A method for preparing a rosuvastatin calcium key intermediate

Abstract

This invention belongs to the technical field of drug synthesis, specifically relating to a method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-carboxaldehyde, a key intermediate for rosuvastatin calcium. The method comprises four steps: S1, preparation of compound I; S2, preparation of compound II; S3, preparation of compound III; and S4, preparation of compound V. This invention completely avoids the DIBAL-H reduction step commonly relied upon in existing technologies, and also avoids the oxidation step with highly corrosive concentrated nitric acid, effectively solving the problems of generating large amounts of acidic waste gas and post-treatment of saline wastewater. This novel retrosynthetic analytical approach breaks the path dependence of existing technologies, fundamentally solving the common problems of high raw material costs, harsh reaction conditions, and severe environmental pollution in existing technologies.

Description

Technical Field

[0001] This invention belongs to the technical field of drug synthesis, specifically relating to a method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-carboxaldehyde, a key intermediate for rosuvastatin calcium. Background Technology

[0002] Rosuvastatin calcium, chemically named bis-[(E)-7-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]-pyrimidin-5-yl-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), CAS number 147098-20-2, is a selective, competitive HMG-CoA reductase inhibitor. Rosuvastatin calcium was first synthesized by Shionogi & Co., Ltd. of Japan and later developed by AstraZeneca. It has been marketed in the United States, Japan, Europe, China, and many other countries and regions for the treatment of hyperlipidemia. As a third-generation fully synthetic HMG-CoA reductase inhibitor, its effect of lowering LDL cholesterol and raising HDL cholesterol is the best among marketed statins.

[0003] 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-carboxaldehyde (compound V) is a key intermediate in the preparation of rosuvastatin calcium, and its structural formula is as follows: ; The aldehyde group in its structure can be linked to the side chain via the Wittig reaction, thereby constructing the complete skeleton of rosuvastatin calcium. Therefore, developing an efficient, economical, and safe synthetic method for this intermediate is of great significance.

[0004] Currently, several documents have reported methods for preparing this key intermediate. For example, patent documents WO2003006439, JP2648897, and EP0521471 report a method for preparing rosuvastatin calcium, which includes the preparation of compound V. The main steps are as follows: ; This method is a common method for preparing compounds of type V. However, DIBAL-H (diisobutylaluminum hydride) is expensive, and the reduction requires a low-temperature reaction, which is not conducive to industrial production. The final step of sodium hypochlorite oxidation can easily over-oxidize the alcohol to acid, resulting in a low reaction yield. Overall, the preparation route is long and the process is complicated.

[0005] Existing technologies include research on methods for preparing improved form V compounds, such as the method for preparing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine-5-carboxaldehyde disclosed in patent document CN101323597B. This method uses isobutyryl acetonitrile, p-fluorobenzaldehyde, and urea as starting materials, and prepares the target intermediate through four steps: cyclization, nitric acid oxidation, sulfonation substitution, and DIBAL-H cyano reduction. The synthetic route is as follows: ; Although this method shortens some steps, it still has obvious shortcomings: First, the oxidation step uses highly corrosive concentrated nitric acid, which releases a large amount of acidic waste gas, requiring high equipment corrosion resistance. The post-treatment neutralization generates a large amount of saline wastewater, resulting in high environmental costs. Second, the final cyano reduction step still relies on high-valence DIBAL-H, and the low-temperature reaction conditions cannot be avoided, resulting in a large amount of aluminum salt byproducts and significant pressure on solid waste treatment. Third, the purification of intermediates in the multi-step reaction depends on crystallization, with large fluctuations in yield per step, leading to high overall production costs.

[0006] For example, patent document CN103951552A discloses a rosuvastatin intermediate and its preparation method. The method uses 4-methyl-3-oxopentanal as a raw material and prepares the target intermediate through a five-step reaction involving acetal protection, condensation with urea and p-fluorobenzaldehyde, oxidation, substitution, and deprotection. The synthetic route is as follows: ; Although this method shortens the reaction steps and increases the overall yield to 54.7%, it adds a step to the protecting group operation, the acetal deprotection step is prone to generating impurities, the solvent consumption is large, the process operation complexity is increased, and it still cannot avoid high-priced reducing reagents.

[0007] For example, the method for synthesizing key intermediates of rosuvastatin calcium disclosed in patent document CN104628653A uses Weilsmeier reagent for one-step halogenation and introduction of aldehyde group, and Suzuki coupling to construct fluorophenyl structure, thus avoiding DIBAL-H. However, it has limitations: First, the preparation of Weilsmeier reagent is highly exothermic, and the low temperature control is required. The chlorinating agent is highly corrosive. Second, the amount of palladium-catalyzed coupling noble metal catalyst is relatively high, and no catalyst recovery and recycling scheme is designed, resulting in high long-term production costs.

[0008] For example, patent document CN114805218A discloses a method for preparing rosuvastatin calcium intermediate, which uses an alkenylpyrimidine intermediate to produce aldehydes via ozone oxidation, thus eliminating DIBAL-H. However, ozone oxidation requires a low temperature of -78℃, resulting in a large investment in refrigeration equipment, high cost of ozone equipment, poor adaptability to continuous production, and significant fluctuations in the yield of the low-temperature reaction with temperature.

[0009] In summary, although existing technologies have made numerous explorations and improvements in the synthesis of key intermediates (compound V) for rosuvastatin calcium, they still generally suffer from common problems such as high raw material costs, harsh reaction conditions, severe environmental pollution, and cumbersome operations. Specifically, most processes still rely on expensive reducing agents (such as DIBAL-H) ​​or highly corrosive oxidants (such as concentrated nitric acid), and involve complex steps such as low-temperature reactions, ozone oxidation, or noble metal catalytic coupling. This not only significantly increases equipment investment and waste treatment costs but also limits the economic efficiency and safety of its industrial production. Therefore, a new technical solution is needed to address the aforementioned technical problems. Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing a key intermediate of rosuvastatin calcium, in order to solve the common problems mentioned in the background art, such as high raw material costs, harsh reaction conditions, serious environmental pollution and cumbersome operation in the current synthesis process of key intermediate of rosuvastatin calcium (compound of formula V).

[0011] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing a key intermediate of rosuvastatin calcium, comprising the following specific steps: S1. Starting with 2-chloropyrimidine-5-carboxaldehyde and N-methylmethanesulfonamide, dissolved in solvent A, and subjected to a Buchwald-Hartwig coupling reaction at 60–110 °C in the presence of a catalyst, ligand, and base, compound I is obtained. The molar ratio of 2-chloropyrimidine-5-carboxaldehyde to N-methylmethanesulfonamide, catalyst, ligand, and base is 1:1.1–1.5:0.02–0.2:0.02–0.2:1.1–2.0. The catalyst is one of Pd2(dba)3, Pd(OAc)2, or tetrakis(triphenylphosphine)palladium. The ligand is one of BrettPhos, RuPhos, or BINAP. The base is one of sodium tert-butoxide, potassium phosphate, or DBU. S2. The compound of formula I obtained in S1 is dissolved in solvent B with isobutyric acid, and a Minisci reaction is carried out at 20-60℃ in the presence of acid, catalyst and oxidant to obtain compound of formula II. The molar ratio of compound of formula I to isobutyric acid, acid, catalyst and oxidant is 1:1.02-1.3:0.1-0.3:0.1-0.3:1.1-1.5; the acid is one of sulfuric acid, trifluoroacetic acid and aluminum trichloride; the catalyst is one of silver nitrate, silver trifluoroacetate, silver oxide and silver tetrafluoroborate; the oxidant is one of ammonium persulfate, sodium persulfate, potassium persulfate and hydrogen peroxide; the solvent B is one or more of dichloromethane, acetonitrile, methanol and water. S3. The compound of formula II obtained in S2 is dissolved in solvent C, and halogenated with a halogenating reagent under acid catalysis to obtain compound III. The molar ratio of compound II to halogenating reagent and acid is 1:1.2-2.0:0.02-0.2:1.5-2.5. The halogenating reagent is one of NCS, NBS, and NIS. The acid is one of p-toluenesulfonic acid, methanesulfonic acid, and ethylenediaminetetraacetic acid. Solvent C is one or more of DMSO, acetonitrile, DMF, dichloromethane, tetrahydrofuran, and water. S4. The compound of formula III obtained in S3 is dissolved in solvent D with 4-fluorophenylboronic acid pinacol ester. Under the presence of a catalyst and a base, a Suzuki coupling reaction occurs to obtain compound V. The molar ratio of compound III to 4-fluorophenylboronic acid pinacol ester, catalyst, and base is 1:1.2:0.02:1.5 to 1:2.0:0.2:2.5. The catalyst is one or more of dichlorodi(triphenylphosphine)palladium, Pd(OAc)2, tetra(triphenylphosphine)palladium, and Pd(dppf)Cl2. The base is one of potassium phosphate, cesium carbonate, potassium carbonate, and sodium carbonate. Solvent D is one of toluene, DMF, DMSO, 1,4-dioxane, acetonitrile, and water. Its synthetic route is as follows: ; X is one of chlorine, bromine, and iodine.

[0012] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention uses 2-chloropyrimidine-5-carboxaldehyde and N-methylmethanesulfonamide as starting materials. A key intermediate compound of formula I is constructed via a Buchwald-Hartwig coupling reaction. The target intermediate compound of formula V is then synthesized in four steps via a Minisci reaction, a halogenation reaction, and a Suzuki coupling reaction. This completely avoids the DIBAL-H reduction step commonly relied upon in existing technologies, and also avoids the oxidation step with highly corrosive concentrated nitric acid. This effectively solves the problems of generating large amounts of acidic waste gas and the post-treatment of saline wastewater. This novel retrosynthetic analytical approach breaks the path dependence of existing technologies and fundamentally solves the common problems of high raw material costs, harsh reaction conditions, and severe environmental pollution in existing technologies.

[0013] 2. This invention uses starting materials with inherent aldehyde groups. The four-step reaction does not destroy the aldehyde group, and there is no need for reduction or secondary oxidation to convert the aldehyde structure, which greatly reduces hazardous waste and energy consumption. Moreover, all reaction temperatures are within the range of 20 to 120°C, and the entire conversion can be completed at room temperature to mild heating. There is no need for ultra-low temperature ozone oxidation equipment at -78°C, eliminating the need for ozone generation and tail gas treatment equipment. The equipment investment and production operation threshold are greatly reduced. The process is compatible with conventional atmospheric pressure reactors and is easy to carry out continuous industrial production.

[0014] 3. The raw materials used in this invention—2-chloropyrimidine-5-carboxaldehyde, N-methylmethanesulfonamide, isobutyric acid, halogenated reagents (NCS / NBS / NIS), and pinacol ester of 4-fluorophenylborate—are all commercially available bulk chemicals, inexpensive and readily available. More importantly, it completely avoids the expensive reducing agent DIBAL-H and high-cost or highly toxic reagents such as DDQ and m-CPBA commonly used in existing technologies, significantly reducing production costs and the burden of waste treatment from the source. Furthermore, the post-processing of each reaction step involves simple extraction, washing, concentration, pulping, or recrystallization, eliminating the need for complex chromatographic purification, resulting in good separation and further reducing production costs.

[0015] 4. This invention introduces isopropyl groups via Minisci radical alkylation. The oxidant used is a mild, water-soluble oxidant such as persulfate or hydrogen peroxide, combined with low-volume organic / inorganic acid catalysis such as sulfuric acid or trifluoroacetic acid. This eliminates the need for a highly corrosive nitration system, produces no nitrogen oxide emissions, and significantly reduces the salinity and corrosivity of the wastewater. Furthermore, the halogenation step utilizes NBS / NCS / NIS solid halogenating reagents, ensuring controllable exothermic reaction, eliminating highly corrosive hydrogen chloride tail gas, minimizing equipment wear, and simplifying the tail gas treatment process.

[0016] 5. The single-step yield of this invention is consistently in the range of 83-92%: Buchwald-Hartwig step 88-92%, Minisci alkylation 85-90%, halogenation 90.1-92%, and Suzuki coupling 83-86%. The overall yield is much higher than that of the traditional redox route. Compared with existing improved technologies, the reaction of this invention is more stable and controllable, with good batch-to-batch yield repeatability and higher capacity utilization in large-scale production. Attached Figure Description

[0017] Figure 1 The 1H NMR spectrum of compound V of the present invention; Figure 2 The carbon NMR spectrum of compound V of the present invention; Figure 3 This is the liquid phase detection spectrum of compound V of the present invention. Detailed Implementation

[0018] The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto. The raw materials and reagents used in the following embodiments are all commercially available analytical grade products, and the room temperature used refers to 20-25°C. Experimental methods not specifically specified in the embodiments were performed under conventional conditions or conditions recommended by the manufacturer.

[0019] Example 1: Preparation of Compound I (Buchwald-Hartwig Coupling Reaction) Add 50 g (0.3508 mol) of 2-chloropyrimidine-5-carboxaldehyde, 42.12 g (0.3859 mol) of N-methylmethanesulfonamide, 37.08 g (0.3859 mol) of sodium tert-butoxide, 6.35 g (0.00702 mol) of BrettPhos (2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl) and 500 mL of anhydrous toluene to a 2000 mL four-necked flask. Purge with nitrogen and protect the mixture. Heat to 105 °C and maintain the temperature for 5 hours. After the reaction was complete, the mixture was slowly cooled to room temperature, and 500 mL of tap water was added. The mixture was stirred and the phases were separated. The organic phase was washed once with 500 mL of tap water and concentrated under reduced pressure at 50 °C to dryness to obtain an off-white solid. Then, 150 mL of anhydrous methanol was added and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, rinsed, and dried under reduced pressure at 50 °C to obtain 67.95 g of white solid, which is the compound of formula I (structural formula as follows), with a molar yield of 90%.

[0020] The following is the structural formula of compound I: .

[0021] Example 2: Preparation of Compound II (Minisci Reaction) Add 65g of compound I (0.302mol) and 27.14g of isobutyric acid (0.308mol) to a 2000mL four-necked flask, dissolve in 650mL of dichloromethane, then add 5.13g of silver nitrate (0.0302mol) and 2.96g of sulfuric acid (0.0302mol), heat to 20℃ and stir for 15 minutes, then add dropwise a solution of 75.8g of ammonium persulfate (0.3322mol) dissolved in 150mL of tap water at room temperature. After the addition is complete, stir the reaction at room temperature for 1 hour. After the reaction was detected by TLC, the mixture was allowed to stand and the phases were separated. The organic phase was washed with 200 mL of tap water twice, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to obtain an off-white solid. Then, 300 mL of anhydrous ethanol was added and the mixture was refluxed and stirred for 1 hour. The mixture was cooled to 0–5 °C and filtered, rinsed, and dried under reduced pressure at 50 °C to obtain 66.05 g of white solid, which is compound II (structural formula below), with a molar yield of 85%.

[0022] The following is the structural formula of compound II: .

[0023] Example 3: Preparation of Compound III (Halogenation Reaction) 60 g (0.2332 mol) of compound II, 62.25 g (0.3498 mol) of NBS (N-bromosuccinimide), 600 mL of acetonitrile, and 4.02 g (0.0233 mol) of p-toluenesulfonic acid were added to a 2000 mL four-necked flask. The mixture was stirred at 20 °C for 8 hours. After the reaction was completed by TLC, 600 mL of water was added to the reaction solution, followed by 500 mL of ethyl acetate for extraction. The mixture was allowed to stand and separate into an organic phase and an aqueous phase. The organic phase was washed with 500 mL of water, dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 70.56 g of a pale yellow oil, which was compound III (structural formula shown below, where X is bromine), with a yield of 90.1%.

[0024] The following is the structural formula of compound III: .

[0025] Example 4: Preparation of compound V (Suzuki coupling reaction) In a 2000 mL four-necked flask, 51.52 g (0.232 mol) of 4-fluorophenylboronic acid pinacol ester (compound of formula IV, the structural formula of which is shown below), 65 g (0.1933 mol) of compound of formula III, 61.55 g (0.2899 mol) of potassium phosphate and 4.47 g (0.0039 mol) of tetra(triphenylphosphine)palladium were added to the reaction flask. Then, 650 mL of 1,4-dioxane and 25 mL of water were added. The mixture was purged with nitrogen three times, and the reaction system was heated to 60 °C and reacted for 16 hours. After the reaction was confirmed to be complete by TLC spot test, the reaction solution was cooled to room temperature, and 3000 mL of ethyl acetate and 850 mL of water were added. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with 2000 mL of saturated brine, dried, filtered, and concentrated. 650 mL of methanol was added to the residue and refluxed for 1 hour. After cooling and filtration, 57.75 g of white solid was obtained, which was compound V (4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-carboxaldehyde), with a yield of 85.1%.

[0026] The following are the liquid chromatography-mass spectrometry (LC-MS) spectra of compounds of formula V (e.g., ...). Figure 3 As shown), 1H NMR spectrum (e.g.) Figure 1 As shown), carbon NMR (such as) spectrum. Figure 2 (As shown) Detection data: LC-MS[M+H]+=351.40; 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.72 (dd, J = 8.8, 5.4 Hz, 2H), 7.47 – 7.38 (m, 2H), 3.94 (h, J = 6.7 Hz, 1H), 3.61 (s, 3H), 3.52 (s,3H), 1.26 (d, J = 6.7 Hz, 6H).; 13C NMR (101 MHz, DMSO-d6) δ 191.25, 178.05, 169.64, 164.10 (d, J =249.0 Hz), 158.77, 133.17 (d, J = 8.9 Hz, 2C), 132.95 (d, J = 3.2 Hz),119.85, 116.24 (d, J = 21.9 Hz, 2C), 42.18, 33.61, 31.73, 21.92(2C).

[0027] The following is the structural formula of compound IV: ; The following is the structural formula of compound V: .

[0028] Example 5: Preparation of Compound I 75 g (0.5262 mol) of 2-chloropyrimidine-5-carboxaldehyde, 74.66 g (0.6841 mol) of N-methylmethanesulfonamide, 11.82 g (0.0526 mol) of Pd(OAc)2 (palladium acetate), 167.54 g (0.7893 mol) of potassium phosphate, 24.55 g (0.05262 mol) of RuPhos (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl) and 750 mL of anhydrous tetrahydrofuran were added to a 2000 mL four-necked flask. The mixture was purged with nitrogen and protected. The temperature was raised to 60 °C and the reaction was maintained for 5 hours. After the reaction was complete, the mixture was slowly cooled to room temperature, and 750 mL of tap water was added. The mixture was stirred and the phases were separated. The organic phase was extracted once again with 750 mL of ethyl acetate. All organic phases were combined and concentrated to dryness under reduced pressure at 50 °C to obtain an off-white solid. Then, 225 mL of anhydrous methanol was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, washed, and dried under reduced pressure at 50 °C to obtain 99.66 g of white solid, which is the compound of formula I, with a molar yield of 88%.

[0029] Example 6: Preparation of Compound II Add 95g of compound I (0.4414mol) and 46.67g of isobutyric acid (0.5297mol) to a 2000mL four-necked flask, dissolve in 950mL of acetonitrile, then add 19.5g of silver trifluoroacetate (0.08828mol) and 10.07g of trifluoroacetic acid (0.08828mol). Heat to 40℃ and stir for 15 minutes. At 40-45℃, add dropwise a solution of 136.63g of sodium persulfate (0.5738mol) dissolved in 150mL of tap water. After the addition is complete, stir the reaction at 40-45℃ for 1 hour. After the reaction was detected by TLC, the mixture was allowed to stand and the phases were separated. The organic phase was washed with 300 mL of tap water twice, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to obtain an off-white solid. Then, 500 mL of anhydrous ethanol was added and the mixture was refluxed and stirred for 1 hour. The mixture was cooled to 0–5 °C, filtered, rinsed, and dried under reduced pressure at 50 °C to obtain 102.22 g of white solid, which is compound II of formula, with a molar yield of 90%.

[0030] Example 7: Preparation of Compound III 100 g (0.3886 mol) of compound II, 138.33 g (0.7773 mol) of NBS, 500 mL of DMSO (dimethyl sulfoxide), and 134.08 g (0.1166 mol) of ethylenediaminetetraacetic acid were added to a 2000 mL four-necked flask. The mixture was stirred at 45 °C for 3 hours. After the reaction was completed by TLC, 500 mL of water was added to the reaction solution, followed by 500 mL of ethyl acetate for extraction. The mixture was allowed to stand and separate into an organic phase and an aqueous phase. The organic phase was washed with 500 mL of water, dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 120.21 g of a pale yellow oil, which was compound III (where X in the structural formula represents bromine), with a yield of 92%.

[0031] Example 8: Preparation of Compound V 116.25 g (0.5235 mol) of 4-fluorophenylborate pinacol ester (compound IV), 110 g (0.3272 mol) of compound III, 213.22 g (0.6544 mol) of cesium carbonate, and 7.35 g (0.03272 mol) of palladium acetate were added to a 2000 mL four-necked flask. DMF (N,N-dimethylformamide) was then added, and the mixture was purged with nitrogen three times. The reaction system was heated to 80 °C and reacted for 16 hours. After TLC detection of complete reaction, the reaction solution was cooled to room temperature, and 3000 mL of ethyl acetate and 2000 mL of water were added. The mixture was allowed to stand for separation, and the organic phase was washed twice with 1000 mL of saturated brine. After drying, the mixture was filtered and concentrated. 1100 mL of methanol was added to the residue and refluxed for 1 hour. After cooling and filtration, 95.43 g of white solid, which was compound V, was obtained, with a yield of 83%.

[0032] Example 9: Preparation of Compound I 100 g (0.7016 mol) of 2-chloropyrimidine-5-carboxaldehyde, 114.86 g (1.0523 mol) of N-methylmethanesulfonamide, 162.14 g (0.1403 mol) of tetrakis(triphenylphosphine)palladium, 213.62 g (1.4032 mol) of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), 87.37 g (0.1403 mol) of BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine is a chemical substance), and 1000 mL of 1,4-dioxane were added to a 2000 mL four-necked flask. The mixture was purged with nitrogen for protection, heated to 80 °C, and reacted for 5 hours. After the reaction was complete, the mixture was slowly cooled to room temperature, and 1000 mL of tap water was added. The mixture was stirred and the phases were separated. The organic phase was extracted once again with 1000 mL of ethyl acetate. All organic phases were combined and concentrated to dryness under reduced pressure at 50 °C to obtain an off-white solid. Then, 300 mL of anhydrous methanol was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, washed, and dried under reduced pressure at 50 °C to obtain 138.92 g of white solid, which is compound I, with a molar yield of 92%.

[0033] Example 10: Preparation of Compound II 130 g of compound I (0.604 mol) and 69.18 g of isobutyric acid (0.7852 mol) were added to a 2000 mL four-necked flask and dissolved in 1300 mL of methanol. Then, 41.99 g of silver oxide (0.1812 mol) and 24.16 g of aluminum trichloride (0.1812 mol) were added. The mixture was heated to 60 °C and stirred for 15 minutes. Then, 102.71 g of 30% hydrogen peroxide (0.906 mol) was added dropwise at 55–60 °C. After the addition was complete, the mixture was stirred at 55–60 °C for 1 hour. After the reaction was detected by TLC, 1300 mL of ethyl acetate was added and stirred. The mixture was allowed to stand and the phases were separated. The aqueous phase was extracted once more with 1300 mL of ethyl acetate. The combined organic phases were washed with 300 mL of tap water twice. The organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to obtain an off-white solid. Then, 650 mL of anhydrous ethanol was added and the mixture was refluxed and stirred for 1 hour. The mixture was cooled to 0–5 °C, filtered, rinsed, and dried under reduced pressure at 50 °C to obtain 136.77 g of white solid, which is compound II, with a molar yield of 88%.

[0034] Example 11: Preparation of Compound III 130 g (0.5052 mol) of compound II, 269.73 g (1.5156 mol) of NBS, 600 mL of DMF, and 24.28 g (0.2526 mol) of methanesulfonic acid were added to a 2000 mL four-necked flask. The mixture was stirred at 30 °C for 3 hours. After the reaction was completed by TLC, 500 mL of water was added to the reaction solution, followed by 500 mL of ethyl acetate for extraction. The mixture was allowed to stand and separate into an organic phase and an aqueous phase. The organic phase was washed with 500 mL of water, dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 154.91 g of a pale yellow oily substance, which was compound III (where X in the structural formula represents bromine), with a yield of 91.2%.

[0035] Example 12: Preparation of Compound V 198.17 g (0.8924 mol) of 4-fluorophenylborate pinacol ester (compound IV), 150 g (0.4462 mol) of compound III, 153.94 g (1.1155 mol) of potassium carbonate, and 62.63 g (0.0892 mol) of dichlorobis(triphenylphosphine)palladium were added to a 2000 mL four-necked flask. DMSO was then added, and the mixture was purged with nitrogen three times. The reaction system was heated to 120 °C and reacted for 16 hours. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature, and 3000 mL of ethyl acetate and 3000 mL of water were added. The mixture was allowed to stand for separation, and the organic phase was washed twice with 1500 mL of saturated brine. After drying, the mixture was filtered and concentrated. 1500 mL of methanol was added to the residue and refluxed for 1 hour. After cooling and filtration, 134.83 g of white solid, which was compound V, was obtained, with a yield of 86%.

[0036] Example 13: Preparation of Formula III compound (halogenation reagent: NCS) Using the same operating steps as in Example 1, except that the halogenating agent NBS is replaced with NCS (N-chlorosuccinimide), and all other conditions remain unchanged, compound III (where X in its structural formula is chlorine) can be obtained.

[0037] Example 14: Preparation of compound of formula III (halogenation reagent is NIS) Using the same operating steps as in Example 1, except that the halogenating agent NBS is replaced with NIS (N-iodosuccinimide), and all other conditions remain unchanged, compound III (where X in its structural formula is iodine) can be obtained.

Claims

1. A method for preparing a key intermediate of rosuvastatin calcium, characterized in that, The specific steps are as follows: S1. Starting with 2-chloropyrimidine-5-carboxaldehyde and N-methylmethanesulfonamide, the compounds were dissolved in solvent A and subjected to a Buchwald-Hartwig coupling reaction in the presence of a catalyst, ligand, and base to obtain compound I. S2. The compound of formula I obtained in S1 is dissolved in solvent B with isobutyric acid, and the Minisci reaction occurs in the presence of acid, catalyst and oxidant to obtain compound of formula II. S3. The compound of formula II obtained in S2 is dissolved in solvent C, and then reacted with a halogenating reagent under acid catalysis to obtain compound of formula III. S4. The compound of formula III obtained in S3 and pinacol 4-fluorophenylborate were dissolved in solvent D, and a Suzuki coupling reaction was carried out in the presence of a catalyst and a base to obtain compound of formula V. Its synthetic route is as follows: ； X is one of chlorine, bromine, and iodine.

2. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S1, the molar ratio of 2-chloropyrimidine-5-carboxaldehyde to N-methylmethanesulfonamide, catalyst, ligand, and base is 1:1.1–1.5:0.02–0.2:0.02–0.2:1.1–2.0; wherein the catalyst is one of Pd2(dba)3, Pd(OAc)2, or tetrakis(triphenylphosphine)palladium; the ligand is one of BrettPhos, RuPhos, or BINAP; and the base is one of sodium tert-butoxide, potassium phosphate, or DBU.

3. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S1, solvent A is one of toluene, tetrahydrofuran, or 1,4-dioxane; the temperature of the Buchwald-Hartwig coupling reaction is 60–110 °C.

4. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S2, the molar ratio of compound I to isobutyric acid, acid, catalyst, and oxidant is 1:1.02-1.3:0.1-0.3:0.1-0.3:1.1-1.5; wherein the acid is one of sulfuric acid, trifluoroacetic acid, and aluminum trichloride; the catalyst is one of silver nitrate, silver trifluoroacetate, silver oxide, and silver tetrafluoroborate; and the oxidant is one of ammonium persulfate, sodium persulfate, potassium persulfate, and hydrogen peroxide.

5. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S2, solvent B is one or more of dichloromethane, acetonitrile, methanol, and water; the temperature of the Minisci reaction is 20–60 °C.

6. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S3, the molar ratio of compound II to halogenated reagent and acid is 1:1.5:0.1 to 1:3.0:0.5; wherein the halogenated reagent is one of NCS, NBS, and NIS; and the acid is one of p-toluenesulfonic acid, methanesulfonic acid, and ethylenediaminetetraacetic acid.

7. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S3, solvent C is one or more of DMSO, acetonitrile, DMF, dichloromethane, tetrahydrofuran, and water.

8. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S4, the molar ratio of compound III to pinacol 4-fluorophenylborate, catalyst, and base is 1:1.2–2.0:0.02–0.2:1.5–2.5; wherein the catalyst is one or more of dichlorobis(triphenylphosphine)palladium, Pd(OAc)2, tetrakis(triphenylphosphine)palladium, and Pd(dppf)Cl2; and the base is one of potassium phosphate, cesium carbonate, potassium carbonate, and sodium carbonate.

9. The method for preparing a key intermediate of rosuvastatin calcium according to claim 1, characterized in that, In S4, solvent D is one of toluene, DMF, DMSO, 1,4-dioxane, acetonitrile, or water.

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