Preparation method of rosuvastatin calcium intermediate

Abstract

The invention provides a preparation method of a rosuvastatin calcium intermediate, and belongs to the technical field of organic synthesis. (S)-4-chloro-3-hydroxybutyronitrile is used as a raw material, and the rosuvastatin calcium intermediate 2-(4R, 6S)-2, 2-dimethyl-6-[(5-methyl-1, 3, 4-thiazole-2-sulfonyl) methyl)-1, 3-dioxane] tert-butyl acetate (YD5-2) is synthesized through the steps of upper protection, addition, deprotection, chiral reduction, upper protection, addition, oxidation and the like. According to the preparation method of the rosuvastatin calcium intermediate, raw materials are easy to obtain, reaction conditions are mild, the safety coefficient is high, operability is high, the process is simple, industrialization is easy to achieve, and the product is high in purity and stable in quality.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a rosuvastatin calcium intermediate. Background Art

[0002] Rosuvastatin Calcium (Rosuvastatin Calcium) chemical name: Bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), developed by Shionogi Co., Ltd. and AstraZeneca, first approved for marketing in the Netherlands in November 2002, approved by the US FDA in August 2003, and approved and marketed in China in 2006; as a selective HMG-Coa reductase inhibitor, it can be used to treat primary, familial hypercholesterolemia and mixed dyslipidemia, with the advantages of high efficiency and low toxicity and side effects, and is one of the widely used statins. Its molecular structure is shown below:

[0003]

[0004] The synthesis of rosuvastatin calcium has been reported in many patents and literatures, such as AstraZeneca patent WO2001085702, Chinese patents CN104788387A, CN104030989A, etc. At present, most of the synthesis processes of rosuvastatin calcium require the use of tert-butyl 2-(4R,6S)-2,2-dimethyl-6-[(5-methyl-1,3,4-thiazole-2-sulfonyl)methyl)-1,3-dioxane]acetate (YD5-2) or its similar structure, but the current synthesis of this intermediate generally has problems such as low yield, high cost, high pollution, and difficulty in industrialization.

[0005] For example, Chinese patent CN111875538A discloses a method for synthesizing pitavastatin tert-butyl ester, which involves reacting (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester with substance A under the action of a first base catalyst to obtain substance B; then oxidizing with an oxidant to obtain substance C (when R is methyl, i.e., 2-(4R,6S)-2,2-dimethyl-6-[(5-methyl-1,3,4-thiazole-2-sulfonyl)methyl)-1,3-dioxane]acetic acid tert-butyl ester), and the reaction route is:

[0006]

[0007] The reaction directly uses (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester as raw material, reacts with 1,4-dioxane and N,N-dimethylformamide, and the post-processing is difficult and the synthesis cost is high.

[0008] For example, patent US5278313A uses LiHMDS and -78°C reaction conditions, which makes industrialization difficult; patent WO2004052823A1 uses chiral catalysis to construct chirality, but has poor purity and low yield; therefore, there is currently a lack of synthesis methods for its key intermediates.

[0009] Therefore, it is necessary to develop a preparation method for a rosuvastatin calcium intermediate with simple preparation operation, high chemical reaction yield, less three wastes, and low raw material cost. Summary of the invention

[0010] Based on the deficiencies of the prior art, the present invention aims to provide a method for preparing a rosuvastatin calcium intermediate, which has the advantages of simple operation, high chemical reaction yield, less three wastes and low raw material cost.

[0011] In order to achieve the above object, the present invention uses (S)-4-chloro-3-hydroxybutyronitrile as a raw material, and synthesizes rosuvastatin calcium intermediate 2-(4R,6S)-2,2-dimethyl-6-[(5-methyl-1,3,4-thiazole-2-sulfonyl)methyl)-1,3-dioxane]acetate tert-butyl ester (YD5-2) through the steps of upper protection, addition, deprotection, chiral reduction, upper protection, addition, oxidation, etc. The specific reaction steps are as follows:

[0012] (1) (S)-4-chloro-3-hydroxybutyronitrile reacts with trimethylsilyl chloride to form compound C1;

[0013] The reaction steps are:

[0014]

[0015] (2) C1 reacts with tert-butyl bromoacetate by addition and deprotection to form compound C2;

[0016] The reaction steps are:

[0017]

[0018] (3) C2 is subjected to chiral reduction to form compound C3;

[0019] The reaction steps are:

[0020]

[0021] (4) C3 is protected by acetone formate to form compound C4;

[0022] The reaction steps are:

[0023]

[0024] (5) C4 reacts with 2-mercapto-5-methyl-1,3,4-thiadiazole to form compound YD5-1, and YD5-1 is oxidized with hydrogen peroxide to form compound YD5-2;

[0025] The reaction steps are:

[0026]

[0027] In some embodiments, the specific operation of the above step (1) is: dissolving (S)-4-chloro-3-hydroxybutyronitrile in an organic solvent, adding trimethylsilyl chloride and a base under temperature control, and reacting at the temperature. After the reaction is completed, quenching with brine, adding ethyl acetate, stirring and extracting, separating the liquids, and concentrating the ethyl acetate to obtain compound C1.

[0028] in,

[0029] The organic solvent is tetrahydrofuran;

[0030] The base is selected from one or more of sodium carbonate, potassium carbonate, triethylamine, pyridine, N,N-diisopropylethylamine (DIEPA) and 2-ethylpyridine;

[0031] Preferably, the base is triethylamine.

[0032] The molar ratio of the (S)-4-chloro-3-hydroxybutyronitrile to the base is 1.0-1.2:1.

[0033] In some implementation schemes, the specific operation of step (2) above is as follows:

[0034] (2.1) Dissolving compound C1 in a solvent to obtain solution 1;

[0035] (2.2) dissolving a reducing agent and methanesulfonic acid in a solvent to obtain solution 2;

[0036] (2.3) dissolving tert-butyl bromoacetate in a solvent to obtain solution 3;

[0037] (2.3) Solution 1 is added dropwise to solution 2 for reflux reaction, and then solution 3 is added dropwise for reflux reaction. After the reaction is completed, the organic solvent is dried, aqueous hydrochloric acid solution is added, ethyl acetate is added, the pH is adjusted to 6-8, the extraction is stirred, the layers are separated, and the ethyl acetate is concentrated to form compound C2.

[0038] in,

[0039] The solvent described in the above steps (2.1), (2.2) and (2.3) is tetrahydrofuran;

[0040] The molar ratio of the compound C1, the reducing agent, methanesulfonic acid and tert-butyl bromoacetate is 1:2.0-3.0:0.1-0.2:1.2-1.5; preferably 1:2.2:0.12:1.25.

[0041] The reducing agent is selected from zinc powder and / or iron powder.

[0042] In some implementation schemes, the specific operation of step (3) is as follows:

[0043] Compound C2 is dissolved in a solvent and then an enzyme is added to react. During the reaction, the pH is controlled at 6.8-7.1 with liquid alkali. After the reaction is completed, hydrochloric acid is added to quench the reaction, the reaction is filtered, ethyl acetate is added, the mixture is stirred and extracted, the layers are separated, and the ethyl acetate is concentrated to obtain compound C3.

[0044] The solvent is a mixture of glucose, phosphate buffer and water, and the mass ratio of the glucose, phosphate buffer and water is 1:4.4-4.8:3.5-3.8; preferably 1:4.6:3.7.

[0045] The enzyme is a mixture of NADPH, ketoreductase and glucose dehydrogenase; the mass ratio of the three is 1:12-30:6-8; preferably 1:12:6.3.

[0046] The mass ratio of the compound C2 to the ketoreductase is 1:0.02-0.06, preferably 1:0.025.

[0047] In some implementation schemes, the specific operation of step (4) above is as follows:

[0048] Compound C3 and 2,2-dimethoxypropane are added to acetone, acid catalyst is added dropwise at room temperature, the temperature is raised to 40-45°C for reaction, and sodium carbonate solution is added after the reaction is completed. The organic solvent is dried by spin drying, ethyl acetate is added, the mixture is stirred for extraction, the layers are separated, and the ethyl acetate is concentrated to obtain compound C4.

[0049] The acid is selected from one or more of HCl, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and anhydrous zinc chloride; preferably p-toluenesulfonic acid.

[0050] The mass ratio of the compound C3, 2,2-dimethoxypropane and acid is 1:0.6-1.8:0.01-0.02; preferably 1:0.65:0.01.

[0051] In some implementation schemes, the specific operation of step (5) is as follows:

[0052] (5.1) Dissolve 2-mercapto-5-methyl-1,3,4-thiadiazole and alkali in water and stir until clear to obtain solution A;

[0053] (5.2) Compound C4 and a catalyst are added to solution A to react. After the reaction is completed, dichloromethane and water are added, stirred, allowed to stand, and separated into layers to obtain a dichloromethane solution of compound YD5-1, which is directly used in the next step reaction;

[0054] (5.3) After cooling the dichloromethane solution of compound YD5-1, a catalyst and ammonium molybdate tetrahydrate are added, and then the temperature is controlled at 10-20°C and hydrogen peroxide is added dropwise. The temperature is kept for reaction. After the reaction is completed, dichloromethane and water are added. The mixture is stirred, allowed to stand, and the layers are separated. Sodium sulfite solution is added to the dichloromethane layer, stirred, and the pH is adjusted to 8.0-9.0 with sodium carbonate solution. The mixture is allowed to stand, and the layers are separated. The dichloromethane layer is spin-dried and isopropanol and water are added for crystallization to obtain compound YD5-2.

[0055] The base described in step (5.1) is selected from one or more of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium hydroxide and magnesium hydroxide; preferably sodium hydroxide.

[0056] The molar ratio of the base to 2-mercapto-5-methyl-1,3,4-thiadiazole is 1.0-3.0:1, preferably 1.0-1.2:1.

[0057] The catalyst described in step (5.2) is selected from one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride; preferably tetrabutylammonium bromide.

[0058] The mass ratio of the catalyst and 2-mercapto-5-methyl-1,3,4-thiadiazole in step (5.2) is 0.1-0.3:1; preferably 0.1-0.15:1.

[0059] The catalyst described in step (5.3) is selected from one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride; preferably tetrabutylammonium bromide

[0060] The mass ratio of the catalyst and 2-mercapto-5-methyl-1,3,4-thiadiazole in step (5.3) is 0.05-0.1:1; preferably 0.05-0.06:1.

[0061] The mass ratio of ammonium molybdate tetrahydrate to 2-mercapto-5-methyl-1,3,4-thiadiazole in step (5.3) is 0.05-0.10:1, preferably 0.06:1.

[0062] The mass of the isopropanol described in step (5.3) is 2.8-3.8 times the mass of 2-mercapto-5-methyl-1,3,4-thiadiazole; preferably 3.2 times.

[0063] The mass of water in step (5.3) is 5.5-6.5 times the mass of 2-mercapto-5-methyl-1,3,4-thiadiazole; preferably 6.4 times.

[0064] Compared with the prior art, the beneficial effects of the present invention are:

[0065] (1) Compared with the previous synthesis method, this method uses an enzyme-catalyzed method to reduce the 3-carbonyl group to prepare compound C3, which has high reaction selectivity and yield, mild reaction conditions, and is suitable for industrialization.

[0066] (2) During the entire preparation process, the reagents used are safe and environmentally friendly, the reaction conditions are mild, no special equipment and raw materials are required, the preparation cycle is short, the handling is simple, easy to operate, and the cost is low.

[0067] The method provided by the invention has high yield, low cost and little pollution, and is therefore particularly suitable for industrial production. DETAILED DESCRIPTION

[0068] The present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention.

[0069] The experimental methods in the following examples are conventional methods unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.

[0070] 1. Preparation of Compound C1

[0071]

[0072] In the following examples, (S)-4-chloro-3-hydroxybutyronitrile is the company's own product, and triethylamine and trimethylsilyl chloride are purchased from MacLean Reagent Company.

[0073] Example 1.1

[0074] In a 1L four-necked bottle, 50g (S)-4-chloro-3-hydroxybutyronitrile and 150ml tetrahydrofuran were added, stirred evenly, cooled to 10°C, 52.3g trimethylsilyl chloride was slowly added dropwise, the temperature was raised to 20°C, 46.6g triethylamine was slowly added dropwise, the internal temperature was controlled at 35-40°C, and the mixture was stirred for 3h. The (S)-4-chloro-3-hydroxybutyronitrile residue was ≤0.5% by HPLC detection. The reaction solution was cooled to 10°C, 200ml of 10% sodium chloride aqueous solution was slowly added, 200ml of ethyl acetate was added, stirred and extracted, the aqueous phase was stripped with 100ml ethyl acetate, the organic phases were combined, and the ethyl acetate was concentrated to obtain 76.7g of light brown liquid with a yield of 95.9%.

[0075] Example 1.2

[0076] In a 1L four-necked bottle, 50g (S)-4-chloro-3-hydroxybutyronitrile and 150ml tetrahydrofuran were added, stirred evenly, cooled to 10°C, 52.3g trimethylsilyl chloride was slowly added dropwise, the temperature was raised to 20°C, 84.6g triethylamine was slowly added dropwise, the internal temperature was controlled at 35-40°C, and the mixture was stirred for 3h. The (S)-4-chloro-3-hydroxybutyronitrile residue was ≤0.5% by HPLC detection. The reaction solution was cooled to 10°C, 200ml of 10% sodium chloride aqueous solution was slowly added, 200ml of ethyl acetate was added, stirred and extracted, the aqueous phase was stripped with 100ml ethyl acetate, the organic phases were combined, and the ethyl acetate was concentrated to obtain 77.1g of light brown liquid with a yield of 96.4%.

[0077] Example 1.3

[0078] In a 1L four-necked bottle, 50g (S)-4-chloro-3-hydroxybutyronitrile and 150ml tetrahydrofuran were added, stirred evenly, cooled to 10°C, 52.3g trimethylsilyl chloride was slowly added dropwise, the temperature was raised to 20°C, 59.5g DIPEA was slowly added dropwise, the internal temperature was controlled at 35-40°C, and the mixture was stirred for 3h. The (S)-4-chloro-3-hydroxybutyronitrile residue was ≤0.5% by HPLC detection. The reaction solution was cooled to 10°C, 200ml of 10% sodium chloride aqueous solution was slowly added, 200ml of ethyl acetate was added, stirred and extracted, the aqueous phase was back-extracted with 100ml ethyl acetate, the organic phases were combined, and the ethyl acetate was concentrated to obtain 72.5g of light brown liquid with a yield of 90.7%.

[0079] 2. Preparation of Compound C2

[0080]

[0081] In the following examples, compound C1 is from Example 1.1; zinc powder was purchased from Xilong Scientific Reagent Company, and methanesulfonic acid and tert-butyl bromoacetate were purchased from MacLean Reagent Company.

[0082] Example 2.1

[0083] In a 1L four-necked flask, 14.1g iron powder, 1.35g methanesulfonic acid and 150ml tetrahydrofuran were added, the temperature was raised to 60°C, stirred for 30min, 22.0g of compound C1 solution dissolved in 100ml tetrahydrofuran was slowly added dropwise, refluxed for 1-2h, 28.5g of tert-butyl bromoacetate solution dissolved in 100ml tetrahydrofuran was slowly added dropwise, refluxed for 1-2h, compound C1 was detected to be ≤0.5% by HPLC, the temperature was lowered by 10°C, 95ml of 2N hydrochloric acid aqueous solution was slowly added, stirred for 1-2h, tetrahydrofuran was evaporated, 2×100ml of ethyl acetate was added for extraction, the ethyl acetate layer was washed with 150ml of saturated sodium bicarbonate solution, and the ethyl acetate was concentrated to obtain a light brown liquid 1, 25.7g, with a yield of 94.5%.

[0084] Example 2.2

[0085] In a 1L four-necked flask, 33g zinc powder, 2.64g methanesulfonic acid and 200ml tetrahydrofuran were added, the temperature was raised to 60°C, stirred for 30min, 43.7g of compound C1 solution dissolved in 150ml tetrahydrofuran was slowly added dropwise, the internal temperature was controlled at 60-65°C and kept warm for 1-2h, 55.9g of tert-butyl bromoacetate solution dissolved in 200ml tetrahydrofuran was slowly added dropwise, the reaction was refluxed for 1-2h, HPLC detected compound C1≤0.5%, the temperature was lowered by 10°C, 150ml of 2N hydrochloric acid aqueous solution was slowly added, the tetrahydrofuran was evaporated and 2×200ml of ethyl acetate was added for extraction, the ethyl acetate layer was washed with 250ml of saturated sodium bicarbonate solution, and the ethyl acetate was concentrated to obtain 53.0g of light brown liquid with a yield of 98%.

[0086] 3. Preparation of Compound C3

[0087]

[0088] In the following examples, NADPH, glucose dehydrogenase, and ketoreductase were purchased from Shangke Biological Reagent Company, and glucose was purchased from MacLean Reagent Company.

[0089] Example 3.1

[0090] 35g of compound C3, 250g of phosphate buffer, 54g of glucose and 200g of water were added to a 1L four-necked bottle, stirred to dissolve, cooled to 0-5°C, 70mg of NADPH, 0.88g of ketoreductase and 0.44g of glucose dehydrogenase were added, and the temperature was controlled to react for 48-55h. During the reaction, the pH was controlled at 7.0 with liquid alkali. HPLC detected that the residue of compound C2 was ≤2.0%, 60g of refined hydrochloric acid was added to quench the reaction, the enzyme was filtered to remove, 200ml of ethyl acetate was added to the filtrate, and the pH was adjusted to 7-8 with 68.8g of liquid alkali, stirred for extraction, separated into layers, the aqueous phase was back-extracted with 200ml of ethyl acetate, the ethyl acetate layers were combined, and the ethyl acetate was concentrated to obtain 32.1g of light brown oil with a yield of 91.1%.

[0091] Example 3.2

[0092] 35g of compound C3, 250g of phosphate buffer, 54g of glucose and 200g of water were added to a 1L four-necked bottle, stirred to dissolve, cooled to 0°C, 70mg of NADPH, 2.1g of ketoreductase and 0.44g of glucose dehydrogenase were added, and the temperature was controlled to react for 35-40h. During the reaction, the pH was controlled at 7.0 with liquid alkali. HPLC detected that the residue of compound C2 was ≤2.0%, 60g of refined hydrochloric acid was added to quench the reaction, the enzyme was filtered to remove, 200ml of ethyl acetate was added to the filtrate, and the pH was adjusted to 7-8 with 68.8g of liquid alkali, stirred for extraction, separated into layers, the aqueous phase was stripped with 200ml of ethyl acetate, the ethyl acetate layers were combined, and the ethyl acetate was concentrated to obtain 33.2g of light brown oil with a yield of 94%.

[0093] 4. Preparation of Compound C4

[0094]

[0095] In the following examples, 2,2-dimethoxypropane, p-toluenesulfonic acid and methanesulfonic acid were purchased from MacLean Reagent Company.

[0096] Example 4.1

[0097] 47.6g of compound C3, 31.3g of 2,2-dimethoxypropane, 200ml of acetone and 0.5g of p-toluenesulfonic acid were added to a 1L four-necked flask, stirred to dissolve, heated to 40°C and kept warm for 2-3h, HPLC detected that the residue of compound C3 was ≤1.0%, evaporated the solvent, added 150ml of 2% sodium bicarbonate-water solution and 250ml of ethyl acetate, stirred for extraction, allowed to stand, separated into layers, the aqueous phase was back-extracted with 200ml of ethyl acetate, and the ethyl acetate layers were combined. The ethyl acetate was concentrated to obtain 53.1g of brown oil with a yield of 95.5%.

[0098] Example 4.2

[0099] Add 60.1g of compound C3, 105.2g of 2,2-dimethoxypropane, and 0.6g of methanesulfonic acid to a 1L four-necked flask, stir to dissolve, heat to 60°C and keep warm for 3-4h, HPLC detection of compound C3 residue ≤1.0%, add 220ml of 2% sodium bicarbonate-water solution and 420ml of ethyl acetate, stir to extract, separate the layers, back-extract the aqueous phase with 200ml of ethyl acetate, combine the ethyl acetate layers, and concentrate the ethyl acetate to obtain 68.4g of brown oil with a yield of 97.5%.

[0100] Example 4.3

[0101] 25.2g of compound C3, 125ml of acetone and 66.1g of 2,2-dimethoxyacetone were added to a 1L four-necked flask, stirred evenly, 15.6g of sulfuric acid was added dropwise at room temperature, stirred at room temperature for 0.5h, heated to 45°C and kept warm for 1-2h, HPLC detected that the residue of compound C3 was ≤1.0%, cooled to 20°C, 31.5g of sodium carbonate and 31.5g of water were added, the solvent was evaporated, 200ml of ethyl acetate and 125ml of water were added to the concentrate, stirred and extracted, separated into layers, the aqueous phase was back-extracted with 100ml of ethyl acetate, and the ethyl acetate layers were combined. The ethyl acetate was concentrated to obtain 53.1g of brown oil with a yield of 95.5%.

[0102] 5. Preparation of Compound YD5-2

[0103]

[0104] In the following examples, 2-mercapto-5-methyl-1,3,4-thiadiazole is the company's own product, and tetrabutylammonium bromide, tetrabutylammonium chloride and ammonium molybdate tetrahydrate are all purchased from MacLean Reagent Company.

[0105] Example 5.1

[0106] Add 100g 2-mercapto-5-methyl-1,3,4-thiadiazole, 84.2g sodium carbonate and 100g water to a 1L four-necked flask, stir to dissolve, add 234g compound C4 and 10g tetrabutylammonium bromide, heat to 95-100°C, keep warm for 20-24h, HPLC detection of compound C4 residue ≤2.0%, cool to 30°C, add 200g dichloromethane and 400g water, stir to extract, separate, extract the water layer with 100g dichloromethane, and combine the dichloromethane layers to obtain a dichloromethane solution of compound YD5-1.

[0107] The dichloromethane solution of YD5-1 was cooled to 10-15°C, 5g of tetrabutylammonium bromide and 10g of ammonium molybdate tetrahydrate were added, 488g of 30% hydrogen peroxide was added dropwise at a temperature of 10-15°C, and the reaction was kept warm for 18-22h. The sulfoxide intermediate state was ≤2.0% by HPLC. 200g of dichloromethane and 400g of water were added, and the liquid was extracted and separated. The water layer was back-extracted with 100g of dichloromethane, and the dichloromethane layers were combined. The pH of the dichloromethane layer was adjusted to neutral with sodium carbonate, and sodium sulfite solution was added until it was non-oxidizing. The layers were allowed to stand and stratified. The dichloromethane was concentrated, 320g of isopropanol and 640g of water were added to the concentrate for crystallization, filtration, and drying to obtain 245.5g of off-white solid in total, with a yield of 79.8%.

[0108] Example 5.2

[0109] Add 100g 2-mercapto-5-methyl-1,3,4-thiadiazole, 31.8g sodium hydroxide and 100g water to a 1L four-necked flask, stir to dissolve, add 234g compound C4 and 10g tetrabutylammonium bromide, heat to 95-100°C, keep warm for 20-24h, HPLC test shows that the residual compound C4 is ≤2.0%, cool to 30°C, add 200g dichloromethane and 400g water, stir, stand, separate, extract the water layer with 100g dichloromethane, and combine the dichloromethane layers to obtain a dichloromethane solution of compound YD5-1.

[0110] The dichloromethane solution of YD5-1 was cooled to 10-15°C, 5g of tetrabutylammonium bromide and 6g of ammonium molybdate tetrahydrate were added, 250g of 30% hydrogen peroxide was added dropwise at a temperature of 10-15°C, and the reaction was kept warm for 18-22h. The sulfoxide intermediate state was ≤2.0% by HPLC. 200g of dichloromethane and 400g of water were added, and the liquid was extracted and separated. The water layer was back-extracted with 100g of dichloromethane, and the dichloromethane layers were combined. The pH of the dichloromethane layer was adjusted to neutral with sodium carbonate, and sodium sulfite solution was added until it was non-oxidizing. The dichloromethane was concentrated, and 350g of isopropanol and 700g of water were added to the concentrate for crystallization, filtration, and drying to obtain 258.1g of off-white solid in total, with a yield of 83.9%.

[0111] Example 5.3

[0112] Add 100g 2-mercapto-5-methyl-1,3,4-thiadiazole, 31.8g sodium hydroxide and 100g water to a 1L four-necked flask, stir to dissolve, add 234g compound C4 and 10g tetrabutylammonium chloride, heat to 95-100°C, keep warm for 20-24h, HPLC detection of compound C4 residue ≤2.0%, cool to 30°C, add 200g dichloromethane and 400g water, stir, stand, separate, extract the water layer with 100g dichloromethane, and combine the dichloromethane layers to obtain a dichloromethane solution of compound YD5-1.

[0113] The dichloromethane solution of YD5-1 was cooled to 10-15°C, 6g of tetrabutylammonium chloride and 6g of ammonium molybdate tetrahydrate were added, 250g of 30% hydrogen peroxide was added dropwise at a temperature of 10-15°C, and the reaction was kept warm for 18-22h. The sulfoxide intermediate state was ≤2.0% by HPLC. 200g of dichloromethane and 400g of water were added, and the liquid was extracted and separated. The water layer was back-extracted with 100g of dichloromethane, and the dichloromethane layers were combined. The pH of the dichloromethane layer was adjusted to neutral with sodium carbonate, and sodium sulfite solution was added until it was non-oxidizing. The dichloromethane was concentrated, and 350g of isopropanol and 700g of water were added to the concentrate for crystallization, filtration, and drying to obtain 247.8g of off-white solid with a yield of 80.6%.

[0114] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a rosuvastatin calcium intermediate, characterized in that: The steps include: (1) dissolving (S)-4-chloro-3-hydroxybutyronitrile in an organic solvent, adding trimethylsilyl chloride and a base under temperature control, and reacting at the temperature. After the reaction is completed, adding brine to quench the reaction, adding ethyl acetate to stir and extract, separating the liquids, and concentrating the ethyl acetate to obtain compound C1; The reaction steps are: (2) C1 is reacted with tert-butyl bromoacetate and then deprotected to form compound C2; The specific steps are: (2.1) Dissolving compound C1 in a solvent to obtain solution 1; (2.2) dissolving a reducing agent and methanesulfonic acid in a solvent to obtain solution 2; (2.3) dissolving tert-butyl bromoacetate in a solvent to obtain solution 3; (2.4) adding solution 1 dropwise to solution 2 for reflux reaction and then adding solution 3 dropwise for reflux reaction. After the reaction is completed, the organic solvent is dried by rotary evaporation, and aqueous hydrochloric acid solution is added. Ethyl acetate is added and the pH is adjusted to 6-8. The mixture is stirred for extraction, the liquids are separated, and the ethyl acetate is concentrated to form compound C2. The reaction steps are: (3) Compound C2 is dissolved in a solvent and then an enzyme is added to react. During the reaction, the pH is controlled at 6.8-7.1 with liquid alkali. After the reaction is completed, hydrochloric acid is added to quench the reaction, the mixture is filtered, ethyl acetate is added, the mixture is stirred and extracted, the layers are separated, and the ethyl acetate is concentrated to obtain compound C3; The reaction steps are: (4) Compound C3 and 2,2-dimethoxypropane are added to acetone, an acid catalyst is added dropwise at room temperature, the temperature is raised to 40-45° C. and the reaction is maintained at this temperature. After the reaction is completed, a sodium carbonate solution is added, the organic solvent is dried by rotary evaporation, ethyl acetate is added, the mixture is stirred for extraction, the layers are separated, and the ethyl acetate is concentrated to obtain compound C4; The reaction steps are: (5) C4 reacts with 2-mercapto-5-methyl-1,3,4-thiadiazole to form compound YD5-1, and YD5-1 is oxidized with hydrogen peroxide to form compound YD5-2; The specific steps are: (5.1) Dissolve 2-mercapto-5-methyl-1,3,4-thiadiazole and alkali in water and stir until clear to obtain solution A; (5.2) Compound C4 and a catalyst are added to solution A to react. After the reaction is completed, dichloromethane and water are added, stirred, allowed to stand, and separated into layers to obtain a dichloromethane solution of compound YD5-1, which is directly used in the next step reaction; (5.3) After cooling the dichloromethane solution of compound YD5-1, a catalyst and ammonium molybdate tetrahydrate are added, and then hydrogen peroxide is added dropwise at a temperature of 10-20°C. The temperature is kept for reaction. After the reaction is completed, dichloromethane and water are added, stirred, allowed to stand, separated into layers, sodium sulfite solution is added to the dichloromethane layer, stirred, and the pH is adjusted to 8.0-9.0 with sodium carbonate solution. The solution is allowed to stand, separated into layers, the dichloromethane layer is dried by rotary evaporation, and isopropanol and water are added for crystallization to obtain compound YD5-2; The reaction steps are:

2. The preparation method according to claim 1, characterized in that: The base described in step (1) is selected from one or more of sodium carbonate, potassium carbonate, triethylamine, pyridine, N,N-diisopropylethylamine and 2-ethylpyridine; the molar ratio of the (S)-4-chloro-3-hydroxybutyronitrile to the base is 1.0-1.2:

1.

3. The preparation method according to claim 1, characterized in that: The reducing agent in step (2.2) is selected from zinc powder and / or iron powder; the molar ratio of compound C1, reducing agent, methanesulfonic acid and tert-butyl bromoacetate is 1:2.0-3.0:0.1-0.2:1.2-1.5; preferably 1:2.2:0.12:1.

25.

4. The preparation method according to claim 1, characterized in that: The solvent described in step (3) is a mixture of glucose, phosphate buffer and water, and the mass ratio of the glucose, phosphate buffer and water is 1:4.4-4.8:3.5-3.8; the enzyme is a mixture of NADPH, ketoreductase and glucose dehydrogenase; the mass ratio of the three is 1:12-30:6-8.

5. The preparation method according to claim 4, characterized in that: The mass ratio of the compound C2 to the ketoreductase is 1:0.02-0.

06.

6. The preparation method according to claim 1, characterized in that: The acid in step (4) is selected from one or more of HCl, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and anhydrous zinc chloride; the mass ratio of compound C3, 2,2-dimethoxypropane and acid is 1:0.6-1.8:0.01-0.02; preferably 1:0.65:0.

01.

7. The preparation method according to claim 1, characterized in that: The base described in step (5.1) is selected from one or more of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium hydroxide and magnesium hydroxide; the molar ratio of the base to 2-mercapto-5-methyl-1,3,4-thiadiazole is 1.0-3.0:

1.

8. The preparation method according to claim 1, characterized in that: The catalyst described in step (5.2) and step (5.3) is selected from one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride.

9. The preparation method according to claim 1, characterized in that: The mass ratio of the catalyst and 2-mercapto-5-methyl-1,3,4-thiadiazole described in step (5.2) is 0.1-0.3:

1.

10. The preparation method according to claim 1, characterized in that: The mass ratio of the catalyst and 2-mercapto-5-methyl-1,3,4-thiadiazole in step (5.3) is 0.05-0.1:1; the mass of the isopropanol is 2.8-3.8 times the mass of 2-mercapto-5-methyl-1,3,4-thiadiazole.

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