A purification method for varduxata active pharmaceutical ingredient

Abstract

This invention belongs to the field of pharmaceutical chemical technology, specifically relating to a purification method for valdoxat raw material. Using crude valdoxat as raw material, it is dissolved in a mixed solvent to form a suspension. The mixed solvent consists of water and a first solvent, which is an alcohol, ketone, or acetonitrile. An antioxidant and an organic amine base are added sequentially to the suspension. After heating to dissolve, activated carbon is used for decolorization. After filtration, the temperature is gradually decreased to 5°C–10°C at a gradient of 0.2°C / min–0.3°C / min to induce crystallization, yielding valdoxat. This invention provides a novel purification method for valdoxat raw material, achieving high yield, good impurity removal, high purity, mild reaction conditions, and simple operation, suitable for industrial-scale purification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a purification method for vardustal active pharmaceutical ingredient. Background Technology

[0002] Vadedustat (CAS: 1000025-07-9), chemically named N-(5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl)glycine, is an oral hypoxia-inducible factor (HIF) stabilizer currently used to treat anemia associated with chronic diseases. Its chemical structural formula is:

[0003] .

[0004] US Patent 20070299086 discloses the synthesis of Vadedustat: starting from 3,5-dichloro-2-cyanopyridine, Vadedustat is obtained through benzyl substitution reaction, hydrolysis, coupling, hydrogenation, substitution, coupling, and hydrolysis, with an overall yield of approximately 9%. The product has low purity, requiring column chromatography purification and recrystallization, which is inconvenient and costly.

[0005] US Patent 20120309977 discloses a method for preparing Vadedustat: using 3-chlorophenylborate and 3,5-dichloro-2-cyanopyridine as starting materials, Vadedustat is obtained through catalytic coupling, methoxy substitution, cyano hydrolysis, condensation, and ester hydrolysis reactions. This five-step synthesis still results in a final product with numerous and complex impurities, requiring two recrystallizations to meet internal quality control standards. However, the crystallization yield is low, the product purity is not high, and there are many impurities. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a purification method for varodoxamine raw material, which solves the issues of low crystallization yield, low product purity, and numerous impurities in existing varodoxamine raw materials.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a method for purifying vardurostat active pharmaceutical ingredient, comprising the following steps: Using crude valdustat as raw material, it is dissolved in a mixed solvent to form a suspension. The mixed solvent consists of water and a first solvent, which is an alcohol, ketone, or acetonitrile. An antioxidant and an organic amine base are added to the mixed solution in sequence. After dissolution, the solution is decolorized with activated carbon. After filtration, the solution is cooled at a gradient of 0.2℃ / min to 0.3℃ / min to 5℃ to 10℃ for crystallization to obtain valdustat.

[0009] Furthermore, the amount of antioxidant added is 0.5wt% to 2wt% of the mass of the mixed solution.

[0010] Furthermore, the antioxidants are vitamin C, vitamin E, vitamin A, butylated hydroxyanisole, butylated hydroxytoluene, sodium sulfite, sodium dithionite, sodium sulfite, stannous chloride, sodium bisulfite, or sodium thiosulfate.

[0011] Furthermore, the amount of organic amine base added is 0.5 wt% to 1 wt% of the mass of the mixed solution.

[0012] Furthermore, the organic amine base is triethylamine, diethylamine, pyridine, or hexahydropyridine.

[0013] Furthermore, the mass ratio of crude valdextrin to the mixed solvent is 1:8 to 14.

[0014] Furthermore, the amount of the first solvent is 90 wt% to 99 wt% of the total mass of the mixed solvents, and the alcohol solvent is methanol, ethanol, isopropanol or ethylene glycol, and the ketone solvent is acetone.

[0015] Furthermore, the amount of activated carbon added is 4wt% to 6wt% of the mass of the mixed solution, the decolorization temperature is 60℃ to 70℃, and the time is 10min to 20min.

[0016] Furthermore, the crystallization time is 5h to 8h. After crystallization, the crystals are filtered and dried. The drying is carried out under vacuum at 50℃ to 60℃ for 8h to 10h.

[0017] Compared with the prior art, the present invention has the following advantages: The purification method for valdoxat raw material provided by this invention utilizes the weak acidity of the carboxyl group in the valdoxat molecule. First, it is dissolved in a mixed solvent composed of a good solvent (such as alcohols, ketones, or acetonitrile) and a poor solvent (such as water) to initially adjust the solubility and create a suitable supersaturation for subsequent crystallization. Then, an organic amine base is added to convert trace impurities with similar structures into highly soluble carboxylates, thereby achieving complete dissolution and removal without precipitation during crystallization. Simultaneously, neutral and basic impurities that do not participate in the reaction are removed by hot filtration and activated carbon adsorption. Subsequently, a gradient cooling rate of 0.2℃ / min to 0.3℃ / min is used to controllably promote the crystallization of valdoxat under supersaturation, ultimately obtaining high-purity valdoxat raw material with uniform particle crystal form. This achieves a high yield of valdoxat, good impurity removal effect, high purity, mild reaction conditions, and simple operation, making it suitable for industrial-scale purification. Attached Figure Description

[0018] Figure 1 The image shows the hydrogen NMR spectrum of valdurostat after purification in Example 1 of this invention.

[0019] Figure 2 The image shows the carbon NMR spectrum of valdurostat after purification in Example 1 of this invention. Detailed Implementation

[0020] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] In this invention, crude vadadustat is synthesized using conventional methods, starting with 3-chlorophenylboronic acid and 3,5-dichloro-2-cyanopyridine, through catalytic coupling, methoxy substitution, cyano hydrolysis, condensation, and ester hydrolysis reactions to obtain vadadustat.

[0022] This invention selects commercially available crude valdoxat as the starting material. The crude valdoxat is provided by Heilongjiang Wusulijiang Pharmaceutical Co., Ltd. The purification of valdoxat is achieved by dissolving it, adding an antioxidant and alkali, followed by decolorization and gradient cooling crystallization. The product has high purity, few impurities (all unknown monomers are less than 0.1 wt%), good flowability, and is not prone to clumping. Specifically, a purification method for valdoxat raw material includes the following steps:

[0023] S1. Using crude vardurostat as raw material, add 8 to 14 times its weight of a mixed solvent to form a suspension; wherein the mixed solvent consists of water and a first solvent, the first solvent accounting for 90 wt% to 99 wt% of the mass of the mixed solvent, the first solvent being an alcohol solvent, a ketone solvent, or acetonitrile, the alcohol solvent being methanol, ethanol, isopropanol, or ethylene glycol, and the ketone solvent being acetone.

[0024] S2. Add a certain amount of antioxidant and organic amine base to the suspension solution in sequence, heat to dissolve, and then decolorize with activated carbon. The amount of antioxidant added is 0.5wt% to 2wt% of the mass of the mixed solution, the amount of organic amine base added is 0.5wt% to 1wt% of the mass of the mixed solution, the amount of activated carbon added is 4wt% to 6wt% of the mass of the mixed solution, the decolorization temperature is 60℃ to 70℃, and the time is 10min to 20min.

[0025] In some embodiments, the antioxidant is an organic antioxidant or an inorganic antioxidant. The amount of organic antioxidant added is 0.5 wt% to 2 wt% of the mass of the mixed solution. The organic antioxidant is vitamin C, vitamin E, vitamin A, butylated hydroxyanisole (BHA), or butylated hydroxytoluene (BHT), etc. The amount of inorganic antioxidant added is 1 wt% to 2 wt% of the mass of the mixed solution. The inorganic antioxidant is sodium sulfite, sodium dithionite, sodium sulfite, stannous chloride, sodium bisulfite, or sodium thiosulfate (sodium sodium thiosulfate).

[0026] In some embodiments, the organic amine base includes, but is not limited to, triethylamine, diethylamine, pyridine, or hexahydropyridine. The valdurostat structure is not destroyed by weaker organic amine bases such as triethylamine, diethylamine, pyridine, or hexahydropyridine.

[0027] S3. After decolorization, perform hot filtration at the decolorization temperature. After filtration, cool the temperature at a gradient of 0.2℃ / min to 0.3℃ / min to 5℃ to 10℃ for crystallization for 5h to 8h. After crystallization, filter the crystals and then vacuum dry them at 50℃ to 60℃ for 8h to 10h to obtain vardurostat.

[0028] In this invention, the synergistic effect of a mixed solvent (typically composed of a good solvent such as alcohols, ketones, or acetonitrile and a poor solvent such as water) and the salt formed by the weak acidity of the carboxyl group in the vardurostat molecule and the weak organic base increases water solubility, thereby removing impurities with similar molecular structures to vardurostat. First, the mixed solvent initially disperses or partially dissolves the crude vardurostat. Upon addition of a base, the carboxyl groups in impurity molecules similar to vardurostat also combine with the organic amine base to form highly soluble carboxylates. At this point, the polar components in the mixed solvent (especially water) greatly stabilize the ionic carboxylates, allowing them to dissolve completely in water. Neutral impurities without carboxyl groups, some basic impurities, and colored tar-like byproducts in the crude product remain suspended due to low solubility in the mixed solvent or incompatibility with the solvent. These are subsequently removed by activated carbon adsorption and filtration. Subsequently, the temperature was gradually reduced to 5℃–10℃ at a rate of 0.2℃ / min–0.3℃ / min. During this process, undesirable solvent components in the mixed solvent reduced the solubility of valdostat in its free acid form. Simultaneously, the slow cooling avoided explosive nucleation, keeping the system in a low-supersaturation state. This controllably promoted the precipitation of high-purity valdostat crystals with uniform particle size and crystal form, while residual impurities, still possessing some solubility in the low-temperature mixed solvent, remained in the mother liquor. This achieved efficient purification, resulting in a high yield of valdostat, excellent impurity removal, high purity, mild reaction conditions, and simple operation, making it suitable for industrial-scale purification.

[0029] The following specific examples will provide further explanation.

[0030] The high-performance liquid chromatography (HPLC) test conditions were as follows: Mobile phase A: 0.1% phosphoric acid aqueous solution; Mobile phase B: acetonitrile. Absorption wavelength: 220 nm. Column: Waters XBridge C18, 4.6 mm × 250 mm, 5 μm. Flow rate: 1.0 mL / min; Column temperature: 30 °C.

[0031] Example 1 A method for purifying varduxat active pharmaceutical ingredient includes the following steps: S1. Take 50.00g of crude vardurostat, provided by Heilongjiang Wusuli River Pharmaceutical Co., Ltd. (batch number 2025031601), add it to a three-necked flask, then add 600.00g of anhydrous ethanol and 10.00g of deionized water, heat and mix to form a mixed solution.

[0032] S2. Add 0.50g butylated hydroxyanisole (BHA) and 0.50g triethylamine to the mixed solution in sequence. After heating and dissolving, add 2.50g activated carbon for decolorization for 20min. During the decolorization process, the temperature is 65℃ and the rotation speed is 200r / min.

[0033] S3. After decolorization, hot filtration is performed at the decolorization temperature. After filtration, the temperature is gradually reduced to 5℃ at a gradient of 0.2℃ / min for crystallization for 5 hours. After crystallization, filtration is performed, and then vacuum drying is carried out at 50℃ for 8 hours to obtain vardurostat, 48.00g, yield 96.00%, white crystalline powder with melting point 151.5℃~152℃.

[0034] The purified valdustat from Example 1 was subjected to high-performance liquid chromatography (HPLC) analysis, and the results are shown in Table 1.

[0035] Table 1. Liquid chromatography results of purified valdustat from Example 1 As shown in Table 1, the impurities and their content meet the internal control targets (≤0.1%), and the impurities are purified to be qualified.

[0036] Figure 1 The image shows the hydrogen NMR spectrum of valdurostat after purification in Example 1 of this invention. Figure 2 This is the carbon NMR spectrum of valdextrin purified in Example 1 of this invention. Figure 1 and Figure 2 As shown, the purified vardurostat in Example 1 has high purity and no obvious impurities.

[0037] Example 2 A method for purifying varduxat active pharmaceutical ingredient includes the following steps: S1. Take 52.00g of crude vardurostat, provided by Heilongjiang Wusulijiang Pharmaceutical Co., Ltd. (batch number 20250602), add it to a three-necked flask, then add 600.00g of anhydrous ethanol and 10.00g of deionized water, heat and mix to form a mixed solution.

[0038] S2. Add 1.10g sodium dithionite and 0.50g diethylamine to the mixed solution in sequence. After heating and dissolving, add 2.50g activated carbon for decolorization for 20min. During the decolorization process, the temperature is 65℃ and the rotation speed is 200r / min.

[0039] S3. After decolorization, hot filtration is performed at the decolorization temperature. After filtration, the temperature is gradually reduced to 5℃ at a gradient of 0.2℃ / min for crystallization for 5 hours. After crystallization, filtration is performed, and then vacuum drying is carried out at 50℃ for 8 hours to obtain vardurostat, 50.80g, yield 97.70%, white crystalline powder with melting point 151.5℃~152℃.

[0040] The purified valdustat from Example 2 was subjected to high-performance liquid chromatography (HPLC) analysis, and the results are shown in Table 2.

[0041] Table 2. Liquid chromatography results of purified valdustat in Example 2 As shown in Table 2, the impurities and their content meet the internal control targets (≤0.1%), and the impurities are purified to be qualified.

[0042] Example 3 A method for purifying varduxat active pharmaceutical ingredient includes the following steps: S1. Take 50.00g of crude vardurostat, provided by Heilongjiang Wusulijiang Pharmaceutical Co., Ltd. (batch number 20250603), add it to a three-necked flask, then add 600.00g of acetonitrile and 60.00g of deionized water, heat and mix to form a mixed solution.

[0043] S2. Add 1.00g of vitamin C and 0.50g of pyridine to the mixed solution in sequence, heat to dissolve, and then add 2.50g of activated carbon for decolorization for 20min. During the decolorization process, the temperature is 65℃ and the rotation speed is 200r / min.

[0044] S3. After decolorization, hot filtration was performed at the decolorization temperature. After filtration, the temperature was gradually reduced to 5℃ at a gradient of 0.2℃ / min for crystallization for 5 hours. After crystallization, filtration was performed, and then vacuum drying was carried out at 50℃ for 8 hours to obtain vardurostat, 48.25g, yield 96.5%, white crystalline powder with melting point 151℃~152℃.

[0045] The purified vardurostat from Example 3 was subjected to high-performance liquid chromatography (HPLC) analysis, and the results are shown in Table 3.

[0046] Table 3. Liquid chromatography results of purified vardurostat from Example 3 As shown in Table 3, the impurities and their content meet the internal control targets (≤0.1%), and the impurities are purified to be qualified.

[0047] Comparative Example 1 A method for purifying varduxat active pharmaceutical ingredient includes the following steps: S1. Take 55.00g of crude vardurostat, provided by Heilongjiang Wusuli River Pharmaceutical Co., Ltd. (batch number 2025031601), add it to a three-necked flask, then add 600.00g of anhydrous ethanol and 10.00g of deionized water, heat and mix to form a mixed solution.

[0048] S2. Add 1.0g of vitamin C to the mixed solution, heat to dissolve, then add 2.50g of activated carbon for decolorization for 20min. During the decolorization process, the temperature is 65℃ and the rotation speed is 200r / min.

[0049] S3. After decolorization, hot filtration is performed at the decolorization temperature. After filtration, the temperature is gradually reduced to 5℃ at a gradient of 0.2℃ / min for crystallization for 5 hours. After crystallization, filtration is performed, and then vacuum drying is carried out at 50℃ for 8 hours to obtain vardurostat, 52.80g, yield 96.00%, white crystalline powder with melting point 151.5℃~152℃.

[0050] The purified valdustat from Comparative Example 1 was subjected to high-performance liquid chromatography (HPLC) testing, and the results are shown in Table 4.

[0051] Table 4. Liquid chromatography results of purified vardurostat from Comparative Example 1 Note: Impurity 1 exceeds the limit (the internal control quality standard for impurity 1 requires ≤0.1%).

[0052] As shown in Table 4, the absence of organic amine base resulted in impurity 1 (0.25%) being greater than 0.1%, failing to meet the quality standard.

[0053] Comparative Example 2 A method for purifying varduxat active pharmaceutical ingredient includes the following steps: S1. Take 51.00g of crude vardurostat, provided by Heilongjiang Wusulijiang Pharmaceutical Co., Ltd. (batch number 20250602), add it to a three-necked flask, then add 600.00g of anhydrous ethanol and 10.00g of deionized water, heat and mix to form a mixed solution.

[0054] S2. Add 0.50g of triethylamine to the mixed solution, heat to dissolve, and then add 2.50g of activated carbon for decolorization for 20min. During the decolorization process, the temperature is 65℃ and the rotation speed is 200r / min.

[0055] S3. After decolorization, hot filtration was performed at the decolorization temperature. After filtration, the temperature was gradually reduced to 5℃ at a gradient of 0.2℃ / min for crystallization for 5 hours. After crystallization, filtration was performed, and then vacuum drying was carried out at 50℃ for 8 hours to obtain vardurostat, 48.20g, yield 94.50%, white crystalline powder with melting point 151.5℃~152℃.

[0056] The purified vardurostat from Example 2 was subjected to high-performance liquid chromatography (HPLC) analysis, and the results are shown in Table 5.

[0057] Table 5. Liquid chromatography results of purified vardurostat from Comparative Example 2 Note: Impurity 1 is out of limit (the internal control quality standard for impurities 1 and 3 requires ≤0.1%).

[0058] As shown in Table 5, without the addition of antioxidants, the results showed that impurity 1 (0.21%) and impurity 3 (0.26%) were greater than 0.1%, which did not meet the quality standards.

[0059] Comparative Example 3 A method for purifying varduxat active pharmaceutical ingredient includes the following steps: S1. Take 53.00g of crude vardurostat, provided by Heilongjiang Wusulijiang Pharmaceutical Co., Ltd. (batch number 2025031603), add it to a three-necked flask, then add 600.00g of anhydrous ethanol and 10.00g of deionized water, heat and mix to form a mixed solution.

[0060] S2. After heating and dissolving, add 2.50g of activated carbon for decolorization for 20min. During the decolorization process, the temperature is 65℃ and the rotation speed is 200r / min.

[0061] S3. After decolorization, hot filtration was performed at the decolorization temperature. After filtration, the temperature was gradually reduced to 5℃ at a gradient of 0.2℃ / min for crystallization for 5 hours. After crystallization, filtration was performed, and then vacuum drying was carried out at 50℃ for 8 hours to obtain vardurostat, 49.20g, yield 92.83%, white crystalline powder with melting point 151.5℃~152℃.

[0062] The purified vardurostat from Example 3 was subjected to high-performance liquid chromatography (HPLC) analysis, and the results are shown in Table 6.

[0063] Table 6. Liquid chromatography results of purified vardurostat from Comparative Example 3 Note: Impurity 1 exceeds the limit (the internal control quality standard for impurity 1 requires ≤0.1%).

[0064] As shown in Table 6, without the addition of antioxidants and organic amine bases, the treatment results showed that impurity 1 (0.30%) was greater than 0.1% and impurity 3 (0.12%) was greater than 0.1%, which did not meet the quality standards.

[0065] Comparative Example 4 A method for purifying varduxat active pharmaceutical ingredient includes the following steps: S1. Take 50.00g of crude vardurostat, provided by Heilongjiang Wusulijiang Pharmaceutical Co., Ltd. (batch number 2025031604), add it to a three-necked flask, then add 600.00g of anhydrous ethanol and 10.00g of deionized water, heat and mix to form a suspension.

[0066] S2. Add 0.50g butylated hydroxyanisole (BHA) and 0.50g sodium hydroxide to the suspension in sequence. After heating and dissolving, add 2.50g activated carbon for decolorization for 20min. During the decolorization process, the temperature is 65℃ and the rotation speed is 200r / min.

[0067] S3. After decolorization, hot filtration is performed at the decolorization temperature. After filtration, the temperature is gradually reduced to 5℃ at a gradient of 0.2℃ / min for crystallization for 5 hours. After crystallization, filtration is performed, and then vacuum drying is carried out at 50℃ for 8 hours to obtain vardurostat, 45.00g, yield 90.00%, white crystalline powder with melting point 152.50℃~154℃.

[0068] The purified vardurostat from Comparative Example 4 was subjected to high-performance liquid chromatography (HPLC) testing, and the results are shown in Table 7.

[0069] Table 7. Liquid chromatography results of purified vardurostat from Comparative Example 4 Note: Impurity 1, Impurity 2 and Impurity 3 all exceeded the limit, and other unknown single impurities also exceeded the limit (the internal control quality standard requirement for Impurity 1, Impurity 2 and Impurity 3 is ≤0.1%, and the requirement for other unknown single impurities is ≤0.1%).

[0070] As shown in Table 7, in Comparative Example 4, after the addition of antioxidants and strong inorganic bases, the test results showed that impurities 1 (0.23%), 2 (0.20%), and 3 (0.41%) were all greater than 0.1%, failing to meet the quality standard. Other unknown single impurities also exceeded the limit (0.15%).

[0071] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described here to avoid redundancy. Although preferred embodiments of the invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of this invention.

[0072] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for purifying vardurostat raw material, characterized in that, Includes the following steps: Using crude valdustat as a raw material, it is dissolved in a mixed solvent to form a suspension solution, wherein the mixed solvent consists of water and a first solvent, which is an alcohol solvent, a ketone solvent, or acetonitrile; Antioxidant and organic amine base were added sequentially to the suspension, heated to dissolve, and then decolorized with activated carbon. After filtration, the temperature was gradually reduced to 5℃~10℃ at a gradient of 0.2℃ / min~0.3℃ / min to crystallize and obtain valdustat.

2. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The amount of antioxidant added is 0.5wt% to 2wt% of the crude product weight.

3. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The antioxidants are vitamin C, vitamin E, vitamin A, butylated hydroxyanisole, butylated hydroxytoluene, sodium sulfite, sodium dithionite, sodium sulfite, stannous chloride, sodium bisulfite, or sodium thiosulfate.

4. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The amount of organic amine base added is 0.5wt% to 1wt% of the crude weight.

5. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The organic amine base is triethylamine, diethylamine, pyridine, or hexahydropyridine.

6. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The weight ratio of crude valdustat to the mixed solvent is 1:8 to 14.

7. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The amount of the first solvent is 90 wt% to 99 wt% of the total mass of the mixed solvents. The alcohol solvent is methanol, ethanol, isopropanol or ethylene glycol, and the ketone solvent is acetone.

8. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The amount of activated carbon added is 4wt% to 6wt% of the mass of the mixed solution, the decolorization temperature is 60℃ to 70℃, and the time is 10min to 20min.

9. The purification method for vardurostat active pharmaceutical ingredient according to claim 1, characterized in that, The crystallization time is 5h to 8h. After crystallization, the crystals are filtered and dried. The drying process is carried out under vacuum at 50℃ to 60℃ for 8h to 10h.

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