CN116120289A - Nilolatinib nitrosation and preparation and detection methods thereof - Google Patents
Nilolatinib nitrosation and preparation and detection methods thereof Download PDFInfo
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- CN116120289A CN116120289A CN202310113482.0A CN202310113482A CN116120289A CN 116120289 A CN116120289 A CN 116120289A CN 202310113482 A CN202310113482 A CN 202310113482A CN 116120289 A CN116120289 A CN 116120289A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- G—PHYSICS
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- 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
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- G—PHYSICS
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- 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
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- G01N30/50—Conditioning of the sorbent material or stationary liquid
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- 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
- G01N30/62—Detectors specially adapted therefor
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Abstract
The invention discloses nitrosation Nilotinib, which is discovered by the compound, can better study possible nitrosation impurities in an antitumor drug Nilotinib (Nilotinib), is favorable for improving the quality and safety of Nilotinib medicines, has obvious economic and technical benefits, and also discloses a preparation and detection method of nitrosation Nilotinib.
Description
Technical Field
The invention belongs to the field of organic synthesis route design, raw material medicine preparation and quality control research, and particularly relates to nitrosation nilotinib, and a preparation and detection method thereof.
Background
Nilotinib (Nilotinib) is a highly selective oral tyrosine kinase inhibitor developed by the company Novartis switzerland. The monohydrochloride monohydrate was approved by the U.S. Food and Drug Administration (FDA) for marketing at month 10 of 2007 under the trade name Tasigna (damcina). Nilotinib hydrochloride is a highly selective, anti-tumor drug of the type of tyrosine kinase inhibition, useful for the effective treatment of patients suffering from chronic myelogenous leukemia who develop drug resistance or intolerance. The medicine is clinically used for treating chronic granulocytic leukemia with ineffectiveness of imatinib mesylate, and has good tolerance, strong selectivity and obvious curative effect.
Nitrosamine impurities belong to the mutagenic and potentially carcinogenic risk impurities described in the ICH M7 guide, and since N-Nitrosodimethylamine (NDMA) was detected in valsartan drug substance in month 7 of 2018, various nitrosamine impurities were successively detected in other drug substances. In order to ensure the safety and quality control of the medicines and realize effective risk control, the national drug administration specially establishes the technical guidelines (trial runs) for researching nitrosamine impurities in chemical medicines in 2022, and aims to provide guidance for researching and controlling nitrosamine impurities in registered and marketed chemical medicines.
Nilotinib has the chemical name: 4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethylphenyl ] -3- [ [4- (pyridin-3-yl) pyrimidin-2-yl ] amino ] benzamide. Because of the inclusion of secondary amine functionality in its chemical structure, corresponding nitrosation impurities may be produced in the production or storage environment if reaction conditions or environments are encountered that induce nitrosation.
The order of nitrosation reaction can be divided into two types, namely, preparation of nitrosation structural fragments, related fragment linking, and direct nitrosation reaction of nilotinib. Nitrosation is a common organic unit reaction, which refers to the substitution of hydrogen in an organic compound molecule by nitroso (-NO). In general, nitrous acid is used as a nitrosation reagent, so that electrophilic substitution nitrosation reaction occurs, and since nitrous acid is unstable, in actual operation, nitrite is often used as a nitrosation reagent, and nitrous acid is formed immediately by adding acid to act on a reaction substrate, so that a nitrosation product is generated. In order to further study the possible nitrosamine impurities of nilotinib, improving the quality and safety of its products, on the one hand, researchers need to obtain the structure of the possible nitrosamine impurities by analysis of its formation mechanism; on the other hand, the compound is prepared and confirmed by an organic synthesis method, so that a standard substance or a reference substance of nitrosation nilotinib required for analysis and research is formed, a powerful technology and a material basis are provided for impurity research and quality improvement of the antitumor drug, and the research shows that the nitroso is unstable, and the target compound cannot be obtained if nitrosation fragments are adopted and then fragment linkage is carried out.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides nitrosation nilotinib, and a preparation and detection method thereof.
In order to achieve the above purpose, the main technical scheme provided by the invention is as follows:
nitrosation nilotinib having a chemical name of 4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethylphenyl ] -3- [ [4- (pyridin-3-yl) pyrimidin-2-yl ] [ N-nitrosation ] amino ] benzamide;
the structure is shown as formula I:
the invention also provides a preparation method of nitrosation nilotinib, which comprises the following steps: nilottinib and sodium nitrite are used as raw materials, and nitrosation reaction is carried out on the raw materials and the sodium nitrite in a solvent under the action of an acidic condition and an oxidant, so as to obtain the nitrosation nilotinib (I).
Further, the feeding mole ratio of the reactants of nilotinib, sodium nitrite, acid and oxidant is 1:3-7:30-70:3-7. Preferably 1:4 to 6:40 to 60:4 to 6, most preferably 1:5:50:5.
Further, the acid added in the nitrosation reaction is hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid, preferably acetic acid or hydrochloric acid, most preferably acetic acid.
Furthermore, the oxidant added in the nitrosation reaction is perchloric acid, hydrogen peroxide or peracetic acid, preferably perchloric acid.
Further, the solvent for the nitrosation reaction includes water, and one of water and ethanol, methanol, acetonitrile or tetrahydrofuran, preferably water.
Further, the nitrosation reaction is carried out at a temperature of 0 to 50 ℃, preferably 20 to 30 ℃.
The invention further provides a detection method of nitronilotinib, wherein the detection of nitronilotinib is high performance liquid chromatography detection, and the method comprises the following steps:
(1) Selecting and determining that the chromatographic column is BEH C18.7 mu m 2.1X50 mm, the column temperature is 20-50 ℃, the wavelength is 230-250 nm and the flow rate is 0.3-0.4 mL/min;
(2) Preparing formic acid solution with mobile phase A of 0.05-0.15%; mobile phase B is methanol; determining the gradient time program of the mobile phase to be 100% -0%/0-15 min;
(3) The chromatograms were measured and recorded.
Further, the column temperature of the chromatographic column is preferably 35 ℃, the wavelength is preferably 240nm, and the flow rate is preferably 0.35mL/min.
Further, the mobile phase a is preferably a 0.1% formic acid solution.
Further, the gradient time program of the mobile phase is preferably 85% -15%/0-7 min.
Compared with the prior art, the invention has the advantages that:
1. the invention selects a method for directly nitrosifying nilotinib to synthesize a target compound, discloses an anti-tumor drug nilotinib nitrosate and a preparation and detection method thereof, and has important practical significance for improving the quality and safety of the anti-tumor drug nilotinib and promotes the further development of the economy and technology of the drug.
2. The invention provides corresponding working reference substances for research through researching the structure, preparation and detection method of nitrosation nilotinib, improves the product quality and safety of the antitumor drug nilotinib, has very important practical significance especially for researching the existence mechanism, control strategy, limit detection and the like of nitrosamine impurities, and can better realize the economic and social benefits of the drug.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of nitrosation nilotinib according to the present invention;
FIG. 2 is a mass spectrum of nitrosation nilotinib according to the present invention;
FIG. 3 is a high performance liquid chromatogram of nitrosation of nilotinib according to the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent, so that those skilled in the art can fully understand the technical contents of the present invention. It is to be understood that the following examples are given by way of illustration of the present invention and are not to be construed as limiting the scope of the present invention, since various modifications and alterations of no particular nature will fall within the scope of the invention as defined by the appended claims. The specific manufacturing process parameters and the like described below are also only one example of suitable ranges, i.e., a person skilled in the art can select from the description herein without limiting to the specific values described below.
Nitrosation nilotinib, having the chemical name 4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethylphenyl ] -3- [ [4- (pyridin-3-yl) pyrimidin-2-yl ] [ N-nitrosation ] amino ] benzamide;
the structure is shown as formula I:
the invention also provides a preparation method of nitrosation nilotinib as a novel chemical substance, which comprises the following steps: nilottinib and sodium nitrite are used as raw materials, and nitrosation reaction is carried out on the raw materials and the sodium nitrite in a solvent under the action of an acidic condition and an oxidant, so as to obtain the nitrosation nilotinib (I).
Further, the molar ratio of the reactants nilotinib, sodium nitrite, acid and oxidant is 1:3-7:30-70:3-7. Preferably 1:4 to 6:40 to 60:4 to 6, most preferably 1:5:50:5.
Further, the acid added in the nitrosation reaction is hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid, preferably acetic acid or hydrochloric acid, most preferably acetic acid.
Furthermore, the oxidant added in the nitrosation reaction is perchloric acid, hydrogen peroxide or peracetic acid, preferably perchloric acid.
Further, the solvent for the nitrosation reaction includes water, and one of water and ethanol, methanol, acetonitrile or tetrahydrofuran, preferably water.
Further, the temperature of the nitrosation reaction is 0 to 50 ℃, preferably 20 to 30 ℃.
According to the invention, nitrosation nilotinib is prepared through nitrosation reaction, and the nitrosation reagent is selected and the reaction conditions are further optimized, so that the purity and the yield of the prepared nitronistinib reach 99% and 85% respectively.
The nilotinib substrate has a functional group of secondary aromatic amine, nitrosation nilotinib generated by reacting with nitrous acid belongs to N-nitroso secondary amine, the nitrosation is generally unstable, especially in a reducing environment, the produced nitroso is easy to remove, and the original secondary amine is obtained.
The invention further provides a detection method of nitrosation nilotinib, which is high performance liquid chromatography detection and comprises the following steps:
(1) Selecting and determining that the chromatographic column is BEH C18.7 mu m 2.1X50 mm, the column temperature is 20-50 ℃, the wavelength is 230-250 nm and the flow rate is 0.3-0.4 mL/min;
(2) Preparing formic acid solution with mobile phase A of 0.05-0.15%; mobile phase B is methanol; determining the gradient time program of the mobile phase to be 100% -0%/0-15 min;
(3) The chromatograms were measured and recorded.
Further, the column temperature of the chromatographic column was 35 ℃, the wavelength was 240nm, and the flow rate was 0.35mL/min.
Further, mobile phase a was a 0.1% formic acid solution.
Further, the gradient time program of the mobile phase is 85% -15%/0-7 min.
The invention discloses a nitrosate of an anti-tumor drug nilotinib, a preparation method and a detection method thereof, and a research result of the nitrosate has important practical significance for improving the quality and the safety of the anti-tumor drug nilotinib, thereby promoting the further development of the economy and the technology of the drug.
The following is a description of the concepts of the invention in conjunction with specific embodiments, but is not intended to limit the invention to the specific embodiments described below. Any particular value within the scope of the invention as described herein may be practiced.
Example 1
Nilotinib (5.29 g,10 mmol) and hydrochloric acid (4M, 125mL,0.5 mol) were added to the reaction flask at room temperature, sodium nitrite (3.45 g,50 mmol) was added in portions with stirring, the temperature was kept at 20-30 ℃, the reaction was stirred for 2-4 hours, and no major product was formed as detected by TLC.
Example two
Nilotinib (5.29 g,10 mmol) and acetic acid (4M, 125mL,0.5 mol) were added to the flask at room temperature, sodium nitrite (3.45 g,50 mmol) was added in portions with stirring, the temperature was kept at 20-30℃and the reaction was stirred for 2-4 hours, as detected by TLC, without the formation of the main product.
Example III
At room temperature, nilotinib (5.29 g,10 mmol) and hydrochloric acid (4M, 125mL,0.5 mol) are added into a reaction bottle, the temperature is reduced to below 10 ℃, hydrogen peroxide (30%, 5.7g,50 mmol) is added, the temperature is raised to 20-30 ℃, sodium nitrite (3.45 g,50 mmol) is added in batches under stirring, the reaction is carried out for 2-4 hours under stirring, TLC detection is carried out, a small amount of new products are generated, and 1.4g of nitrosation nilotinib (I) light yellow solid is obtained through post treatment and column chromatography (the volume ratio of methanol/dichloromethane is 1/3), and the yield is 25.1%.
Example IV
Nilotinib (5.29 g,10 mmol) and acetic acid (4M, 125mL,0.5 mol) are added into a reaction bottle at room temperature, the temperature is reduced to below 10 ℃, peroxyacetic acid (15%, 25.3g,50 mmol) is added, the temperature is raised to 20-30 ℃, sodium nitrite (3.45 g,50 mmol) is added in batches under stirring, the reaction is carried out for 2-4 hours under stirring, TLC detection is carried out, a small amount of new product is generated, and the pale yellow solid of 2.7g of nitrosation nilotinib (I) is obtained through post-treatment and column chromatography (the volume ratio of methanol/dichloromethane is 1/3), and the yield is 48.4%.
Example five
At room temperature, nilotinib (5.29 g,10 mmol) and hydrochloric acid (4M, 125mL,0.5 mol) are added into a reaction bottle, the temperature is reduced to below 10 ℃, perchloric acid (5.03 g,50 mmol) is added, the temperature is raised to 20-30 ℃, sodium nitrite (3.45 g,50 mmol) is added in batches under stirring, the reaction is carried out for 2-4 hours under stirring, TLC detection is carried out, a small amount of new products are generated, and 3.1g of nitrosation nilotinib (I) light yellow solid is obtained through post treatment and column chromatography (the volume ratio of methanol/dichloromethane is 1/3), and the yield is 55.5%.
Example six
Nilotinib (5.29 g,10 mmol) and acetic acid (4M, 125mL,0.5 mol) are added into a reaction bottle at room temperature, the temperature is reduced to below 10 ℃, perchloric acid (5.03 g,50 mmol) is added, the temperature is raised to 20-30 ℃, sodium nitrite (3.45 g,50 mmol) is added in batches under stirring, the reaction is carried out for 2-4 hours under stirring, TLC detection is carried out, new products are generated, and 4.7g of nitrosation nilotinib (I) light yellow solid is obtained through post treatment and column chromatography (the volume ratio of methanol to dichloromethane is 1/3), the yield is 84.2%, the HPLC purity is 99.6%, and the method is shown in the attached figure 3; 1 H-NMR (400 mhz, dmso-d 6) δ:10.65 (s, 1H), 9.31 (d, j=2.0 hz, 1H), 9.00 (d, j=5.2 hz, 1H), 8.77 (d, j=1.6 hz, 1H), 8.76 (d, j=1.6 hz, 1H), 8.51 (m, 2H), 8.26 (m, 1H), 8.15 (m, 2H), 7.80 (d, j=1.6 hz, 1H), 7.73 (s, 1H), 7.68 (m, 1H), 7.61 (m, 1H), 7.48 (s, 1H), 2.17 (s, 3H), 2.10 (s, 3H); LCMS-EI: m/z 559 (M+H), nuclear magnetic resonance hydrogen spectrogram and mass spectrogram are shown in figures 1 and 2 respectively.
Example seven
The nitrosation nilotinib (I) according to the present invention is detected by high performance liquid chromatography, comprising the steps of:
(1) The chromatographic column was selected and determined to be BEH C18.7 μm 2.1X150 mm, column temperature 35 ℃, wavelength 240nm and flow rate 0.35mL/min;
(2) Preparing a formic acid solution with a mobile phase A of 0.1%; mobile phase B is methanol; determining the gradient time program of the mobile phase to be 85% -15%/0-7 min; the detailed gradient is designed as follows:
| time (min) | Mobile phase A% | Mobile phase B% |
| 0 | 85 | 15 |
| 0.5 | 85 | 15 |
| 5.5 | 30 | 70 |
| 5.6 | 85 | 15 |
| 7 | 85 | 15 |
(3) The chromatogram was determined and recorded, see fig. 3.
The invention discloses a nitrosation product of an antitumor drug nilotinib, namely a production mechanism, a preparation and a detection method of the nitrosation nilotinib. The research result has practical significance for quality control, quality improvement and medicine safety of nilotinib, and promotes the further development of economy and technology of the medicine.
It should be noted that the foregoing description of the preferred embodiments is merely illustrative of the technical concept and features of the present invention, and is not intended to limit the scope of the invention, as long as the scope of the invention is defined by the claims and their equivalents. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (10)
1. Nitrosation nilotinib characterized by the chemical name 4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethylphenyl ] -3- [ [4- (pyridin-3-yl) pyrimidin-2-yl ] [ N-nitrosation ] amino ] benzamide;
the structure is shown as formula I:
2. the process for preparing nitrosylated nilotinib according to claim 1, characterized in that it comprises the following steps: nilottinib is taken as a raw material, and nitrosation reaction is carried out with sodium nitrite in a solvent under the action of an acidic condition and an oxidant, so as to obtain nitrosation nilotinib.
3. The preparation method of nitrosation nilotinib according to claim 2, characterized in that the molar ratio of nilotinib, sodium nitrite, acid and oxidant is 1:3-7:30-70:3-7.
4. A process for the preparation of nitrosylated nilotinib according to claim 3, characterized in that the acid is hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid.
5. A process for the preparation of nitrosation nilotinib according to claim 3, characterised in that the oxidising agent is perchloric acid, hydrogen peroxide or peracetic acid.
6. The process for the preparation of nitrosylated nilotinib according to claim 2, characterized in that the solvent is water and one of water and ethanol, methanol, acetonitrile or tetrahydrofuran.
7. The process for the preparation of nitrosation nilotinib according to claim 2, characterized in that the nitrosation reaction is carried out at a temperature of 0-50 ℃.
8. The method for detecting nitronilotinib according to claim 1, characterized in that the nitronilotinib detection is a high performance liquid chromatography detection, comprising the steps of:
(1) Selecting and determining that the chromatographic column is BEH C18.7 mu m 2.1X50 mm, the column temperature is 20-50 ℃, the wavelength is 230-250 nm and the flow rate is 0.3-0.4 mL/min;
(2) Preparing formic acid solution with mobile phase A of 0.05-0.15%; mobile phase B is methanol; determining the gradient time program of the mobile phase to be 100% -0%/0-15 min;
(3) The chromatograms were measured and recorded.
9. The method for detecting nitronilotinib according to claim 8, characterized in that the column temperature of the chromatographic column is preferably 35 ℃, the wavelength is preferably 240nm, and the flow rate is preferably 0.35mL/min.
10. The method for detecting nitronilotinib according to claim 8, characterized in that the mobile phase a is preferably a 0.1% formic acid solution, and the gradient time program of the mobile phase is preferably 85% -15%/0-7 min.
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