Preparation method of high-optical-purity Pinefibrate

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and discloses a preparation method of high-optical-purity Pinefibrate. According to the method, a mixed alkali system consisting of organic alkali (such as pyridine) and inorganic alkali (such as sodium hydroxide) in a specific ratio of (0.7: 1)-(1.25: 1) is adopted, and a hydrolysis reaction is carried out at a low temperature (0-30 DEG C). According to the method, racemization of a chiral center is remarkably inhibited through the synergistic effect of the mixed base and low-temperature control, the proportion of harmful (S)-isomer impurities is reduced to 0.3% or below, meanwhile, the reaction time is shortened, and unification of high optical purity and high reaction efficiency is achieved. The method is simple in process operation, low in cost and suitable for industrial production of high-purity Pinefibrate bulk drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology and relates to a method for preparing pemafibrate with high optical purity. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Pemafibrate, chemically named (R)-2-{3-[N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenoxy}butyric acid, is an important lipid-lowering drug. Its molecule contains a chiral center, and its pharmacological activity primarily derives from the (R)-configuration. The final synthetic step typically involves the hydrolysis of the corresponding ester precursor (as shown in the formula below, CAS: 907192-61-4) under alkaline conditions to obtain the target product.

[0004]

[0005] In conventional industrial production routes (refer to patent EP1852426), this hydrolysis step is typically carried out using an inorganic base (such as sodium hydroxide or lithium hydroxide) in an alcohol / water mixed solvent. However, the applicant has discovered that even when using optically pure ester precursors, approximately 0.5%–2.0% of (S)-configuration isomer impurities are still detected in the final product. This impurity may originate from partial racemization of the chiral center under hydrolysis conditions.

[0006] The presence of chiral impurities can affect drug safety and efficacy, and also poses challenges to meeting increasingly stringent pharmaceutical quality standards (such as ICH guidelines). Therefore, developing a simple and effective method to inhibit racemization of chiral centers during hydrolysis and improve the optical purity and reaction efficiency of the product has significant industrial application value. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a hydrolysis method that is simple to operate and can significantly improve the optical purity of the final pemabet product. In the final ester hydrolysis step, this invention employs a mixed alkali system composed of organic and inorganic bases in a specific ratio to suppress racemization of the chiral center, increase the reaction rate, and improve the optical purity of the final product.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides a method for preparing high-optical-purity pemabet, comprising: Pemafibrate n-butyl ester and mixed bases are mixed evenly in a solvent and then hydrolyzed to obtain pemafibrate. The mixed alkali includes: organic alkali and inorganic alkali; The organic base is selected from at least one of pyridine, 2,6-dimethylpyridine, and triethylamine.

[0009] In a second aspect, the present invention provides pemabet prepared by the method described above.

[0010] A third aspect of the present invention provides the application of a mixed alkali system in improving the optical purity of Pemabet, wherein the mixed alkali comprises: an organic alkali and an inorganic alkali; The organic base is selected from at least one of pyridine, 2,6-dimethylpyridine, and triethylamine.

[0011] Beneficial effects of the present invention (1) Synergistic effect to significantly improve optical purity: By combining organic and inorganic bases in a specific ratio, the organic base effectively buffers local pH spikes and inhibits the racemization pathway of the chiral center; while the inorganic base ensures sufficient initial reaction driving force. The two work synergistically to significantly reduce the proportion of (S)-isomer impurities from about 1.0% in conventional methods to below 0.3%.

[0012] (2) Improved reaction efficiency: The mixed alkali system can still maintain a high reaction rate at low temperature, and the reaction time is shortened by about 30%-50% compared with the single alkali system under the same low temperature conditions, resulting in high production efficiency.

[0013] (3) Strong process robustness: The combination of specific alkali ratio and low temperature conditions reduces the sensitivity of the process to operational fluctuations (such as feeding speed) and improves the reproducibility of scale-up and batch consistency. Attached Figure Description

[0014] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. Exemplary embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0015] Figure 1 Pemmabite mass spectrometry prepared in Example 1; Figure 2 : The 1H Pemmabett spectrum prepared in Example 1; Figure 3 Carbon spectra of Pemafid prepared in Example 1; Figure 4 : Liquid phase spectrum corresponding to Example 1; Figure 5 Example 2 corresponds to the liquid phase spectrum; Figure 6 Example 3 corresponds to the liquid phase spectrum; Figure 7 Comparative Example 1 corresponds to the liquid phase spectrum; Figure 8 Comparative Example 2: Liquid phase spectrum; Figure 9 Comparative Example 3 corresponds to the liquid phase spectrum; Figure 10 Comparative Example 4: Liquid phase spectrum. Detailed Implementation

[0016] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods in the art or product instructions. Similarly, unless otherwise specified, the test methods of this invention are performed in accordance with conventional methods in the art or industry-standard methods or practices. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0018] This invention provides a method for preparing high-optical-purity pemabet, comprising: Pemafibrate n-butyl ester and mixed bases are mixed evenly in a solvent and then hydrolyzed to obtain pemafibrate. The mixed alkali includes: organic alkali and inorganic alkali; The organic base is selected from at least one of pyridine, 2,6-dimethylpyridine, and triethylamine.

[0019] The ratio of organic base to inorganic base affects the purity and synthesis efficiency of pemabet. Therefore, this invention studies the molar ratio of organic base to inorganic base. Preferably, the molar ratio of organic base to inorganic base is 1:2-2:1, more preferably, it is 0.7:1-1.25:1, and even more preferably, it is 1:1, in order to obtain higher purity and improve synthesis efficiency.

[0020] To achieve better hydrolysis results, the present invention screens the types of inorganic bases. Preferably, the inorganic base is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide to obtain better hydrolysis results.

[0021] The amount of mixed alkali used affects the purity and synthesis efficiency of pemafibrate. Therefore, this invention studies the molar ratio of pemafibrate n-butyl ester to mixed alkali. Preferably, the molar ratio of pemafibrate n-butyl ester to mixed alkali is 1:4-5 to better improve the purity and synthesis efficiency of pemafibrate.

[0022] The hydrolysis reaction of the present invention can be carried out at low temperature and room temperature. Preferably, the temperature of the hydrolysis reaction is 0°C-30°C, more preferably 15°C-25°C.

[0023] Solvents can also affect the reaction rate and purity. Therefore, this invention has studied the types of solvents. Preferably, the solvent is tetrahydrofuran to obtain a better reaction rate and product purity.

[0024] The order of mixing affects the efficiency of the reaction and the purity of the product. Therefore, this invention has studied the order of mixing. Preferably, the mixing specifically includes: first mixing pemafibrate n-butyl ester and organic base in a solvent, and then adding an inorganic base solution to improve the reaction efficiency and facilitate industrial production.

[0025] The present invention does not impose any particular limitation on the separation method of the crude product. Preferably, after the reaction is completed, the reaction solution is neutralized to pH 5-6, and most of the organic solvent is removed by vacuum concentration; water is added to the remaining aqueous phase, and the pH is adjusted to 2-3 with concentrated hydrochloric acid; the mixture is extracted with methyl tert-butyl ether; the organic phases are combined, washed with saturated brine, and dried with anhydrous sodium sulfate; the mixture is filtered and concentrated to dryness under vacuum to obtain a white solid crude product, thereby improving the yield of the crude product.

[0026] The present invention does not impose any special limitations on the purification method of the crude product. Preferably, the crude product is recrystallized with ethyl acetate / cyclohexane to obtain a white powder of pemafibrate, thereby obtaining higher purity.

[0027] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the specific embodiments are explanations of the present invention and not limitations thereof.

[0028] Example 1: The Method of the Invention Add pemafibrate n-butyl ester (CAS: 907192-61-4, 10.0 g, 16.3 mmol), tetrahydrofuran (80 mL), and pyridine (2.6 g, 32.6 mmol) to a 250 mL reaction flask and stir to dissolve. Maintain the reaction solution at 20 ± 2 °C. While stirring, slowly add a 20 mL solution of sodium hydroxide (1.3 g, 32.6 mmol) in water (at this point, the molar ratio of the organic base pyridine to the inorganic base NaOH is 1:1). After the addition is complete, stir the reaction at 20 °C. The reaction was completed in approximately 1.5 hours as monitored by HPLC.

[0029] After the reaction was complete, the reaction solution was neutralized to pH 5-6 and concentrated under reduced pressure to remove most of the tetrahydrofuran. Water (100 mL) was added to the remaining aqueous phase, and the pH was adjusted to 2-3 with concentrated hydrochloric acid. Extraction was performed with methyl tert-butyl ether (100 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness under reduced pressure to give a white crude solid. The crude solid was recrystallized from an ethyl acetate / cyclohexane mixture (volume ratio 1:5) to give a white powder of pemafibrate (8.5 g, yield 91%), with the (S)-isomer content in the product being 0.178%.

[0030] Example 2: The method of the present invention uses 2,6-dimethylpyridine instead. The procedure was the same as in Example 1, except that 2,6-dimethylpyridine was used instead, and the reaction was completed in approximately 70 minutes. The content of the (S)-isomer in the product was 0.197%.

[0031] Example 3: The method of the present invention (organic base: inorganic base = 2:1) The procedure was the same as in Example 1, except that the amount of pyridine used was changed to (5.2 g, 65.2 mmol) (at this point, the molar ratio of organic base pyridine to inorganic base NaOH was 2:1), and the reaction was completed in about 1 hour. The content of (S)-isomer in the product was 0.247%.

[0032] Comparative Example 1: Conventional method (single inorganic base, room temperature) The procedure was the same as in Example 1, but without pyridine; only sodium hydroxide (2.6 g, 65.2 mmol) was used. The reaction took 3 hours to complete. The (S)-isomer content in the product was 1.032%.

[0033] Comparative Example 2: Conventional method (single inorganic base, low temperature) The procedure was the same as in Comparative Example 1, but the reaction temperature was controlled at 0-5°C to suppress racemization. The reaction rate decreased significantly, and the reaction was still incomplete after 8 hours. After treatment, the (S)-isomer content in the product was 0.849%, and the yield was only 46%.

[0034] Comparative Example 3: Mixed Alkali (High Temperature) The procedure was the same as in Example 1, but the reaction temperature was controlled at 40°C. The reaction rate was accelerated, completing in 10 minutes, but the content of (S)-isomers in the product increased to 1.426%, indicating that racemization was intensified at high temperatures.

[0035] Comparative Example 4: Conventional method (single inorganic base, high temperature) The procedure was the same as in Example 1, but the reaction temperature was controlled at 40°C. The reaction rate was accelerated, completing in 10 minutes, but the content of (S)-isomers in the product increased to 8.004%, indicating that racemization was intensified at high temperatures.

[0036] Comparative Example 5: Conventional method (single organic base, room temperature) The procedure was the same as in Example 1, but sodium hydroxide was not added; only pyridine (5.2 g, 65.2 mmol) was used. After 24 hours, hydrolysis was still not complete.

[0037] Comparison of effects: Chiral HPLC analysis was performed on the pemafibrate products obtained in the examples and comparative examples, and the results are shown in the table below: project Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 alkaline system Mixed alkali Mixed alkali Mixed alkali NaOH alone NaOH alone Mixed alkali NaOH alone / reaction temperature 20℃ 20℃ 20℃ 20℃ 0-5℃ 40℃ 40℃ / reaction time 1.5h 75min 1h 3h >8h (not complete) 10min 10min / (R)-Peemafibrate content 99.822% 99.803% 99.752% 98.929% 99.151% 98.134% 91.163% / (S)-Isomeric Impurity Content 0.178% 0.197% 0.247% 1.032% 0.849% 1.426% 8.004% / This invention, through the synergistic control of the mixing ratio of alkali and the reaction temperature, significantly improves the reaction efficiency while ensuring high optical purity, thus resolving the contradiction between "purity" and "efficiency" in traditional processes.

[0038] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing high optical purity pedmabet, characterized in that, include: Pemafibrate n-butyl ester and mixed bases are mixed evenly in a solvent and then hydrolyzed to obtain pemafibrate. The mixed alkali includes: organic alkali and inorganic alkali; The organic base is selected from at least one of pyridine, 2,6-dimethylpyridine, and triethylamine.

2. The method for preparing high optical purity pemabet as described in claim 1, characterized in that, The molar ratio of the organic base to the inorganic base is 1:2-2:1, 0.7:1-1.25:1, or 1:

1.

3. The method for preparing high optical purity pemabet as described in claim 1, characterized in that, The inorganic base is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

4. The method for preparing high optical purity pemabet as described in claim 1, characterized in that, The molar ratio of the pemafibrate n-butyl ester to the mixed base is 1:4-5.

5. The method for preparing high optical purity pemabet as described in claim 1, characterized in that, The hydrolysis reaction is carried out at a temperature of 0°C-30°C or 15°C-25°C.

6. The method for preparing high optical purity pemabet as described in claim 1, characterized in that, The solvent is tetrahydrofuran.

7. The method for preparing high optical purity pemabet as described in claim 1, characterized in that, The mixing process specifically includes: first mixing pemafibrate n-butyl ester and an organic base in a solvent, and then adding an inorganic base solution.

8. The method for preparing high optical purity pemabet as described in claim 7, characterized in that, After the reaction was completed, the reaction solution was neutralized to pH 5-6, and concentrated under reduced pressure to remove most of the organic solvent; water was added to the remaining aqueous phase, and the pH was adjusted to 2-3 with concentrated hydrochloric acid; the solution was extracted with methyl tert-butyl ether; the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate; the solution was filtered and concentrated under reduced pressure to dryness to obtain a white solid crude product. Alternatively, the crude product can be recrystallized from ethyl ester / cyclohexane to obtain a white powdery pemabet.

9. Pemabet prepared by the method according to any one of claims 1-8.

10. The application of a mixed alkali system in improving the optical purity of Peppermet, characterized in that, The mixed alkali includes: organic alkali and inorganic alkali; The organic base is selected from at least one of pyridine, 2,6-dimethylpyridine, and triethylamine.

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