Residual agent in rosaxostat medicine and detection method of residual agent
Rosalstat residue was prepared and high-performance liquid chromatography to detect rosalstat residues, which solved the problem of residual agent research and control in the rosalstat intermediate process, and achieved controllability of drug quality and reliability of detection .
Patent Information
- Application Number
- CN202411133784.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-19
- Publication Date
- 2025-01-07
AI Technical Summary
The prior art lacks research and control of residual agents in the process of rosalstat intermediates, affecting the quality and purity of drugs, especially 2,2'-dimethyl (thiobis(methylene)) bis(4- The preparation and detection methods of phenoxybenzoate) have not been reported, resulting in difficulty in detecting drug quality.
Rosalstat residue 2,2'-dimethyl (thiobis(methylene))bis(4-phenoxybenzoate) was prepared by two-step reaction and was carried out by high performance liquid chromatography The reaction step includes the synthesis of the intermediate product under argon conditions, followed by reaction with sodium sulfide and purification by silica gel chromatography, which uses an octadecylsilane-bonded silica gel chromatography column and acetonitrile-formic acid mobile phase.
It realizes efficient synthesis and quality control of rosalstat residues, ensures the purity and reliability of quality detection of drugs, and provides a simple and low-cost synthesis route and detection method.
Smart Images
Figure CN119264023A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a rosuvastatin drug analysis and detection method, belongs to the field of pharmaceutical chemical industry, and specifically relates to a rosuvastatin residual agent analysis and detection method. Background Art
[0002] Rosuvastatin, whose chemical name is [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, has the following chemical structure:
[0003] Roxadustat is the first new oral drug for renal anemia approved for marketing in China. It is used to treat renal anemia in dialysis patients. As the world's first hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), roxadustat effectively promotes erythropoiesis by promoting endogenous erythropoietin production, improving iron absorption, and reducing hepcidin. Roxadustat has been shown to induce erythropoiesis. In multiple subpopulations of patients with chronic kidney disease, roxadustat can maintain erythropoietin levels at or near the normal physiological range, thereby increasing the number of red blood cells, while not being affected by the inflammatory state and avoiding intravenous iron supplementation.
[0004] As a new drug launched in recent years, in the process development of the above-mentioned new preparation method of roxadustat, there is still a lack of research on residual agents in the intermediate process. It is well known that the research and control of residual agents in drugs is an important work content to improve drug purity and control drug quality, and the residual agents introduced by the production process are an important source of drug residual agents. It is even more challenging to study the types and sources of residual agents produced in novel synthetic routes that have not been reported in the literature, and thereby achieve effective control of drug quality and purity. Therefore, it is necessary to identify the residual agents produced in the process and develop an efficient residual agent synthesis route in order to obtain a sufficient amount of residual agent reference substances, so as to ensure the smooth implementation of the quality inspection of each batch of raw materials.
[0005] In view of the fact that the quality research and control of the residual agents in the preparation process of rosuvastat are crucial to controlling the quality of the final product rosuvastat, no reports have been found so far on the residual agent of rosuvastat - 2,2'-dimethyl (thiobis (methylene)) bis (4-phenoxybenzoate). Based on this, it is necessary to develop a preparation process method and supporting detection methods for the residual agent of rosuvastat - 2,2'-dimethyl (thiobis (methylene)) bis (4-phenoxybenzoate). Summary of the invention
[0006] The technical problem to be solved by the present invention is to provide a method for preparing rosuvastatin raw material medicine and residual agent 2,2'-dimethyl (thiobis (methylene)) bis (4-phenoxybenzoate) in preparation.
[0007] Roxadustat residual agent - 2,2'-dimethyl (thiobis (methylene)) bis (4-phenoxybenzoate), English name: dimethyl 2,2'-(thiobis (methylene)) bis (4-phenoxybenzoate), molecular formula: C 30 H 26 O6S molar molecular weight: 514.59, its structural formula is as follows:
[0008]
[0009] This method is achieved through the following technical solutions:
[0010] A residual agent in rosuvastatin, which is mainly prepared by the following two reactions:
[0011] Reaction step 1:
[0012]
[0013] In one embodiment, reactant A is first dissolved in ultra-dry xylene (16 mL), and a mixture of BTEAC (benzyltriethylammonium chloride), BF3-Et2O, and SOCl2 under Ar conditions at 0°C is added in sequence into a sealed tube at 0°C.
[0014] In one embodiment, stirring is carried out at 120° C. for 10 hours and cooling to room temperature.
[0015] In one embodiment, 8 ml of methanol is added and stirred for 30 minutes.
[0016] In one embodiment, saturated NaCl solution is added and the mixture is extracted with ethyl acetate (3 x 200 mL).
[0017] In one embodiment, the organic layer is washed with saturated NaCl solution and dried over Na2SO4.
[0018] In one embodiment, concentration in vacuo and purification by silica gel chromatography PE:EA=50:1 afforded 5.9 g of yellow solid B with a purity greater than 90%.
[0019] Reaction step 2:
[0020]
[0021] In one embodiment, the substance B obtained in step 1 is dissolved in ethanol and added to a reaction bottle, sodium sulfide is added at room temperature, and the mixture is stirred and reacted at 50° C. for 8 hours.
[0022] In one embodiment, the reaction system is directly concentrated in vacuo, and the product is purified by silica gel chromatography PE:EA=50:1 to obtain the product I as a yellow solid with a purity greater than 95%.
[0023] In another aspect, the technical problem to be solved by the present invention is to provide a method for analyzing and detecting the residual agent 2,2'-dimethyl (thiobis (methylene)) bis (4-phenoxybenzoate) in rosuvastatin raw materials and preparations, and the method is achieved by the following technical scheme:
[0024] A method for analyzing and detecting the residual agent 2,2'-dimethyl(thiobis(methylene))bis(4-phenoxybenzoate) in roxadustat raw materials and preparations, wherein the detection method adopts high performance liquid chromatography.
[0025] In one embodiment, the detection conditions of the high performance liquid chromatography are: mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid.
[0026] Time (minutes) Mobile phase A% Mobile phase B% 0 5 95 15 90 10 30 90 10
[0027] In one embodiment, the chromatographic column in the high performance liquid chromatography is: octadecylsilane bonded silica gel as a filler (C18, 4.6×250 mm, 5 μm).
[0028] In one embodiment, the detection wavelength is 254 nm.
[0029] In one embodiment, column temperature: room temperature.
[0030] In one embodiment, flow rate: 1.0 mL / min.
[0031] In one embodiment, the run time is 30 min.
[0032] Beneficial effects of this method:
[0033] 1. Provided is a residual agent synthesis process, which is simple to synthesize, low in cost, short in route, simple in operation steps, high in reaction yield, and high in product purity.
[0034] 2. The method of the present invention can effectively detect the content of the residual agent 2,2'-dimethyl (thiobis (methylene)) bis (4-phenoxybenzoate) in roxadustat, ensuring the quality of roxadustat and its preparations can be controlled. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] Figure 1 : High performance liquid chromatogram of the residual agent 2,2'-dimethyl(thiobis(methylene))bis(4-phenoxybenzoate);
[0037] Figure 2: Mass spectrum of the residual agent 2,2'-dimethyl(thiobis(methylene))bis(4-phenoxybenzoate);
[0038] Figure 3 : 1HNMR nuclear magnetic resonance spectrum of the residual agent 2,2'-dimethyl(thiobis(methylene))bis(4-phenoxybenzoate);
[0039] Figure 4 : 13CNMR nuclear magnetic resonance spectrum of the residual agent 2,2'-dimethyl(thiobis(methylene))bis(4-phenoxybenzoate); DETAILED DESCRIPTION
[0040] In order to make the purpose, technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0041] Example
[0042] The following examples are provided to illustrate the present invention. It should be understood by those skilled in the art that the examples are merely illustrative and not limiting. The present invention is limited only by the scope of the appended claims.
[0043] Embodiment 1:
[0044] Intermediate B The preparation reaction is as follows:
[0045]
[0046] 1. Bill of Materials
[0047]
[0048]
[0049] 2. Experimental operation steps:
[0050] The reaction was carried out under argon conditions by adding a mixture of the reactant (6.78 g, 30 mmol), BTEAC (benzyltriethylammonium chloride) (0.45 g, 0.2 mmol), BF3-Et2O (0.72 mL), SOCl2 (6 mL) and ultra-dry xylene (16 mL) into a sealed tube at 0°C.
[0051] Furthermore, the reaction conditions are: stirring at 120° C. for 10 hours, cooling to room temperature, and obtaining a mixed solution.
[0052] Furthermore, 8 ml of methanol was added to the mixed solution, and the mixture was stirred for 30 minutes.
[0053] Then saturated NaCl solution was added and the mixture was extracted with ethyl acetate (3 x 200 mL).
[0054] The organic layer was then washed with saturated NaCl solution and dried over Na2SO4.
[0055] Finally, the mixture was concentrated in vacuo and purified by silica gel chromatography with PE:EA=50:1 to obtain 5.9 g of yellow solid intermediate product B with a purity greater than 90%.
[0056] Example 2
[0057] The preparation of the final product I, the reaction formula is as follows:
[0058]
[0059] 1. Bill of Materials
[0060]
[0061]
[0062] 2. Experimental operation steps:
[0063] The intermediate product B (553 mg) was dissolved in 5 ml of ethanol and added to a reaction bottle. 156 mg of sodium sulfide was added at room temperature, and the mixture was reacted at 50° C. with a magnetic stirrer for 8 hours.
[0064] Furthermore, the reaction system was directly concentrated in vacuo, and the product was purified by silica gel chromatography (PE:EA=50:1) to obtain 322 mg of a yellow solid product with a purity greater than 95%.
[0065] Embodiment 3:
[0066] Based on the results of 1H NMR, 13CNMR and MS, the molecular structure of this product is determined as follows:
[0067]
[0068] 2.1 Nuclear magnetic resonance spectra (1HNMR, 13CNMR)
[0069] Determination solvent: d 6-DMSO Determination results: The 1HNMR and 13CNMR spectra of the sample are consistent with the molecular structure of the residual agent, see attached Figure 3 , Attachment Figure 4 .
[0070] 2.2 Mass spectrometry (MS)
[0071] Instrument model: Waters IA20199 Measurement method: ESI electrospray, positive ion mode Measurement results: See the attached figure for mass spectrum Spectrum analysis: The stronger ion peak at RT = 3.074min in the mass spectrum corresponds to the [M+Na]+ ion of the sample, and the molecular weight is determined to be 514.5, see the attached figure Figure 2 .
[0072] Conclusion: The molecular weight of the sample is consistent with that of the residual agent.
[0073] 2.3 Conclusion
[0074] Based on the results of nuclear magnetic resonance spectra (1HNMR, 13CNMR) and mass spectrometry (MS), it can be determined that the molecular structure of the sample is consistent with that of the residual agent.
[0075] Embodiment 4:
[0076] Purity determination
[0077] Instrument model: Shimadzu LC-20AT Determination method: Use high performance liquid chromatography to determine the purity of this product Chromatographic conditions: Mobile phase A: acetonitrile; Mobile phase B: 0.1% formic acid Time (minutes) Mobile phase A% Mobile phase B% 0 5 95 15 90 10 30 90 10 Chromatographic column: Octadecylsilane bonded silica as filler (C18, 4.6×250mm, 5μm) Detection wavelength: 254nm Column temperature: room temperature Flow rate: 1.0mL / min Run time: 30min Determination results: See the attached HPLC spectrum Figure 1 , calculated by area normalization method, the chromatographic purity of this product is 99.258%.
[0078] The above embodiments are only preferred technical solutions of the present invention and should not be regarded as limitations of the present invention. The embodiments and features in the embodiments of the present application can be arbitrarily combined with each other without conflict. The protection scope of the present invention shall be the technical solutions recorded in the claims, including the equivalent replacement solutions of the technical features in the technical solutions recorded in the claims. That is, equivalent replacement improvements within this scope are also within the protection scope of the present invention.
Claims
1. A residual agent in a rosuvastatin drug, the structural formula of which is shown in I: I, characterized in that Prepared by the following steps: Step 1: reactant A Dissolve in ultra-dry xylene, add benzyltriethylammonium chloride, boron trifluoride diethyl ether, SOCl2 in sequence, the reaction conditions are in argon, the initial temperature is 0°C, rise to 120°C and stir for 10 hours, then add methanol, stir for 30 minutes, and finally purify to obtain intermediate B Step 2: Dissolve the intermediate product B in ethanol, add sodium sulfide at room temperature to obtain the final product I.
2. The method for preparing the residual agent in a rosuvastatin drug according to claim 1, characterized in that: In step 1, the purification method is: add saturated NaCl solution, extract the mixture with ethyl acetate, then wash the organic layer with saturated NaCl solution, dry it with Na2SO4, concentrate it in vacuum, and purify it with silica gel chromatography PE:EA=50:1 to obtain intermediate product B.
3. The method for preparing the residual agent in a rosuvastatin drug according to claim 1, characterized in that: In step 2, the purified intermediate product B is dissolved in ethanol, sodium sulfide is added at room temperature, the temperature is raised to 50° C., and the mixture is stirred for reaction for 8 hours. The mixture is then dried to vacuum using a rotary evaporator and concentrated. The product is purified using silica gel chromatography with a PE:EA ratio of 50:1 to obtain the final product I.
4. A method for detecting residual agent in roxadustat drug according to claim 1, characterized in that: The detection method adopts high performance liquid chromatography.
5. The method for detecting residual agent in roxadustat drug according to claim 4, characterized in that: The detection conditions of the high performance liquid chromatography method are as follows: mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid.
6. The method for detecting residual agent in roxadustat drug according to claim 4, characterized in that: The chromatographic column in the high performance liquid chromatography was: octadecylsilane bonded silica gel as filler (C18, 4.6×250mm, 5μm).
7. The method for detecting residual agent in rosuvastatin according to claim 4, characterized in that: The detection wavelength is 254 nm.
8. The method for detecting residual rosuvastatin in the drug according to claim 4, characterized in that: Column temperature: room temperature, flow rate: 1.0 mL / min, running time: 30 min.