Preparation method of rosaxostat crystal form A

Abstract

The invention relates to a preparation method of a rosaxostat crystal form A. The preparation method comprises the following steps: step 1, stirring and dissolving a rosaxostat crude product in an organic solvent; step 2, filtering or filter-pressing the crude product solution to remove solid impurities; 3, a heterogeneous organic solvent is added into the filtrate for crystallization, and after crystallization is completed, cooling and heat preservation aging are carried out; step 4, filtering the aged system, taking a filter cake, carrying out temperature-controlled pulp washing with a heterogeneous organic solvent, filtering, and draining; and step 5, drying the filter cake after pumping to obtain the crystal form A of the rosaxostat. The preparation method does not involve the addition of seed crystals, and is simple and convenient to operate; an organic solvent is used for crystallization, is consistent with a cleaning solvent used in the cleaning process and is an organic compound, and waste liquid components are simple; the difference between boiling points of different types of used organic solvents is large, so that the organic solvents are convenient to recycle; meanwhile, the advantage that the target product is not separated out before crystallization treatment is still kept, and matching with the production process of a clean area is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and relates to a method for preparing a specific crystal form of roxadustat, and in particular to a method for preparing roxadustat crystal form A. Background Art

[0002] Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that is primarily used to treat anemia caused by chronic kidney disease (CKD), especially in patients undergoing dialysis and non-dialysis treatments.

[0003] Rosuvastatin, as a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), promotes the production of endogenous erythropoietin, improves iron absorption and utilization, reduces hepcidin, and is not affected by the negative effects of inflammation on hemoglobin and erythropoiesis, thereby effectively promoting erythropoiesis and achieving the purpose of correcting anemia.

[0004] Two phase III multicenter randomized double-blind controlled clinical studies of roxadustat in China were conducted on dialysis and non-dialysis patients, respectively, with erythropoietin (EPO) and placebo as control drugs. Both studies achieved the primary endpoint, showing that roxadustat can effectively correct and maintain the patient's hemoglobin (Hb) level with good safety. In addition, a phase III double-blind randomized study from Japan demonstrated that roxadustat may be beneficial for patients with low responsiveness to erythropoietin-stimulating agent (ESA).

[0005] In chronic kidney disease, especially in the uremic stage, there are multiple inflammatory reactions in the body, and rosuvastatin is still effective under inflammatory conditions, and there is no need for intravenous iron supplementation at the same time. In addition, as an oral dosage form, rosuvastatin is not affected by diet, which greatly improves treatment compliance.

[0006] Rosuvastatin has been marketed in Japan and many European countries, providing more treatment options for patients with anemia caused by chronic kidney disease, and its market prospects are promising.

[0007] The relevant information about the chemical structure of roxadustat is as follows: Chinese chemical name: [[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-)carbonyl]-amino]-acetic acid Chemical structure: Molecular formula: C 19 H 16 N2O5 Molecular weight: 352.34 There are 10 crystal forms of rosuvastatin reported in the literature, including crystal form A to crystal form tromethamine salt, among which crystal form A is the most commonly used pharmaceutically stable crystal form.

[0008] There are many existing methods for preparing rosuvastatin crystal form A, but they often have certain defects. For example: some preparation processes of rosuvastatin crystal form A use a large amount of organic solvents such as ketones, alcohols, ethers or nitriles, which are costly and have a high residual risk; some preparation processes of rosuvastatin crystal form A involve the addition of seed crystals, which are difficult to operate and will increase the cost of quality control and warehouse management, as well as the research and development costs of seed crystal quality research and stability during the research and development process; some preparation processes of rosuvastatin crystal form A involve crystal transformation, which has the problem of long crystal transformation time and the risk of incomplete crystal transformation, which is not conducive to energy conservation and emission reduction and cost control, and leads to a sharp increase in quality risks.

[0009] In order to solve the problem caused by the large amount of organic solvents such as ketones, alcohols, ethers or nitriles used in the preparation process of roxadustat crystal form A, the Chinese invention patent with publication number CN117756716A provides a preparation method of roxadustat crystal form A, which uses water as a solvent and performs a chemical reaction in an aqueous phase to prepare roxadustat crystal form A. Although this preparation method has a low preparation cost, it is inevitable to use organic solvents in the cleaning process of actual production, resulting in a certain amount of organic solvents in the wastewater, which increases the cost of wastewater treatment and solvent recovery.

[0010] Therefore, in view of the defects in the preparation process of the above-mentioned rosuvastatin crystal form A, especially the difficulty in recovering the wastewater after the aqueous phase reaction, the present invention proposes a preparation method of rosuvastatin crystal form A to solve the above-mentioned problems. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a method for preparing rosuvastatin crystal form A, which is simple to operate, convenient for solvent recovery, and conducive to matching the clean area production process.

[0012] In order to solve the above technical problems, the technical solution of the present invention is: a method for preparing rosuvastatin crystal form A, the innovation of which is: comprising the following steps: Step 1, stirring and dissolving the crude rosuvastatin in an organic solvent to obtain a crude product solution; Step 2, filtering or filter pressing the crude product solution to remove solid impurities to obtain a filtrate; Step 3, adding a heterogeneous organic solvent to the filtrate for crystallization, cooling and heat-insulating for aging after the crystallization is complete, to obtain an aged system; Step 4: The aged system is filtered, the filter cake is washed with a different organic solvent at a controlled temperature, filtered and dried; Step 5: Dry the filter cake after being drained to obtain Rosuvastatin Form A.

[0013] Furthermore, the organic solvent is dimethyl sulfoxide or N,N-dimethylformamide, preferably dimethyl sulfoxide.

[0014] Furthermore, in the dissolution process of step 1, the weight of the organic solvent is 2 to 3 times, preferably 2.25 times, the weight of the crude rosuvastatin.

[0015] Furthermore, in the step 2, before filtering or filtering the crude solution, the crude solution is heat-insulated and decolorized using activated carbon.

[0016] Furthermore, the heterogeneous organic solvent is methanol, ethanol or acetone, preferably methanol.

[0017] Furthermore, in the crystallization process of step 3, the weight of the heterogeneous organic solvent used is 1 / 4 to 1 / 2, preferably 1 / 3 of the weight of the organic solvent in step 1, and the rate of adding the heterogeneous organic solvent should allow the solid to precipitate slowly without agglomeration.

[0018] Furthermore, in step 3, the crystallization temperature ranges from 35 to 65°C, preferably from 40 to 50°C.

[0019] Furthermore, in step 3, after the crystallization process is completed, the target temperature for cooling is -10~10°C, preferably -5~5°C, and the insulation aging time is controlled to be 1~2h.

[0020] Furthermore, in step 4, the temperature of the slurry washing process with the heterogeneous organic solvent is -10 to 10°C, preferably -5 to 5°C, and the slurry washing time is controlled at 0.5 to 1 hour.

[0021] Furthermore, the drying temperature in step 5 is 40-90° C., preferably 50-60° C., and the drying pressure range is ≤-0.05 MPa, preferably ≤-0.08 MPa.

[0022] The advantages of the present invention are: The preparation method of the present invention carries out a chemical reaction of a non-aqueous system in an organic solvent, does not involve the addition of crystal seeds, and is easy to operate; the organic solvent used for crystallization is consistent with the cleaning solvent used in the cleaning process, both of which are organic compounds, and the waste liquid component is simple; the boiling point difference between the different types of organic solvents used is large, which is convenient for recovery; at the same time, the advantage of no precipitation of the target product before crystallization treatment is still maintained, which is conducive to matching the clean area production process. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0024] Figure 1 It is the characteristic morphology of the X-ray powder diffraction pattern of rosuvastatin Form A.

[0025] Figure 2 The X-ray powder diffraction pattern of the product of Example 1 of the present invention is shown in FIG.

[0026] Figure 3 The X-ray powder diffraction pattern of the product of Example 2 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0027] In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the specific implementation mode, structure, characteristics and effects of the present invention are described in detail below in combination with the accompanying drawings and preferred embodiments.

[0028] The compound rosuvastatin of the present invention has a chemical name of [[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-)carbonyl]-amino]-acetic acid, and its corresponding chemical structural formula is: The rosuvastatin crystal form A of the present invention has a characteristic morphology of its X-ray powder diffraction spectrum as shown in Figure 1 As shown. In the X-ray powder diffraction pattern of roxadustat crystal form A, the 2θ angle values ​​of the characteristic peaks are: 8.5°, 12.8°, 16.2°, 16.9°, 17.5°, 21.6°, 22.9°, 25.8°, 27.4°±0.2° (the characteristic morphology of the X-ray powder diffraction pattern of roxadustat crystal form A here is only a reference pattern, and the 2θ angle values ​​of the characteristic peaks are also reference values. In actual testing, they may change due to various factors, and even some diffraction peaks may be missing. Such situations should not be used as the only way to judge the roxadustat crystal form).

[0029] Example 1 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 225 g of dimethyl sulfoxide into the three-necked bottle in sequence, control the temperature at 45°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 45°C, slowly add 75 g of methanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool to 0°C, keep warm and age for 1 hour to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 40 g of methanol at 0°C for 0.5 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 55° C. and a pressure of −0.08 MPa to obtain 82.8 g of rosuvastatin Form A product.

[0030] The X-ray powder diffraction pattern of the product corresponding to the rosuvastatin crystal form A obtained in this example is shown in the attached Figure 2 .

[0031] Example 2 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 10L reaction bottle, add 1.25kg of rosuvastatin crude product and 2.8kg of dimethyl sulfoxide into the reaction bottle in sequence, control the temperature at 50°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 10L reaction bottle, control the temperature in the bottle to 50°C, slowly add 0.95kg of methanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool down to 3°C, keep warm and age for 1h to obtain the aged system; Step 4: The aged system is filtered, and the filter cake is washed with 0.5 kg of methanol at 3°C ​​for 1 hour, filtered and dried; Step 5: The filter cake after being drained is dried at a temperature of 60° C. and a pressure of -0.09 MPa to obtain 1.02 kg of rosuvastatin Form A product.

[0032] The X-ray powder diffraction pattern of the product corresponding to the rosuvastatin crystal form A obtained in this example is shown in the attached Figure 3 .

[0033] Example 3 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 300 g of dimethyl sulfoxide into the three-necked bottle in sequence, control the temperature at 40°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 40°C, slowly add 150 g of methanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool to -5°C, keep warm and age for 2 hours to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 100 g of methanol at -5°C for 1 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 60° C. and a pressure of -0.06 MPa to obtain 80.1 g of rosuvastatin Form A product.

[0034] Example 4 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 200 g of dimethyl sulfoxide into the three-necked bottle in sequence, control the temperature at 65°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 65°C, slowly add 100 g of methanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool to 8°C, keep warm and age for 2 hours to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 60 g of methanol at 8°C for 0.8 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 50° C. and a pressure of −0.05 MPa to obtain 79.4 g of rosuvastatin Form A product.

[0035] Example 5 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 240 g of dimethyl sulfoxide into the three-necked bottle in sequence, stir and dissolve at 35°C, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 35°C, slowly add 60 g of ethanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool to -7°C, keep warm and age for 1.5 hours to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 40 g of ethanol at -7°C for 0.8 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 40° C. and a pressure of −0.07 MPa to obtain 73.9 g of rosuvastatin Form A product.

[0036] Example 6 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 250 g of dimethyl sulfoxide into the three-necked bottle in sequence, control the temperature at 60°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 60°C, slowly add 125 g of acetone, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool down to 2°C, keep warm and age for 1.5 hours to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 85 g of acetone at 2°C for 0.5 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 40° C. and a pressure of −0.07 MPa to obtain 84.4 g of rosuvastatin Form A product.

[0037] Example 7 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 225 g of N,N-dimethylformamide into the three-necked bottle in sequence, control the temperature at 45°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 45°C, slowly add 75 g of methanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool to 0°C, keep warm and age for 1 hour to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 40 g of methanol at 0°C for 0.5 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 55° C. and a pressure of -0.08 MPa to obtain 76.5 g of rosuvastatin Form A product.

[0038] Example 8 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 10L reaction bottle, add 1.25kg of rosuvastatin crude product and 2.8kg of N,N-dimethylformamide into the reaction bottle in sequence, control the temperature at 50°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 10L reaction bottle, control the temperature in the bottle to 50°C, slowly add 0.95kg of methanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool down to 3°C, keep warm and age for 1h to obtain the aged system; Step 4: The aged system is filtered, and the filter cake is washed with 0.5 kg of methanol at 3°C ​​for 1 hour, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 60° C. and a pressure of -0.09 MPa to obtain 0.91 kg of rosuvastatin Form A product.

[0039] Example 9 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 240 g of N,N-dimethylformamide into the three-necked bottle in sequence, stir and dissolve at 35°C, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 35°C, slowly add 60 g of ethanol, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool to -10°C, keep warm and age for 1.5 hours to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 40 g of ethanol at -10°C for 0.8 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 40° C. and a pressure of −0.07 MPa to obtain 71.4 g of rosuvastatin Form A product.

[0040] Example 10 This embodiment provides a method for preparing rosuvastatin crystal form A, comprising the following steps: Step 1, take a 2L three-necked bottle, add 100 g of rosuvastatin crude product and 250 g of N,N-dimethylformamide into the three-necked bottle in sequence, control the temperature at 60°C and stir to dissolve, keep warm and stir for 0.5h to obtain a crude product solution; Step 2, after the crude product solution is decolorized by heat preservation using activated carbon, the crude product solution is filtered to remove solid impurities to obtain a filtrate; Step 3, take the filtrate into a 2 L three-necked bottle, control the temperature in the bottle to 60°C, slowly add 125 g of acetone, slowly precipitate the solid, ensure that there is no agglomeration, and after the crystallization is complete, slowly cool down to 2°C, keep warm and age for 1.5 hours to obtain an aged system; Step 4: The aged system is filtered, and the filter cake is washed with 85 g of acetone at 2°C for 0.5 h, filtered and dried; Step 5: The filter cake after being drained was dried at a temperature of 40° C. and a pressure of −0.07 MPa to obtain 80.9 g of rosuvastatin Form A product.

[0041] The preparation method of the present invention is to carry out a chemical reaction of a non-aqueous system in an organic solvent, does not involve the addition of crystal seeds, is easy to operate, and has a high yield of the crystal form A product; the organic solvent used for crystallization is consistent with the cleaning solvent used in the cleaning process, which is an organic compound, and the waste liquid component is simple; the boiling point difference between different types of organic solvents used is large, which is convenient for recovery; at the same time, the advantage of no precipitation of the target product before crystallization treatment is still maintained, which is conducive to matching the clean area production process.

[0042] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technical personnel in this field can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for preparing rosuvastatin crystal form A, characterized in that: The following steps are involved: Step 1, stirring and dissolving the crude rosuvastatin in an organic solvent to obtain a crude product solution; Step 2, filtering or filter pressing the crude product solution to remove solid impurities to obtain a filtrate; Step 3, adding a heterogeneous organic solvent to the filtrate for crystallization, cooling and heat-insulating for aging after the crystallization is complete, to obtain an aged system; Step 4: The aged system is filtered, the filter cake is washed with a different organic solvent at a controlled temperature, filtered and dried; Step 5: Dry the filter cake after being drained to obtain Rosuvastatin Form A.

2. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: The organic solvent is dimethyl sulfoxide or N,N-dimethylformamide.

3. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: During the dissolution process of step 1, the weight of the organic solvent is 2 to 3 times the weight of the crude rosuvastatin.

4. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: In the step 2, before filtering or filtering the crude solution, the crude solution is heat-insulated and decolorized using activated carbon.

5. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: The heterogeneous organic solvent is methanol, ethanol or acetone.

6. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: In the crystallization process of step 3, the weight of the heterogeneous organic solvent used is 1 / 4 to 1 / 2 of the weight of the organic solvent in step 1, and the rate of adding the heterogeneous organic solvent should allow the solid to precipitate slowly without agglomeration.

7. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: In step 3, the crystallization temperature ranges from 35 to 65°C.

8. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: In step 3, after the crystallization process is completed, the target temperature of the cooling is -10~10°C, and the insulation aging time is controlled at 1~2h.

9. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: The temperature of the pulping process of the heterogeneous organic solvent in step 4 is -10~10°C, and the pulping time is controlled at 0.5~1h.

10. The method for preparing roxadustat crystal form A according to claim 1, characterized in that: The drying temperature in step 5 is 40-90° C., and the drying pressure range is ≤-0.05 MPa.

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