Key intermediate impurity of fenerenone and preparation method thereof
By preparing compound 1, a key intermediate impurity compound for fenelitone, the problem of excessive impurities during the synthesis process was solved, enabling reliable control of product quality and improving the safety and stability of fenelitone.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-18
- Publication Date
- 2026-03-27
AI Technical Summary
During the synthesis of fenelone, decarboxylation impurities and unknown oxidative impurities are generated, exceeding the limits specified by ICH, affecting product quality and safety. A reliable reference standard is needed for qualitative and quantitative studies to control the impurity content.
A key intermediate impurity compound 1 for fenelitone was prepared by decarboxylation reaction and oxidation with an oxidant under acidic conditions. Its detection method was established to control the quality of fenelitone intermediates and active pharmaceutical ingredients.
It provides a simple and mild preparation method, ensuring the quality stability and safety of fenelone products and reducing the risk of toxic side effects.
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Figure CN121735940A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medicine, in particular to a non-key intermediate impurity of finerenone and a preparation method thereof. BACKGROUND
[0002] Finerenone is a non-steroidal selective mineralocorticoid receptor antagonist, which can block the harmful effects of excessive activation of mineralocorticoid receptors in preclinical studies. Its innovative non-steroidal structure has high selectivity, inhibits fibrosis, and basically does not affect blood sugar and blood pressure, and is suitable for chronic kidney disease in adult patients with type 2 diabetes (estimated glomerular filtration rate [eGFR] ≥ 25 to < 75 mL / min / 1.73 m2 with albuminuria), which can reduce the risk of sustained decline in eGFR and end-stage renal disease, and directly bring clinical benefits to the patient's kidney and heart.
[0003] In July 2021, finerenone was approved by the FDA in the United States, and on June 29, 2022, Bayer Company was approved for listing in China. Its structural formula is shown as compound 4:
[0004]
[0005] In the process of synthesizing finerenone, a key intermediate compound 2 is needed, and its structural formula is shown as follows:
[0006]
[0007] Researchers found that during the scale-up production of the synthesis of the key intermediate compound 2, a decarboxylation impurity was produced, and an unknown oxidation impurity was inevitably produced, as shown in Figure 1, the content of the unknown impurity peak (peak 8) is 0.75%, which is higher than the limit value of 0.5% of the general impurity content. According to the requirements of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), in order to ensure the safety of drug use, it is necessary to conduct safety evaluation on each impurity in the active pharmaceutical ingredient (API). The structure of the new impurity is confirmed, which provides a basis for toxicology research, and establishes the impurity content limit to ensure its safety, which can provide a reference for the control of API synthesis conditions, and also meet the requirements of drug preparation and quality. Therefore, it is necessary to study the new impurity found in the synthesis process of the intermediate of finerenone. SUMMARY
[0008] The purpose of the present application is to provide a key intermediate impurity of finerenone, a new substance compound 1, which provides a reliable reference for the qualitative and quantitative research of impurities in the development and production of finerenone, and ensures the development of quality research work, so as to further reduce the toxic side effects of the product and improve the product quality and stability.
[0009] Another object of the present application is to provide a method for preparing a non-neliriglitide key intermediate impurity under mild conditions with simple operation.
[0010] In order to achieve the above-mentioned objects, the present application adopts the following technical solutions:
[0011] The non-neliriglitide intermediate impurity compound 1 has the following structure:
[0012]
[0013] The inventors found the non-neliriglitide intermediate unknown impurity compound 1 during research, increased the content of the impurity by destroying intermediate compound 2, separated and purified it, obtained its molecular weight by LC-Ms, and then identified its chemical structure, thereby confirming the chemical structure of the impurity compound 1. Further research found that the impurity is DNA-reactive (mutagenic) and has certain genetic toxicity side effects, which affects the final quality of the product. The present application has important significance for effectively controlling the quality of non-neliriglitide intermediates, bulk drugs and their preparations by synthesizing the target impurity compound 1 and establishing a detection method for the target impurity compound 1.
[0014] The method for preparing the non-neliriglitide intermediate impurity has the following specific synthesis steps:
[0015] (1) Compound 2 is decarboxylated under acidic conditions in an organic solvent aqueous solution, and then oxidized by an oxidizing agent to obtain compound 3:
[0016]
[0017] (2) Compound 3 is heated in an organic solvent and oxidized by an oxidizing agent to obtain compound 1:
[0018]
[0019] In step (1) of the method for preparing the non-neliriglitide intermediate impurity, the organic solvent aqueous solution is one or a mixture of more than one of tetrahydrofuran aqueous solution, methanol aqueous solution, ethanol aqueous solution, 1,4-dioxane aqueous solution and acetonitrile aqueous solution, and the volume ratio of the amount of the organic solvent aqueous solution to compound 2 is 2-8, preferably the volume ratio of tetrahydrofuran aqueous solution to compound 2 is 5.0.
[0020] In step (1) of the method, the acidic conditions are one or a mixture of more than one of hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid, and the volume ratio of the amount of the acid to compound 2 is 0.1-1.0, preferably the volume ratio of hydrochloric acid to compound 2 is 0.2.
[0021] In step (1) of the method, the oxidant is one or a mixture of more than one of manganese dioxide, potassium permanganate, chromium trioxide, and hydrogen peroxide. The molar ratio of the amount of oxidant to compound 2 is 1.0-3.0, preferably manganese dioxide, and the molar ratio of the amount of manganese dioxide to compound 2 is 2.0.
[0022] The organic solvent in step (2) of the method is one or more of tetrahydrofuran, methanol, ethanol, acetonitrile, and 1,4-dioxane. The volume ratio of the organic solvent to compound 3 is 5-15, preferably tetrahydrofuran, and the volume ratio of the organic solvent to compound 3 is 5.0.
[0023] The heating conditions in step (2) of the method are 50-70°C, preferably 65°C.
[0024] The oxidant in step (2) of the method is one or more of hydrogen peroxide, manganese dioxide, potassium permanganate, and chromium trioxide, with hydrogen peroxide being preferred.
[0025] Benefits:
[0026] This invention discloses for the first time a novel compound 1 and provides a method for its preparation. This method is simple to operate and operates under mild conditions, providing a reliable reference standard for the qualitative and quantitative analysis of impurities in the research and production of fenelazol, ensuring the smooth progress of quality research, and thereby further reducing the toxicity and side effects of the product and improving its quality and stability. In the preparation of fenelazol intermediates, this invention is used as an impurity reference standard to monitor the content of impurity compound 1, thus ensuring the quality and safety of the fenelazol active pharmaceutical ingredient. Attached Figure Description
[0027] Figure 1 a To discover the HPLC chromatogram of impurity compound 1;
[0028] Figure 1 b To discover the HPLC chromatographic data of impurity compound 1;
[0029] Figure 2 The mass spectrum of impurity compound 1;
[0030] Figure 3 The 1H NMR spectrum of impurity compound 1;
[0031] Figure 4 The HPLC chromatogram of impurity compound 1 prepared in Example 3 is shown. Detailed Implementation
[0032] The present invention will be further illustrated by the following examples to enable those skilled in the art to have a more comprehensive understanding of the invention, but it is not intended to limit the scope of the invention.
[0033] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood in the technical field of this invention. The terminology used herein in the description of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention.
[0034] Example 1
[0035] Preparation and separation of impurity compound 1:
[0036] Compound 2 was added to 1N hydrochloric acid and stirred for 4 hours. A sample was taken for HPLC analysis, and the total impurity content was reduced to 1.46%. TLC was performed, and the results showed that colorimetric separation was possible. Preparative chromatography was used for separation, yielding three peaks, in elution order: peak 1, peak 2, and peak 3. Peak 1 had a retention time of 22 s, peak 2 had a retention time of 11 min 28 s, and peak 3 had a retention time of 3 min 31 s. Reverse localization confirmed that peak 1 corresponded to the elution position of the unknown oxidized impurity. The results of LC-MS and 1H NMR spectroscopy are as follows: Figure 2 and Figure 3 As shown, peak 1 has a molecular weight of 349. 1H-NMR (400MHz, DMSO-d6): δ=0.69-0.72(t, 3H), 2.51(s, 3H), 2.65(s, 3H), 3.69(s, 3H), 3.86-4.02(m, 2H), 7.24-7.26(d, 1H), 7.46-7.48(d, 1H), 7.53-7.54(s, 1H), 7.82(s, 1H), 9.01(s, 1H), identifying impurity compound 1 of the present invention.
[0037] Example 2
[0038] Analysis revealed that impurity compound 1 contains a NO structure, which meets the genotoxicity warning structure of aromatic ring N-oxides in the paper "Development of structural alerts for the in vivo micronucleus assay in rodents". Therefore, in accordance with the ICH guidance document "M7 Industry Guidance on the Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risks", Lhasa computer software was used to assess and investigate the DNA reactivity (mutagenicity) of compound 1.
[0039] Lhasa computer software prediction results showed that the structure of compound 1 was positive in Derek Nexus, indicating that the impurity was DNA reactive (mutagenic).
[0040] Example 3
[0041] (1) Preparation of compound 3
[0042] Compound 2 (10.0 g, 0.026 mol) was added to a mixed solvent of tetrahydrofuran and 50 ml of water (V tetrahydrofuran:V water = 1:1), and 2.0 ml of hydrochloric acid was added. The mixture was heated to 65 °C and reacted for 10 h. Then, manganese dioxide (4.52 g, 0.052 mol) was added, and the reaction was continued at 65 °C for another 10 h. The mixture was filtered while hot, and the tetrahydrofuran was concentrated. The mixture was extracted with 100 ml of dichloromethane, dried over sodium sulfate, and the dichloromethane was evaporated under reduced pressure to obtain 5.2 g of crude oily compound 3, which was directly fed into the next reaction step.
[0043] (2) Preparation of compound 1
[0044] 5.2 g of compound 3 was added to 50 ml of tetrahydrofuran, and 20.8 ml of hydrogen peroxide (H2O2) was slowly added dropwise. After the addition was complete, the temperature was raised to 65 °C, and the reaction was allowed to proceed for 12 h. The tetrahydrofuran was concentrated under reduced pressure, and the mixture was extracted twice with 50 ml of dichloromethane. The dichloromethane was combined, washed twice with 50 ml of water, dried over anhydrous sodium sulfate, and the dichloromethane was evaporated under reduced pressure to obtain 2.5 g of an oily liquid. The oily liquid was subjected to preparative separation chromatography to obtain 1.1 g of compound 1, a white solid with a purity of 95.45%. See [link to relevant documentation]. Figure 3 .
[0045] Example 4
[0046] (1) Preparation of compound 3
[0047] Compound 2 (20.0 g, 0.052 mol) was added to a mixed solvent of tetrahydrofuran and water (V tetrahydrofuran:V water = 1:1), 4.0 ml hydrochloric acid was added, and the mixture was heated to 65 °C and reacted for 10 h. Then, manganese dioxide (9.04 g, 0.104 mol) was added, and the reaction was continued at 65 °C for another 10 h. The mixture was filtered while hot, and the tetrahydrofuran was concentrated. The mixture was extracted with 200 ml dichloromethane, dried over sodium sulfate, and the dichloromethane was evaporated under reduced pressure to obtain 10.8 g of crude oily compound 3, which was directly fed into the next reaction step.
[0048] (2) Preparation of compound 1
[0049] 10.8 g of compound 3 was added to 100 ml of tetrahydrofuran, and 43.2 ml of hydrogen peroxide (H2O2) was slowly added dropwise. After the addition was complete, the temperature was raised to 65 °C and the reaction was allowed to proceed for 12 h. The tetrahydrofuran was concentrated under reduced pressure, and the mixture was extracted twice with 100 ml of dichloromethane. The dichloromethane was combined and washed twice with 100 ml of water. The mixture was dried over anhydrous sodium sulfate, and the dichloromethane was evaporated under reduced pressure to obtain 4.8 g of an oily liquid. The oily liquid was separated by preparative separation chromatography to obtain 2.5 g of compound 1, a white solid with a purity of 96.8%.
[0050] Example 5
[0051] (1) Preparation of compound 3
[0052] Compound 2 (5.0 g, 0.013 mol) was added to a mixed solvent of tetrahydrofuran and 25 ml of water (V tetrahydrofuran:V water = 1:1), and 1.0 ml of hydrochloric acid was added. The mixture was heated to 65 °C and reacted for 10 h. Then, manganese dioxide (2.26 g, 0.026 mol) was added, and the reaction was continued at 65 °C for another 10 h. The mixture was filtered while hot, and the tetrahydrofuran was concentrated. The mixture was extracted with 50 ml of dichloromethane, dried over sodium sulfate, and the dichloromethane was evaporated under reduced pressure to obtain 2.9 g of crude oily compound 3, which was directly fed into the next reaction step.
[0053] (2) Preparation of compound 1
[0054] 2.9 g of compound 3 was added to 30 ml of tetrahydrofuran, and 11.6 ml of hydrogen peroxide (H2O2) was slowly added dropwise. After the addition was complete, the temperature was raised to 65 °C and the reaction was allowed to proceed for 12 h. The tetrahydrofuran was concentrated under reduced pressure, and the mixture was extracted twice with 25 ml of dichloromethane. The dichloromethane was combined and washed twice with 25 ml of water. The mixture was dried over anhydrous sodium sulfate, and the dichloromethane was evaporated under reduced pressure to obtain 1.2 g of an oily liquid. The oily liquid was separated by preparative separation chromatography to obtain 0.4 g of compound 1, a white solid with a purity of 95.9%.
Claims
1. A non-nelinone key intermediate impurity, the structural formula of which is shown in Formula 1:
2. A method for preparing the phenelzine intermediate impurity as described in claim 1, characterized in that... The following synthesis steps: (1) Compound 2 is decarboxylated in an aqueous solution of an organic solvent under acidic conditions, and then oxidized by an oxidizing agent to obtain compound 3: (2) Compound 3 was heated in an organic solvent and oxidized by an oxidizing agent to obtain compound 1:
3. The method for preparing a non-nelitone intermediate impurity according to claim 2, characterized in that: In step (1), the organic solvent aqueous solution is one or a mixture of more than one of tetrahydrofuran aqueous solution, methanol aqueous solution, ethanol aqueous solution, 1,4-dioxane aqueous solution, and acetonitrile aqueous solution, and the volume ratio of the organic solvent aqueous solution to compound 2 is 2-8.
4. The method for preparing a non-nelitone intermediate impurity according to claim 2, characterized in that: In step (1), the acidic conditions are one or more of hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid, and the volume ratio of the acid to compound 2 is 0.1-1.
0.
5. The method for preparing a non-nelitone intermediate impurity according to claim 2, characterized in that: In step (1), the oxidant is one or more of manganese dioxide, potassium permanganate, chromium trioxide, and hydrogen peroxide, and the molar ratio of the amount of oxidant to compound 2 is 1.0-3.
0.
6. The method for preparing a non-nelitone intermediate impurity according to claim 2, characterized in that: The organic solvent in step (2) is one or more of tetrahydrofuran, methanol, ethanol, acetonitrile, and 1,4-dioxane, and the volume ratio of the organic solvent to compound 3 is 5-15.
7. The method for preparing a non-nelitone intermediate impurity according to claim 2, characterized in that: The heating conditions in step (2) are 50-70℃.
8. The method for preparing a non-nelitone intermediate impurity according to claim 2, characterized in that: The oxidant in step (2) is one or more of hydrogen peroxide, manganese dioxide, potassium permanganate, and chromium trioxide.