A rosuvastatin calcium intermediate and a preparation method thereof

Abstract

The application discloses a rosuvastatin calcium intermediate and a preparation method thereof, and belongs to the technical field of medicinal chemistry and organic synthesis. + [R-CH(OH)-SO3] ‑ , wherein R is 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)pyrimidin-5-yl, A + is Na + , K + or NH4 + . Pyrimidine-5-formaldehyde is reacted with a corresponding bisulfite in water and a water-miscible organic solvent, a reverse solvent is added, crystallization is performed by cooling, filtration and drying are performed to obtain a crystalline addition product; active pyrimidine-5-formaldehyde is converted into a crystalline bisulfite addition product, the degree of oxidation and other degradation reactions of an aldehyde group in a storage process is reduced, and the content retention rate of the intermediate under long-term and accelerated storage conditions is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry and organic synthesis technology, specifically relating to a rosuvastatin calcium intermediate and a method for preparing the intermediate by crystallization. Background Technology

[0002] Rosuvastatin calcium is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. Its chemical synthesis typically involves steps such as the construction of a fluorophenylpyrimidine core, introduction of side chains, removal of protecting groups, hydrolysis, and calcium salting.

[0003] 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde is an important intermediate connecting the pyrimidine core and the chiral side chain. Its purity and stability affect the conversion rate, geometric selectivity, and impurity level of the final product in subsequent olefin formation reactions.

[0004] The pyrimidine-5-carboxaldehyde contains an active aldehyde group, making it susceptible to the effects of oxygen, water, temperature, light, and the pH of the system during separation, concentration, transportation, and storage. In particular, when residual oxidants, metal ions, or acidic / alkaline impurities are present in the raw material, the free aldehyde content is prone to decrease, color darkening, increased oxidized impurities, and an increase in unknown impurities with high retention times.

[0005] When free aldehydes are crystallized directly, they are quite sensitive to solvent composition, initial purity, concentration, seed crystal addition, and cooling process, and are prone to problems such as oiling, small crystal size, difficulty in filtration, and impurity entrainment.

[0006] Existing processes can purify pyrimidine-5-carboxaldehyde using column chromatography, but column chromatography suffers from problems such as high consumption of packing materials and organic solvents, long operation cycles, difficulty in scale-up, and long product exposure time, which are not conducive to industrial production.

[0007] Another method of protection is to convert the aldehyde into an acetal before storage, followed by acidic hydrolysis before subsequent use. Acetal protection typically requires the use of polyols such as ethylene glycol, acidic catalysts, and dehydration conditions; deprotection requires acidic hydrolysis, neutralization, extraction, and concentration, involving multiple process steps.

[0008] Unreacted aldehydes and acid-catalyzed degradation impurities may remain during acetal preparation; during deprotection, incompletely hydrolyzed acetals, hemiacetal-related impurities, aldehyde oxidative acids, and high-retention-time degradation impurities may also remain. These impurities will reduce the purity and overall yield of the regenerated aldehydes.

[0009] Bisulfites can form hydroxysulfonate adducts with some aldehydes. However, different aldehydes have significant differences in electronic effects, steric hindrance, and water solubility. Whether a crystalline adduct can be formed that can be independently isolated, has sufficient purity and storage stability, and can be regenerated in high yield cannot be determined directly based on general reaction principles alone.

[0010] For pyrimidine-5-carboxaldehyde containing fluoroaryl, isopropyl, pyrimidine ring and N-methyl-N-methanesulfonylamino groups, the type of bisulfite, solvent composition, order of addition, reaction pH, amount of antisolvent, and dissociation conditions all affect the reaction equilibrium, crystal precipitation, impurity entrainment, and aldehyde regeneration.

[0011] Therefore, it is necessary to provide a rosuvastatin calcium intermediate that can stably store the pyrimidine-5-carboxaldehyde in crystalline solid form, has a purification effect, and can regenerate free aldehydes in high yield under mild conditions, as well as a method for preparing the same. Summary of the Invention

[0012] The purpose of this invention is to provide a rosuvastatin calcium intermediate and its preparation method, in order to solve the problems of insufficient storage stability of pyrimidine-5-carboxaldehyde, low efficiency of direct crystallization purification, large solvent consumption in column chromatography, and numerous acetal protection and deprotection steps.

[0013] Another object of the present invention is to provide a method for regenerating pyrimidine-5-carboxaldehyde by dissociation of the intermediate, which enables the intermediate to release free aldehyde under relatively mild alkaline conditions and achieves the separation of aldehyde from inorganic salt by methyl tert-butyl ether extraction.

[0014] To achieve the above objectives, the present invention provides the following technical solution: a rosuvastatin calcium intermediate, wherein the intermediate is a pyrimidine formaldehyde bisulfite adduct of formula (I): A + [R—CH(OH)—SO3] - (I); Wherein, R is 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl, A + Selected from Na + K + or NH4 + .

[0015] When A + for Na + In this case, the intermediate is sodium 1-hydroxy-1-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]methanesulfonate.

[0016] Preferably, the intermediate is a crystalline solid.

[0017] The purity of the intermediate, as determined by high performance liquid chromatography area normalization, is not less than 98.0%, preferably not less than 99.0%; wherein the content of unreacted 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde is not more than 1.0%, preferably not more than 0.5%.

[0018] A method for preparing a rosuvastatin calcium intermediate includes the following steps: Step 1: Add 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde to a mixed solvent consisting of water and a water-miscible organic solvent to obtain the raw material solution; Step 2: The raw material solution is contacted with an aqueous solution of AHSO3 and an addition reaction is carried out at 0–35°C and pH 3.5–6.5 to obtain a reaction solution containing the pyrimidine formaldehyde bisulfite adduct shown in formula (I), wherein the bisulfite is selected from sodium bisulfite, potassium bisulfite or ammonium bisulfite. Step 3: Adjust the content of organic solvent in the reaction solution and cool down to crystallize. Filter, wash and dry the obtained crystals to obtain the rosuvastatin calcium intermediate.

[0019] The water-miscible organic solvent is selected from one or more of ethanol, isopropanol, or acetone.

[0020] Preferably, the water-miscible organic solvent is ethanol, isopropanol, or a mixture of ethanol and acetone.

[0021] The molar ratio of pyrimidine-5-carboxaldehyde to AHSO3 is 1:1.02 to 1.30, preferably 1:1.08 to 1.22, and more preferably 1:1.12 to 1.18.

[0022] The mass concentration of the AHSO3 aqueous solution is 15% to 40%, preferably 20% to 35%.

[0023] The addition reaction takes 1 to 6 hours, preferably 2 to 4 hours.

[0024] The volume ratio of water to water-miscible organic solvent in the mixed solvent is 1:0.5 to 4, preferably 1:1 to 3.

[0025] In this instruction manual, the mass concentration of pyrimidine-5-carboxaldehyde in the feed solution refers to the number of grams of pyrimidine-5-carboxaldehyde contained in every 100 mL of feed solution.

[0026] The mass concentration of pyrimidine-5-carboxaldehyde in the raw material solution is 5% to 25%, preferably 10% to 20%.

[0027] When the water-miscible organic solvent contains acetone, the acetone accounts for 5% to 30% of the total volume of water and all water-miscible organic solvents.

[0028] Acetone is preferably used in combination with ethanol to reduce the impact of competitive addition between acetone and bisulfite on the effective bisulfite concentration.

[0029] Preferably, the raw material liquid is added dropwise to an aqueous solution of AHSO3 to ensure that bisulfite remains in excess relative to the local aldehyde concentration during the feeding process.

[0030] During the dropwise addition, the reaction temperature is controlled at 10–25℃ and the pH of the reaction system is controlled at 4.2–5.8; after the dropwise addition is completed, the reaction is kept at the temperature for 1–4 hours.

[0031] The antisolvent is selected from acetone or acetonitrile.

[0032] The volume ratio of the antisolvent to the addition reaction solution is 0.5 to 4:1, preferably 1 to 3:1.

[0033] After adding the antisolvent, the system is cooled to -5 to 10°C and crystallized for 1 to 8 hours.

[0034] The obtained crystals were washed with acetone, isopropanol, or acetonitrile with a water content not exceeding 5 wt%, and then subjected to a temperature of 25–50 °C and a gauge pressure of [insert pressure here]. 0.060~ Dry to constant weight under a vacuum of 0.095 MPa.

[0035] A method for regenerating 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde from the rosuvastatin calcium intermediate comprises the following steps: The rosuvastatin calcium intermediate is added to water to form a solution or suspension, and then methyl tert-butyl ether is added to form a two-phase system. The amount of water used is 2 to 8 mL and the amount of methyl tert-butyl ether is 4 to 12 mL per 1 g of the intermediate. An alkaline aqueous solution with a mass concentration of 5% to 20% is added at 10 to 30°C to adjust the pH of the aqueous phase to 8.0 to 10.5, causing the intermediate to dissociate and generate the pyrimidine-5-carboxaldehyde. The methyl tert-butyl ether phase was separated, washed with water, dried, and concentrated under reduced pressure to obtain the pyrimidine-5-carboxaldehyde.

[0036] The alkaline aqueous solution is selected from sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, or potassium carbonate aqueous solution.

[0037] Preferably, the amount of water used is 4 to 6 mL and the amount of methyl tert-butyl ether is 6 to 10 mL per 1 g of the intermediate.

[0038] Preferably, the dissociation temperature is 15–25°C and the pH of the aqueous phase is 8.8–9.8.

[0039] Reaction mechanism The carbonyl carbon of the pyrimidine-5-carboxaldehyde can accept nucleophilic addition of bisulfite to form α-hydroxysulfonate.

[0040] The resulting adduct is ionic and has a certain solubility in aqueous alcohol solvents. However, its solubility decreases after the addition of acetone or acetonitrile and the temperature is lowered, allowing it to precipitate as a crystalline solid.

[0041] Some non-aldehyde organic impurities in the original free aldehyde do not form the same bisulfite adduct, or their adducts have different solubilities than the target adduct, and therefore can be partially removed in the reaction mother liquor and washing solution. This process combines aldehyde group protection and crystallization purification.

[0042] When the pH of the system increases to 8.0–10.5, the bisulfite addition equilibrium shifts towards the free aldehyde.

[0043] The generated free aldehyde preferentially enters the methyl tert-butyl ether phase, while sulfites, sulfates, and sodium, potassium, or ammonium salts are mainly retained in the aqueous phase, thereby achieving the separation of free aldehydes from inorganic salts.

[0044] Compared with the prior art, the present invention provides a rosuvastatin calcium intermediate and its preparation method, which has the following beneficial effects: converting active pyrimidine-5-carboxaldehyde into a crystalline bisulfite adduct, reducing the degree of oxidation and other degradation reactions of the aldehyde group during storage, and improving the content retention rate of the intermediate under long-term and accelerated storage conditions.

[0045] This invention utilizes the selective addition of the target aldehyde to the bisulfite and the difference in solubility of the resulting adduct to achieve product separation through crystallization, filtration and washing, thereby reducing the amount of column chromatography packing and organic solvents used.

[0046] Under optimal conditions, pyrimidine-5-carboxaldehyde raw material with a purity of 94%–95% can yield crystalline adducts with a purity higher than 99%, indicating that there is a synergistic purification effect between the addition reaction and antisolvent crystallization.

[0047] The intermediate of this invention can dissociate under mild alkaline conditions and obtain high-purity free aldehydes by extraction with methyl tert-butyl ether, avoiding the strong acidic conditions and long reaction time required for acetal deprotection.

[0048] Adding the raw material solution dropwise to the bisulfite aqueous solution can reduce the local concentration of free aldehydes and the precipitation of viscous substances, thereby improving the conversion rate, crystal size and filtration performance.

[0049] This invention provides embodiments for sodium salts, potassium salts, and ammonium salts, as well as embodiments for ethanol, isopropanol, and acetone-containing mixed solvents, which can be selected according to raw material supply, equipment conditions, and downstream process requirements.

[0050] This invention uses common industrial solvents and reagents, and the reaction temperature is relatively low. The product can be separated by crystallization and filtration, which has the basis for further scale-up applications. Attached Figure Description

[0051] Figure 1 The above is the hydrogen nuclear magnetic resonance spectrum of the sodium bisulfite adduct obtained in Example 2 of this invention; Figure 2 The carbon nuclear magnetic resonance spectrum of the sodium bisulfite adduct obtained in Example 2 of this invention; Figure 3 This is a high-resolution mass spectrum in negative ion mode of the sodium bisulfite adduct obtained in Example 2 of the present invention; Figure 4 This is the powder X-ray diffraction pattern of the potassium bisulfite adduct obtained in Example 4 of the present invention. Detailed Implementation

[0052] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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 of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0053] Please see Figures 1-4 This invention provides a technical solution for a rosuvastatin calcium intermediate and its preparation method: 1. Raw materials and reagents Unless otherwise stated, the 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde used in the examples were from the same batch, with a high performance liquid chromatography purity of 94.82% and a water content of 0.21%.

[0054] Sodium bisulfite, potassium bisulfite, ammonium bisulfite, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, toluene, ethylene glycol, p-toluenesulfonic acid monohydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate are all of analytical grade or industrial grade.

[0055] The reference standards used for performance testing were confirmed by nuclear magnetic resonance, mass spectrometry, and high-performance liquid chromatography.

[0056] 2. Current testing standards All tests for this application will be conducted in 2026, adopting the relevant general rules and guidelines of Part IV of the 2025 edition of the Pharmacopoeia of the People's Republic of China.

[0057] For high performance liquid chromatography (HPLC) detection, refer to General Rule 0512, High Performance Liquid Chromatography.

[0058] Moisture content determination shall be performed in accordance with General Rule 0832 Moisture Determination Method, and in conjunction with GB / T 6283—2008 Determination of Moisture Content in Chemical Products - Karl Fischer Method (General Method)

[0059] The detection of residual solvents shall be performed in accordance with General Rule 0861, Method for Determination of Residual Solvents.

[0060] Stability testing shall be conducted in accordance with Guideline 9001, Guideline for Stability Testing of Active Pharmaceutical Ingredients and Formulations.

[0061] Analytical method validation shall refer to Guideline 9101 Analytical Method Validation Guideline.

[0062] 3. High Performance Liquid Chromatography (HPLC) Detection Method Product purity, free aldehyde content, reaction conversion rate, and related substances were determined by high performance liquid chromatography.

[0063] The chromatographic column is an octadecylsilane-bonded silica column with dimensions of 250 mm × 4.6 mm and 5 μm.

[0064] Mobile phase A was an aqueous solution containing 10 mmol / L tetrabutylammonium hydrogen sulfate, with the pH adjusted to 5.0 using phosphate buffer; mobile phase B was acetonitrile.

[0065] The flow rate was 1.0 mL / min, the column temperature was 30 °C, the detection wavelength was 242 nm, and the injection volume was 10 μL.

[0066] The gradient elution procedure is as follows: 0–5 min, mobile phase B is 30%; Within 5–20 minutes, the mobile phase B increased linearly from 30% to 70%. For 20–25 minutes, mobile phase B is maintained at 70%. 25.1–32 min, mobile phase B recovers and remains at 30%.

[0067] The adduct sample was dissolved in a mixture of water and acetonitrile at a volume ratio of 60:40, with a sample concentration of 0.5 mg / mL. The test solution was prepared and analyzed within 2 hours.

[0068] The free aldehyde sample was dissolved in acetonitrile and diluted with the initial mobile phase.

[0069] The reaction conversion rate is calculated according to the following formula: Reaction conversion rate = (Aldehyde peak area correction value before reaction - Aldehyde peak area correction value after reaction) ÷ Aldehyde peak area correction value before reaction × 100%.

[0070] Product purity was calculated using the area normalization method, and the content of the target substance was verified using the external standard method.

[0071] 4. Aldehyde equivalent yield To eliminate the influence of differences in molecular weight between sodium, potassium, and ammonium salts, the yield of the adduct is expressed as aldehyde equivalent yield: Aldehyde equivalent yield = product quality × product content × relative molecular mass of pyrimidine-5-formaldehyde ÷ relative molecular mass of adduct ÷ mass of aldehyde fed × 100%.

[0072] 5. Detection of moisture and residual solvents Moisture content was determined using the Karl Fischer volumetric method.

[0073] Residual ethanol, isopropanol, acetone, acetonitrile, toluene, and methyl tert-butyl ether were determined by headspace gas chromatography.

[0074] The residual solvent detection method was validated for specificity, linearity, accuracy, precision, limit of quantitation, and robustness.

[0075] 6. Structural Confirmation The structure and solid-state properties were confirmed by methods such as hydrogen nuclear magnetic resonance spectroscopy, carbon nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, high-resolution mass spectrometry, and powder X-ray diffraction.

[0076] Compared to the free aldehyde, the aldehyde hydrogen signal disappears in the adduct and a hydrogen signal with -CH(OH)SO3 appears. - Corresponding new signals: the characteristic absorption of aldehyde carbonyl in the infrared spectrum was significantly weakened, and sulfonate-related absorption appeared; the corresponding adduct anion signals were detected in sodium salt, potassium salt and ammonium salt in negative ion mode.

[0077] 7. Storage stability test Each sample was placed in a double-layer polyethylene bag, then covered with an aluminum-plastic composite bag and sealed.

[0078] The long-term test conditions were 25℃±2℃ and relative humidity 60%±5%, and the observation period was 12 months.

[0079] The accelerated testing conditions were 40℃±2℃ and relative humidity 75%±5%, and the observation period was 6 months.

[0080] Long-term trials were conducted at 0, 3, 6, 9, and 12 months.

[0081] Accelerated tests were conducted at 0, 1, 2, 3, and 6 months.

[0082] The test measures the content of the target substance, total impurities, maximum single impurity, free aldehyde content, appearance, and regenerated aldehyde yield.

[0083] 8. Regenerated aldehyde yield The yield of regenerated aldehydes is calculated using the following formula:

[0084] The relative molecular mass conversion factor is the mass ratio of the theoretically releasable pyrimidine-5-carboxaldehyde in the corresponding adduct.

[0085] 9. Filtration performance After crystallization, vacuum filtration was performed using the same filtration area and the same pressure difference, and the time required from the start of filtration until there was no continuous liquid layer on the surface of the filter cake was recorded.

[0086] The shorter the filtration time, the more suitable the crystal particle size and filter cake permeability are for industrial operation.

[0087] Example 1 Weigh 20.00g of pyrimidine-5-carboxaldehyde and add it to a mixed solvent consisting of 266.7mL of water and 133.3mL of ethanol, so that the volume ratio of water to ethanol is 1:0.5 and the mass concentration of pyrimidine-5-carboxaldehyde is 5%.

[0088] Weigh 6.04 g of sodium bisulfite and prepare a 15% sodium bisulfite aqueous solution. The molar ratio of sodium bisulfite to pyrimidine-5-carbaldehyde is 1.02:1.

[0089] The raw material solution was cooled to 0°C, sodium bisulfite aqueous solution was added, the pH of the system was adjusted to 3.5, and the reaction was carried out at 0°C for 1 hour.

[0090] After the reaction was complete, acetone was added at 0.5 times the volume of the reaction liquid, and the system was cooled to -5°C and kept at that temperature for 1 hour to crystallize.

[0091] The filter cake was filtered, washed with anhydrous acetone, and dried to constant weight at 25°C and a vacuum of -0.060 MPa to obtain the sodium bisulfite adduct.

[0092] Example 2 Weigh 20.00g of pyrimidine-5-carboxaldehyde, add 44.4mL of water and 88.9mL of ethanol to make the volume ratio of water to ethanol 1:2, and the mass concentration of pyrimidine-5-carboxaldehyde 15%.

[0093] Weigh 6.81 g of sodium bisulfite and prepare a 25% sodium bisulfite aqueous solution. The molar ratio of sodium bisulfite to pyrimidine-5-carbaldehyde is 1.15:1.

[0094] Sodium bisulfite aqueous solution was placed in a reaction vessel and the temperature was controlled at 18°C. The raw material solution was added dropwise to the sodium bisulfite aqueous solution over 60 minutes.

[0095] The pH was maintained at 5.0 during the dropwise addition. After the addition was complete, the reaction was continued at 18°C ​​for 2 hours.

[0096] After the reaction was complete, acetone was added at twice the volume of the reaction liquid, the system was cooled to 2°C, and crystallization was carried out at this temperature for 4 hours.

[0097] The filter cake was filtered, washed with acetone with a water content of less than 0.5 wt%, and dried to constant weight at 40 °C and a vacuum of -0.080 MPa to obtain the sodium bisulfite adduct.

[0098] The resulting product is an off-white crystalline powder.

[0099] Example 3 Weigh 20.00g of pyrimidine-5-carboxaldehyde, add 16.0mL of water and 64.0mL of ethanol to make the volume ratio of water to ethanol 1:4, and the mass concentration of pyrimidine-5-carboxaldehyde 25%.

[0100] Weigh 7.70 g of sodium bisulfite and prepare a 40% sodium bisulfite aqueous solution. The molar ratio of sodium bisulfite to pyrimidine-5-carbaldehyde is 1.30:1.

[0101] The raw material solution was mixed with an aqueous solution of sodium bisulfite at 35°C, the pH of the system was adjusted to 6.5, and the reaction was carried out at 35°C for 6 hours.

[0102] After the reaction was complete, acetone was added at a volume of 4 times the volume of the reaction liquid, and the mixture was crystallized at 10°C for 8 hours.

[0103] The filter cake was filtered, washed with acetone containing 5 wt% water, and dried to constant weight at 50°C and a vacuum of -0.095 MPa to obtain the sodium bisulfite adduct.

[0104] Example 4 Except for replacing 6.81g of sodium bisulfite with 7.86g of potassium bisulfite in Example 2 and adjusting the pH with potassium hydroxide aqueous solution, the other conditions were the same as in Example 2, and a potassium bisulfite adduct was obtained.

[0105] Example 5 Except for replacing 6.81g of sodium bisulfite with 6.49g of ammonium bisulfite in Example 2 and adjusting the pH with dilute ammonia, the other conditions were the same as in Example 2, and the ammonium bisulfite adduct was obtained.

[0106] Ammonium bisulfite aqueous solution should be freshly prepared before use and used under sealed conditions.

[0107] Example 6 Except for replacing the ethanol in Example 2 with an equal volume of isopropanol, the other basic conditions are the same as in Example 2.

[0108] The temperature of the raw material solution added dropwise to the sodium bisulfite aqueous solution was controlled at 10℃. During the dropwise addition, the pH was maintained at 4.2. After the dropwise addition was completed, the reaction continued for 1 hour.

[0109] Acetone was then added at twice the volume of the reaction liquid, and the mixture was crystallized at 2°C for 4 hours. After filtration, washing, and drying, the sodium bisulfite adduct was obtained.

[0110] Example 7 Weigh 20.00g of pyrimidine-5-carboxaldehyde, add 44.4mL of water, 48.9mL of ethanol and 40.0mL of acetone, so that the total volume ratio of water to organic solvent is 1:2, and acetone accounts for 30% of the total volume of the mixed solvent.

[0111] The amount, concentration, and molar ratio of sodium bisulfite were the same as in Example 2.

[0112] The raw material solution was added dropwise to an aqueous solution of sodium bisulfite at 25°C, while maintaining the pH at 5.8 during the addition process. After the addition was completed, the reaction continued for 4 hours.

[0113] After the reaction was complete, acetonitrile was added at twice the volume of the reaction liquid, and the system was cooled to 2°C and allowed to crystallize for 4 hours.

[0114] The filter cake was filtered, washed with acetonitrile, and dried to constant weight at 40°C and a vacuum of -0.080 MPa to obtain the sodium bisulfite adduct.

[0115] Example 8 Weigh 20.00g of pyrimidine-5-carboxaldehyde, add 44.4mL of water, 82.2mL of ethanol and 6.7mL of acetone, so that acetone accounts for 5% of the total volume of the mixed solvent.

[0116] The remaining conditions were the same as in Example 2, and the sodium bisulfite adduct was obtained.

[0117] Example 9 Add 2.22L of water and 4.45L of ethanol to a 50L reactor, then add 1.000kg of pyrimidine-5-carboxaldehyde and stir to dissolve.

[0118] 340.7g of sodium bisulfite was prepared into an aqueous solution with a mass concentration of 25% and added to another reaction vessel.

[0119] The system temperature was controlled at 20℃, and the raw material solution was added dropwise over 90 minutes, maintaining the pH at 5.0±0.2 during the addition. After the addition was completed, the reaction continued for 2 hours.

[0120] After the reaction is complete, add acetone equivalent to twice the volume of the reaction liquid, cool the system to 2°C and crystallize for 4 hours.

[0121] The filter cake was filtered, washed with acetone, and dried to constant weight at 40°C and a vacuum of -0.085 MPa to obtain the sodium bisulfite adduct.

[0122] Example 10 Weigh 100.0g of the sodium bisulfite adduct obtained in Example 2, and add 200mL of water and 400mL of methyl tert-butyl ether.

[0123] The system temperature was controlled at 10℃, and a 5% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the aqueous phase to 8.0. Stirring was continued for 20 minutes.

[0124] The phase was allowed to stand and separate into layers, and the methyl tert-butyl ether phase was separated. The aqueous phase was extracted once with methyl tert-butyl ether, and the organic phases were combined, washed with water, dried, and concentrated under reduced pressure to obtain pyrimidine-5-carboxaldehyde.

[0125] Example 11 Weigh 100.0g of the sodium bisulfite adduct obtained in Example 2, and add 500mL of water and 800mL of methyl tert-butyl ether.

[0126] The system temperature was controlled at 20℃, and a 10% potassium carbonate aqueous solution was added dropwise to adjust the pH of the aqueous phase to 9.2. The mixture was then stirred for 20 minutes.

[0127] After standing and separating, the mixture was extracted, washed, dried and concentrated according to the method of Example 10 to obtain pyrimidine-5-carboxaldehyde.

[0128] Example 12 Weigh 100.0g of the sodium bisulfite adduct obtained in Example 2, and add 800mL of water and 1200mL of methyl tert-butyl ether.

[0129] The system temperature was controlled at 30℃, and a 20% potassium hydroxide aqueous solution was added dropwise to adjust the pH of the aqueous phase to 10.5. The mixture was then stirred for 20 minutes.

[0130] After standing and separating, the mixture was processed according to the method in Example 10 to obtain pyrimidine-5-carboxaldehyde.

[0131] Example 13 Except for replacing the potassium carbonate aqueous solution in Example 11 with a sodium carbonate aqueous solution with a mass concentration of 10% and adjusting the pH of the aqueous phase to 9.0, the other operations are the same as in Example 11.

[0132] Comparative Example 1: 20.00 g of pyrimidine-5-carboxaldehyde was weighed and added to a mixed solvent of water and ethanol in the same volume and proportion as in Example 2. Without adding sodium bisulfite, the same volume of acetone as in Example 2 was added, and the mixture was crystallized at 2°C for 4 hours. Filtration, washing, and drying were performed under the same conditions as in Example 2 to obtain free pyrimidine-5-carboxaldehyde. The obtained free aldehyde was stored under the same packaging and stability conditions as the product of Example 2.

[0133] Comparative Example 2 (I) Preparation of ethylene glycol acetal Add 20.00 g pyrimidine-5-carboxaldehyde, 4.24 g ethylene glycol, and 160 mL toluene to a 500 mL four-necked reaction flask equipped with a mechanical stirrer, thermometer, reflux condenser, and water separator.

[0134] The amount of pyrimidine-5-carboxaldehyde is 56.9 mmol, the amount of ethylene glycol is 68.3 mmol, and the molar ratio of ethylene glycol to pyrimidine-5-carboxaldehyde is 1.20:1.

[0135] Add 0.54 g of p-toluenesulfonic acid monohydrate, which is equivalent to 0.05 molar equivalents of pyrimidine-5-carbaldehyde.

[0136] Under nitrogen protection, the mixture is heated to reflux with toluene, and the temperature of the reaction solution is controlled at 108-112°C, so that the generated water enters the water separator along with the toluene in an azeotropic reaction.

[0137] During the reaction, the volume of the water layer in the separator was recorded every 1 hour and samples were taken for high performance liquid chromatography detection.

[0138] Heating was stopped when the water volume in the separator no longer increased significantly for 1 hour, and the peak area content of unreacted pyrimidine-5-carboxaldehyde in the reaction solution was no higher than 1.0%. The reaction time was 6 hours, and the water layer collected in the separator was approximately 0.9–1.0 mL, which is close to the theoretical water production calculated based on the feed amount.

[0139] Cool the reaction solution to 25–30°C, and slowly add 80 mL of a 5% sodium bicarbonate aqueous solution to adjust the pH of the aqueous phase to 7.0–8.0.

[0140] The mixture was allowed to stand and separate into layers, and the toluene phase was separated. The toluene phase was washed successively with 50 mL of water and 50 mL of saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate.

[0141] The desiccant was removed by filtration, and the mixture was concentrated under reduced pressure at a temperature not exceeding 45°C until the remaining volume was approximately 45 mL.

[0142] 120 mL of n-heptane was slowly added with stirring, the system was cooled to 5 °C and kept at that temperature for 3 h to crystallize.

[0143] The filter cake was filtered, washed with 20 mL of cold n-heptane, and dried under vacuum at 40 °C to constant weight to obtain 21.10 g of pyrimidine-5-carboxaldehyde ethylene glycol acetal.

[0144] The acetal had a high performance liquid chromatography purity of 98.41% and an aldehyde equivalent yield of 93.1% based on pyrimidine-5-carbaldehyde.

[0145] The main impurities in the obtained acetal include unreacted pyrimidine-5-carboxaldehyde, aldehyde oxidizing acid, and a small amount of impurities with unknown high retention times.

[0146] (ii) Storage of acetal The obtained ethylene glycol acetal was packaged into double-layer polyethylene bags, with the same aldehyde equivalent as the adduct in Example 2, and then covered with an aluminum-plastic composite bag and sealed.

[0147] Store under the same long-term and accelerated testing conditions as in Example 2.

[0148] (III) Deprotection of ethylene glycol acetal Weigh 20.00g of the ethylene glycol acetal and add it to a mixed solvent consisting of 120mL acetone and 40mL water.

[0149] The system temperature was controlled at 20-25℃, and 2 mol / L hydrochloric acid aqueous solution was added dropwise to adjust the pH of the system to 1.5.

[0150] The system was heated to 50°C and reacted for 4 hours. Samples were taken every hour during the reaction for high-performance liquid chromatography (HPLC) detection.

[0151] The reaction ends when the acetal peak area content is not higher than 0.5% and the change in acetal peak area between two consecutive samples does not exceed 0.1 percentage points.

[0152] Cool the reaction solution to 20–25°C, slowly add a 10% sodium bicarbonate aqueous solution, and adjust the pH of the aqueous phase to 7.0–7.5.

[0153] Add 160 mL of methyl tert-butyl ether, stir for 10 min, and allow to stand for phase separation. Separate the organic phase, and extract the aqueous phase twice more with 80 mL of methyl tert-butyl ether.

[0154] The organic phases were combined, washed successively with water and saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate.

[0155] The desiccant was removed by filtration, and the mixture was concentrated under reduced pressure at a temperature not exceeding 35°C to obtain free pyrimidine-5-carboxaldehyde.

[0156] The yield of free aldehyde in the acetal deprotection step was 91.2%, and the purity of the obtained free aldehyde was 98.63%.

[0157] The total aldehyde equivalent yield of the two steps of acetal preparation and deprotection was 84.9%.

[0158] The main impurities in the free aldehydes obtained after deprotection include residual acetals, hemiacetal-related peaks, aldehyde oxidative acids, and degradation impurities with unknown retention times.

[0159] Among them, residual acetals were confirmed by the retention time and mass spectrometry of acetal reference standards; aldehyde oxidases were confirmed by the retention time and mass spectrometry of the corresponding reference standards; hemiacetal-related peaks and high retention time unknown impurities were classified only according to their relative retention time and mass spectrometry characteristics, and were not described as specific compounds whose structures had been confirmed.

[0160] Comparative Example 3 was identical to Example 2 except that the order of adding materials was changed to adding sodium bisulfite aqueous solution to pyrimidine-5-carboxaldehyde raw material solution dropwise within 60 minutes.

[0161] Comparative Example 4 was the same as Example 2 except that the reaction pH in Example 2 was adjusted from 5.0 to 7.2.

[0162] Comparative Example 5 was the same as Example 2 except that the ethanol in Example 2 was replaced with an equal volume of tetrahydrofuran.

[0163] Comparative Example 6 was identical to Example 2 except that the volume ratio of acetone to addition reaction solution in Example 2 was adjusted from 2:1 to 0.2:1.

[0164] Preparation performance test Both the examples and comparative examples underwent three independent parallel batch tests. The data in Table 1 are the average values ​​of the three batches.

[0165] Table 1. Preparation performance of the examples and comparative examples

[0166] The aldehyde equivalent yield of Comparative Example 2 was the total yield of the two steps of acetal preparation and deprotection, and the product purity was the purity of the free aldehyde obtained after deprotection.

[0167] As shown in Table 1, within the scope of this invention, the aldehyde conversion rate of Examples 1-9 is 98.3%-99.8%, the aldehyde equivalent yield is 88.6%-93.8%, and the product purity is 98.32%-99.45%. The product purity of Example 2 is increased from 94.82% of the raw material to 99.45%, and column chromatography purification is not required. Examples 4 and 5 demonstrate that both potassium and ammonium salts can form separable crystalline adducts. Examples 6-8 demonstrate that isopropanol and mixed solvents containing 5%-30% acetone can be used to prepare the adducts. Comparative Example 3, which only changed the order of addition, had lower conversion rate, yield, purity, and filtration performance than Example 2. Comparative Example 4 shows that the degree of addition reaction decreases when the reaction pH is increased to 7.2. Comparative Example 5 shows that the product crystal purity and filtration performance decrease when tetrahydrofuran is used. Comparative Example 6 shows that when the amount of antisolvent is insufficient, the residual amount of the target product in the mother liquor increases, leading to a decrease in the aldehyde equivalent yield.

[0168] Table 2. Stability test results under long-term storage conditions

[0169] Table 3. Stability test results under accelerated storage conditions

[0170] Sodium and potassium salts both exhibited high content retention rates under long-term and accelerated conditions.

[0171] Compared to free aldehydes, the sodium salt of Example 2 showed a 14.1 percentage point increase in content retention after 12 months of long-term storage and a 27.1 percentage point increase after 6 months of accelerated storage. Ethylene glycol acetals possess a certain degree of storage stability, but still require acidic hydrolysis after storage, resulting in a lower free aldehyde regeneration yield compared to the sodium and potassium salts of this invention.

[0172] Table 4. Aldehyde regeneration performance under different dissociation conditions

[0173] Using potassium carbonate or sodium carbonate aqueous solution at pH 9.0–9.2 can yield high regenerated aldehyde yield and purity.

[0174] Compared with the acidic acetal hydrolysis of Comparative Example 2, the present invention has a lower dissociation temperature, shorter operation time, and higher yield and purity of the obtained free aldehyde.

[0175] Table 5. Comparison of processes with different protection and purification methods

[0176] The formation of the sodium bisulfite adduct, combined with antisolvent crystallization, yields a crystalline product with a purity of 99.45% from a starting material with a purity of 94.82%, while maintaining an aldehyde equivalent yield of 93.8%. Although ethylene glycol acetal has a certain protective effect, its preparation, post-treatment, and acidic deprotection processes are lengthy, resulting in lower overall yield and post-storage regeneration yield compared to this invention.

[0177] Related substances were analyzed for the regenerated aldehyde of Example 11, the free aldehyde of Comparative Example 1 after long-term storage for 12 months, and the free aldehyde obtained by deprotection of acetal in Comparative Example 2. The results are shown in Table 6.

[0178] Table 6. Impurity spectra of free aldehydes obtained by different treatment methods

[0179] In Example 11, the residual adduct content in the regenerated aldehyde was low, and no hemiacetal-related peaks were detected. In Comparative Example 2, the free aldehyde obtained after deprotection showed residual acetal and hemiacetal-related peaks, indicating that there were specific impurities caused by incomplete hydrolysis or hydrolysis equilibrium during the acetal deprotection process. After long-term storage, the free aldehyde in Comparative Example 1 showed a significant increase in aldehyde oxidizing acid and impurities with unknown retention times.

[0180] The above results indicate that the bisulfite adduct of the present invention can yield free aldehydes with low impurity levels through mild alkaline dissociation after storage, and its impurity profile differs from that of direct storage of free aldehydes and deprotection schemes of ethylene glycol acetal.

[0181] Table 7. Moisture and Residual Solvents of Representative Products

[0182] By controlling the water content of the washing solvent and the vacuum drying conditions, a crystalline product with lower moisture content can be obtained. In Comparative Example 2, acetone, toluene, and methyl tert-butyl ether residues were simultaneously detected in the deprotected aldehyde, reflecting the use of a variety of solvents in the acetal preparation and deprotection routes.

[0183] Figure 1 In the sample, the solution was dissolved in deuterated dimethyl sulfoxide and analyzed using a 400 MHz nuclear magnetic resonance spectrometer at 25 °C. The x-axis represents chemical shift, and the y-axis represents relative signal intensity. In the spectrum, the aldehyde hydrogen signal of the free aldehyde disappears, and —CH(OH)SO3 appears. - The new signal corresponding to the structure indicates that the bisulfite ion has undergone an addition reaction with the aldehyde group.

[0184] Figure 2 In the analysis, the sample was dissolved in deuterated dimethyl sulfoxide and subjected to broadband proton decoupling analysis using a 100 MHz carbon NMR spectrometer at 25 °C. The x-axis represents chemical shift, and the y-axis represents relative signal intensity. The signal of the free aldehyde carbonyl carbon disappeared in the spectrum, and —CH(OH)SO3 appeared.- The new carbon signal corresponding to the structure indicates that the target adduct has been formed.

[0185] Figure 3 In the analysis, the sample was dissolved in a water-acetonitrile mixed solvent and detected using an electrospray quadrupole-time-of-flight high-resolution mass spectrometer. The x-axis represents the mass-to-charge ratio, and the y-axis represents the relative abundance. [M-Na] appeared in the spectrum. - The corresponding target ion peaks and isotope peak clusters support the molecular composition and structure of the adduct.

[0186] Figure 4 In the experiment, the sample was lightly ground and then flattened into a sample cell. Cu Kα radiation was used for scanning at room temperature. The horizontal axis represents the diffraction angle 2θ, and the vertical axis represents the relative intensity. The graph shows several well-defined and sharp characteristic diffraction peaks, indicating that the obtained potassium bisulfite adduct has good crystallinity.

[0187] Comprehensive test results show that the bisulfite adduct of the present invention has high crystal purity and aldehyde equivalent yield, and the sodium and potassium salts have good storage stability.

[0188] The intermediate of this invention, after being dissociated by an alkaline aqueous solution, can regenerate pyrimidine-5-carboxaldehyde with high yield and purity; compared with the ethylene glycol acetal route, it can also reduce residual acetal and hemiacetal related peaks and acid deprotection degradation impurities.

Claims

1. A rosuvastatin calcium intermediate, characterized in that, The rosuvastatin calcium intermediate is the pyrimidine formaldehyde bisulfite adduct of formula (I): A + [R—CH(OH)—SO3] - (I); Wherein, R is 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl, A + Selected from Na + K + or NH4 + .

2. The rosuvastatin calcium intermediate according to claim 1, characterized in that, The A + for Na + The intermediate of rosuvastatin calcium is sodium 1-hydroxy-1-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]methanesulfonate.

3. The rosuvastatin calcium intermediate according to claim 1, characterized in that, The A + For K + or NH4 + The rosuvastatin calcium intermediate is a crystalline solid with a purity of not less than 98.0% as determined by high performance liquid chromatography area normalization method, wherein the content of free 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde is not higher than 1.0%.

4. A method for preparing a rosuvastatin calcium intermediate, characterized in that, Includes the following steps: (1) 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde is added to a mixed solvent consisting of water and a water-miscible organic solvent to obtain a raw material solution, wherein the water-miscible organic solvent is selected from one or more of ethanol, isopropanol or acetone; (2) The raw material solution is contacted with an aqueous solution of AHSO3 and an addition reaction is carried out at 0-35°C and pH 3.5-6.5 to obtain a reaction solution containing pyrimidine formaldehyde bisulfite adduct, wherein the bisulfite is selected from sodium bisulfite, potassium bisulfite or ammonium bisulfite. (3) Add acetone or acetonitrile to the reaction solution as an antisolvent, and cool down to crystallize. The resulting crystals are filtered, washed and dried to obtain the rosuvastatin calcium intermediate shown in formula (I).

5. The method for preparing a rosuvastatin calcium intermediate according to claim 4, characterized in that, The molar ratio of pyrimidine-5-carboxaldehyde to AHSO3 is 1:1.02 to 1.30, the mass concentration of the AHSO3 aqueous solution is 15% to 40%, and the addition reaction time is 1 to 6 hours.

6. A method for preparing a rosuvastatin calcium intermediate according to claim 4 or 5, characterized in that, The volume ratio of water to water-miscible organic solvent in the mixed solvent is 1:0.5 to 4, and the mass concentration of pyrimidine-5-carboxaldehyde in the raw material solution is 5% to 25%; when the water-miscible organic solvent contains acetone, the volume content of acetone in the mixed solvent is 5% to 30%.

7. A method for preparing a rosuvastatin calcium intermediate according to any one of claims 4 to 6, characterized in that, The raw material solution was added dropwise to an AHSO3 aqueous solution. During the dropwise addition, the temperature of the reaction system was controlled at 10–25°C and the pH was controlled at 4.2–5.

8. After the dropwise addition was completed, the reaction was continued at this temperature for 1–4 hours.

8. A method for preparing a rosuvastatin calcium intermediate according to any one of claims 4 to 7, characterized in that, In step (3), an antisolvent selected from acetone or acetonitrile is added to the reaction solution, and the volume ratio of the antisolvent to the addition reaction solution is 0.5 to 4:

1. After adding the antisolvent, the system is cooled to -5 to 10°C and crystallized for 1 to 8 hours.

9. A method for preparing a rosuvastatin calcium intermediate according to any one of claims 4 to 8, characterized in that, The crystals obtained by washing with acetone, isopropanol, or acetonitrile with a water content not exceeding 5 wt% are then subjected to a temperature of 25–50 °C and a gauge pressure of [insert pressure here]. 0.060~ Dry to constant weight under a vacuum of 0.095 MPa.

10. A method for preparing a rosuvastatin calcium intermediate according to any one of claims 4 to 9, characterized in that, It also includes intermediate dissociation and recovery steps: The rosuvastatin calcium intermediate to be recovered is added to water to form a solution or suspension, and methyl tert-butyl ether is added to form a two-phase system. The amount of water used is 2 to 8 mL and the amount of methyl tert-butyl ether is 4 to 12 mL relative to 1 g of the rosuvastatin calcium intermediate. An alkaline aqueous solution with a mass concentration of 5% to 20% is added at 10 to 30°C to adjust the pH of the aqueous phase to 8.0 to 10.5, causing the rosuvastatin calcium intermediate to dissociate and generate 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde. The alkaline aqueous solution is selected from sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, or potassium carbonate aqueous solution. The methyl tert-butyl ether phase was separated, washed with water, dried and concentrated under reduced pressure to obtain the recovered pyrimidine-5-carboxaldehyde, and the recovered pyrimidine-5-carboxaldehyde was returned to step (1) for the preparation of the rosuvastatin calcium intermediate.

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