KR20120092788A - New statin intermediate, the preparation of the same and the preparation of rosuvastatin using the same - Google Patents

Abstract

PURPOSE: A method for preparing rosuvastatin hemicalcium salt using methyl 2-((4R,6S)-6-(triphenylphosphoranylidenemehtyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate is provided to obtain statin of high purity and high yield. CONSTITUTION: A method for preparing a compound of chemical formula 4 comprises: a step of reacting a compound of chemical formula 3 with 2,2-dimethoxypropane under the presence of acid; and a step of adding alkaline to the reacted solution to prepare the compound of chemical formula 4. The acid includes methane sulfonic acid, paratoluene sulfonic acid, perchloric acid, hydrochloric acid, nitric acid, acetic acid, sulfuric acid, or trifluoreacetic acid. The alkaline includes sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, triethylamine, and ammonium hydroxide.

Description

Statin intermediate, preparation method thereof, and method for preparing rosuvastatin using the same {New Statin intermediate, the preparation of the same and the preparation of Rosuvastatin using the same}

The present invention relates to a statin intermediate, a method for preparing the same, and a method for preparing rosuvastatin using the same.

Statins inhibit cholesterol biosynthesis in the body by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A ('HMG-Co A') reducing agents. The HMG-CoA reducing agent catalyzes the conversion of HMG to mevalonate, which is a rate determining step in the biosynthesis of cholesterol. Therefore, when statins reduce the amount of cholesterol synthesized, the number of LDL receptors is increased, thereby decreasing the concentration of LDL particles in the blood stream, thereby reducing the risk of developing coronary artery disease. Statins are used to treat hypercholesterolemia, hyperlipidemia, and atherosclerosis, such as lovastatin, simvastatin, atorvastain, pravastatin, fluvastatin, Cerivastatin, rosuvastatin, pitavastatin. Their structures are as follows, and they have a (3R, 5R) -dihydroxy carboxylic acid structure in common, as indicated by "circles" in the structural formula below.

Thus, if an intermediate with a moiety of "(3R, 5R) -dihydroxy carboxylic acid" denoted as "circle" in the above scheme is developed, this has the advantage that it can be used for all of the statin synthesis listed above.

On the other hand, studies on the production of statins and their intermediates exemplified above are currently being actively conducted. For example, an intermediate of Rosuvastatine and a method for preparing the same are described in European Patent EP 521471 (Korean Patent Publication No. 1996-0005951); WO 00/49014; WO 06/067456; WO 07/007119; WO 067456; WO 06/091771; WO 03/016317; WO 06/106526; WO 07/039287; WO 08/053334; WO 07/125547 and the like.

Specifically, EP 521471 discloses a method for preparing rosuvastatin hemicalcium salt using Compound A and Compound B as starting materials, as shown in Scheme 1 below.

[Reaction Scheme 1]

In other words, the above known method is a method of obtaining Compound RO-2 by first reacting Compounds A and B, and then reacting the resulting Compound RO-1 with a deprotecting agent such as a fluorine ion source or an inorganic acid such as HF. And reacting compound RO-2 with sodium borohydride at −78 ° C. to produce R 0-3.

However, when R0-1 is reacted with a strong acid as described above, the fluoro group of the phenyl group may be desfluorination (see Organic Syntheses, 4 , p 964 (1963), Organic Syntheses, 39 , p 75 (1959)). Material is present as a flexible material). Moreover, when the product is used in the next reaction without purification after the deprotection reaction as in the above patent, impurities are impossible to crystallize the product thereafter, resulting in poor product yield (see Korean Patent Publication No. 10-2007-0100970). (H), it is difficult to manufacture high-yield and high-purity rosuvastatin calcium due to the increase of lead substances.

In addition, the condition of adding diethylmethoxyborane solution at about −78 ^° C. to obtain a RO-3 material is not only a ketone group, but also a double bond (α, β- in the α, β-unsaturated ketone form of Compound R0-2. The unsaturated portion can also be reduced, so there is a disadvantage in that a large number of side reactions occur, and these impurities are not well separated from the compound R0-3. Therefore, when proceeding to the next reaction as it is without purification, there is a disadvantage that can not obtain the final product rosuvastatin calcium salt in high yield, high purity.

As described above, the rosuvastatin hemicalcium salt manufacturing method known to date is relatively easy to produce on a commercially acceptable scale, and thus, there is a need to develop a simpler and cheaper rosuvastatin hemicalcium salt manufacturing process.

Accordingly, an object of the present invention is to provide a novel intermediate of statin, a method for preparing the same, and a method for preparing rosuvastatin hemicalcium salt including the same, which enables the mass production of statins simply and efficiently.

The present invention comprises the steps of: a) reacting a compound of formula 3 with 2,2-dimethoxypropane in the presence of an acid; And b) adding a base to the reaction solution after step a) and reacting to provide a method for preparing the compound of [Formula 4] (hereinafter, referred to as 'preparation method 1'). do):

(3)

[Formula 4]

"은 이중결합 또는 단일결합을 의미하며, Y가 PPh₃인 경우 이중결합을 의미하고, Y가 P(O)(OEt)₂ 또는 P(O)Ph₂인 경우 단일결합을 의미하며, Wherein "Y" is PPh ₃ , P (O) (OEt) ₂ or P (O) Ph ₂ , and "

"Means a double bond or a single bond, and if Y is PPh ₃ , it means a double bond, and if Y is P (O) (OEt) ₂ or P (O) Ph ₂ , it means a single bond,

"R" is C1 to C4 lower alcohol.

Lower alcohol of C1 to C4 in the present invention means methyl, ethyl, n-propane, iso-propane, n-butyl, iso-butyl, t-butyl.

In the preparation method 1 of the present invention, the molar ratio of the compound of Formula 3 and 2,2-dimethoxypropane is preferably 1:10 to 20.

In Preparation Method 1 of the present invention, 2,2-dimethoxypropane can be purchased commercially and used.

In Preparation Method 1 of the present invention, in the compound of [Formula 3] and [Formula 4], Y is PPh ₃ And R is methyl.

In the production method 1 of the present invention, an acid may be selected from methanesulfonic acid, paratoluenesulfonic acid, perchloric acid, hydrochloric acid, nitric acid, acetic acid, sulfuric acid, trifluoroacetic acid, and trifluoroacetic acid.

In the preparation method 1 of the present invention, the base may be selected from sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, triethylamine, and ammonium hydroxide.

In Preparation Method 1 of the present invention, the reaction can be carried out at 0 to 50 ° C., preferably at room temperature. In the present invention, room temperature means 15 to 30 ℃.

In the preparation method 1 of the present invention, the solvent may be a conventional organic solvent used in the field of organic chemistry, for example, acetone, methanol and the like can be used.

In Preparation Method 1 of the present invention, the reaction time may vary depending on the reaction temperature and / or the reaction solvent, preferably about 6 to 24 hours.

In Preparation Method 1 of the present invention, the compound [Formula 3] is a) reacting the compound [Formula 1] with an acid (acid) to deprotect the hydroxy group of the compound [Formula 1] to prepare a compound [Formula 2] ; And b) reacting the compound of Formula 2 with diethylmethoxyborane and sodium borohydride (NaBH ′) to produce the compound of Formula 3 (hereinafter, referred to as 'Production Method' 2 ').

[Formula 1]

[Formula 2]

Wherein Y and R are as defined in Preparation Method 1, X is a hydroxy protecting group.

In the preparation method 2 of the present invention, a hydroxy protecting group means a hydroxy protecting group commonly used in the field of organic synthesis, and may be, for example, t-butyldimethylsilyl, trimethylsilyl, triethylsilyl or allyloxycarbonyl, and the like. , t-butyldimethylsilyl group is preferable.

In the preparation method 2 of the present invention, the compound of [Formula 1] can be purchased commercially. For example, if X is t-butyldimethylsilyl, it can be purchased from Sigma-Aldrich, and if X is trimethylsilyl, triethylsilyl or allyloxycarbonyl, it can also be purchased from Sigma-Aldrich. Do.

In step a) of Preparation Method 2 of the present invention, the molar ratio of the compound of Formula 1 and acid is preferably 1: 1.1 to 2.5.

In step a) of Preparation Method 2 of the present invention, the acid may be selected from hydrogen fluoride, hydrogen chloride, P-toluenesulfonic acid, and potassium fluoride, which may be in the form of an aqueous solution dissolved in water. have.

In step a) of Preparation Method 2 of the present invention, the reaction solvent may be a conventional organic solvent, and tetrahydrofuran, dichloromethane, or the like may be used.

In step b) of the Preparation Method 2 of the present invention, the reaction molar ratio of the compound of Formula 2 and sodium borohydride (NaBH ′) is preferably 1: 0.5 to 2, and the reaction temperature is preferably minus 78 ° C.

In step b) of Preparation Method 2 of the present invention, the reaction solvent is more preferably a mixture of methanol and anhydrous THF.

In Production Method 2 of the present invention, it is preferable that Y is PPh ₃ and R is methyl.

The present invention also provides a compound of Formula 4a:

[Chemical Formula 4a]

Wherein R is methyl or ethyl.

The compound of formula 4a of the present invention may be used as an intermediate of statin, and more preferably, may be used as an intermediate of rosuvastatin, pitavastatin, fluvastatin, and cerivastatin. The compound of formula 4a of the present invention, since the 3, 5-dihydroxy group is already protected by acetal when coupling with an intermediate having an aromatic ring in preparing a statin, The product is small and has the effect of providing high purity statins in high yield.

The present invention also comprises the steps of: a) preparing a compound represented by the following Chemical Formula 6 by reacting a compound of the following Chemical Formula 5 with an organic solvent;

b) reacting a compound with an acid and then reacting with a base to deprotect the acetal protecting group to prepare a compound of Formula 7; And

c) After reacting a solution of a compound of the following formula in an organic solvent and an aqueous sodium hydroxide solution, the aqueous layer is separated, and calcium chloride is added to the aqueous layer to provide a method for producing rosuvastatin hemicalcium salt (hereinafter, 'the manufacturing method' 3 '):

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

"은 제조방법 1에서 정의한 바와 같으며, "R"은 메틸 또는 에틸이다.Wherein "Y" and "

"Is as defined in Preparation Method 1, and" R "is methyl or ethyl.

In the step a) of Preparation Method 3 of the present invention, the reaction mole ratio of the compound of Formula 5 and the compound of Formula 4 is preferably 1: 1.1 to 2.0.

In step a) of Preparation Method 3 of the present invention, a base may be further added as necessary, and the base may be, for example, potassium carbonate, sodium carbonate, lithium hydroxide, lithium hydroxide hydrate, sodium It may be selected from hydroxide, potassium hydroxide, potassium t-butoxide and sodium methoxide.

In step a) of Preparation Method 3 of the present invention, the reaction solvent may be a conventional organic solvent, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, toluene, dioxane, tetrahydrofuran, diethyl ether , An ether solvent such as diisopropyl ether, or an organic solvent such as a halogenated solvent such as methylene chloride, 1,2-dichloroethane, chloroform and the like, and these solvents may be used alone or as a mixed solvent. The reaction temperature is preferably reflux heating, and when the base is added to the reaction, the reaction temperature may be lower than the reflux heating.

Reaction conditions of step b) of the production method 3 of the present invention means deacetal reaction conditions used in conventional organic synthesis, acid may be hydrochloric acid, sulfuric acid, acetic acid, etc. Sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be used. At this time, the amount of the base is preferably an amount such that the pH of the reaction solution is 8 to 9.

Reaction solvent of step b) of the preparation method 3 of the present invention means an organic solvent used in the deacetal reaction conditions used in conventional organic synthesis, for example, tetrahydrofuran (THF), acetonitrile, methanol, etc. Can be used.

In step c) of Preparation Method 3 of the present invention, the addition temperature of the sodium hydroxide aqueous solution and the addition temperature of calcium chloride are preferably -10 to 10 ° C, and the reaction is preferably performed at room temperature.

In step c) of Preparation Method 3 of the present invention, the reaction solvent may be a C1 to C4 alcohol, acetone acetonitrile, dioxane, tetrahydrofuran and the like. Preferably ethanol is preferred.

The present invention provides a method for preparing rosuvastatin hemicalcium salt, including preparation method 1 and preparation method 3 of the present invention.

The novel intermediate of the present invention provides statins in high purity and high yield, the method for preparing intermediates of the present invention and the method for preparing rosuvastatin hemicalcium salts comprising the same lower the content of the flexible substance in the final product, There is an easier effect.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Hereinafter, the reagents used in the examples are purchased from Aldrich, TCI, and Acros, unless otherwise noted, and ¹ H-NMR is measured using a Varian Inova 500 MHz FT-NMR (manufacturer Varian). .

Example 1 Preparation of Compound 2 {methyl (3R) -3-hydroxy-5-oxo-6-triphenylphosphoranylidenehexanoate}

Scheme 2

A solution of compound 1 {methyl (3R) -3- (tert-butyldimethylsilyloxy) -5-oxo-6-triphenylphosphoranylidenehexanoate} (14.1 g, 26.3 mmol, purchased from Nanjing Prochem, China) in 100 ml of tetrahydrofuran (THF) To 0 ^° C. was added dropwise a hydrogen fluoride solution (13.2 mL, 52.6 mmol) dissolved in 4 mol of water, warmed to room temperature and stirred for 1.5 hours. The reaction mixture was neutralized with sodium bicarbonate and extracted with ether, and the organic layer was washed with sodium chloride and dried. The ether was distilled off under reduced pressure to obtain 11.1 g (yield: 100%) of compound 2.

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.01 (m, 1H), 2.41-2.72 (m, 4H), 3.64 (s, 3H), 4.08 (m, 1H), 4.11 (m, 1H), 7.26 -7.36 (m, 15 H)

Example 2 Preparation of Compound 3 {methyl (3R, 5S) -dihydroxy-6-triphenylphosphoranylidenehexanoate}

Scheme 3

Compound 2 (11.1 g, 26.3 mmol) prepared in Example 1 was dissolved in a mixed solvent of 35 ml of anhydrous THF and 90 ml of methanol, and 29.7 ml of 1M-diethylmethoxyborane-THF was added at -78 ° C, and at the same temperature. Stir for 30 minutes. Thereafter, NaBH ₄ (1.3 g, 34.9 mmol) was added to the solution, stirred for 3 hours, 16 ml of acetic acid was added, and the pH of the solution was adjusted to 8 with saturated sodium bicarbonate. Thereafter, the reaction solution was extracted with ether, the organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and then the ether was distilled off under reduced pressure. 20 ml of methanol was added to the obtained residue, and the product was concentrated by distillation under reduced pressure. The obtained concentrate was subjected to silica gel column chromatography (eluate: methylene chloride / ether = 3/1 (v / v)) to give compound 3 10.1 g (23.7 mmol) (yield: 90%) were obtained.

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.01 (m, 2H), 2.43-2.76 (m, 4H), 3.68 (s, 3H), 4.04 (m, 1H), 4.14 (m, 1H), 7.32 -7.40 (m, 15H)

< Example  3> compound 4 { methyl  2-((4R, 6S) -6- ( triphenylphosphoranylidenemethyl ) -2,2-dimethyl-1,3-dioxan-4-yl) acetate}

Scheme 4

9.8 g (23.1 mmol) of compound 3 was dissolved in 30 ml of acetone, and 26.5 g (254 mmol) of 2,2-dimethoxypropane was added under room temperature and nitrogen atmosphere, and then 0.19 g (2 mmol) of methanesulfonic acid was added to room temperature, It was added under nitrogen atmosphere and stirred at room temperature for 12 hours. After the reaction was completed, 100 g of 5% aqueous sodium hydrogen carbonate solution and 200 ml of ethyl acetate were added and stirred for 15 minutes, and then the water layer and the organic layer were separated, the solvent and the low boiling organic substance were distilled off from the organic layer, and the silica gel column chromatography was removed from the residue. Graphiation (eluent: n-hexane / ethyl acetate = 4/1 (v / v)) was carried out to give 10.3 g (22.2 mmol) of compound 4 (yield: 96%).

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.41 (t, 6H), 1.51-1.83 (m, 2H), 2.26-2.51 (m, 2H), 3.55 (s, 3H), 3.88 (m, 1H) , 4.43 (m, 1 H), 7.32-7.40 (m, 15 H)

Example 4 Compound 6 {methyl 2-[(4R, 6S) -6-{(1E)-[4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin -5-yl] -ethylene} -2,2-dimethyl-1,3-dioxan-4-yl] acetate}

Scheme 5

A solution of compound 5 (19 g, 54 mmol), compound 4 (38.9 g, 84.2 mmol) and 500 ml of acetonitrile was heated to reflux for 14 hours and the acetonitrile was distilled off under reduced pressure.

The resulting residue was subjected to silica gel column chromatography (eluent: methylene chloride) to give 26.0 g 48.6 mmol (yield: 90%) of compound 6.

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.29 (dd, 6H), 1.42 (dd, 6H), 1.51-1.76 (m, 2H), 2.26-2.51 (m, 5H), 2.84 (s, 3H) , 3.12 (m, 1H), 3.67 (t, 3H), 4.42-4.48 (m, 2H), 6.25 (m, 1H), 6.62 (m, 1H), 7.03 (d, 2H), 7.46 (d, 2H) )

Example 5 Compound 7 {methyl (6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino] pyrimidin-5-yl)-(3R, 5S ) -dihydroxyhept-6-enoate} Preparation

[Reaction Scheme 6]

Compound 6 (11.4 g, 21.25 mmol) was dissolved in THF 33 mL at room temperature, and 2N-HCl (21.2 mL) was added thereto. The solution was stirred at room temperature for 1 hour and then saturated aqueous sodium hydrogen carbonate solution was added until the pH of the reaction solution reached 8-9. n-hexane (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, and the organic layer was separated. The organic layer was washed sequentially with saturated sodium bicarbonate (50 mL) and water (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After drying, the mixture was concentrated under reduced pressure. Ethyl acetate (5ml) was added to the concentrated solution, and the solution was dissolved in solution. N-hexane (50ml) was added thereto, and crystallized at room temperature for 3 to 5 hours. The solid was filtered under reduced pressure, washed with cold solvent (10 ml) of cold n-hexane: ethyl acetate = 20: 1 (v / v), followed by n-hexane (10 ml). (Light brown solid, 5.1 g) Ethyl acetate (5 ml) was added to the obtained solid, which was heated to 50 ° C for dissolution. The mixture was cooled to room temperature, n-hexane (10 ml) was added, and the solid was formed slowly. Then, the temperature was decreased to 0 ° C. Cool and slurry for 1 hour. The resulting solid was filtered under reduced pressure, washed with cold solvent (10 ml) of cold n-hexane: ethyl acetate = 20: 1 (v / v), and then recrystallized by washing with n-hexane (100 ml). The resulting solid was dried under reduced pressure at room temperature to give 10 g (20.18 mmol) of compound 7 (yield 95%).

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.26 (dd, 6H), 1.63 (m, 2H), 2.02 (m, 2H), 2.28-2.53 (m, 5H), 2.84 (s, 3H), 3.12 (m, 1H), 3.62 (t, 3H), 3.85-3.90 (m, 2H), 6.25 (m, 1H), 6.63 (m, 1H), 7.04 (d, 2H), 7.45 (d, 2H)

Example 6 Preparation of Rosuvastatin Calcium Salt

[Reaction Scheme 7]

Compound 7 (17.64 g, 35.6 mmol) was dissolved in ethanol (200 ml), cooled to 0 ° C., 2N-NaOH aqueous solution (19.6 ml, 39.2 mmol) was added to the reaction solution, and the reaction temperature was raised to room temperature and stirred for 1 hour. I was. The reaction solution was washed with diethyl ether (100 ml × 2), the aqueous layer was cooled to 0 ° C. and a solution of CaCl ₂ (4.35 g, 39.2 mmol) in water (70 ml) was slowly added dropwise. The reaction solution was stirred at room temperature overnight, and the resulting white solid was filtered, washed with water (50 ml x 2) and hexane (50 ml x 2) and dried under reduced pressure. The dried solid was suspended in 20 ml of isopropyl alcohol, stirred for 10 hours, filtered, washed with isopropyl alcohol and n-hexane, and dried under reduced pressure to obtain a white solid rosuvastatin hemicalcium salt (14.8 g). Yield 94%).

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.15-1.22 (m, 6H), 1.26-1.32 (m, 1H), 1.45-1.50 (m, 1H), 2.28-2.53 (m, 1H), 3.40- 3.43 (m, 4H), 3.53 (s, 3H), 3.74 (m, 1H), 4.18-4.21 (m, 1H), 5.53 (dd, 1H), 6.49 (d, 1H), 7.27 (t, 2H) , 7.65-7.72 (m, 2H)

Claims (10)

a) reacting the following compound with 2,2-dimethoxypropane in the presence of an acid; And b) adding a base to the reaction solution after step a) and reacting to prepare a compound of the following Chemical Formula 4.
(3)

[Chemical Formula 4]

Wherein "Y" is PPh ₃ , P (O) (OEt) ₂ or P (O) Ph ₂ , and "

"Means a double bond or a single bond, and if Y is PPh ₃ , it means a double bond, and if Y is P (O) (OEt) ₂ or P (O) Ph ₂ , it means a single bond,
"R" is C1 to C4 lower alcohol. The method of claim 1, wherein the acid is selected from methanesulfonic acid, paratoluenesulfonic acid, perchloric acid, hydrochloric acid, nitric acid, acetic acid, sulfuric acid, trifluoroacetic acid, and trifluoroacetic acid. . The method of claim 1, wherein the base is selected from sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, triethylamine, and ammonium hydroxide. According to claim 1, wherein in the compound [Formula 3] and [Formula 4], Y is PPh ₃ And R is methyl. The method of claim 1, wherein the compound [Formula 3] comprises the steps of: a) reacting the compound [Formula 1] with an acid (acid) to deprotect the hydroxy group of the compound [Formula 1] to prepare a compound [Formula 2]; And b) reacting the compound of Formula 2 with diethylmethoxyborane and sodium borohydride (NaBH ′) to produce the compound of Formula 3; Manufacturing Method:
[Formula 1]

(2)

Wherein Y and R are as defined in claim 1 and X is a hydroxy protecting group. The method of claim 5, wherein the acid is selected from hydrogen fluoride, hydrogen chloride, P-toluenesulfonic acid, and potassium fluoride. The method of claim 5, wherein the compound of Formula 3 is Y is PPh ₃ and R is methyl. The following Formula [4a] compound;
[Chemical Formula 4a]

Wherein R is methyl or ethyl. a) reacting the following [Formula 4] compound with the following [Formula 5] compound in an organic solvent to prepare the following [Formula 6] compound; And
b) reacting a compound with an acid and then reacting with a base to deprotect the acetal protecting group to prepare a compound of Formula 7; And
c) a method of preparing rosuvastatin hemicalcium salt by reacting a solution of a compound of the following formula in an organic solvent with an aqueous sodium hydroxide solution, separating the aqueous layer, and adding calcium chloride to the aqueous layer:
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

Wherein Y is PPh ₃ , P (O) (OEt) ₂ or P (O) Ph ₂ ; "

"Means a double bond or a single bond, where Y is PPh ₃ , means a double bond, and when Y is P (O) (OEt) ₂ or P (O) Ph ₂ , it means a single bond;" R " Is methyl or ethyl. a) reacting a compound of the following Chemical Formula 3 with 2,2-dimethoxypropane in the presence of an acid, followed by addition of a base to react to prepare a compound of the following Chemical Formula 4;
b) preparing a compound of Chemical Formula 6 by reacting the following Chemical Formula 4 compound with the following Chemical Formula 5 compound in an organic solvent;
c) reacting a compound with an acid and then reacting with a base to deprotect the acetal protecting group to produce a compound of Formula 7; And
d) A method of preparing rosuvastatin hemicalcium salt by reacting a solution of a compound of the following formula in an organic solvent with an aqueous sodium hydroxide solution, separating the aqueous layer, and adding calcium chloride to the aqueous layer:
(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

Wherein Y is PPh ₃ , P (O) (OEt) ₂ or P (O) Ph ₂ ; "

"Means a double bond or a single bond, where Y is PPh ₃ , means a double bond, and when Y is P (O) (OEt) ₂ or P (O) Ph ₂ , it means a single bond;" R " Is methyl or ethyl.