CN113620868A - Torasemide new impurity and preparation method thereof - Google Patents
Torasemide new impurity and preparation method thereof Download PDFInfo
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- CN113620868A CN113620868A CN202010384905.9A CN202010384905A CN113620868A CN 113620868 A CN113620868 A CN 113620868A CN 202010384905 A CN202010384905 A CN 202010384905A CN 113620868 A CN113620868 A CN 113620868A
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- torasemide
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- imp07
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- 239000012535 impurity Substances 0.000 title claims abstract description 40
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229960005461 torasemide Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 12
- DGIINIBYHCODIH-UHFFFAOYSA-N 4-chloropyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CN=CC=C1Cl DGIINIBYHCODIH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000013558 reference substance Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- KCNWYJPUGJYMNO-UHFFFAOYSA-N 4-chloropyridine-3-sulfonyl chloride Chemical compound ClC1=CC=NC=C1S(Cl)(=O)=O KCNWYJPUGJYMNO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000003908 quality control method Methods 0.000 claims description 2
- 238000007086 side reaction Methods 0.000 claims description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 239000003480 eluent Substances 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 238000003756 stirring Methods 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000006482 condensation reaction Methods 0.000 description 5
- -1 4-chloro-3-pyridinesulfonyl chloride hydrochloride Chemical compound 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- YITRQCQYMPXGMU-UHFFFAOYSA-N 1-butyl-3-[4-(3-methylanilino)pyridin-3-yl]sulfonylurea Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 YITRQCQYMPXGMU-UHFFFAOYSA-N 0.000 description 1
- ZPXQRKMODMEHCM-UHFFFAOYSA-N 1-ethyl-3-[4-(3-methylanilino)pyridin-3-yl]sulfonylurea Chemical compound CCNC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 ZPXQRKMODMEHCM-UHFFFAOYSA-N 0.000 description 1
- RTGDFNSFWBGLEC-TVPGTPATSA-N 2-morpholin-4-ylethyl (z)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(\C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-TVPGTPATSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- QMCVPDNHQUBJPG-UHFFFAOYSA-N 4-(3-methylphenyl)-1,1-dioxopyrido[4,3-e][1,2,4]thiadiazin-3-one Chemical compound CC1=CC=CC(N2C3=CC=NC=C3S(=O)(=O)NC2=O)=C1 QMCVPDNHQUBJPG-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
Images
Classifications
-
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Abstract
A novel impurity of torasemide and a preparation method thereof. The invention relates to a novel impurity of torasemide, namely TL-Imp 07: 4-m-toluylamino-N- [ (4-m-toluylamino-pyridin-3-yl) sulfonyl ] pyridine-3-sulfonamide; the preparation method of TL-Imp07 is obtained by condensing, ammoniating and purifying 4-chloro-3-pyridine sulfonamide. The group of impurities has novel structures, the invention is reported for the first time, and has great significance for controlling the quality of the torasemide bulk drug and the preparation, and meanwhile, the preparation method has the characteristics of simple method, convenient operation, high product purity and the like, and can be applied to the research of impurity reference substances of torasemide.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel impurity of torasemide and a preparation method thereof.
Background
Torasemide is a new generation of highly effective loop diuretics, marketed in germany in 1993 and in the next year in the united states. Clinical application for more than 20 years proves that the torasemide is wide in adaptation disease, rapid, strong and durable in diuretic effect, low in adverse reaction incidence rate, more meets the requirement of medicinal economics, and is a high-efficiency diuretic worthy of popularization clinically.
The formula of torasemide is as follows:
related impurities of torasemide reported in the literature and data at present are mainly as follows: the structural formula of the EP impurities A-E is as follows:
EP impurity a, chemical name: 4- (3-methylphenyl) -2H-pyrido [4,3-e ] -1,2, 4-thiadiazin-3 (4H) -one 1, 1-dioxide; structural formula (xvi):
EP impurity B, chemical name: 4- [ (3-methylphenyl) amino ] pyridine-3-sulfonamide; structural formula (xvi):
EP impurity C, chemical name: 1-ethyl-3- [ [4- [ (3-methylphenyl) amino ] pyridin-3-yl ] sulfonyl ] urea; structural formula (xvi):
EP impurity D, chemical name: 1-butyl-3- [ [4- [ (3-methylphenyl) amino ] pyridin-3-yl ] sulfonyl ] urea; structural formula (xvi):
EP impurity E, chemical name: [ [4- [ (3-methylphenyl) amino ] pyridin-3-yl ] sulfonyl ] carbonic acid ethyl ester; structural formula (xvi):
the synthesis of the torasemide bulk drug can generate various side reaction impurities in the multi-step chemical reaction process, part of the impurities are easy to generate and are not easy to completely remove in the existing production process, and the impurities are remained in the torasemide bulk drug and further introduced into the torasemide preparation to become unknown impurities. Unknown new impurities have great influence on the safety, effectiveness and the like of medicines, so that research on new impurities of torasemide is urgent. The research on the new impurities is beneficial to the quality research of the torasemide raw material medicine and the preparation, improves the quality standard of the torasemide raw material medicine and the preparation, and improves the medication safety of the torasemide preparation.
Disclosure of Invention
The invention provides a new impurity of torasemide, which comprises process impurities generated in the synthesis process of three raw material medicines. Respectively as follows:
TL-Imp07, chemical name: 4-m-toluylamino-N- [ (4-m-toluylamino-pyridin-3-yl) sulfonyl ] pyridine-3-sulfonamide. The structural formula is as follows:
the invention also provides a method for preparing the novel impurity of the torasemide as shown in the formula TL-Imp 07.
The preparation method of TL-Imp07 comprises the following steps: 4-chloro-3-pyridine sulfonamide and 4-chloro-3-pyridine sulfonyl chloride are subjected to condensation reaction and then are subjected to ammoniation reaction with m-toluidine to obtain a crude product, and the crude product is separated by column chromatography to obtain an impurity pure product. The reaction equation for the method of synthesis of TL-Imp07 is specified below:
the invention reports a new impurity of torasemide for the first time and provides a preparation method of the impurity. The group of impurities has important significance on the quality research of torasemide bulk drugs and preparations, and the inventor also requests to protect the application of the compound shown as the formula TL-Imp07 and the related substances thereof as impurity reference substances in the content analysis and quality control of the torasemide bulk drugs and preparations.
Drawings
FIG. 1 is a liquid chromatogram for detecting characteristic raw material drug in the new impurity research process.
Fig. 2 is a typical pure liquid chromatogram of the new impurity.
FIG. 3 is a nuclear magnetic hydrogen spectrum of the new impurity.
Fig. 4 is a typical mass spectrum of the new impurity.
Detailed Description
The invention is described in further detail below with reference to specific examples, which are provided only for the purpose of further illustrating the invention, but are not to be construed as limiting the invention in any way.
Example 1: preparation of TL-Imp07 intermediate
4-chloro-3-pyridine sulfonamide and 4-chloro-3-pyridine sulfonyl chloride are subjected to condensation reaction and then are subjected to ammoniation reaction with m-toluidine to obtain a crude product, and the crude product is separated by column chromatography to obtain an impurity pure product
Adding 4-chloro-3-pyridinesulfonamide (20 g), 4-chloro-3-pyridinesulfonyl chloride hydrochloride (28 g) and dichloromethane (200 ml) into a 500ml round-bottom flask, starting stirring, adding potassium carbonate (30 g), continuing stirring at room temperature for about 4-5 h, filtering, adding 100ml of water into filtrate, separating, extracting the organic phase with water for 2 times, drying with anhydrous sodium sulfate, and concentrating to dryness to obtain the TL-Imp07 intermediate.
Example 2: preparation of TL-Imp07
The TL-Imp07 intermediate obtained above, m-toluidine (30 g) and N, N-dimethylformamide (200 ml) were added to a 500ml round bottom flask with stirring, potassium carbonate (40 g) was added and the reaction continued for about 24h after heating to 80 ℃, cooled to room temperature and concentrated to dryness, the crude product was dissolved with methanol (30 ml) and silica gel (20 g) was added with stirring thoroughly and concentrated to dryness, the residue was taken up in dichloromethane: methanol =18:1 column chromatography gave TL-Imp07 (9.65 g, 97.1% HPLC purity).
Example 3: preparation of TL-Imp07 intermediate
4-chloro-3-pyridine sulfonamide and 4-chloro-3-pyridine sulfonyl chloride are subjected to condensation reaction and then are subjected to ammoniation reaction with m-toluidine to obtain a crude product, and the crude product is separated by column chromatography to obtain an impurity pure product
Adding 4-chloro-3-pyridinesulfonamide (20 g), 4-chloro-3-pyridinesulfonyl chloride hydrochloride (28 g) and dichloromethane (200 ml) into a 500ml round-bottom flask, starting stirring, adding triethylamine (20 ml), continuing stirring at room temperature for reaction for about 4-5 h, filtering, adding 100ml water into filtrate, separating, extracting an organic phase for 2 times by using water, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain a TL-Imp07 intermediate.
Example 4: preparation of TL-Imp07
The TL-Imp07 intermediate obtained above, m-toluidine (31 g) and N, N-dimethylformamide (200 ml) were added to a 500ml round bottom flask with stirring, triethylamine (20 ml) was added and the reaction was continued for about 24h after heating to 80 ℃, cooled to room temperature and concentrated to dryness, the crude product was dissolved with methanol (30 ml) and silica gel (20 g) was added with stirring thoroughly and concentrated to dryness, the residue was taken up in dichloromethane: methanol =18:1 column chromatography gave TL-Imp07 (8.09 g, 94.6% HPLC purity).
Example 5: preparation of TL-Imp07 intermediate
4-chloro-3-pyridine sulfonamide and 4-chloro-3-pyridine sulfonyl chloride are subjected to condensation reaction and then are subjected to ammoniation reaction with m-toluidine to obtain a crude product, and the crude product is separated by column chromatography to obtain an impurity pure product
Adding 4-chloro-3-pyridinesulfonamide (20 g), 4-chloro-3-pyridinesulfonyl chloride hydrochloride (28 g) and dichloromethane (200 ml) into a 500ml round-bottom flask, starting stirring, adding sodium hydroxide (20 g), continuing stirring at room temperature for reaction for about 4-5 h, filtering, adding 100ml water into filtrate, separating, extracting an organic phase for 2 times by using water, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain a TL-Imp07 intermediate.
Example 6: preparation of TL-Imp07
The TL-Imp07 intermediate obtained above, m-toluidine (30 g) and N, N-dimethylformamide (200 ml) were added to a 500ml round bottom flask with stirring, sodium hydroxide (21 g) was added and the reaction continued for about 24h after heating to 90 ℃, cooled to room temperature and concentrated to dryness, the crude product was dissolved with methanol (30 ml) and silica gel (20 g) was added with stirring thoroughly and concentrated to dryness, the residue was taken up in dichloromethane: methanol =18:1 column chromatography gave TL-Imp07 (3.11 g, HPLC purity 92.0%).
Example 7: preparation of TL-Imp07 intermediate
4-chloro-3-pyridine sulfonamide and 4-chloro-3-pyridine sulfonyl chloride are subjected to condensation reaction and then are subjected to ammoniation reaction with m-toluidine to obtain a crude product, and the crude product is separated by column chromatography to obtain an impurity pure product
Adding 4-chloro-3-pyridinesulfonamide (20 g), 4-chloro-3-pyridinesulfonyl chloride hydrochloride (28 g) and dichloromethane (200 ml) into a 500ml round-bottom flask, starting stirring, adding potassium hydroxide (30 g), continuing stirring at room temperature for about 4-5 h, filtering, adding 100ml of water into filtrate, separating, extracting an organic phase for 2 times by using water, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain a TL-Imp07 intermediate.
Example 8: preparation of TL-Imp07
The TL-Imp07 intermediate obtained above, m-toluidine (29 g) and N, N-dimethylformamide (200 ml) were added to a 500ml round bottom flask with stirring, potassium hydroxide (28 g) was added and the reaction continued for about 24h after heating to 85 ℃, cooled to room temperature and concentrated to dryness, the crude product was dissolved with methanol (30 ml) and silica gel (20 g) was added with stirring thoroughly and concentrated to dryness, the residue was taken up in dichloromethane: methanol =18:1 column chromatography gave TL-Imp07 (1.59 g, 94.1% HPLC purity).
Claims (7)
1. A new impurity of torasemide, number TL-Imp07, detailed structure is as follows.
TL-Imp07, chemical name: 4-m-toluylamino-N- [ (4-m-toluylamino-pyridin-3-yl) sulfonyl ] pyridine-3-sulfonamide.
3. The structural formula is as follows:
the novel impurity of torasemide according to claim 1 is generated by side reactions during the production of the drug substance.
4. The novel impurity of torasemide according to claim 1 can be used as an impurity reference substance in content analysis and quality control of torasemide bulk drugs and preparations.
5. The process for the preparation of the novel impurity of torasemide (TL-Imp 07) according to claim 2, comprising the following steps:
1) reacting the torasemide intermediate (4-chloro-3-pyridinesulfonamide) with 4-chloro-3-pyridinesulfonyl chloride under alkaline conditions;
2) concentrating the reaction solution to dryness to obtain a product, and reacting the product with m-toluidine;
and (3) carrying out column chromatography separation on the crude product obtained by treating the reaction solution to obtain an impurity pure product.
6. The column chromatography method of claim 4, wherein: the eluent is a mixed solvent of dichloromethane and methanol.
7. The method of claim 4 wherein the base is selected from the group consisting of: sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, lithium hydroxide, preferably potassium carbonate and triethylamine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989077A (en) * | 2022-06-22 | 2022-09-02 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and synthetic method thereof |
| CN115219631A (en) * | 2022-07-27 | 2022-10-21 | 康普药业股份有限公司 | Method for detecting Torasemide intermediate toluidine |
-
2020
- 2020-05-06 CN CN202010384905.9A patent/CN113620868A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 陈皓;: "HPLC法测定托拉塞米胶囊中的有关物质" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989077A (en) * | 2022-06-22 | 2022-09-02 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and synthetic method thereof |
| CN115219631A (en) * | 2022-07-27 | 2022-10-21 | 康普药业股份有限公司 | Method for detecting Torasemide intermediate toluidine |
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