Method for purifying and separating acipimox

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a method for purifying and separating acipimox. The method comprises the following steps: (1) dissolving: dissolving an acipimox crude product in hot water, and filtering to obtain filtrate; (2) acidification crystallization: cooling the filtrate, dropwise adding hydrochloric acid, separating out solids, cooling in an ice bath, standing, carrying out suction filtration, collecting crystals, and washing with deionized water to obtain a pretreated crude product; (3) solvent recrystallization: dissolving the pretreated crude product in ethanol, adding deionized water, heating until the crude product is completely dissolved, and preserving heat; carrying out gradient cooling and standing; (4) filtering and drying: carrying out suction filtration to collect crystals, washing with an ethanol-water mixed solution, and carrying out vacuum drying to obtain a recrystallized product; and (5) HPLC fine purification: dissolving the recrystallized product in an acetonitrile-water mixed solution, filtering, sampling, collecting the product, carrying out rotary evaporation to remove acetonitrile, and drying to obtain the high-purity acipimox. The method disclosed by the invention is high in recovery rate, and the prepared acipimox is high in purity.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a method for purifying and separating acipimox. Background Art

[0002] Acipimox, chemically known as 5-methylpyrazine-2-carboxylic acid-4-oxide, inhibits the release of free fatty acids from adipose tissue, reducing their entry into the liver. It is primarily used to treat hypertriglyceridemia (type IV), hypercholesterolemia types IIa and IIb, and hyperlipoproteinemia types III and V.

[0003] Acipimox is synthesized using 5-methylpyrazine-2-carboxylic acid as the starting material and is obtained through oxidation. There are two main methods: indirect and direct. The direct oxidation method offers a shorter route and higher yields and is currently used by most manufacturers. In the direct oxidation method of acipimox, when hydrogen peroxide is used as the oxidant and sodium tungstate as the catalyst, nitrogen oxide isomers and dinitrogen oxides are produced as byproducts.

[0004] Chinese patent CN 118271253 A discloses the preparation of high-purity acipimox and its use in preparations. The acipimox prepared by this process has a purity greater than 99.9% and a single impurity less than 0.03%.

[0005] Therefore, a method for purifying and separating acipimox is urgently needed. Summary of the Invention

[0006] The purpose of the present invention is to provide a method for purifying and separating acipimox.

[0007] In order to achieve the above object, the present invention provides the following technical solutions: A method for purifying and separating acipimox comprises the following steps: (1) Dissolution: Dissolve the crude acipimox in hot water and filter to obtain a filtrate; (2) Acidification and crystallization: Cool the filtrate, add hydrochloric acid dropwise to precipitate solids, cool in an ice bath, let stand, collect the crystals by suction filtration, and wash with deionized water to obtain the pretreated crude product; (3) Solvent recrystallization: dissolve the pretreated crude product in ethanol, add deionized water, heat until completely dissolved, and keep warm; perform gradient cooling and let stand; (4) Filtration and drying: Collect the crystals by suction filtration, wash with an ethanol-water mixture, and vacuum dry to obtain a recrystallized product; (5) HPLC fine purification: The recrystallized product was dissolved in an acetonitrile-water mixture, filtered and injected, the product was collected, the acetonitrile was removed by rotary evaporation, and dried to obtain high-purity acipimox.

[0008] Preferably, in step (1), the solid-to-liquid ratio of crude acipimox to water is 1 g: (20-30) mL.

[0009] Preferably, in step (2), 0.5-1.5 mol / L hydrochloric acid is first added dropwise to a pH of 4.5-5.0, stirred for 10-15 min, and then slowly adjusted to a pH of 3.8-4.0 to precipitate a solid.

[0010] The present invention selects to adjust the pH in stages to reduce the supersaturation gradient during crystallization of the target product and avoid uncontrolled nucleation caused by local overacidity.

[0011] Preferably, the solid-to-liquid ratio of the crude product after pretreatment in step (3) to ethanol is 1:15 to 1:20.

[0012] Preferably, the volume ratio of ethanol to water in step (3) is 1:3-4.

[0013] Preferably, in step (3), the temperature is gradually lowered: first, the temperature is lowered to 40-45°C at a rate of 0.4-0.6°C / min; then, the temperature is lowered to 25-20°C at a rate of 0.1-0.3°C / min; and then, the temperature is ice-bathed to 0-5°C and allowed to stand for 15-20h.

[0014] The present invention utilizes a specific ratio of ethanol and deionized water as solvents and performs gradient cooling to achieve recrystallization, thereby improving the purity and yield of acipimox. The ethanol-water mixed solvent, at a specific ratio, can reduce the surface tension of the solution, accelerating the diffusion of molecules toward the crystal surface. This, combined with the slow growth phase of the gradient cooling, forms a dense crystal structure. During the gradient cooling process, different impurity types are precipitated at different temperature ranges. The variable ratio characteristics of the mixed solvent dynamically adjust the solubility of impurities, enabling in-situ online purification.

[0015] Preferably, in step (4), the product is washed 2-3 times with an ethanol-water mixture in a volume ratio of 1:(3-5), and then vacuum dried to obtain a recrystallized product.

[0016] Preferably, the volume ratio of acetonitrile to water in the acetonitrile-water mixture with a volume ratio of 1:1 in step (5) is (1.0-1.5):1.

[0017] Preferably, in step (5), the product with a chromatographic peak time of 8.2-9.8 min is collected.

[0018] Preferably, the chromatographic conditions in step (5) are as follows: chromatographic column: C18 reverse phase column, mobile phase: phase A: 0.1 (v / v)% trifluoroacetic acid aqueous solution; phase B: acetonitrile containing 0.1 (v / v)% trifluoroacetic acid; gradient program: 0-10 min, the proportion of phase B is from 20 (v / v)% to 35 (v / v)%, 10-15 min, the proportion of phase B is from 35 (v / v)% to 20 (v / v)%; the flow rate is 50 mL / min, and the detection wavelength is 254 nm.

[0019] Compared with the prior art, the advantages and beneficial effects of the present invention are: The present invention provides an efficient method for purifying acipimox, which is particularly suitable for purifying crude products produced during the direct oxidation synthesis process. This method ensures that the final acipimox has higher purity, ensuring the safety and effectiveness of the drug. This method not only enhances the market competitiveness of the product, but also provides a greener and more efficient production strategy for the pharmaceutical industry.

[0020] 2. Traditional direct oxidation processes are often accompanied by high rates of byproduct formation. The method of the present invention is simple to operate, readily applicable industrially, and does not require complex equipment or extreme reaction conditions, significantly reducing production costs. This efficient and environmentally friendly production process aligns with the current pharmaceutical industry's pursuit of sustainable development, helping companies achieve a win-win situation in both economic efficiency and environmental protection. More importantly, obtaining high-purity acipimox is of great significance for improving drug quality and ensuring patient safety.

[0021] 3. The method of the present invention can improve the yield of the target product. A high yield means that more finished products can be obtained with less raw material input during the production process. This directly reduces costs and improves economic benefits for pharmaceutical companies. Efficient production processes make companies more competitive in the market, not only giving them a price advantage, but also ensuring the stability of the supply chain, meeting market demand without being affected by fluctuations in raw material supply. From an environmental protection perspective, improving purification yield is usually accompanied by process optimization and efficiency improvement, which means reducing waste generation. This is in line with the principles of green chemistry and helps promote the sustainable development of the pharmaceutical industry.

[0022] 4. The purity of the target product of the method of the present invention is greater than 99.5%. High-purity acipimox means higher drug quality and less impurity interference for medical efficacy, thereby ensuring drug safety and efficacy for patients. High-quality drugs not only better exert their therapeutic effects but also reduce the probability of adverse reactions. The method of the present invention is not only a technological advancement, but also brings significant economic value, environmental benefits, and social health benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a purity detection spectrum of acipimox prepared in Example 1.

[0024] Figure 2 This is the purity detection spectrum of acipimox prepared in Example 2.

[0025] Figure 3 This is the purity detection spectrum of acipimox prepared in Example 3.

[0026] Figure 4 This is the purity detection spectrum of Acipimox prepared in Comparative Example 1.

[0027] Figure 5 This is the purity detection spectrum of Acipimox prepared in Comparative Example 2.

[0028] Figure 6 This is the purity detection spectrum of acipimox prepared in Comparative Example 3.

[0029] Figure 7 This is the purity detection spectrum of acipimox prepared in Comparative Example 4.

[0030] Figure 8 This is the purity detection spectrum of acipimox prepared in Comparative Example 5. DETAILED DESCRIPTION

[0031] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0032] In the following examples and comparative examples, the purity of the crude acipimox prepared by direct oxidation method was 93.8%, the purity of the nitrogen oxide isomer was 1.31%, and the purity of the dinitrogen oxide was 4.53%.

[0033] Example 1 This embodiment provides a method for purifying and separating acipimox, comprising the following steps: (1) Dissolution: Dissolve the crude acipimox in water at a solid-liquid ratio of 1 g:25 mL in 85°C water, and filter with filter paper while hot to obtain a filtrate; (2) Acidification and crystallization: The filtrate was cooled to 55°C, 1 mol / L hydrochloric acid was added dropwise to pH 4.7, stirred for 10 min, and then slowly adjusted to pH 3.9 to precipitate solids. The solids were cooled to 4°C in an ice bath, allowed to stand for 3 h, and the crystals were collected by filtration. The crystals were washed four times with 4°C deionized water to obtain the pretreated crude product. (3) Solvent recrystallization: The crude product after pretreatment was dissolved in ethanol at 65°C, with a solid-liquid ratio of 1 g:17 mL of the crude product after pretreatment and ethanol. Deionized water was added, with a volume ratio of ethanol:deionized water of 1:3. After heating until completely dissolved, the product was kept warm for 10 min. The product was cooled in a gradient manner: first cooled to 42°C at a rate of 0.5°C / min; then cooled to 25°C at a rate of 0.3°C / min; then placed in an ice bath to 2°C and allowed to stand for 16 h.

[0034] (4) Filtration and drying: The crystals were collected by filtration, washed three times with a mixture of ethanol and water in a volume ratio of 1:4, and vacuum dried for 6 hours to obtain a recrystallized product; (5) HPLC fine purification: The recrystallized product was dissolved in a mixture of acetonitrile and water in a volume ratio of 1:1, filtered through a 0.22 μm filter membrane, and injected. The chromatographic conditions were as follows: Column: C18 reverse phase column (particle size 10 μm, column size 250×50 mm). Mobile phase: Phase A: 0.1 (v / v)% trifluoroacetic acid aqueous solution; Phase B: acetonitrile containing 0.1 (v / v)% trifluoroacetic acid; Gradient program: 0-10 min, Phase B ratio from 20 (v / v)% to 35 (v / v)%, 10-15 min, Phase B ratio from 35 (v / v)% to 20 (v / v)%. Flow rate: 50 mL / min, detection wavelength 254 nm, collect the product between retention time 8.2-9.8 min, remove acetonitrile by rotary evaporation, and dry to obtain high-purity acipimox.

[0035] Example 2 This embodiment provides a method for purifying and separating acipimox, comprising the following steps: (1) Dissolution: Dissolve the crude acipimox in 90°C water at a solid-liquid ratio of 1 g:20 mL, and filter with filter paper while hot to obtain a filtrate; (2) Acidification and crystallization: The filtrate was cooled to 50°C, 1 mol / L hydrochloric acid was added dropwise to pH 5.0, stirred for 10 min, and then slowly adjusted to pH 3.8 to precipitate solids. The solids were cooled to 5°C in an ice bath, allowed to stand for 2 h, and the crystals were collected by filtration. The crystals were washed three times with 5°C deionized water to obtain the pretreated crude product. (3) Solvent recrystallization: The crude product after pretreatment was dissolved in ethanol at 70°C, with the solid-liquid ratio of the crude product after pretreatment and ethanol being 1g:15mL. Deionized water was added, with the volume ratio of ethanol:water being 1:4. After heating until completely dissolved, the product was kept warm for 10 minutes. The temperature was then gradually cooled: first, the temperature was cooled to 40°C at a rate of 0.5°C / min; then, the temperature was cooled to 25°C at a rate of 0.3°C / min; then, the product was placed in an ice bath to 5°C and allowed to stand for 15 hours.

[0036] (4) Filtration and drying: The crystals were collected by filtration, washed three times with a mixture of ethanol and water in a volume ratio of 1:4, and vacuum dried for 6 hours to obtain a recrystallized product; (5) HPLC fine purification: The recrystallized product was dissolved in a mixture of acetonitrile and water in a volume ratio of 1:1, filtered through a 0.22 μm filter membrane, and injected. The chromatographic conditions were as follows: Column: C18 reverse phase column (particle size 10 μm, column size 250×50 mm). Mobile phase: Phase A: 0.1 (v / v)% trifluoroacetic acid aqueous solution; Phase B: acetonitrile containing 0.1 (v / v)% trifluoroacetic acid; Gradient program: 0-10 min, Phase B ratio from 20 (v / v)% to 35 (v / v)%, 10-15 min, Phase B ratio from 35 (v / v)% to 20 (v / v)%. Flow rate: 50 mL / min, detection wavelength 254 nm, collect the product between retention time 8.2-9.8 min, remove acetonitrile by rotary evaporation, and dry to obtain high-purity acipimox.

[0037] Example 3 This embodiment provides a method for purifying and separating acipimox, comprising the following steps: (1) Dissolution: Dissolve the crude acipimox in water at a solid-liquid ratio of 1 g:30 mL in 80°C water, and filter with filter paper while hot to obtain a filtrate; (2) Acidification and crystallization: The filtrate was cooled to 60°C, 1 mol / L hydrochloric acid was added dropwise to pH 4.5, stirred for 10 min, and then slowly adjusted to pH 4.0 to precipitate solids. The filtrate was cooled to 2°C in an ice bath, allowed to stand for 4 h, and the crystals were collected by filtration. The crystals were washed five times with 2°C deionized water to obtain the pretreated crude product. (3) Solvent recrystallization: The crude product after pretreatment was dissolved in ethanol at 60°C, with a solid-liquid ratio of 1 g:20 mL of the crude product after pretreatment and ethanol. Deionized water was added, with a volume ratio of ethanol:water of 1:3. After heating until completely dissolved, the product was kept warm for 15 min. The product was cooled in a gradient manner: first cooled to 40°C at a rate of 0.5°C / min; then cooled to 25°C at a rate of 0.3°C / min; then placed in an ice bath to 2°C and allowed to stand for 20 h.

[0038] (4) Filtration and drying: The crystals were collected by filtration, washed twice with a mixture of ethanol and water in a volume ratio of 1:4, and vacuum dried for 6 hours to obtain a recrystallized product; (5) HPLC fine purification: The recrystallized product was dissolved in a mixture of acetonitrile and water in a volume ratio of 1:1, filtered through a 0.22 μm filter membrane, and injected. The chromatographic conditions were as follows: Column: C18 reverse phase column (particle size 10 μm, column size 250×50 mm). Mobile phase: Phase A: 0.1 (v / v)% trifluoroacetic acid aqueous solution; Phase B: acetonitrile containing 0.1 (v / v)% trifluoroacetic acid; Gradient program: 0-10 min, Phase B ratio from 20 (v / v)% to 35 (v / v)%, 10-15 min, Phase B ratio from 35 (v / v)% to 20 (v / v)%. Flow rate: 50 mL / min, detection wavelength 254 nm, collect the product between retention time 8.2-9.8 min, remove acetonitrile by rotary evaporation, and dry to obtain high-purity acipimox.

[0039] Comparative Example 1 The difference between this comparative example and Example 1 is that the volume ratio of ethanol and deionized water used in the recrystallization in step (3) is 1:1.

[0040] Comparative Example 2 The difference between this comparative example and Example 1 is that the volume ratio of ethanol and deionized water used in the recrystallization in step (3) is 1:7.

[0041] Comparative Example 3 The difference between this comparative example and Example 1 is that in step (2), the filtrate is cooled to 55°C, 1 mol / L hydrochloric acid is added dropwise to pH 3.9, solid is precipitated, ice bath is cooled to 4°C, the mixture is allowed to stand for 3 h, the crystals are collected by filtration, and washed four times with 4°C deionized water to obtain a pretreated crude product.

[0042] Comparative Example 4 The difference between this comparative example and Example 1 is that no gradient cooling is performed in step (3).

[0043] Specifically: the pretreated crude product was dissolved in ethanol at 65°C, with a solid-liquid ratio of the pretreated crude product and ethanol of 1:17, deionized water was added, and the volume ratio of ethanol: water was 1:3. After heating until completely dissolved, the temperature was kept warm for 10 minutes; cooled to 25°C at a rate of 1°C / min, then ice-bathed to 2°C, and allowed to stand for 16 hours.

[0044] Comparative Example 5 This comparative example is the method of Example 1, which is disclosed in Chinese patent CN 118271253 A, which discloses the preparation of high-purity acipimox and its application in preparations.

[0045] Performance Testing 1. Purity test: The purity of the high-purity acipimox in Examples 1-3 and Comparative Examples 1-5 was determined using HPLC using a C18 analytical column (4.6×250 mm, 5 μm) with a mobile phase of acetonitrile-0.1% phosphoric acid aqueous solution (25:75) at a flow rate of 1.0 mL / min and a detection wavelength of 265 nm.

[0046] 2. Yield calculation: Yield = actual mass of acipimox obtained ÷ theoretical mass of acipimox × 100%.

[0047] The results are shown in Table 1.

[0048] Table 1 Performance test results Serial number purity% Yield % Example 1 99.961 94.3 Example 2 99.954 94.0 Example 3 99.957 94.1 Comparative Example 1 99.712 92.9 Comparative Example 2 99.038 93.2 Comparative Example 3 99.873 93.7 Comparative Example 4 99.856 93.4 Comparative Example 5 99.958 92.1 From Table 1 and Figure 1-8 It can be seen that the purity of the methods of Examples 1-3 is greater than 99.5%, and the yield is greater than 93.5%, which is significantly improved compared to the prior art.

[0049] In Comparative Examples 1 and 2, the ethanol-water ratio used for recrystallization was changed, resulting in decreased purity and yield. Analysis suggests that the high ethanol ratio makes acipimox too soluble at high temperatures, preventing sufficient supersaturation during cooling, resulting in insufficient crystal precipitation and a decreased yield. When the water ratio is too high, the solvent polarity is too strong, and acipimox may not be completely dissolved at high temperatures, causing undissolved crude product to be directly encapsulated in the crystals and introducing original impurities.

[0050] In Comparative Example 3, when the pH was directly adjusted to 3.9, impurities and the target product precipitated simultaneously, resulting in crystals encapsulating the impurities. Rapid addition of hydrochloric acid to pH 3.9 caused the solution to be locally overacidified, triggering rapid nucleation of acipimox, forming fine crystals that encapsulated the impurities in the mother liquor.

[0051] In Comparative Example 4, the purity and yield of acipimox decreased without the gradient cooling treatment. This is because the rapid cooling caused the solution to rapidly enter an unstable region, triggering the explosive formation of a large number of tiny crystal nuclei.

[0052] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for purifying and separating acipimox, characterized in that: The following steps are involved: (1) Dissolution: Dissolve the crude acipimox in hot water and filter to obtain a filtrate; (2) Acidification and crystallization: Cool the filtrate, add hydrochloric acid dropwise to precipitate solids, cool in an ice bath, let stand, collect the crystals by suction filtration, and wash with deionized water to obtain the pretreated crude product; (3) Solvent recrystallization: dissolve the pretreated crude product in ethanol, add deionized water, heat until completely dissolved, and keep warm; perform gradient cooling and let stand; (4) Filtration and drying: Collect the crystals by suction filtration, wash with an ethanol-water mixture, and vacuum dry to obtain a recrystallized product; (5) HPLC fine purification: The recrystallized product was dissolved in an acetonitrile-water mixture, filtered and sampled, the product was collected, the acetonitrile was removed by rotary evaporation, and dried to obtain high-purity acipimox.

2. The method for purifying and separating acipimox according to claim 1, wherein In the step (1), the solid-to-liquid ratio of the crude acipimox to water is 1 g: (20-30) mL.

3. The method for purifying and separating acipimox according to claim 1, wherein In step (2), 0.5-1.5 mol / L hydrochloric acid is first added dropwise to a pH of 4.5-5.0, stirred for 10-15 minutes, and then slowly adjusted to a pH of 3.8-4.0 to precipitate a solid.

4. The method for purifying and separating acipimox according to claim 1, wherein The solid-liquid ratio of the crude product after pretreatment in step (3) and ethanol is 1 g: (15-20) mL.

5. The method for purifying and separating acipimox according to claim 1, wherein: The volume ratio of ethanol to water in step (3) is 1:(3-4).

6. The method for purifying and separating acipimox according to claim 1, wherein: In step (3), the temperature is gradually lowered to 40-45°C at a rate of 0.4-0.6°C / min; then the temperature is lowered to 25-20°C at a rate of 0.1-0.3°C / min; then the temperature is cooled to 0-5°C in an ice bath and allowed to stand for 15-20 hours.

7. The method for purifying and separating acipimox according to claim 1, wherein: In the step (4), the product is washed 2-3 times with an ethanol-water mixture in a volume ratio of 1:(3-5), and vacuum dried to obtain a recrystallized product.

8. The method for purifying and separating acipimox according to claim 1, wherein: In the step (5), the volume ratio of acetonitrile to water in the acetonitrile-water mixture is (1.0-1.5):

1.

9. The method for purifying and separating acipimox according to claim 1, wherein: In the step (5), the product with a chromatographic peak time of 8.2-9.8 min is collected.

10. The method for purifying and separating acipimox according to claim 1, characterized in that: The chromatographic conditions in step (5) are as follows: chromatographic column: C18 reverse phase column, mobile phase: phase A: 0.1 (v / v)% trifluoroacetic acid aqueous solution; phase B: acetonitrile containing 0.1 (v / v)% trifluoroacetic acid; gradient program: 0-10 min, the proportion of phase B is from 20 (v / v)% to 35 (v / v)%, 10-15 min, the proportion of phase B is from 35 (v / v)% to 20 (v / v)%; the flow rate is 50 mL / min, and the detection wavelength is 254 nm.

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