A method for synthesizing a chiral intermediate of atorvastatin calcium

Abstract

The application belongs to the technical field of synthesis of medical intermediates, and particularly relates to a synthesis method of a chiral intermediate of atorvastatin calcium. 1,3-propanediol is used as raw material, a silicon-based protection reaction is carried out, and then oxidation is carried out, a ring addition reaction occurs under the catalysis of a chiral catalyst and a lithium salt, and a first chiral center is introduced; then, t-butyl acetate is added to carry out a ring opening reaction, a Narasaka-Prasad reduction reaction is carried out to induce a second chiral center; 2,2-dimethoxypropane is added to protect cis diol, finally, tetrabutylammonium fluoride is added to remove the silicon-based reaction, and a Fukuyama amine synthesis method is used to replace the hydroxyl group with the amino group to obtain the chiral intermediate of atorvastatin calcium. The application uses 1,3-propanediol which is cheap and easy to obtain as raw material, and various dangerous, toxic and expensive drugs are not used in the synthesis route process, the method has a simple route, high yield and good repeatability, and can be used for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing a chiral intermediate of atorvastatin calcium. Background Technology

[0002] Atorvastatin calcium is a potent lipid-lowering drug developed by Pfizer. It is an inhibitor of HMG-CoA reductase, blocking the intracellular hydroxymethylglutaryl-CoA pathway, reducing intracellular cholesterol synthesis, thereby stimulating an increase in the number and activity of low-density lipoprotein receptors on the cell surface, increasing serum cholesterol clearance, and lowering cholesterol levels. Its chemical name is (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(anilineformyl)-5-isopropylpyrrole-1-yl]-3,5-dihydroxyheptanoate calcium, marketed as Lipitor. Its structural formula is as follows:

[0003]

[0004] US Patent 4,681,893 first reported the synthetic route for racemic atorvastatin lactone. US Patent 5,373,995 first reported a method for synthesizing chiral atorvastatin calcium, but the reaction conditions in these two routes are harsh and not easily applicable to industrial production. Furthermore, many of the published methods are quite environmentally harmful.

[0005] Currently, (4R-Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-hexanoate tert-butyl ester, synthesized industrially, is a key chiral intermediate in the synthesis of atorvastatin calcium. However, the chemical synthesis of this intermediate requires highly toxic potassium cyanide and expensive periodic acid. Therefore, the production conditions are harsh, the cost is high, and the environmental impact is significant. Furthermore, the enzymes required for existing biocatalytic synthesis are difficult to preserve and easily deactivated, making them unsuitable for industrial production. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a method for synthesizing a chiral intermediate of atorvastatin calcium, using inexpensive and readily available 1,3-propanediol as a raw material. The synthetic route does not involve the use of various dangerous, highly toxic, or expensive drugs. This method is simple, has a high yield, and good reproducibility, and can be used for industrial production.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] The purpose of this invention is to provide a method for synthesizing a chiral intermediate of atorvastatin calcium, comprising the following steps:

[0009] Using 1,3-propanediol as a raw material, oxidation is carried out after silicon-based protection reaction, followed by cycloaddition reaction under the catalysis of chiral catalyst and lithium salt, introducing the first chiral center; then tert-butyl acetate is added to carry out ring-opening reaction, and a second chiral center is induced to form through Narasaka-Prasad reduction reaction; cis-diol is then protected by adding 2,2-dimethoxypropane, and finally tetrabutylammonium fluoride is added to remove the silicon group, and the amino group is replaced with hydroxyl group by Fukuyama amine synthesis method to obtain the chiral intermediate of atorvastatin calcium.

[0010] Preferably, it includes the following steps:

[0011] Step 1: Using 1,3-propanediol as a raw material, tert-butyldiphenylchlorosilane and triethylamine were added to obtain compound 2 through a silicon-based protection reaction. Compound 2 was then oxidized by adding Dess-Martin reagent to obtain compound 3.

[0012] Step 2: Dissolve the chiral catalyst and lithium salt in a solvent, add diisopropylethylamine to form a reaction system, then add compound 3 and acetyl chloride. Under the catalysis of the chiral catalyst and lithium salt, the acetyl chloride undergoes an asymmetric 2+2 cycloaddition reaction to obtain compound 4, introducing the first chiral center.

[0013] Step 3: Add tert-butyl acetate to compound 4 to give compound 5. Add diethylmethoxyborane and sodium borohydride to compound 5 in sequence to induce the formation of a second chiral center through an asymmetric Narasaka-Prasad reduction reaction to give compound 6.

[0014] Step 4: Add p-toluenesulfonic acid and 2,2-dimethoxypropane to compound 6 to protect the cis-diol and obtain compound 7. Then add tetrabutylammonium fluoride to remove the silicon group and obtain compound 8.

[0015] Step 5: Add triphenylphosphine and 2-nitrobenzenesulfonamide to compound 8, then add diethyl azodicarbonate to obtain compound 9 via Fukuyama amine synthesis. Add potassium carbonate and thiophenol to compound 9 to replace the amino group with hydroxyl group to obtain atorvastatin calcium chiral intermediate 10. The atorvastatin calcium chiral intermediate 10 is (4R-Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxolane-tert-butyl hexanoate.

[0016] The synthesis reaction equation is as follows:

[0017]

[0018] In compounds 2-7, R is a silicon-based protecting group. 。

[0019] Preferably, in step 1, the molar ratio of 1,3-propanediol, tert-butyldiphenylchlorosilane, triethylamine, and Desmond-Martin reagent is 1:1-1.2:2-4:1-1.5. The solvent used for synthesizing compound 2 and compound 3 is dichloromethane. Compound 2 is synthesized by stirring overnight at room temperature under an inert gas atmosphere, and compound 3 is synthesized by reacting at room temperature for 5 hours.

[0020] Preferably, in step 2, the molar ratio of the chiral catalyst, lithium salt, and diisopropylethylamine is 0.05-0.5:1.5-3:2-4; and the molar ratio of the chiral catalyst, compound 3, and acetyl chloride is 0.05-0.5:1:1.5-4.

[0021] The solvents were dichloromethane and methyl tert-butyl ether, with a volume ratio of 2:1. The cycloaddition reaction was carried out at -78°C with stirring for 3 hours.

[0022] Preferably, in step 2, the chiral catalyst is trimethylsilyl or methoxyquinidine; and the lithium salt is lithium perchlorate or lithium iodide.

[0023] Preferably, in step 3, the molar ratio of compound 4 to tert-butyl acetate is 1:2-5; the solvent used to synthesize compound 5 is tetrahydrofuran, and the reaction is carried out under an inert gas atmosphere at -78°C for 5 hours with stirring.

[0024] Preferably, in step 3, the molar ratio of compound 5, diethylmethoxyborane, and sodium borohydride is 1:1-1.2:1-1.2; the solvent used to synthesize compound 6 is tetrahydrofuran and methanol, with a volume ratio of tetrahydrofuran to methanol of 5:1, and the reaction is carried out under an inert gas atmosphere at -10°C for 5 hours.

[0025] Preferably, in step 4, the molar ratio of the compound 6, p-toluenesulfonic acid, and 2,2-dimethoxypropane is 1:0.1-0.2:2-4; the solvent used to synthesize compound 7 is acetone, and the reaction is carried out under an inert gas atmosphere at room temperature for 6 hours.

[0026] The molar ratio of the ester compound 7 to tetrabutylammonium fluoride is 1:1-2.5; the solvent used to synthesize compound 8 is tetrahydrofuran acetone, and the reaction is carried out by stirring at room temperature for 6 hours.

[0027] Preferably, in step 5, the molar ratio of compound 8, triphenylphosphine, 2-nitrobenzenesulfonamide, and diethyl azodicarbonate is 1:1.5-3:1.5-3:2-4; the solvent used to synthesize compound 9 is toluene, and the mixture is stirred overnight at room temperature under an inert gas atmosphere.

[0028] Preferably, in step 5, the molar ratio of compound 9, potassium carbonate, and thiophenol is 1:2-4:2-4; the solvent used to synthesize compound 10 is acetonitrile, and the mixture is stirred for 5 hours at 50°C under an inert gas atmosphere.

[0029] Compared with the prior art, the present invention has the following advantages:

[0030] The method for synthesizing atorvastatin calcium chiral intermediate provided by this invention uses inexpensive and readily available 1,3-propanediol as a raw material. The synthetic route does not use various dangerous, highly toxic, and expensive drugs. The method is simple, has a high yield and good reproducibility, and can be used for industrial production. Detailed Implementation

[0031] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0032] It should be noted that the technical terms used in this invention are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of this invention. Unless otherwise specified, all raw materials, reagents, instruments and equipment used in the following embodiments of this invention can be purchased from the market or prepared by existing methods.

[0033] A method for synthesizing a chiral intermediate of atorvastatin calcium includes the following steps:

[0034] Using 1,3-propanediol as a starting material, the product undergoes a silane-protected reaction followed by oxidation. A cycloaddition reaction then occurs under the catalysis of a chiral catalyst and lithium salt, introducing the first chiral center. Next, tert-butyl acetate is added to initiate a ring-opening reaction, inducing the formation of a second chiral center via an asymmetric Narasaka-Prasad reduction reaction. 2,2-Dimethoxypropane is added to protect the cis-diol, followed by the addition of tetrabutylammonium fluoride to remove the silane group. Finally, the amino group is substituted with a hydroxyl group via the Fukuyama amine synthesis method to obtain the chiral intermediate of atorvastatin calcium.

[0035] Specifically, the following steps are included:

[0036] Step 1: Using 1,3-propanediol as a raw material, tert-butyldiphenylchlorosilane and triethylamine were added to obtain compound 2 through a silicon-based protection reaction. Compound 2 was then oxidized by adding Dess-Martin reagent to obtain compound 3.

[0037] Step 2: Dissolve the chiral catalyst and lithium salt in a solvent, add diisopropylethylamine to form a reaction system, and then add compound 3 and acetyl chloride. Under the catalysis of the chiral catalyst and lithium salt, the acetyl chloride undergoes an asymmetric 2+2 cycloaddition reaction to obtain compound 4, introducing the first chiral center.

[0038] Step 3: Add tert-butyl acetate to compound 4 to give compound 5. Add diethylmethoxyborane and sodium borohydride to compound 5 in sequence to induce a second chiral center through an asymmetric Narasaka-Prasad reduction reaction to give compound 6.

[0039] Step 4: Add p-toluenesulfonic acid and 2,2-dimethoxypropane to compound 6 to protect the cis-diol and obtain compound 7. Then add tetrabutylammonium fluoride to remove the silicon group and obtain compound 8.

[0040] Step 5: Add triphenylphosphine and 2-nitrobenzenesulfonamide to compound 8, then add diethyl azodicarbonate to obtain compound 9 via Fukuyama amine synthesis. Add potassium carbonate and thiophenol to compound 9 to replace the amino group with hydroxyl group to obtain atorvastatin calcium chiral intermediate 10. The atorvastatin calcium chiral intermediate 10 is (4R-Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxolane-tert-butyl hexanoate.

[0041] The synthesis reaction equation is as follows:

[0042]

[0043] In compounds 2-7, R is a silicon-based protecting group. 。

[0044] Example 1

[0045] The method for synthesizing aldehyde compound 3 includes the following steps:

[0046] S1. Dissolve 8.26 g (108.56 mol) of 1,3-propanediol (compound 1) in 260 mL of dichloromethane, add 28.23 mL (108.56 mol) of tert-butyldiphenylchlorosilane TBDPSCl and 30.18 mL (217.11 mol) of triethylamine, stir overnight at room temperature under argon atmosphere, quench with saturated ammonium chloride solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, and distill under reduced pressure to obtain primary alcohol compound 2;

[0047] S2. Primary alcohol compound 2 was dissolved in 300 mL of dichloromethane, and 50.65 g (119.42 mol) of Dess-Martin reagent was added. The reaction was carried out at room temperature for 5 h. The mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 32.79 g of white solid (aldehyde compound 3), with a two-step yield of 80%. The synthetic route is shown below:

[0048]

[0049] Example 2

[0050] The method for synthesizing lactone compound 4 includes the following steps:

[0051] 1.43 g (3.61 mol) of methoxyquinidine (TMS-Quinidine) and 7.69 g (72.32 mol) of lithium perchlorate (LiClO4) were dissolved in 72 mL of dichloromethane and 36 mL of methyl tert-butyl ether. The mixture was stirred at room temperature for 5 min under an argon atmosphere, then transferred to -78 °C. 11.70 mL (90.40 mol) of diisopropylethylamine was added, and the mixture was stirred for 15 min. 11.30 g (36.16 mol) of aldehyde compound 3 was dissolved in 36 mL of dichloromethane and added to the reaction system. After 15 min, 5.14 mL (72.32 mol) of acetyl chloride was dissolved in 36 mL of dichloromethane and added to the reaction system. The mixture was stirred at -78 °C for 3 h. The solvent was removed by vacuum distillation, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). 8.30 g of a white solid (lactone compound 4) was obtained, with a yield of 74% and an optical purity of 89% ee. The synthetic route is shown below:

[0052]

[0053] Example 3

[0054] The method for synthesizing ester compound 5 includes the following steps:

[0055] 1.62 mL (11.52 mol) of diisopropylamine was dissolved in 20 mL of tetrahydrofuran. 4.37 mL of n-butyllithium (2.5 M in THF) was added at -78 °C, and the mixture was stirred for 30 min under an argon atmosphere. 1.47 mL (10.93 mol) of tert-butyl acetate was added, and the mixture was stirred for 30 min. Then, 1.00 g (2.96 mol) of lactone compound 4 was added, and the mixture was stirred for 5 h. The mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1). 1.23 g of a yellow oil (ester compound 5) was obtained, with a yield of 88%. The synthetic route is shown below:

[0056]

[0057] Example 4

[0058] The method for synthesizing diol compound 6 includes the following steps:

[0059] 24.30 g (51.62 mol) of ester compound 5 was dissolved in 200 mL of tetrahydrofuran and 40 mL of methanol. 7.39 mL (56.79 mol) of diethylmethoxyborane was added at -10 °C, and the mixture was stirred for 30 min under an argon atmosphere. Then, 2.15 g (56.79 mol) of sodium borohydride was added, and the mixture was stirred for 5 h. The mixture was quenched with acetic acid, and methanol was removed by vacuum distillation. The solution was diluted with water, extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). 21.70 g of a yellow oil (diol compound 6) was obtained, with a yield of 89%. The synthetic route is shown below:

[0060]

[0061] Example 5

[0062] The method for synthesizing ester compound 7 includes the following steps:

[0063] 21.70 g (45.91 mol) of diol compound 6 was dissolved in 200 mL of acetone, and 873.23 mg (4.59 mol) of p-toluenesulfonic acid p-TsOH and 14.11 mL (114.77 mol) of 2,2-dimethoxypropane were added. The mixture was stirred at room temperature for 6 h under an argon atmosphere. The mixture was quenched with triethylamine, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give 12.77 g of a yellow oil (ester compound 7), with a yield of 75%. The synthetic route is shown below:

[0064]

[0065] Example 6

[0066] The method for synthesizing compound 8 includes the following steps:

[0067] 15.73 g (60.14 mol) of tetrabutylammonium fluoride and 15.42 g (30.07 mol) of ester compound 7 were dissolved in 150 mL of tetrahydrofuran and stirred at room temperature for 6 h. The mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give 7.91 g of a yellow oil (compound 8) in 96% yield. The synthetic route is shown below:

[0068]

[0069] Example 7

[0070] The method for synthesizing compound 9 includes the following steps:

[0071] 8.11 g (29.56 mol) of compound 8, 13.18 g (50.25 mol) of triphenylphosphine, and 17.92 g (88.68 mol) of 2-nitrobenzenesulfonamide were dissolved in 350 mL of toluene. Then, 7.91 mL (50.25 mol) of diethyl azodicarbonate (DEAD) was added at 0 °C. The mixture was stirred overnight at room temperature under an argon atmosphere. The solvent was removed by vacuum distillation, and the mixture was filtered. The sample was washed three times with methyl tert-butyl ether, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). 10.30 g of a yellow oil (compound 9) was obtained, with a yield of 76%. The synthetic route is shown below:

[0072]

[0073] Example 8

[0074] The method for synthesizing compound 10 includes the following steps:

[0075] 10.30 g (22.46 mol) of compound 9 and 12.42 g (89.95 mol) of potassium carbonate were dissolved in 220 mL of acetonitrile, and then 6.89 mL (67.39 mol) of thiophenol were added. The mixture was stirred at 50 °C for 5 h under an argon atmosphere. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was separated by silica gel column chromatography [MeOH (0.5% Et3N)]. 4.27 g of a yellow oil (compound 10(4R-Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxolane-tert-butyl hexanoate) was obtained in 74% yield. The synthetic route is shown below:

[0076]

[0077] The key intermediate 10 (4R-Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxolane-tert-butyl hexanoate was reacted with compound 11 in the presence of tert-valerate to give compound 12. Then, the propylene protecting group on compound 12 was removed to give compound 13. Following a saponification reaction, an aqueous solution of calcium acetate was added, causing atorvastatin calcium to precipitate. The synthetic reaction equation is as follows:

[0078]

[0079] Example 9

[0080] The method for synthesizing compound 12 includes the following steps:

[0081] 4.26 g (15.58 mol) of compound 10 and 5.21 g (12.47 mol) of compound 11 were dissolved in 120 mL of hexane, 15 mL of toluene, and 15 mL of tetrahydrofuran. 1.60 mL (14.03 mol) of pentyl acid was added, and the mixture was stirred at 90 °C for 36 h under an argon atmosphere. The mixture was then distilled under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1). Recrystallization from petroleum ether:ethyl acetate = 8:1 gave 6.56 g of a white solid (compound 12) in 80% yield, with an optical purity of 99% ee. The synthetic route is shown below:

[0082]

[0083] Example 10

[0084] The method for synthesizing compound 13 includes the following steps:

[0085] 261.93 mg (0.40 mol) of compound 12 was dissolved in 6 mL of methanol, and 1 mL of hydrochloric acid (1 N) was added. The mixture was stirred at room temperature for 3 h. The solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to give 203.20 mg of a white solid (compound 13) in 83% yield. The synthetic route is shown below:

[0086]

[0087] Example 11

[0088] The method for synthesizing compound 14 includes the following steps:

[0089] 98.70 mg (0.16 mol) of compound 13 was dissolved in 1 mL of methanol, and 0.4 mL of sodium hydroxide (1 M) was added. The mixture was stirred at 0 °C for 30 min, and 0.2 mL of 5% Ca(OAc)₂ solution was added dropwise. The mixture was stirred for 1 h. The solution was filtered, washed with water, and dried under vacuum to give 88.83 mg of a white solid (compound 14) in 90% yield. The synthetic route is shown below:

[0090]

[0091] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described here to avoid redundancy. Although preferred embodiments of the invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of this invention.

[0092] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for synthesizing a chiral intermediate of atorvastatin calcium, characterized in that, Includes the following steps: Using 1,3-propanediol as a starting material, the product is oxidized after a silane-protected reaction to obtain an oxidation product. Under the catalysis of a chiral catalyst and lithium salt, the oxidation product undergoes an asymmetric 2+2 cycloaddition reaction with acetyl chloride, introducing the first chiral center. Then, tert-butyl acetate is added to undergo a ring-opening reaction, and a second chiral center is induced to form through a Narasaka-Prasad reduction reaction. 2,2-Dimethoxypropane is then added to protect the cis-diol. Finally, tetrabutylammonium fluoride is added to remove the silane group, and the chiral intermediate of atorvastatin calcium is obtained by substituting the hydroxyl group with an amino group through the Fukuyama amine synthesis method.

2. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 1, characterized in that, Specifically, the following steps are included: Step 1: Using 1,3-propanediol as a raw material, tert-butyldiphenylchlorosilane and triethylamine were added to obtain compound 2 through a silicon-based protection reaction. Compound 2 was then oxidized by adding Dess-Martin reagent to obtain compound 3. Step 2: Dissolve the chiral catalyst and lithium salt in a solvent, add diisopropylethylamine to form a reaction system, then add compound 3 and acetyl chloride. Under the catalysis of the chiral catalyst and lithium salt, the acetyl chloride undergoes an asymmetric 2+2 cycloaddition reaction to obtain compound 4, introducing the first chiral center. Step 3: Add tert-butyl acetate to compound 4 to give compound 5. Add diethylmethoxyborane and sodium borohydride to compound 5 in sequence to induce the formation of a second chiral center through an asymmetric Narasaka-Prasad reduction reaction to give compound 6. Step 4: Add p-toluenesulfonic acid and 2,2-dimethoxypropane to compound 6 to protect the cis-diol and obtain compound 7. Then add tetrabutylammonium fluoride to remove the silicon group and obtain compound 8. Step 5: Triphenylphosphine and 2-nitrobenzenesulfonamide are added to compound 8, and then diethyl azodicarbonate is added to obtain compound 9 via Fukuyama amine synthesis. Potassium carbonate and thiophenol are added to compound 9 to remove the amino protecting group and obtain atorvastatin calcium chiral intermediate 10. The atorvastatin calcium chiral intermediate 10 is (4R-Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxolane-tert-butyl hexanoate. The synthesis reaction equation is as follows: In compounds 2-7, R is a tert-butyldiphenylsilane protecting group.

3. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 1, the molar ratio of 1,3-propanediol, tert-butyldiphenylchlorosilane, triethylamine, and Desmond-Martin reagent is 1:1-1.2:2-4:1-1.

5. The solvent used for synthesizing compounds 2 and 3 is dichloromethane. Compound 2 is synthesized by stirring overnight at room temperature under an inert gas atmosphere, and compound 3 is synthesized by reacting at room temperature for 5 h.

4. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 2, the molar ratio of the chiral catalyst, lithium salt, and diisopropylethylamine is 0.05-0.5:1.5-3:2-4; the molar ratio of the chiral catalyst, compound 3, and acetyl chloride is 0.05-0.5:1:1.5-4. The solvents were dichloromethane and methyl tert-butyl ether, with a volume ratio of 2:

1. The cycloaddition reaction was carried out at -78°C with stirring for 3 h.

5. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 2, the chiral catalyst is trimethylsilyl or methoxyquinidine; the lithium salt is lithium perchlorate or lithium iodide.

6. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 3, the molar ratio of compound 4 to tert-butyl acetate is 1:2-5; the solvent used to synthesize compound 5 is tetrahydrofuran, and the reaction is carried out under an inert gas atmosphere at -78°C for 5 h with stirring.

7. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 3, the molar ratio of compound 5, diethylmethoxyborane, and sodium borohydride is 1:1-1.2:1-1.2; the solvent used to synthesize compound 6 is tetrahydrofuran and methanol, with a volume ratio of tetrahydrofuran to methanol of 5:1, and the reaction is stirred for 5 h under an inert gas atmosphere at -10℃.

8. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 4, the molar ratio of compound 6, p-toluenesulfonic acid, and 2,2-dimethoxypropane is 1:0.1-0.2:2-4; acetone is used as the solvent for synthesizing compound 7, and the reaction is carried out under an inert gas atmosphere at room temperature for 6 hours. The molar ratio of compound 7 to tetrabutylammonium fluoride is 1:1-2.5; the solvent used to synthesize compound 8 is tetrahydrofuran acetone, and the reaction is carried out at room temperature with stirring for 6 h.

9. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 5, the molar ratio of compound 8, triphenylphosphine, 2-nitrobenzenesulfonamide, and diethyl azodicarbonate is 1:1.5-3:1.5-3:2-4; toluene is used as the solvent for synthesizing compound 9, and the mixture is stirred overnight at room temperature under an inert gas atmosphere.

10. The method for synthesizing the chiral intermediate of atorvastatin calcium according to claim 2, characterized in that, In step 5, the molar ratio of compound 9, potassium carbonate, and thiophenol is 1:2-4:2-4; the solvent used to synthesize compound 10 is acetonitrile, and the mixture is stirred for 5 h at 50°C under an inert gas atmosphere.

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