectrometry, infrared characterization and ultraviolet characterization graphs are shown in FIGS. 1-5.
EXAMPLE 3 preparation of impurity Compounds of formula (II)
The methazolamide sample was dissolved in 80% methanol and separated by DAC50 preparation system to give impurity C. The method comprises the following steps:
(1) First separation: the separation preparation condition is a reversed phase C18 column (10 um), the flow rate is 50.0mL/min, the ultraviolet wavelength is 290nm, the mobile phase is a mixed mobile phase of 20mM sodium sulfate and acetonitrile, and the volume ratio is 75: sodium sulfate can improve the peak shape of chromatographic separations. The fractions containing impurity C were collected (rt=45 min) and then concentrated under reduced pressure to give crude impurity C.
(2) And (3) separating for the second time: again through the same C18 column, the flow rate is 50.0mL/min, the ultraviolet wavelength is 290nm, and the volume ratio is 75:25, 0.1% formic acid-water and acetonitrile, collecting impurity C component (rt=45 min), and freeze-drying to obtain pure sample (172 mg).
EXAMPLE 4 preparation of impurity Compounds of formula (II)
15g of methazolamide, 7.78g of triethylamine, 50ml of DMF and stirring at-20 ℃ are added, then 20.32g of sulfonyl chloride intermediate is added for reaction for 5h, then 500ml of water, 300ml of dichloromethane are added, extraction is carried out, and the organic layer is concentrated. The obtained organic layer was subjected to silica gel column chromatography, and the eluting solvent was ethyl acetate: ethanol=10:1, and the impurity compound (II) was collected in a purity of 98% and a yield of 60%.
EXAMPLE 5 structural characterization of impurity Compound (II)
2.1 wave data:
UV-Visλ(CH 3 OH)nm:202,255,292(λ max )；IR(KBr)ν max cm -1 :3455(m,br),2931(m),2853(m),1731(s),1495(s),1379(s),1308(s)； 1 H NMR(500MHz；DMSO-d6；TMS)ppm:δ H 2.25(6H,s,H-7/7’),3.86(6H,s,H-8/8’)； 13 C NMR(125MHz；DMSO-d6；TMS)ppm:δ C 26.38(C-7/7’),38.00(C-8/8’),158.88(C-5/5’),164.42(C-2/2’),179.52(C-6/6’)；ms([M+H] + )m/z:455.9884(Calc.455.9883)；ms([2M+H] + )m/z:910.9678(Calc.910.9693)；ms([M-H] - )m/z:453.9790(Calc.453.9737)；([M-CH 3 CO] - )m/z:411.9683(Calc.411.9632).
2.2 liquid phase spectrogram, mass spectrum, infrared characterization, ultraviolet characterization, hydrogen spectrum and carbon spectrum are shown in fig. 6-16.
Example 6
The impurities prepared in examples 1 and 4 are used as standard substances, and the impurity content in the methazolamide drug is detected.
The detection step comprises: methanozolomide analysis method
Sample solution preparation: the solution with the ratio of mobile phase A to mobile phase B of 18:82 is taken as a solvent to dissolve a sample, and the concentration is 0.5mg/ml
Standard substance solution preparation: solvent sample solution, concentration 5. Mu.g/ml
Chromatographic column: agilent phenyl column
Mobile phase A acetonitrile
Mobile phase B monopotassium phosphate (6.8 g/L)
Gradient elution:
| Time | B(％) |
| 0 | 82 |
| 10 | 82 |
| 30 | 40 |
| 35 | 40 |
| 35.1 | 82 |
| 45 | 82 |
wavelength: 290/250
Flow rate: 1mL/min
Sample injection amount: 5 mu L
Detection result: the content of the impurity I is about 0.03-0.05%, and the content of the impurity II is about 0.06-0.12%. The impurity preparation method provided by the application is simple, and can be used as a standard substance to realize effective detection of the corresponding impurity in the methazolamide medicine, so that the quality control of the methazolamide medicine is further enhanced.
Example 6 impurity toxicity test
The LD50 of the mice with the impurity I and the impurity II being orally taken is measured, and the LD50 of the mice with the impurity I of methazolamide is 624mg/kg; the oral LD50 of the methazolamide impurity II mice is 383mg/kg, which is obviously lower than that of the methazolamide.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (11)
1. An methazolamide impurity compound represented by the following formula (I),
2. the process for preparing an methazolamide impurity compound represented by the structure of formula (I) according to claim 1, which is characterized by comprising the steps of:
(1) Mixing sulfonyl chloride intermediate, benzylamine, alkali and solvent, and reacting to obtain a reaction solution;
(2) Concentrating the reaction liquid obtained in the step (1) under reduced pressure until the reaction liquid is dry, and eluting through a column to obtain an impurity compound shown in the formula (I);
wherein, the structural formula of the sulfonyl chloride intermediate in the step (1) is as follows:
3. the method of claim 2, wherein in step (1), the reaction conditions are: stirring at room temperature for 2-5 hours, heating to 40-70 ℃ and stirring for 0.5-3 hours; the alkali is sodium carbonate; the solvent is a solvent without hydroxyl.
4. The method according to claim 2, wherein in the step (2), the eluent is a mixture of n-hexane and ethyl acetate.
5. The method according to claim 4, wherein the eluent is a mixed solution of n-hexane and ethyl acetate in a volume ratio of 1:1.
6. An methazolamide impurity compound represented by the following formula (II),
7. a process for the preparation of an methazolamide impurity compound represented by the formula (II) according to claim 6, characterized by comprising the steps of:
taking 5-amino-2-mercapto-1, 3, 4-thiadiazole as a raw material, performing condensation, acetylation, methylation, oxidation and amination reaction to obtain methazolamide, dissolving the methazolamide in a solvent, and separating the methazolamide by a DAC50 system to obtain an impurity compound (II); the specific steps of the separation are as follows: carrying out first separation, collecting a part containing the impurity compound (II), concentrating under reduced pressure to obtain a crude product, and then carrying out second separation, and collecting the impurity compound (II); the solvent is at least one selected from methanol, acetonitrile and water;
wherein the first separation is a reverse C18 column separation and the second separation is a reverse C18 column separation.
8. The method according to claim 7, wherein the conditions for the first separation are:
flow rate: 45.0-55.0mL/min;
ultraviolet wavelength: 285-295nm;
mobile phase: a mixed mobile phase of sodium sulfate and acetonitrile,
the conditions for the second separation are:
flow rate: 45.0-55.0mL/min;
ultraviolet wavelength: 285-295nm;
mobile phase: formic acid-water and acetonitrile.
9. A process for the preparation of an methazolamide impurity compound represented by the formula (II) according to claim 6, characterized by comprising the steps of: mixing methazolamide, triethylamine and a solvent, stirring, adding a sulfonyl chloride intermediate for reaction, adding water and dichloromethane for extraction, concentrating an organic layer, performing silica gel column chromatography on the obtained organic layer, eluting ethyl acetate and ethanol with a volume ratio of 5-15:1, and collecting to obtain an impurity compound (II);
wherein, the structural formula of the sulfonyl chloride intermediate is as follows:
10. the application of any one of the methazolamide impurity compound shown in the formula (I) in claim 1 and the methazolamide impurity compound shown in the formula (II) in claim 6 in quality control of methazolamide.
11. The method for detecting the methazolamide impurity is characterized in that any one of the methazolamide impurity compound shown in the formula (I) in the claim 1 and the methazolamide impurity compound shown in the formula (II) in the claim 6 is used as a standard substance, and the method is characterized by comprising the following steps:
sample solution preparation: the solution with the ratio of mobile phase A to mobile phase B of 18:82 is taken as a solvent to dissolve the sample, the concentration is 0.1-10mg/ml,
standard substance solution preparation: solvent sample solution, concentration 0.1-10 mug/ml,
chromatographic column: phenyl column
Mobile phase A acetonitrile
Mobile phase B, monopotassium phosphate 6.8g/L
Gradient elution:
wavelength: 290/250
Flow rate: 0.8-1.2mL/min
Sample injection amount: 5. Mu.L.
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