Rosuvastatin calcium side chain containing sulfone structure, rosuvastatin calcium key intermediate and preparation method of rosuvastatin calcium side chain

Abstract

The invention provides a rosuvastatin calcium side chain containing a sulfone structure, a rosuvastatin calcium key intermediate and a preparation method of the rosuvastatin calcium side chain and the rosuvastatin calcium key intermediate, and relates to the technical field of medicine synthesis. The preparation method comprises the following steps: by taking a substance A and a substance B as raw materials, coupling to obtain an intermediate 1, oxidizing to obtain an intermediate 2, and carrying out Julia-Lythgoe olefination reaction on the intermediate 2 and a substance C to obtain a substance R1; the raw material reagents used in the method are easy to obtain or prepare, precious metal reagents are not used, the method is safe and environmentally friendly, the reaction condition is mild, operation is convenient and controllable, the method is suitable for industrial production, and a new method and choice are provided for industrialization of rosuvastatin calcium.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to a rosuvastatin calcium side chain containing a sulfone structure, a rosuvastatin calcium key intermediate and a preparation method thereof. Background Art

[0002] Rosuvastatin calcium is a fully synthetic single enantiomer of a new generation of statin lipid-regulating drugs. It is an HMG-CoA reductase inhibitor that can reduce elevated low-density cholesterol, total cholesterol, triglycerides and apoprotein B concentrations, while increasing high-density cholesterol concentrations. It can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and is known as a super statin. Substance R1 is a key intermediate of rosuvastatin calcium. At present, a mature commercial route for the synthesis of substance R1 is to use 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxaldehyde as a parent nucleus and a chiral side chain containing a sulfone structure to undergo a Julia-Lythgoe olefination reaction. During this process, a large number of chiral side chains with sulfone structures were studied. Among them, US6875867B2, WO2011104725A2, WO2011121595A1, and CN107298675A all reported chiral side chains with one or more sulfone structures, such as sulfones containing benzimidazoles (see formula 1) or tetrazoles (see formula 2) or phenyls (see formula 3).

[0003]

[0004] At the same time, a large number of chiral side chains of thiadiazole sulfone structures are still reported. CN114805164 and CN112028881 reported the application of 5-methyl-1,3,4-thiadiazole-sulfone (see formula four), CN111875538 reported the application of 5-methyl-1,3,4-thiadiazole-sulfone (see formula four), 5-phenyl-1,3,4-thiadiazole-sulfone (see formula five), and 5-cyclopropyl-1,3,4-thiadiazole-sulfone (see formula seven), and CN112592336 reported the application of 5-methyl-1,3,4-thiadiazole-sulfone (see formula four), 5-phenyl-1,3,4-thiadiazole-sulfone (see formula five), and 5-ethyl-1,3,4-thiadiazole-sulfone (see formula six).

[0005]

[0006] Julia-LythgoeJuli olefination reaction is a reaction in which sulfone and aldehyde or ketone are converted into olefins through nucleophilic addition and reduction elimination. Sulfone, as one of the reactants, has a lot of research space. At present, there is still a lot of work to be carried out and promoted in the industrial production process of rosuvastatin calcium and chiral side chains containing sulfone structure, so as to find a safe and environmentally friendly route with mild reaction conditions, convenient and controllable operation, high purity of the prepared material R1, good yield, and adaptability to industrialization. Summary of the invention

[0007] 1. Technical issues to be resolved

[0008] In view of the deficiencies in the prior art, the present invention provides a rosuvastatin calcium side chain containing a sulfone structure, a rosuvastatin calcium key intermediate and a preparation method thereof.

[0009] (II) Technical solution

[0010] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0011] In a first aspect, the present invention provides a method for preparing a key intermediate of rosuvastatin calcium, 2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, i.e., substance R1, comprising the following steps: using substance A and substance B as raw materials, coupling to obtain intermediate 1, then oxidizing to obtain intermediate 2, and performing Julia-Lythgoe olefination reaction on intermediate 2 and substance C to obtain substance R1;

[0012] The synthetic route is:

[0013]

[0014] Preferably, the preparation method of the substance R1 comprises the following steps:

[0015] S1. Take substance A, substance B, solvent and alkali, stir evenly, react at temperature T1, and after the reaction, remove the solvent, wash with petroleum ether, discard the organic layer, add dichloromethane, wash with water, wash with alkali, and concentrate to obtain intermediate 1;

[0016] S2, take intermediate 1, catalyst, and solvent, stir evenly, add oxidant dropwise, react at temperature T2, after the reaction is completed, quench with sodium bicarbonate, purify with isopropanol, heat and reflux, cool, crystallize, and dry to obtain intermediate 2;

[0017] S3. Take intermediate 2, substance C and solvent, stir evenly, add alkali at T3 temperature, react at T4, continue to react at T5 temperature, after the reaction, wash with alkali, concentrate the organic layer, cool, crystallize, and purify with n-butanol to obtain substance R1.

[0018] Preferably, in the S1, substance A is one of (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester and (4R-Cis)-6-bromo-methyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester.

[0019] Furthermore, in the S1, substance B is one of 2-mercapto-5-cyclohexyl-1,3,4-thiadiazole, 2-mercapto-5-cyclopentyl-1,3,4-thiadiazole, and 2-mercapto-5-furanyl-1,3,4-thiadiazole;

[0020] Furthermore, in the S1, the mass ratio of substance A to substance B is 1:1-4, preferably 1:1.1-2.0;

[0021] Furthermore, in the S1, the solvent is one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP), preferably N,N-dimethylformamide (DMF);

[0022] Further, in S1, the base is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium bicarbonate;

[0023] Furthermore, in the S1, the mass ratio of substance A to alkali is 1:2-6, preferably 1:2.5-4.0;

[0024] Furthermore, in the S1, the temperature T1 is 80 to 160°C, preferably 100 to 140°C;

[0025] Further, in the S2, the solvent is one of methanol, dichloromethane and isopropanol, preferably isopropanol;

[0026] Further, in the S2, the catalyst is one of sodium tungstate, potassium tungstate, and ammonium phosphotungstate, preferably sodium tungstate;

[0027] Further, in said S2, the mass ratio of the intermediate 1 to the catalyst is 1:0.02-1, preferably 1:0.05-0.07;

[0028] Further, in the S2, the oxidant is one of 20% hydrogen peroxide, 30% hydrogen peroxide, and 50% hydrogen peroxide, preferably 20% hydrogen peroxide;

[0029] Further, in said S2, the mass ratio of the intermediate 1 to the oxidant is 1:3-8, preferably 1:3-5;

[0030] Furthermore, in the S2, the temperature of T2 is 10 to 80°C, preferably 25 to 40°C;

[0031] Further, in said S3, substance C is 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carbaldehyde;

[0032] Further, in said S3, the mass ratio of intermediate 2 to substance C is 1:1-2, preferably 1:1.04-1.2;

[0033] Further, in the S3, the solvent is any one of toluene, dichloromethane, and 1,2-dichloroethane, preferably 1,2-dichloroethane;

[0034] Furthermore, in said S3, the temperature of T3 is -20 to 20°C, preferably -5 to 5°C;

[0035] Further, in said S3, the base is any one of 60% sodium hydride, sodium methoxide, and potassium tert-butoxide, preferably 60% sodium hydride;

[0036] Further, in said S3, the mass ratio of the intermediate 2 to the alkali is 1:1-8, preferably 1:2-4;

[0037] Further, in said S3, the temperature of T4 is -10 to 30°C, preferably -10 to 4°C;

[0038] Furthermore, in said S3, the temperature of T5 is -10 to 50°C, preferably -10 to 7°C;

[0039] In a second aspect, the present invention provides 2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (substance R1) obtained by the preparation method described in the first aspect, and its structural formula is as follows:

[0040]

[0041] In a third aspect, the present invention provides a rosuvastatin calcium side chain containing a sulfone structure, the structural formula of which is shown in the following intermediates 2-1, 2-2, and 2-3, which are used to prepare the substance R1 as described in the second aspect,

[0042]

[0043] (III) Beneficial effects

[0044] The present invention provides a rosuvastatin calcium side chain containing a sulfone structure, a rosuvastatin calcium key intermediate and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects:

[0045] The invention provides a method for preparing a key intermediate of rosuvastatin calcium, 2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (substance R1). The method comprises the following steps: using substance A as a raw material, coupling to obtain intermediate 1, oxidizing to obtain intermediate 2, and subjecting intermediate 2 to Julia-Lythgoe olefination reaction with substance C to obtain substance R1. The raw materials and reagents used are easy to obtain or prepare, and reagents containing precious metals are not used. The method is safe and environmentally friendly, the reaction conditions are mild, the operation is convenient and controllable, and the method is suitable for industrial production. The method provides a new method and option for the industrialization of rosuvastatin calcium. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] The invention relates to a rosuvastatin calcium side chain containing a sulfone structure and the preparation of a key intermediate R1 of rosuvastatin calcium, which are used for preparing a key intermediate 2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (substance R1) of rosuvastatin calcium. The invention uses substance A as a raw material, obtains intermediate 1 by coupling, and then obtains intermediate 2 by oxidation, and intermediate 2 undergoes Julia-Lythgoe olefination reaction with substance C to obtain substance R1. The reaction conditions of the invention are mild and controllable, the reaction conditions of Julia-Lythgoe olefin synthesis do not require ultra-low temperature reaction, the operation is convenient and simple, the stereoselectivity is good, the yield is high, the synthesized substance R1 has high purity, and is suitable for industrial production.

[0048] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.

[0049] Example 1

[0050] This embodiment provides a method for preparing a key intermediate of rosuvastatin calcium, which specifically comprises the following steps:

[0051]

[0052] S1. Synthesis of Intermediate 1

[0053] Substance A (278.8 g, 1.0 mol), substance B (202.7 g, 1.1 mol), sodium bicarbonate (210.2 g, 2.5 mol), and 800 mL of DMF were added to the reaction bottle, stirred evenly, and the temperature was raised to 120°C for reaction for 8 h. After the reaction was completed, the solvent was concentrated, water was added, and the water layer was washed twice with petroleum ether. The organic layer was discarded, dichloromethane was added, the organic layer was separated, the organic layer was washed twice with water, and once with sodium carbonate, and the mixture was concentrated under reduced pressure until almost no fraction was distilled out to obtain intermediate 1, weighing 408.2 g, with a yield of 95.7%, which was directly used in the next step.

[0054] 1 H NMR (400MHz, CDCl3) δ = 7.98 (dd, J = 1.6, 0.9Hz, 1H), 7.62 (t, J = 1.5Hz, 1H), 6.90 (t, J = 1.0Hz, 1H), 4.32 (dd, J = 10.5, 5.4Hz, 1H), 4.24–4.15 (m, 1H),4.10-3.99(m,2H),2.46(dd,J=15.3,6.4Hz,1H),2.31(dd,J=15.3,6.3Hz,1H),1.76-1.72(m,2H),1.47(s,3H),1.43(s,9H),1.40(s,3H); 13 C NMR (150MHz, CDCl3) δ = 171.0, 170.0, 159.6, 143.3, 142.2, 123.5, 109.1, 100.9, 80.6, 70.8, 65.3, 42.2, 37.3, 36.9, 27.8, 25.3.

[0055] S2. Synthesis of Intermediate 2

[0056] Add intermediate 1 (theoretical weight 213.3 g, 0.5 mol), 800 mL of methanol, and sodium tungstate (7.4 g, 0.025 mol) to the reaction bottle, stir evenly, control the temperature at 10 ° C, slowly add 20% hydrogen peroxide (425 g, 2.5 mol), and after the addition, control the temperature at 40 ° C to react for 18 h. After the reaction, add 200 mL of baking soda solution to quench, filter to obtain the wet product, add isopropanol, heat, reflux for 1 hour, cool to 5 ° C, crystallize, filter, and dry to obtain 335 kg of off-white solid with a yield of 91.5% and a purity of 99.7%.

[0057] 1H NMR (400MHz, CDCl3) δ = 8.12 (dd, J = 1.6, 0.8Hz, 1H), 7.59 (t, J = 1.6Hz, 1H), 6.87 (t, J = 1.0Hz, 1H), 4.42 (dd, J = 10.6, 5.2Hz, 1H), 4.34–4.19 (m, 1H),4.10-3.49(m,2H),2.63(dd,J=15.8,6.3Hz,1H),2.31(dd,J=15.8,6.3Hz,1H),1.79-1.70(m,2H),1.42(s,3H),1.40(s,9H),1.32(s,3H); 13 C NMR (150MHz, CDCl3) δ = 172.1, 162.8, 160.4, 143.5, 142.4, 122.7, 109.8, 100.3, 80.1, 67.7, 65.5, 61.5, 42.9, 35.7, 27.3, 25.2.

[0058] S3. Synthesis of substance R1

[0059] Add intermediate 2 (229.3 g, 0.5 mol), substance C (182.7 g, 0.52 mol), and 600 mL of 1,2-dichloroethane to the reaction bottle, stir evenly, cool to -5 ° C, add 60% sodium hydride (40 g, 1.0 mol) in batches, control the temperature not to exceed 4 ° C, react for 5 h, heat to 7 ° C, and continue to react for 10 h. After the reaction is complete, add 400 mL of sodium bicarbonate solution to quench, separate the organic layer, remove part of the solvent, cool to 0 ° C, filter, and obtain a white solid. Add 900 mL of n-butanol, heat to dissolve, and cool to 5 ° C to obtain substance R1, weighing 265.7 g, with a yield of 92% and a purity of 99.8%.

[0060] 1H NMR (400MHz, CDCl3) δ = 7.75 (dd, J = 8.9, 5.4Hz, 2H), 7.18 (t, J = 8.9Hz, 2H), 6.54 (dd, J = 16.4, 1.2 Hz,1H),5.66(dd,J=16.4,5.4Hz,1H),4.32(dd,J=10.5,5.4Hz,1H),4.24–4.15(m,1H),3.53(s,3 H),3.50(s,3H),3.38(dt,J=13.6,6.8Hz,1H),2.46(dd,J=15.3,6.3Hz,1H),2.31(dd,J=15.3,6. 4Hz,1H),1.72-1.76(m,2H),1.47(s,3H),1.43(s,9H),1.40(s,3H),1.25(dd,J=6.8,3.2Hz,6H); 13 C NMR(150MHz, CDCl3)δ=171.2,164.7,162.8,162.7,157.8,155.6,133.5,133.0,133.0,129.5,129.5, 121.2,121.2,115.6,115.4,101.3,80.1,71.0,67.7,42.9,37.9,37.5,30.5,30.1,27.3,25.6,21.4.

[0061] Example 2

[0062] This embodiment provides a method for preparing a key intermediate of rosuvastatin calcium, which specifically comprises the following steps:

[0063]

[0064] S1. Synthesis of Intermediate 1

[0065] Substance A (323.2 g, 1.0 mol), substance B (220.4 g, 1.1 mol), potassium carbonate (553 g, 4.0 mol) and 700 mL NMP were added to the reaction bottle, stirred evenly, heated to 140 ° C and reacted for 6 h. After the reaction was completed, the solvent was concentrated, water was added, and the water layer was washed twice with petroleum ether. The organic layer was discarded, dichloromethane was added, the organic layer was separated, and the organic layer was washed twice with water. The organic layer was concentrated under reduced pressure until there was almost no distillate to obtain intermediate 1, weighing 414.3 g, with a yield of 93.6%, which was directly used in the next step.

[0066] 1H NMR(400MHz, CDCl3)δ=4.35(dd,J=10.4,5.4Hz,1H),4.27–4.16(m,1H),4.12-3.97(m,2H),3.19(p,J=5.6Hz,1H),2.44(dd,J=15.2,6.4Hz,1H),2 .31(dd,J=15.2,6.3Hz,1H),2.20–2.01(m,2H),1.87-1.64(m,6H),1.62 –1.50(m,2H),1.48(s,3H),1.47–1.44(m,2H),1.41(s,9H),1.38(s,3H); 13 C NMR (150MHz, CDCl3) δ = 173.5, 171.1, 163.0, 100.3, 80.1, 67.7, 65.7, 61.2, 42.2, 38.5, 35.7, 32.2, 27.3, 26.3, 25.9, 25.2.

[0067] S2. Synthesis of Intermediate 2

[0068] Add intermediate 1 (theoretical weight 221.3 g, 0.5 mol), 600 mL of isopropanol, and potassium tungstate (10.0 g, 0.035 mol) to the reaction bottle, stir evenly, control the temperature at 5 ° C, slowly add 50% hydrogen peroxide (102 g, 1.5 mol), and after the addition, control the temperature at 25 ° C to react for 16 h. After the reaction, add 300 mL of baking soda solution to quench, filter to obtain the wet product, add isopropanol, heat, reflux for 1 hour, cool to 0 ° C, crystallize, filter, and dry to obtain 217.3 g of off-white solid with a yield of 91.2% and a purity of 99.2%.

[0069] 1 H NMR(400MHz, CDCl3)δ=4.37(dd,J=10.5,5.2Hz,1H),4.29–4.14(m,1H),4.13-3.95(m,2H),3.19(p,J=5.9Hz,1H),2.42(dd,J=15.4,6.2Hz,1H),2 .33(dd,J=15.4,6.3Hz,1H),2.25–2.03(m,2H),1.89-1.62(m,6H),1.61 –1.49(m,2H),1.48(s,3H),1.47–1.42(m,2H),1.40(s,9H),1.36(s,3H); 13C NMR (150MHz, CDCl3) δ = 174.2, 172.1, 165.0, 102.9, 80.6, 69.7, 66.5, 61.6, 42.29, 38.7, 36.9, 34.2, 28.3, 27.2, 26.0, 25.4.

[0070] S3. Synthesis of substance R1

[0071] Add intermediate 2 (237.3 g, 0.5 mol), substance C (193.3 g, 0.55 mol), and 800 mL of dichloromethane to the reaction bottle, stir evenly, cool to 5°C, add sodium methoxide (108 g, 2.0 mol) in batches, control the temperature not to exceed 0°C, react for 7 hours, heat to 5°C, and continue to react for 12 hours. After the reaction is complete, add 300 mL of sodium carbonate solution to quench, separate the organic layer, remove part of the solvent, cool to 0°C, filter, and obtain a white solid. Add 600 mL of n-butanol, heat to dissolve, and cool to 0°C to obtain substance R1, weighing 263 g, with a yield of 91% and a purity of 99.7%.

[0072] Example 3

[0073] This embodiment provides a method for preparing a key intermediate of rosuvastatin calcium, which specifically comprises the following steps:

[0074] S1. Synthesis of Intermediate 1

[0075]

[0076] Substance A (278.8 g, 1.0 mol), substance B (372.6 g, 2.0 mol), sodium carbonate (858 g, 3 mol), and 1200 mL DMAC were added to the reaction flask, stirred evenly, and heated to 130 ° C for 8 h. After the reaction, the solvent was concentrated, water was added, and the water layer was washed twice with petroleum ether. The organic layer was discarded, dichloromethane was added, the organic layer was separated, and the organic layer was washed twice with water. The organic layer was concentrated under reduced pressure until almost no fraction was distilled out to obtain intermediate 1, weighing 403.8 g, with a yield of 94.2%, which was directly used in the next step.

[0077] 1H NMR (400MHz, CDCl3) δ=4.32(dd,J=10.5,5.4Hz,1H),4.24–4.15(m,1H),3.90-3.79(m,2H),3.25–3.18(m,1H),2.46(dd,J=1 5.3, 6.4Hz, 1H), 2.31 (dd, J = 15.3, 6.3Hz, 1H), 2.05-1.81 (m, 4H), 1.78-1.65 (m, 4H), 1.47 (s, 3H), 1.43 (s, 9H), 1.40 (s, 3H); 13 CNMR(150MHz, CDCl3)δ=172.1,171.0,168.7,100.9,80.6,70.8,65.3,43.4,42.9,37.3,36.9,34.2,27.3,25.0,25.2.

[0078] S2. Synthesis of Intermediate 2

[0079] Add intermediate 1 (theoretical weight 175.8 g, 0.5 mol), 1000 mL of dichloromethane, and ammonium phosphotungstate (12 g, 0.03 mol) to the reaction bottle, stir evenly, control the temperature at 0 ° C, slowly add 30% hydrogen peroxide (227 g, 2 mol), and after the addition, control the temperature at 40 ° C to react for 18 h. After the reaction, add 600 mL of baking soda solution to quench, filter to obtain the wet product, add isopropanol, heat, reflux for 1 hour, cool to 0 ° C, crystallize, filter, and dry to obtain 208.9 g of an off-white solid with a yield of 90.7% and a purity of 99.5%.

[0080] 1 H NMR(400MHz, CDCl3)δ=4.35(dd,J=10.4,5.2Hz,1H),4.29–4.18(m,1H),4.15-3.92(m,2H),3.45–3.38(m,1H),2.76(dd,J=1 5.2, 6.3Hz, 1H), 2.41 (dd, J = 15.3, 6.3Hz, 1H), 2.09-1.85 (m, 4H), 1.82-1.76 (m, 4H), 1.57 (s, 3H), 1.46 (s, 9H), 1.35 (s, 3H); 13 CNMR(150MHz, CDCl3)δ=172.0,168.5,163.0,100.3,80.1,67.6,65.7,61.6,42.9,42.2,35.7,34.1,27.8,25.9,25.4.

[0081] S3. Synthesis of substance R1

[0082] Add intermediate 2 (276.4 g, 0.5 mol), substance C (210.8 g, 0.6 mol) and 1000 mL of toluene to the reaction bottle, stir evenly, cool to 0°C, add potassium tert-butoxide (108 g, 1.5 mol) in batches, control the temperature not to exceed 2°C, react for 6 h, heat to 6°C, continue to react for 14 h, after the reaction is complete, add 400 mL of sodium carbonate solution to quench, separate the organic layer, remove part of the solvent, cool to 5°C, filter to obtain a white solid, add 500 mL of n-butanol, heat to dissolve, cool to 0°C to obtain substance R1, weight 264.3 g, yield 91.5%, purity 99.8%.

[0083] In summary, compared with the prior art, the present invention has the following beneficial effects:

[0084] The invention provides a rosuvastatin calcium side chain containing a sulfone structure, a rosuvastatin calcium key intermediate and a preparation method thereof. The method has readily available raw materials, is environmentally friendly, has a novel route, does not use precious metals, and the prepared rosuvastatin calcium key intermediate substance R1 has good purity and high yield, and is suitable for industrial production.

[0085] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0086] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0087] The present invention illustrates the detailed process flow of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed process flow, that is, it does not mean that the present invention must rely on the above-mentioned detailed process flow to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing a key intermediate of rosuvastatin calcium, characterized in that: The method comprises the following steps: using substance A and substance B as raw materials, coupling to obtain intermediate 1, then oxidizing to obtain intermediate 2, and performing Julia-Lythgoe olefination reaction between intermediate 2 and substance C to obtain key intermediate R1 of rosuvastatin calcium; Its synthetic route is:

2. The preparation method according to claim 1, characterized in that The steps include: S1, taking the substance A, substance B, solvent, and alkali, stirring evenly, reacting at temperature T1, after the reaction, removing the solvent, washing with petroleum ether, discarding the organic layer, adding dichloromethane, washing with water, washing with alkali, and concentrating to obtain intermediate 1; S2, taking the intermediate 1, the catalyst, and the solvent, stirring evenly, adding the oxidant dropwise, reacting at a temperature of T2, quenching with sodium bicarbonate, refining with isopropanol, heating and reflux, cooling, crystallizing, and drying to obtain the intermediate 2; S3, taking the intermediate 2, the substance C, and the solvent, stirring evenly, adding alkali at T3 temperature, reacting at T4 temperature, and continuing the reaction at T5 temperature. After the reaction is completed, washing with alkali, concentrating the organic layer, cooling, crystallizing, and refining with n-butanol to obtain substance R1.

3. The preparation method according to claim 2, characterized in that: S1 satisfies at least one of the following conditions: The mass ratio of substance A to substance B is 1:1-4, preferably 1:1.1-2.0; The mass ratio of substance A to alkali is 1:2-6, preferably 1:2.5-4.0; The T1 temperature is 80 to 160°C, preferably 100 to 140°C.

4. The preparation method according to claim 2 or 3, characterized in that: S1 satisfies at least one of the following conditions: Substance A is selected from one of (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester and (4R-Cis)-6-bromo-methyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester; Substance B is selected from one of 2-mercapto-5-cyclohexyl-1,3,4-thiadiazole, 2-mercapto-5-cyclopentyl-1,3,4-thiadiazole, and 2-mercapto-5-furyl-1,3,4-thiadiazole; The solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, preferably N,N-dimethylformamide; The base is selected from one of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium bicarbonate; The structural formula of the intermediate 1 is shown below:

5. The preparation method according to claim 2, characterized in that: S2 satisfies at least one of the following conditions: The mass ratio of intermediate 1 to catalyst is 1:0.02-1, preferably 1:0.05-0.07; The mass ratio of intermediate 1 to oxidant is 1:3-8, preferably 1:3-5; The temperature T2 is 10 to 80°C, preferably 25 to 40°C.

6. The preparation method according to claim 2 or 5, characterized in that: S2 satisfies at least one of the following conditions: The solvent is selected from one of methanol, dichloromethane and isopropanol, preferably isopropanol; The catalyst is selected from sodium tungstate, potassium tungstate, and ammonium phosphotungstate, preferably sodium tungstate; The oxidant is selected from 20% hydrogen peroxide, 30% hydrogen peroxide, and 50% hydrogen peroxide, preferably 20% hydrogen peroxide; The structural formula of the intermediate 2 is shown below:

7. The preparation method according to claim 2, characterized in that: S3 satisfies at least one of the following conditions: The mass ratio of intermediate 2 to substance C is 1:1-2, preferably 1:1.04-1.2; T3 temperature is -20 to 20°C, preferably -5 to 5°C; The mass ratio of intermediate 2 to alkali is 1:1-8, preferably 1:2-4; T4 temperature is -10 to 30°C, preferably -10 to 4°C; The T5 temperature is -10 to 50°C, preferably -10 to 7°C.

8. The preparation method according to claim 2 or 7, characterized in that: S3 satisfies at least one of the following conditions: Substance C is 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carbaldehyde; The solvent is selected from any one of toluene, dichloromethane and 1,2-dichloroethane, preferably 1,2-dichloroethane; The base is selected from any one of 60% sodium hydride, sodium methoxide, and potassium tert-butoxide, preferably 60% sodium hydride.

9. A key intermediate of rosuvastatin calcium obtained by the preparation method according to any one of claims 1 to 8, characterized in that: Its structural formula is as follows:

10. A rosuvastatin calcium side chain containing a sulfone structure, characterized in that: Its structural formula is shown in the following intermediates 2-1, 2-2, and 2-3, which are used to prepare the key intermediate of rosuvastatin calcium as claimed in claim 9,

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