KR101292743B1 - Novel statins intermediates and method for synthesizing pitavastain, rosuvastatin, cerivastatin and fluvastatin by using statins intermediates - Google Patents

Abstract

PURPOSE: Statin intermediates are provided to remarkably reduce the amount of an organic solvent used by having excellent solubility into organic solvents such as THF, diethyl ester, or the likes. CONSTITUTION: Statin intermediate is represented by chemical formula 1. In chemical formula 1, n is 1, 2, and 3. Ar is a phenyl group, a C1-4 alkyl or C6-10 aryl-substituted phenyl group, a naphthyl group, a C1-C4 alkyl or C6-10 aryl-substituted naphthyl group, an anthracene group, or a C1-C4 alkyl or C6-10 aryl-substituted anthracene group; R1 is a C1-8 alkyl, dialkyl, trialkyl, aryl, or aralkyl. A manufacturing method of a statin-based precursor includes a step of conducting a wittig reaction of the ketone compound represented by chemical formula 1 and an ylide compound under the presence of a base.

Description

Novel statins intermediates and method for synthesizing pitavastain, rosuvastatin, cerivastatin and fluvastatin by using statins intermediates, and a novel statin intermediate and a method for preparing pitavastatin, rosuvastatin, cerivastatin and fluvastatin

The present invention relates to a novel intermediate used for the synthesis of statins and a method for preparing the same, and a method for preparing pitavastatin, rosuvastatin, cerivastatin, fluvastatin using the statin intermediates. .

HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl Coenzyme A reductase) is known to be present in liver tissue and plays an important role in the production of cholesterol in the blood. Substances that inhibit cholesterol production by inhibiting the activity of HMG-CoA reductase are commonly called 'statins', and representative statin compounds include atorvastatin, pitavastatin, and flu. Vastatin, Rosuvastatin, Cerivastatin and the like are well known.

These statins are mainly used to treat dyslipidemia or cardiovascular diseases such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and the structure of pitavastatin, rosuvastatin, cerivastatin and fluvastatin. Is represented by the following formula, and is generally marketed as a hemicalcium salt formulation.

[Pitavastatin]

[Rosuvastatin]

[Serivastatin]

[Fluvastatin]

The statin compounds described above differ in their parent nucleus (aromatic ring) structure but have the same dihydroxy structure. Many studies have already been carried out on synthetic intermediates, including pitavastatin, see European Patent EP 00304063, EP 0520406; US Patents US 5,399,722, US 5,998,633; Related arts are disclosed in WO 2002/63028, WO 2004/070717, and the like.

WO 2003/070733 discloses an intermediate of the formula wherein the dihydroxy group (diol group) of the ester compound is protected using arylboronic acid. Such intermediates can be usefully used for the synthesis of atorvastatin, cerivastatin, rosuvastatin.

Wherein Ar is aryl or heteroallyl

In addition, US Pat. No. 6,867,306 uses t-butyl 6-cyano-3,5-dihydroxyhexanoate using arylboronic acid as an intermediate for preparing atorvastatin. It describes a boronate compound of the following formula protecting a diol group of (protected).

(Wherein R is hydrogen, methyl, 3-nitro group)

Arylboronic acids, such as phenylboronic acid, used in WO 2003/070733 and US Pat. No. 6,867,306, are generally Grignard reactions of aryl halides (Ar-X) and boronate compounds. The aryl halides, such as phenyl halide, are synthesized by Grignard reaction, and have low solubility with respect to organic solvents required for the Grignard reaction, that is, tetrahydrofuran (THF), diethyl ester, and the like. Therefore, an excessive organic solvent must be used for a sufficient Grignard reaction, so the manufacturing cost is high, and the Grignard reagent is often precipitated at a temperature below room temperature.

The present invention provides novel statin intermediates that can solve the problems of the conventional boronate compounds used in the production of statins, and effectively prepares pitavastatin, rosuvastatin, cerivastatin and fluvastatin using these intermediates. The purpose is to provide a way to.

In order to achieve the above object, the present invention provides a novel statin intermediate represented by the following formula (1).

[Formula 1]

(Wherein,

n = 1, 2, 3,

Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,

R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)

Since the boronate compound of the present invention has one or more carbon chains (-CH _2- ) between the aromatic ring and boron (B), it is easily dissolved in the organic solvent in the Grignard reaction, so the organic solvent during mass production By reducing the amount, the manufacturing cost can be greatly reduced, and the reaction product is easily crystallized, and boronic acid, which is released after deprotecting, also has very good crystallinity and has an advantage of being recovered and reused.

As shown in Scheme 1, the boronate compound of Chemical Formula 1 (a) reacts an aralkyl halide of Chemical Formula 6 with magnesium to prepare a Granar reagent, and then trimethoxyboran. Synthesizing an aralkyl boronic acid of Formula 5 by performing a Grignard reaction with Grignard reaction; (b) reacting the aralkyl boronic acid of Formula 5 with an acetate compound represented by Formula 4 to synthesize a boronate ester compound of Formula 3; (c) deprotecting the boronate ester compound of Formula 3 using a weak acid catalyst to produce a compound of Formula 2; (d) The compound of Formula 2 may be prepared in high yield, including the step of oxidizing with oxalyl chloride or pyridinium chloro chromate.

[Reaction Scheme 1]

(Wherein,

n is 1 to 3,

X is Br, Cl or I,

Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,

R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl,

R ₂ is tetrahydropyranyl, t-butyldimethylsilyl or trityl.)

On the other hand, the present invention provides a synthetic statin intermediate represented by the following formula 7 to 10 using the boronate compound of the formula (1).

[Formula 7]

[Formula 8]

[Chemical Formula 9]

[Formula 10]

Wherein n is 1 to 3, Ar is a phenyl group, C ₁ to C ₄ alkyl or C ₆ to C ₁₀ aryl substituted with phenyl group, naphthyl group, C ₁ to C ₄ alkyl or C ₆ to A naphthyl group substituted with aryl of C ₁₀ , anthracene group, or an alkylene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl, R ₁ is alkyl of C ₁ -C ₈ , secondary- Alkyl, tert-alkyl, aryl or aralkyl.)

Statin intermediate according to the present invention has at least one carbon chain (-CH _2- ) between the aromatic ring (Aromatic ring) and boron (B), THF, diethyl compared to the conventional aryl boronic acid without a carbon chain Since it is easily dissolved in organic solvents such as esters, it is possible to reduce the production cost by drastically reducing the amount of organic solvent used in mass production.The reaction product is easily crystallized, and boronic acid, which is released after deprotection, is also highly crystallized and recovered. It has the advantage of being reusable.

The present invention provides a novel boronate compound represented by the following formula (1). The boronate compound is used as an intermediate for preparing statins.

[Formula 1]

(Wherein,

n = 1, 2, 3,

Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,

R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)

The statin intermediate of Formula 1 is preferably the following Formulas 1-1, 1-2, 1-3, 1-4 or 1-5.

[Formula 1-1]

(Wherein R ₁ , R ₂ , R ₃ are each independently H, C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl.)

[Formula 1-2]

(Wherein R ₁ is H or C ₁ to C ₄ alkyl, R ₂ , R ₃ are each independently H, C ₁ to C ₄ alkyl or C ₆ to C ₁₀ aryl groups.)

[Formula 1-3]

(Wherein R ₁ , R ₂ and R ₃ are each independently H, C ₁ to C ₄ alkyl or C ₆ to C ₁₀ aryl groups.)

[Formula 1-4]

(Wherein R ₁ , R ₂ , R _{3 , and} R ₄ are each independently H, C ₁ to C ₄ alkyl, or C ₆ to C ₁₀ aryl groups.)

[Formula 1-5]

(Wherein R ₁ , R ₂ , R _3, R ₄ , R ₅ are each independently H, C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl groups.)

As shown in Scheme 1, the statin intermediate of Chemical Formula 1 is prepared by aralkyl boronic acid of Chemical Formula 5 and 1,3-diol compound of Chemical Formula 4 under an organic solvent such as toluene, xylene, dichloromethane, carbon tetrachloride, The reaction is carried out at 90 to 120 ° C. for 10 to 15 hours to protect the diol group with a boron (B) group, followed by deprotection by leaving the R ₂ group, followed by oxidation of the remaining hydroxyl group to be converted into an aldehyde compound.

The aralkyl boronic acid of Formula 5 is prepared by treating the magnesium metal with aralkyl halide of Formula 6 under an organic solvent such as tetrahydrofuran (THF), ethyl ester, etc. to prepare a Grignard reagent, and then trimethoxyborane. ) Is slowly added dropwise to the Grignard reaction.

[Reaction Scheme 1]

The 1,3-diol compound of Formula 4 may be prepared by a known method.

The boronate compound of Formula 1 obtained as described above was subjected to a wittig reaction in the presence of a base and a base of the statin represented by the following Formulas 7a to 10a with a base, thereby yielding the (E) -isomer in a high yield. It is possible to obtain various statin compounds or salts thereof by deprotecting the boronic acid.

[Formula 7a]

[Chemical Formula 8a]

[Formula 9a]

[Chemical Formula 10a]

In Chemical Formulas 7a to 10a,

Y is PPh ₃ ⁺ X ⁻ (X = halide) or P (O) (OEt) ₂ .

[Formula 7]

[Formula 8]

[Chemical Formula 9]

[Formula 10]

(In the above formulas 7 to 10,

n is 1 to 3,

Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,

R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)

The base used in the Wittich reaction is preferably a metal hydrate, a metal oxide or a metal carbonate. For example, it is preferable that it is at least one selected from lithium hydroxide, lithium hydroxide hydrate, potassium sodium hydroxide, potassium hydroxide, potassium t-butoxide and sodium methoxide. The equivalent ratio of bases used is 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, relative to the starting compound. The reaction time is preferably about 2 to 10 hours.

 Synthesis of the compounds of formulas 7 to 10 of the present invention may be carried out by ethers such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide, toluene, acetonitrile, tetrahydrofuran (THF), diethyl ether, diisopropyl ether and the like. Solvent, or an organic solvent such as a halogenated solvent such as methylene chloride (MC), 1,2-dichloroethane, chloroform and the like, and these solvents may be used alone or as a mixed solvent. The reaction temperature is suitably in the range of 0 to 150 ° C, more preferably 30 to 100 ° C.

Synthesis of the compounds of formulas 7 to 10 of the present invention selectively provides (E) -isomers very predominantly (a ratio of type (E) to type (Z) is about 99: 1 molar ratio). Thus, a simple recrystallization method can yield compounds of formulas (7) that are at least 99% (E) -isomers. The solvent used for recrystallization may include polar solvents such as methyl chloride, ethyl acetate, isopropyl alcohol, methanol, diethyl ether, sulfolane and the like, as well as nonpolar solvents such as hexane, pentane, heptane, and one of these solvents. The above can be selected and used as a mixed solvent.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example  T-butyl 2-((4R, 6S) -2-benzyl-6- Formyl -1,3,2- Dioxaborinan 4-yl) acetate synthesis:

(a) 3.65 g (0.15 mole) of magnesium and 36.0 g (0.3 mole) of THF were added under a 20 ° C. nitrogen atmosphere, followed by stirring for about 2 hours. Then, 17.1 g (0.1 mole) of bromomethylbenzene was slowly added dropwise and stirred for about 6 hours. Grignard reagent was prepared. After cooling the Grignard reagent in an ice bath, 10.4 g (0.1 mol) of trimethoxyborane was slowly added dropwise and stirred for about 1 hour to remove the solvent, thereby obtaining 12.8 g of benzylboronic acid. Obtained. Yield: 94.8%

(b) 16 g (0.05 mol) of (3R, 5S) -t-butyl 3,5-dihydroxy-6-tetrahydropyranyloxy-hexanoate was diluted with 50 ml of toluene and 6.8 g of benzylboronic acid ( 0.05 mole), followed by azotropic distillation while refluxing for 10 hours to remove water. Toluene was removed under reduced pressure, 50 ml of diethyl ether was added, the mixture was cooled to 5 ° C. or lower, and the precipitate was separated to separate t-butyl 2-((4R, 6S) -2-benzyl-6-tetrahydropyranyloxymethyl-1,3 18.6 g of, 2-dioxaborinan-4-yl) acetate were obtained. Yield: 92%

(c) 18.6 g of t-butyl 2-((4R, 6S) -2-benzyl-6-tetrahydropyranyloxymethyl-1,3,2-dioxaborinane-4-yl) acetate obtained above 60 ml of methylene chloride (MC) and 15 ml of TFA were added, followed by stirring at room temperature for about 8 hours. The organic layer was dried and t-butyl 2-((4R, 6S) -2-benzyl-6- (hydroxymethyl) -1 14.2 g of 3,2-dioxaborinane-4-yl) acetate were obtained.

(d) Oxalyl chloride (10 ml) was dissolved in MC and maintained at -78 ° C. Then, DMSO (13 ml) was added dropwise and stirred for about 15 minutes, followed by t-butyl 2- ( A solution of 14.2 g of (4R, 6S) -2-benzyl-6- (hydroxymethyl) -1,3,2-dioxavoran-4-yl) acetate in MC was slowly added dropwise and stirred for about 15 minutes. After addition, triethylamine (30 ml) was added dropwise and stirred for 10 minutes, and then the reaction temperature was gradually raised to room temperature to react. The obtained organic layer was washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give 13.6 g of a compound of formula (I). Yield 95%

Example  T-butyl 2-((4R, 6S) -2-biphenyl-6- Formyl -1,3,2- Dioxaborinan 4-yl) acetate synthesis: (Formula II)

Instead of bromomethylbenzene used in Example 1, 44.7 g (0.1 mol) of 4-bromomethyl biphenyl was used as a starting material, and 18.8 g of a boronate compound of Formula II was obtained by the same method as in Example 1. . Yield: 91%

[Formula II]

Example  3.t-butyl 2-((4R, 6S) -2-((naphthalen-2-yl) methyl ) -6- Formyl -1,3,2- Dioxaborinan 4-yl) acetate synthesis:

Instead of bromomethylbenzene used in Example 1, 22.1 g (0.1 mol) of 2-bromomethyl naphthalene was used as a starting material to obtain 16.1 g of a boronate compound of Formula III. Yield: 89%

[Formula III]

Example  4.t-butyl 2-((4R, 6S) -2-((anthracen-2-yl) methyl ) -6- Formyl -1,3,2- Dioxaborinan 4-yl) acetate synthesis:

Instead of bromomethylbenzene used in Example 1, 2-bromomethylanthracene [9- (bromomethyl) anthracene] 27.1 g (0.1 mol) was used as a starting material in the same manner as in Example 1 18.3 g of Nate compound were obtained. Yield: 86%

[Formula IV]

Example  5.t-butyl 2-((4R, 6S) -2-((anthracene-9-yl) methyl ) -6- Formyl -1,3,2- Dioxaborinan 4-yl) acetate synthesis:

Instead of bromomethylbenzene used in Example 1, 27.1 g (0.1 mol) of 9-bromomethylanthracene [9- (bromomethyl) anthracene] was used as a starting material in the same manner as in Example 1 17.8 g of nate compound were obtained. Yield: 84%

[Formula V]

Example  6.t-butyl 2-((4R, 6S) -6-((E) -2- (2- Cyclopropyl -4- (4- Florophenyl Preparation of (quinolin-3-yl) vinyl) -2-benzyl-1,3-dioxan-4-yl) acetate:

30.8 g (0.05 mol) of [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] methyltriphenylphosphonium bromide was added to THF / acetonitrile (20/1 ratio, 100 ml) as a statin nucleus. After melting in, the temperature was raised to 60 ° C. 2.8 g of lithium hydroxide hydrate was added to the reaction solution, and t-butyl 2-((4R, 6S) -6-formyl-2-benzyl-1,3-dioxan-4-yl) prepared in Example 1 was used. A solution of 16 g (0.05 mol) of acetate in THF / acetonitrile (10/1 ratio, 50 ml) was added dropwise under stirring for 3 hours, followed by cooling to room temperature and concentration under reduced pressure. The concentrate was dissolved in heptane (300ml) and washed with 0.1N HCl (200ml × 2) and saturated brine (200ml). The organic layer obtained was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was recrystallized using ethyl acetate and hexane to obtain 26.2 g of pitavastatin precursor of formula VI in solid form. (Yield 91%, E / Z = 99/1)

Formula VI

Example  7.t-butyl 6-[(1E) -2- [4- (4- Fluorophenyl ) -6-isopropyl-2- [methyl ( Methylsulfonyl ) Amino] -5- Pyrimidinyl ] Ettenal ] -2-Benzyl-1,3-dioxane-4-acetate:

Always carried out in the same manner as in Example 6, except that [4- (4-fluorophenyl) -6-isopropyl-2-[(2-N-methyl-N-methylsulfonyl) was used as a statin mother nucleus (aromatic ring). 33.8 g (0.05 mol) of amino] pyrimidin-5-yl] methyltriphenylphosphonium bromide was used to obtain 27.4 g of rosuvastatin precursor of formula (VII). Yield 86%, E / Z = 99/1

[Formula Ⅶ]

Example  8. t-butyl 2-((4R, 6S) -2-benzyl-6-((E) -2- (6- (dimethylamino) -4- (4- Fluorophenyl ) -2-isopropyl-5- ( Methoxymethyl ) Pyridin-3-yl) vinyl) -1,3,2- Dioxaborinan -4-yl) acetate preparation:

Always carried out in the same manner as in Example 6, except that [4- (4-fluorophenyl) -6-isopropyl-2- [dimethylamino] pyrimidin-5-yl] methyltrie was used as a statin nucleus (aromatic ring). 32.8 g (0.05 mol) of phenylphosphonium bromide was used to obtain 27.7 g of cerivastatin precursor of formula (VII). Yield 90%, E / Z = 99/1

[Formula Ⅷ]

Example  9.t-butyl 2-((4R, 6S) -2-benzyl-6-((E) -2- (3- (4- Fluorophenyl ) -1-isopropyl-1H-indol-2-yl) vinyl) -1,3,2- Dioxaborinan -4-yl) acetate preparation:

Performed in the same manner as in Example 6, except that [3- (4-fluorophenyl) -1-isopropyl-1H-indol-2-yl] methyltriphenylphosphonium bromide 30.4 was used as a statin nucleus (aromatic ring). 24.7 g of fluvastatin precursor of Formula (VII) was obtained using g (0.05 mol). Yield 87%, E / Z = 99/1

[Formula Ⅸ]

Example  10. t-butyl- Pitavastatin  Produce

T-butyl 2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) prepared in Example 6) 26.2 g of -2-benzyl-1,3-dioxan-4-yl) acetate was dissolved in ethanol (50 ml), then 1N aqueous sodium hydroxide solution (100 ml) was added dropwise and stirred for 2 hours, followed by addition of water (100 ml). Then extracted with diethyl ether (100 ml x 2). The organic layer was discarded, the aqueous layer was adjusted to pH 1.0 with concentrated hydrochloric acid and stirred for about 1 hour. Then, the mixture was extracted with chloroform (100 ml × 2), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and 20.6 g of t-butyl-pitavastatin was obtained. Yield 95%

Claims (13)

Statin intermediate represented by the following formula (1).
[Chemical Formula 1]

(Wherein,
n = 1, 2, 3,
Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,
R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)
The statin intermediate according to claim 1, which is a compound represented by the following Chemical Formula 1-1.
[Formula 1-1]

(Wherein,
R ₁ , R ₂ , R ₃ are each independently H, C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl.)
The statin intermediate of claim 2, which is a compound represented by the following Chemical Formula 1-2.
[Formula 1-2]

(Wherein,
R ₁ is H or C ₁ -C ₄ alkyl,
R ₂ and R ₃ are each independently H, C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl group.)
The statin intermediate according to claim 1, which is a compound represented by the following Chemical Formula 1-3.
[Formula 1-3]

(Wherein,
R ₁ , R ₂ and R ₃ are each independently H, C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl group.)
The statin intermediate of claim 1, which is a compound represented by the following Chemical Formula 1-4.
[Formula 1-4]

(Wherein,
R ₁ , R ₂ , R _{3 , and} R ₄ are each independently H, C ₁ -C ₄ alkyl, or C ₆ -C ₁₀ aryl group.)
The statin intermediate of claim 1, which is a compound represented by the following Chemical Formula 1-5.
[Formula 1-5]

(Wherein R ₁ , R ₂ , R _{3 ,} R ₄ , and R ₅ are each independently H, C ₁ to C ₄ alkyl or C ₆ to C ₁₀ aryl groups.)
(a) Aralkyl halide of Chemical Formula 6 is reacted with magnesium to prepare a Granar reagent, and then trimethoxyboran and Grignard reaction are performed to produce a Grignard reaction of Aralkyl bo of Chemical Formula 5 Synthesizing arnic boronic acid;
(b) reacting the aralkyl boronic acid of Formula 5 with an acetate compound represented by Formula 4 to synthesize a boronate ester compound of Formula 3;
(c) deprotecting the boronate ester compound of Formula 3 using a weak acid catalyst to produce a compound of Formula 2;
(d) oxidizing the compound of Formula 2 using oxalyl chloride or pyridinium chloro chromate;
Method for producing a statin intermediate represented by the formula (1) comprising a.
Scheme 1

(Wherein,
n is 1 to 3,
X is Br, Cl or I,
Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,
R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl,
R ₂ is tetrahydropyranyl, t-butyldimethylsilyl or trityl.)
Phytavastatin intermediate represented by the following formula (7).
[Formula 7]

(Wherein,
n is 1 to 3,
Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,
R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)
Rosuvastatin intermediate represented by the following formula (8).
[Formula 8]

(Wherein,
n is 1 to 3,
Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,
R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)
Cerivastatin intermediate represented by the following formula (9).
[Formula 9]

(Wherein,
n is 1 to 3,
Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,
R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)
Fluvastatin intermediate represented by the following formula (10).
[Formula 10]

(Wherein,
n is 1 to 3,
Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,
R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)
To prepare a statin precursor according to any one of claims 8 to 11 by wittig reaction of the ketone compound represented by the formula (1) and the lide compound selected from the formulas (7a to 10a) in the presence of a base Way.
[Chemical Formula 1]

(Wherein,
n = 1, 2, 3,
Ar is a phenyl group, C ₁ ~ C ₄ alkyl or C ₆ ~ C a phenyl group substituted with aryl of _10, a naphthyl group, a C ₁ ~ C ₄ alkyl or C ₆ ~ a naphthyl group, an anthracene group substituted with aryl of C ₁₀ Or an anthracene group substituted with C ₁ -C ₄ alkyl or C ₆ -C ₁₀ aryl,
R ₁ is C ₁ to C ₈ alkyl, secondary-alkyl, tert-alkyl, aryl or aralkyl.)

[Formula 7a]

[Formula 8a]

[Formula 9a]

[Formula 10a]

In the above equations,
Y is PPh ₃ ⁺ X ⁻ (X = halide) or P (O) (OEt) ₂ .
A method for preparing a hemicalcium salt compound of statins by hydrolyzing the statin intermediate according to claim 12 with sodium hydroxide and then adding calcium acetate.