CN115521260A

CN115521260A - Synthetic method of rosuvastatin calcium tert-butyl ester

Info

Publication number: CN115521260A
Application number: CN202211181632.3A
Authority: CN
Inventors: 何义; 童林; 罗威; 庞小召; 曹蒙; 张维冰
Original assignee: Jiangsu Alpha Pharmaceutical Co ltd
Current assignee: Jiangsu Alpha Pharmaceutical Co ltd
Priority date: 2022-09-27
Filing date: 2022-09-27
Publication date: 2022-12-27

Abstract

The invention discloses a method for synthesizing rosuvastatin calcium tert-butyl ester, which comprises the following steps of reacting a compound I with magnesium powder to synthesize a Grignard reagent, reacting the Grignard reagent with trimethylsilane under the action of a catalyst to obtain a compound III (4R-CIS) -6-trimethylsilyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate, reacting the compound III with a compound IV under the action of a catalyst to obtain a compound V, and hydrolyzing the compound V under alkaline or acidic conditions to obtain rosuvastatin tert-butyl ester, wherein the method has the following beneficial effects: the compound III is prepared by the reaction of the format reagent and trimethylsilane, the yield of the synthesis of the calcium side chain of rosuvastatin is improved, and the selectivity of the olefination reaction is effectively increased and the generation of byproducts and three wastes is reduced by selecting a cesium fluoride catalyst for catalysis of the Peterson olefination reaction.

Description

Synthetic method of rosuvastatin calcium tert-butyl ester

Technical Field

The invention relates to the technical field related to medicine synthesis, in particular to a method for synthesizing rosuvastatin calcium tert-butyl ester.

Background

Rosuvastatin (Rosuvastatin) is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase (HMG-CoA reductase) and is useful in the treatment of hypercholesterolemia and mixed dyslipidemia and can reduce elevated concentrations of low density cholesterol, total cholesterol, triglycerides and apo-protein B while elevating concentrations of high density cholesterol; can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and is called super statin.

Rosuvastatin is administered as a single enantiomer calcium salt and is marketed in several countries and regions of the united states, japan, europe, china, etc., under the 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) having the following chemical structure:

the key steps of the main synthetic method of rosuvastatin are to synthesize the rosuvastatin calcium pyrimidine by constructing a carbon-carbon double bond connecting a rosuvastatin calcium pyrimidine parent nucleus and a key chiral side chain, and at present, the synthetic route of rosuvastatin calcium mainly depends on two schemes:

scheme one

The method comprises the steps of constructing a carbon-carbon double bond connecting a rosuvastatin calcium pyrimidine parent nucleus and a key chiral side chain through a Witting olefination reaction, preparing an intermediate rosuvastatin calcium tert-butyl ester through the Witting reaction of the key intermediate pyrimidine parent nucleus and the key chiral side chain, and preparing the rosuvastatin calcium bulk drug through deprotection, hydrolysis, salification and other processes of the rosuvastatin calcium tert-butyl ester. The main classification is as follows: (1) Aldehyde group is introduced into a pyrimidine mother nucleus, a side chain is made into a Wittig reagent, a trans-olefin intermediate is obtained through a Wittig reaction, and a product is obtained through further conversion (shown in a scheme 1); (2) Introducing ylide reagent or other reagents into the pyrimidine mother nucleus, preparing an aldehyde compound from a side chain, obtaining a trans-olefin intermediate through a Wittig reaction, and further converting to obtain the product.

Route 1

Route 2

Scheme two

The synthesis method for constructing the carbon-carbon double bond connecting the rosuvastatin calcium pyrimidine parent nucleus and the key chiral side chain through Julia olefination is suitable for industrial production, two key intermediate pyrimidine parent nuclei and the key chiral side chain are subjected to Julia reaction to prepare an intermediate rosuvastatin calcium tert-butyl ester, and the rosuvastatin calcium tert-butyl ester is subjected to deprotection, hydrolysis, salification and other processes to prepare the rosuvastatin calcium bulk drug, the synthesis route is similar to witting reaction, and the main synthesis route is shown as the following scheme 3,4:

route 3

Route 4

The side chain starting material in the route 1 is expensive, the butt stereoselectivity is not ideal, a large number of isomers exist, the yield is low, the industrial production is difficult, and the cost of the route is high. The reaction of the route 2 is carried out at the extremely low temperature of-75 ℃, the reaction conditions are harsh, the butt stereoselectivity is not ideal, the yield is low, and the large-scale industrial production is not facilitated. Although the butt joint stereoselectivity of the route 3 is well solved, the side chain is difficult to obtain through oxidation, the yield of the prepared side chain is low, the cost is high, the atom economy of the reaction is poor, the temperature of the olefination reaction is-60 ℃, the requirement on equipment is high, and the industrial production of the route is difficult. The route 4 overcomes the defects that the side chain in the route 3 is difficult to be completely oxidized and raw materials are difficult to obtain, but the butt-joint reaction is an ultralow temperature reaction (-60 ℃), and the olefination reaction yield is only about 50 percent, so the energy consumption is high, the cost is high, and the industrial production is difficult to realize.

The chemical invention publication CN104829600B discloses a synthesis process of (4R, 6S, E) -2- {6- [2- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl (methylsulfonyl) amino) pyrimidin-5-yl ] vinyl ] -2,2-dimethyl-1,3-epoxyhex-4-yl } acetic acid alkyl ester, and the synthesis route is as follows:

4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) -5-trimethylsilylmethylpyrimidine was prepared by reacting 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) -5-methylsulfanyl with trimethylchlorosilane under the action of a catalyst, and rosuvastatin calcium intermediate 6- [ (1E) -2- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -5-pyrimidine ] vinyl ] -2,2-dimethyl-1,3-dioxane-4-acetic acid alkyl ester was prepared by Peterson olefination under mild conditions, higher stereoselectivity than Wittivity than the Witting reaction, higher overall yield than the Julia reaction, but lower yield of 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) -5-methylpyrimidine by reacting 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) -5-methylchlorosilane with a catalyst.

In conclusion, the problem that reaction conditions are harsh, stereoselectivity is poor, byproducts are more, total yield is low and the like exists when rosuvastatin tert-butyl ester is prepared by the existing synthetic route of rosuvastatin calcium.

Aiming at the defects of the existing synthetic route, the invention provides a synthetic method of rosuvastatin calcium tert-butyl ester by improving the Peterson olefination reaction process provided by the open document CN104829600B, and the synthetic route is as follows:

disclosure of Invention

Aiming at the problems of poor stereoselectivity, harsh reaction conditions and lower yield when the existing rosuvastatin calcium preparation method is used for preparing rosuvastatin tert-butyl ester, the invention provides the synthesis method of the rosuvastatin calcium tert-butyl ester, which has mild reaction conditions, good stereoselectivity and high yield of Gao Rui by improving the Peterson olefination reaction process.

A method for synthesizing rosuvastatin tert-butyl ester comprises the following steps:

firstly, (4R-CIS) -6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate (compound I) reacts with magnesium powder to obtain a Grignard reagent (compound II);

secondly, reacting the compound II with trimethylsilane under the action of a catalyst to prepare (4R-CIS) -6-trimethylsilyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate;

and thirdly, further reacting the compound III with 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde (compound IV) under the action of a catalyst, and after the reaction is finished, extracting, separating and purifying to obtain 6- [ (1E) -2- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -5-pyrimidine ] vinyl ] -2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (compound V).

And fourthly, hydrolyzing the compound V under acidic or alkaline conditions to obtain rosuvastatin tert-butyl ester.

Further, the first solvent is anhydrous THF, methyl tertiary ether or diethyl ether, and THF is preferred.

Furthermore, the molar ratio of the magnesium chips in the first step reaction to the solvent is 1:5-7, preferably 1:6.2.

further, the reaction temperature of the first step reaction is 30 ℃, and the reaction time is 2h.

Further, the solvent selected in the second step is an aprotic solvent THF.

Further, the molar ratio of the Grignard reagent to trimethylsilane in the second reaction step is 1.6 to 1:1, preferably 1.8,

further, the reaction temperature of the second step is 62-65 ℃, preferably 65 ℃.

Further, the catalyst selected in the third step of reaction is cesium fluoride, and the amount of the catalyst is 5-10% of the mass of the compound III.

Further, the solvent for the third step reaction is an aprotic polar solvent selected from DMF, DMSO and NMP, and the reaction temperature in the third step reaction is 80-150 ℃.

The invention has the beneficial effects that: the rosuvastatin tert-butyl ester preparation method provided by the invention has the advantages that raw materials are easy to obtain, the yield of side chains synthesized by a Grignard reagent method is high, the selectivity of Peterson olefination reaction is good, the atom economy is good, the reaction conditions are mild and the operation is facilitated, byproducts such as magnesium chloride, silicide and the like generated in the reaction process are easy to separate and convenient to process, reaction product intermediates III and IV are solid, the solid is convenient to refine, the purity of an intermediate R1 in the next step is high, impurities are reduced and the product purification is facilitated, so that the total yield and purity of final products are high, the post-treatment of the products is simple, the production cost is greatly reduced, and the large-scale production is facilitated.

Drawings

FIG. 1 is a schematic diagram of the reaction scheme of the present invention;

FIG. 2 is the structural formula of rosuvastatin calcium;

FIG. 3 is a schematic diagram of reaction schemes 1 and 2 of Witting olefination reaction scheme;

FIG. 4 is a schematic representation of the reaction scheme 3,4 of Julia olefination;

FIG. 5 is a schematic diagram of the reaction scheme of CN104829600B as a comparison document.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

Under the protection of nitrogen, 8.75g (0.36 mol) of magnesium chips are added into a 1000ml four-neck flask, 150ml of THF reagent is added, 100g of compound I is slowly added into the solution, the solution is stirred for 30min, bromoethane serving as an initiator is added at 27 ℃, 65ml of THF is continuously added after initiation, the stirring is continuously carried out, the temperature is controlled at 30 ℃, the temperature is kept for 2 hours, and after the reaction is finished, the excessive magnesium chips are removed by filtering to obtain a compound II, wherein the yield is 89.6%.

Example 2

Under the protection of nitrogen, 8.75g (0.36 mol) of magnesium chips are added into a 1000ml four-neck flask, 150ml of THF reagent is added, 100.3g of compound I is added into the solution, the solution is stirred for 30min, bromoethane serving as an initiator is added at 27 ℃, 120ml of THF is continuously added after initiation, the stirring is continuously carried out, the temperature is controlled at 30 ℃, the reaction is carried out for 2 hours, and after the reaction is finished, the excessive magnesium chips are removed by filtering to obtain a compound II, wherein the yield is 93.6%.

Example 3

Under the protection of nitrogen, 8.75g (0.36 mol) of magnesium chips are added into a 1000ml four-neck flask, 150ml of THF reagent is added, 100.3g of compound I is added into the solution, the solution is stirred for 30min, bromoethane serving as an initiator is added at 27 ℃, 150ml of THF is continuously added after initiation, the stirring is continuously carried out, the temperature is controlled at 30 ℃, the temperature is kept for 2 hours, and after the reaction is finished, the excessive magnesium chips are removed by filtering, so that a compound II is obtained, wherein the yield is 93.8%.

Example 4

Dropwise adding 31.3g (0.288 mol) of trimethylchlorosilane into the Grignard reagent obtained in the first step, controlling the reaction temperature to be between 62 and 67 ℃, heating and refluxing for 2 hours at 65 ℃ after the dropwise adding is finished, cooling to be below 10 ℃, hydrolyzing by 5-percent HCl, separating liquid, washing an organic phase by saturated saline solution for 2 times, drying by anhydrous sodium sulfate, and evaporating a solvent to obtain a compound III, wherein the yield is 96.3 percent, and the purity is 99.5 percent.

Example 5

Dropwise adding 39.1 g (0.36 mol) of trimethylchlorosilane into the Grignard reagent obtained in the first step, controlling the reaction temperature to be between 62 and 67 ℃, heating and refluxing for 2 hours at 65 ℃ after the dropwise adding is finished, cooling to be below 10 ℃, hydrolyzing by 5 percent HCl, separating liquid, washing an organic phase by saturated saline solution for 2 times, drying by anhydrous sodium sulfate, and evaporating a solvent to obtain a compound III, wherein the yield is 90.2 percent, and the purity is 99.5 percent.

Example 6

Dropwise adding 23.4g (0.216 mol) of trimethylchlorosilane into the Grignard reagent obtained in the first step, controlling the reaction temperature to be between 62 and 67 ℃, heating and refluxing for 2 hours at 65 ℃ after the dropwise adding is finished, cooling to be below 10 ℃, hydrolyzing by 5-percent HCl, separating liquid, washing an organic phase by saturated saline solution for 2 times, drying by anhydrous sodium sulfate, and evaporating a solvent to obtain a compound III, wherein the yield is 89.3 percent, and the purity is 99.5 percent.

Example 7

In a 250ml three-necked flask, a thermometer, a pH meter, and a constant pressure dropping funnel were attached and magnetic stirring was performed. 10g of Compound II, 100ml of DMF, 11g of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-carbaldehyde and 0.5g of cesium fluoride were added to a reaction flask at room temperature, and the mixture was stirred for 1 hour. Then heating to 120 ℃, preserving heat for 2 hours, cooling, pouring into 200ml of ice water, using toluene 150ml x 2 for layered extraction, decompressing and concentrating, using methanol 100ml for dissolving, cooling to normal temperature, preserving heat for 6 hours for crystallization, filtering, decompressing and drying to obtain the product (4R, 6S, E) -2- {6- [2- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl (methylsulfonyl) amino) pyrimidine-5-yl ] vinyl ] -2,2-dimethyl-1,3-dioxane-4-yl } acetic acid tert-butyl ester 15.41g, the yield is 85%, and the HPLC purity is 99.5%.

Example 8

In a 250ml three-necked flask, a thermometer, a pH meter and a constant pressure dropping funnel were attached and magnetically stirred. 10g of Compound III, 100ml of DMSO, 11g of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-carbaldehyde and 0.5g of cesium fluoride were placed in a reaction flask at room temperature, and the mixture was stirred for 1 hour. Then heating to 90-92 ℃, preserving heat for 4 hours, cooling, pouring into ice water of 200ml, carrying out layered extraction by using toluene of 150ml by 2, decompressing and concentrating, dissolving by using methanol of 100ml, cooling to normal temperature, preserving heat for 6 hours, crystallizing, filtering, decompressing and drying to obtain the product (4R, 6S, E) -2- {6- [2- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl (methylsulfonyl) amino) pyrimidin-5-yl ] vinyl ] -2,2-dimethyl-1,3-dioxane-4-yl } methyl acetate of 14.86g yield of 82%, and HPLC purity of 99.3%.

Example 9

In a 250ml three-necked flask, a thermometer, a pH meter, and a constant pressure dropping funnel were attached and magnetic stirring was performed. 10g of Compound II, 100ml of NMP, 11g of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-carbaldehyde and 0.5g of cesium fluoride were placed in a reaction flask at room temperature, and stirred for 1 hour. Then heating to 130 ℃, preserving heat for 1.5 hours, cooling, pouring into ice water of 200ml, using toluene 150ml x 2 for layered extraction, decompressing and concentrating, using methanol of 100ml for dissolving, cooling to normal temperature, preserving heat for 6 hours for crystallization, filtering, decompressing and drying to obtain the product (4R, 6S, E) -2- {6- [2- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl (methylsulfonyl) amino) pyrimidine-5-yl ] vinyl ] -2,2-dimethyl-1,3-dioxane-4-yl } acetic acid tert-butyl ester of 13.23g, the yield is 73%, and the HPLC purity is 99.4%.

Example 10

In a 250ml three-necked flask, a thermometer, a pH meter, and a constant pressure dropping funnel were attached and magnetic stirring was performed. 10g of Compound II, 100ml of DMF, 11g of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-carbaldehyde and 1.0g of cesium fluoride were added to a reaction flask at room temperature, and the mixture was stirred for 1 hour. Then heating to 120 ℃, preserving heat for 2 hours, cooling, pouring into 200ml of ice water, using toluene 150ml x 2 for layered extraction, decompressing and concentrating, using methanol 100ml for dissolving, cooling to normal temperature, preserving heat for 6 hours for crystallization, filtering, decompressing and drying to obtain the product compound V (4R, 6S, E) -2- {6- [2- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl (methylsulfonyl) amino) pyrimidine-5-yl ] ethenyl ] -2,2-dimethyl-1,3-dioxane-4-yl } acetic acid tert-butyl ester 15.05g, yield 83%, HPLC purity 99.5%.

Example 11

Adding 100g (0.173 mol) of compound V and 700mL of acetonitrile into a 2000mL four-neck round-bottom flask, slowly heating to about 40 ℃, stirring to dissolve, slowly dropwise adding 80mL of hydrochloric acid with the concentration of 0.05mol/L, preserving heat after dropwise adding for reaction for 2h, detecting that raw materials are completely converted through HPLC, cooling to 0 ℃, dropwise adding a saturated sodium carbonate aqueous solution to adjust the pH of a reaction system to about 7, continuously stirring for 3h, filtering, washing, drying to obtain 87g of white rosuvastatin tert-butyl ester, wherein the purity of HPLC is 99.5%.

Comparison document (CN 104829600B) example 1

In a 500ml four-necked flask, the N2 guard was fitted with a thermometer, and a constant pressure dropping funnel and magnetic stirring. At normal temperature, 14 g of compound I is added into a reaction bottle, about 150ml of THF is added, stirring is carried out for dissolving, then the temperature is slowly reduced to-5 to-10 ℃, 30ml of N-hexane solution of N-butyl lithium (2.5N) is slowly added, the temperature is maintained at-10 ℃ to 0 ℃, the adding time is about 45min, the temperature is increased to 0 ℃ to 10 ℃, the temperature is kept for 30min, the temperature is reduced to-15 ℃,2,2,6,6-tetramethylpiperidine 11g/THF20ml mixed solution is added dropwise, the adding time is about 30min, the temperature is controlled at-15 +/-2 ℃, chlorosilane is kept for 2h, trimethyl/THF (8 g/20 ml) is slowly added for 3h (cyclohexane: ethyl acetate =20 1) after reaction is completed, the mixture is poured into ice water 300ml, 200ml of toluene is used for extraction for 2 times, saturated sodium bicarbonate water 100ml is used for washing once, the mixture is concentrated under reduced pressure to be dry, 20ml of N-heptane, 1ml of ethyl acetate is added, heating is dissolved, the mixture is slowly cooled to-5 ℃ to be cooled to more than 6 hours, and the product II is filtered and dried under reduced pressure to obtain the yield of 2.63.

Comparison document (CN 104829600B) example 2

In a 250ml three-necked flask, a thermometer, a pH meter, and a constant pressure dropping funnel were attached and magnetic stirring was performed. 10g of Compound II, 100ml of DMF, and 0.4g of cesium fluoride (6.5 g of t-butyl (4R-cis) -6-formyl-2,2-dimethyl-1,3-dioxane-4-acetate) were added to a reaction flask at room temperature, and the mixture was stirred for 1 hour. Then heating to 120 ℃, preserving heat for 2 hours, cooling, pouring into ice water 200ml, using toluene 150ml x 2 for layered extraction, decompressing and concentrating, using methanol 100ml for dissolving, cooling to normal temperature, preserving heat for 6 hours for crystallization, filtering, decompressing and drying to obtain the product (4R, 6S, E) -2- {6- [2- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl (methylsulfonyl) amino) pyrimidine-5-yl ] vinyl ] -2,2-dimethyl-1,3-dioxane-4-yl } acetic acid tert-butyl ester 11.0g yield 77.8%.

According to the above examples, compared with 60% preparation yield of rosuvastatin side chain of CN104829600B, the yield of preparing rosuvastatin tert-butyl ester is 49.0%, the preparation yield of rosuvastatin side chain of the present invention is over 90%, and the yield of Peterson olefination reaction is up to 80%, which is higher than the technical scheme disclosed in the publication.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims

1. A synthetic method of rosuvastatin calcium tert-butyl ester is characterized by comprising the following steps:

secondly, reacting the compound II with trimethylchlorosilane under the action of a catalyst to prepare (4R-CIS) -6-trimethylsilyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate;

thirdly, the compound III and 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde (compound IV) react further under the action of a catalyst, and after the reaction is finished, extraction, separation and purification are carried out to obtain 6- [ (1E) -2- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -5-pyrimidine ] vinyl ] -2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (compound V);

and fourthly, hydrolyzing the compound V under acidic or basic conditions to prepare rosuvastatin tert-butyl ester (compound VI).

2. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: the first step reaction solvent is anhydrous THF, methyl tertiary ether or diethyl ether.

3. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: the molar ratio of the magnesium chips in the first step to the solvent is 1:5-7.

4. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: the reaction temperature of the first step reaction is 30 ℃, and the reaction time is 2h.

5. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: the solvent selected in the second step is the aprotic solvent THF.

6. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: the molar ratio of the Grignard reagent to trimethylsilane in the second step is 1.6-1:1.

7. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: the reaction temperature of the second step is 62-65 ℃.

8. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: and the catalyst selected in the third step is cesium fluoride, and the dosage of the catalyst is 5-10% of the mass of the compound III.

9. The method for synthesizing rosuvastatin calcium tert-butyl ester according to claim 1, wherein: the third step reaction solvent is an aprotic polar solvent DMF, DMSO or NMP, and the third step reaction temperature is 80-150 ℃.