WO2010077062A2

WO2010077062A2 - Preparation method of statin compound and benzothiazolyl sulfone compound used therein

Info

Publication number: WO2010077062A2
Application number: PCT/KR2009/007881
Authority: WO
Inventors: Hee Seock Kim; Won Jeoung Kim; Hee Cheol Kim; Jae Yi Sim; Seong Mi Cho; Eun Young Byun; Ji Young Jeon; Yoon Ju Lee; Kwee Hyun Suh; Gwan Sun Lee
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2008-12-29
Filing date: 2009-12-29
Publication date: 2010-07-08
Also published as: WO2010077062A3; KR20100080432A

Abstract

The inventive method comprising subjecting a novel benzothiazolyl sulfone compound to a reaction with an aldehyde to obtain a vinyl intermediate and removing the hydroxy and carboxy protective groups of the vinyl intermediate is simple and efficient in preparing a statin compound or a salt thereof which is useful for treating hyperlipemia.

Description

PREPARATION METHOD OF STATIN COMPOUND AND BENZOTHIAZOLYL SULFONE COMPOUND USED THEREIN

FIELD OF THE INVENTION

The present invention relates to a preparation method of a statin compound useful for treating hyperlipemia and to a benzothiazolyl sulfone compound used therein.

BACKGROUND OF THE INVENTION

Statin derivatives, e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatin, are generally effective in reducing the concentration of low density lipoprotein (LDL) which transports cholesterol and triglyceride from the liver to various tissues through the blood, and thus, they are used for treating and preventing hyperlipidemic diseases such as hypercholesterinemia, hyperlipo-protemia, and atherosclerosis.

A high LDL concentration in blood is known to raise the blood lipid level, which causes coronary arteries-related symptoms such as blood flow disruption, blood vessel rupture, and blood clot formation {see L. L. Branton, J. S. Lazo and K. L. Parker, Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 948-953, 1 lth Ed., 2006, McGraw-Hill.)

Pravastatin of formula (Ia) ((3R,5S,6E)-7-[2-cycloρropyl-4-(4-fluorophenyl> 3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid) and rosuvastatin of formula (Ib) ((3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5- pyrimidmyl]-3,5-dihydroxy-6-heptenoic acid) which have similar structures as disclosed in EP 0,304,063 and EP 0,521,471, respectively, are each used as its calcium salt in the preparation of various medicines.

The structural similarity between pitavastatin and rosuvastatin stems from the common 3,5-dihydroxyheptenoic acid moiety in which the 3- and 5 -position carbons each having a hydroxy group are chiral having R and S configurations, respectively, and the double bond at 6-position carbon has E geometry. Various methods for preparing pitavastatin and rosuvastatin have been disclosed in the art.

For example, PCT Publication WO 95/11898 discloses a method for preparing pitavastatin by treating diphenylphosphine oxide with a base such as lithium 2,2,6,6-tetramethylρiperidine (LiTMP) at -78 ⁰C, followed by treating the resulting mixture with an aldehyde to introduce a double bond. PCT Publication

WO 2007/132482 also discloses a method for preparing pitavastatin by conducting a reaction of triphenylphosphonium bromide with an aldehyde to introduce a double bond. Furthermore, US Patent No. 5,284,953 discloses a method for preparing pitavastatin by resolving racemic pitavastatin using D-(H-)-phenethylamine, a resolving agent, to obtain a diastereomeric salt of pitavastatin.

Similarly, US Patent No. 6,844,437 discloses a method for preparing rosuvastatin by treating diphenylphosphine oxide with a base such as sodium hexamethyldisilazide (NaHMDS) at a temperature of -70 ⁰C or less, followed by treating the resulting mixture with an aldehyde to introduce a double bond. PCT

Publication WO 2006/67456 discloses a method for preparing rosuvastatin by subjecting a bromo intermediate to a reaction with a vinyl derivative over a period of 4 days in the presence of an expensive palladium catalyst, to introduce a double bond. PCT Publication WO 2007/07119 also discloses a method for preparing rosuvastatin by carrying out a reaction of a bromo pyrimidine compound with a vinyl boronate derivative in the presence of a palladium catalyst to obtain an intermediate having a double bond and treating the intermediate with a silyl enol ether in the presence of a titanium catalyst.

However, these conventional methods have the problem that the employment of a very low reaction temperature or a high-priced catalyst is required, the intermediate used therein is prepared by using complicated reaction steps under moisture-free condition, the overall yield is low, the stereoselectivities of the reaction sequences, particularly the E-selectivity (or trans-selectivity) of the introduced double bond, is unsatisfactorily low, or a combination thereof.

Accordingly, the inventors have endeavored to develop a novel, improved method of preparing pitavastatin or rosuvastatin and unexpectedly found that the objective statin compound can be prepared easily and efficiently when a benzothiazolyl sulfone compound is used to introduce an E-double bond.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide an efficient method for preparing pitavastatin, rosuvastatin, or a salt thereof by using a benzothiazolyl sulfone compound to introduce an E- double bond.

It is another object of the present invention to provide a benzothiazolyl sulfone compound used therein.

In accordance with one aspect of the present invention, there is provided a method for preparing a statin compound of formula (1) or pharmaceutically acceptable salt thereof, comprising the steps of: a) subjecting a benzothiazolyl sulfone compound of formula (3) to a reaction with an aldehyde of formula (4) at a temperature ranging from -50 ⁰C to room temperature in the presence of a base of sodium hydride or potassium fert-butoxide in tetrahydrofuran to obtain a vinyl compound of formula (2); and b) removing the hydroxy and carboxy protective groups of the vinyl compound of formula (2) by hydrolysis in the presence of an acid or a base in a water-miscible organic solvent or a mixture thereof with water:

wherein, R is methyl, ethyl, or tert-butyl; and Q is the substituent group of formula (6) or (7):

In accordance with another aspect of the present invention, there is provided a benzothiazolyl sulfone compound of formula (3) which is used as a starting material in the inventive method.

According to the inventive method, pravastatin, rosuvastatin, or a salt thereof which are useful in treating hyperlipemia can be prepared easily and efficiently when a benzothiazolyl sulfone compound is used to introduce an E- double bond.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the preparation method according to the present invention is described in detail.

Step a) of Inventive Method

Step a) is conducted by subjecting a benzothiazolyl sulfone compound of formula (3) to a reaction with an aldehyde of formula (4) at a temperature ranging from -50 ⁰C to room temperature in the presence of sodium hydride or potassium

/er/-butoxide in tetrahydrofuran to obtain a vinyl compound of formula (2). This step may be conducted by dissolving a benzothiazolyl sulfone compound of formula

(3) and an aldehyde of formula (4) in tetrahydrofuran; adding a base thereto; and subjecting the resulting mixture to a reaction to obtain the compound of formula (2).

In this step, the base may be used in an amount of 1.0 to 2.0 mole equivalents based on the benzothiazolyl sulfone compound, and the aldehyde of formula (4) may be used in an amount of 0.5 to 2.0 mole equivalents based on the benzothiazolyl sulfone compound.

The present invention also provides a novel benzothiazolyl sulfone compound of formula (3) which is used as a starting material in preparing pitavastatin and rosuvastatin according to the present invention.

The benzothiazolyl sulfone compound of formula (3) may be prepared by oxidizing a sulfide compound of formula (5):

wherein, Q has the same meaning as defined in formula (3).

The oxidizing agent which is used in the oxidation of the sulfide compound may be m-chloroperoxybenzoic acid (mCPBA); trifluoroperoxyacetic acid; peroxypropionic acid; peroxyphthalic acid; hypochlorous acid; manganese dioxide; pyridinum chlorochromate (PCC); potassium persulfate; a metal coordinated oxidizer-acetic acid mixture such as potassium permanganate-acetic acid mixture, and sodium perborate-acetic acid mixture; or a hydrogen peroxide-metal coordinated oxidizer mixture such as hydrogen peroxide-selenium dioxide mixture, hydrogen peroxide-sodium tungstate mixture, hydrogen peroxide-sodium orthovanadate mixture, hydrogen peroxide-ammonium heptamolybdate mixture, and hydrogen peroxide-vanadium pentoxide mixture. Preferably, the oxidizing agent is m-chloroperoxybenzoic acid, potassium persulfate, potassium permanganate-acetic acid mixture, or hydrogen peroxide-vanadium pentoxide mixture.

The solvent and the other conditions for reaction may be selected depending on the oxidizing agent used in the reaction according to the conventional manner which is well known to the person skilled in the art.

For example, when m-chloroperoxybenzoic acid is used as the oxidizing agent, the solvent is preferably selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, and 1,4-dioxane, and the reaction may be conducted at a temperature ranging from

-30 ⁰C to the boiling point of the solvent.

The amount of the oxidizing agent used in the oxidation may be 1.0 to 4.0 mole equivalents based on the sulfide compound of formula (5).

The sulfide compound of formula (5) may be prepared by subjecting a compound of formula (12) to a reaction with a thiol compound of formula (13) in the presence of a base in an organic solvent or in a mixture of a water-miscible organic solvent with water .

^Q^X (12)

wherein, Q has the same meaning as defined in formula (3); and X is chloro, bromo, iodo, methanesulfonyl, trifluoromethanesulfonyl, 4-toluenesulfonyl, or benzenesulfonyl.

Examples of the organic solvent or the water-miscible organic solvent used therein, are dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, N,N-dimethylformamide, dimethylsulfoxide, methanol, ethanol, 1-propanol, and 2-propanol. Further, examples of the base are sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, ammonium hydroxide, triethylamine, diisopropylethylamine, 1 ,4-diazabicyclo[5.4.0]undec-7~ene(DBU), and l,4-diazabicyclo[2.2.2]octane (DABCO). The base may be selected depending on the solvent used in the reaction according to the conventional manner which is well known to the person skilled in the art. The amount of the base used therein is preferably 1.0 to 3.0 mole equivalents based on the compound of formula (13), and the reaction temperature is preferable in the ranging from -10 ⁰C to the boiling point of the solvent.

The compound of formula (12) may be prepared according to the method by T. Hiyama et al. [see Bull. Chem. Soc. Jpn. 68, 364 (1995)] or by the method disclosed in WO 00/49014.

Meanwhile, the aldehyde of formula (4) may be prepared in a conventional manner. For example, a compound of formula (4) whose R is fert-butyl, i.e. formula (4a), may be prepared according to the method disclosed in EP 0,319,847. O^ O

O (4a)

Step b) of Inventive Method

Step b) is conducted by removing the hydroxy and carboxy protective groups of the vinyl compound of formula (2) by hydrolysis reaction in the presence of an acid or a base in a water-miscible organic solvent or a mixture thereof with water to obtain the statin compound of formula (1) or a pharmaceutically acceptable salt thereof. For example, the hydroxy protective group may be removed by treating the vinyl compound of formula (2) with dilute HCl in a water-miscible solvent, such as methanol, ethanol, 2-propanol, acetonitrile, and tetrahydrofuran, or in a mixture thereof with water. Then, the carboxy protective group may be removed by treating the vinyl compound with sodium hydroxide in a water-miscible solvent such as methanol, ethanol, 2-propanol, acetonitrile, and tetrahydrofuran, or in a mixture thereof with water.

Generally, the hydroxy and carboxy protective groups of the vinyl compound can be removed according to the methods provided by P.G.M. Wuts and T. W. Green (see Protective Groups in Organic Synthesis, 4th Ed. 2007, Wiely & Sons) which are well known to the person skilled in the art, or by variations thereof.

After the hydroxy and carboxy protective groups of the vinyl compound of formula (2) are removed, a statin compound of formula (1) may be prepared by adding HCl to the vinyl compound to neutralize to pH 4-5, extracting the resulting solution with an organic solvent such as ethyl acetate, ethyl ether, tert-butyl methyl ether, dichloromethane and chloroform, and distilling the residue.

Moreover, the statin compound of formula (1) may be further reacted with a metal salt to prepare a pharmaceutically acceptable salt of the statin compound. Examples of the salt of the statin compound of formula (1) are, but are not limited thereto, a salt of an alkali or an alkaline earth metal such as lithium, sodium, potassium, magnesium, calcium, strontium; or ammonium salt having one or more C]-₆alkyl, Ci-βCycloalkyl, aryl, or arylalkyl substituents. For example, a calcium salt of the statin compound of formula (1) may be prepared according to any one of the following methods i) to iii): i) removing the hydroxy and carboxy protective groups of a vinyl compound of formula (2) to obtain a statin compound of formula (1); subjecting the statin compound of formula (1) to a reaction with sodium hydroxide in a mixture of water and a water-miscible solvent such as methanol, ethanol, 2-propanol, acetonitrile, and tetrahydrofuran; and adding calcium chloride or calcium acetate thereto; ii) removing the hydroxy protective group of a vinyl compound of formula (2) followed by subjecting to a reaction under alkaline condition to remove the carboxy protective group; and adding calcium chloride or calcium acetate thereto; and iii) removing the hydroxy protective group of a vinyl compound of formula (2) followed by subjecting to a reaction under alkaline condition to remove the carboxy protective group; adding HCl to the resulting alkaline solution to neutralize to pH 4-5; extracting the resulting solution with an organic solvent such as ethyl acetate, ethyl ether, tert-butyl methyl ether, dichloromethane and chloroform, followed by distillation; heating the residue in toluene to obtain the lactone compound of formula (14); subjecting the lactone compound of formula (14) to a reaction with sodium hydroxide in an aqueous solution; and adding calcium chloride or calcium acetate thereto:

wherein, Q has the same meaning as defined in formula (2).

The following Examples are intended to further illustrate the present invention without limiting its scope.

Example 1. Preparation of 3-[[(benzothiazol-2-yl)thio]methyl]-2-cycIopropyl- 4-(4-fluorophenyl)quinoline

1.3 g (7.7 mmol) of 2-mercaptobenzothiazole was dissolved in 20 niL of methanol, and 9.6 mL of 1 N aqueous sodium hydroxide and 2 g (6.4 mmol) of 3-chloromethyl-2-cyclopropyl-4-(4-fluorophenyl)quinoline were added thereto. The resulting mixture was stirred at room temperature for 12 hours, distilled under a reduced pressure, and 40 mL of water was added thereto. The resulting mixture was extracted with 50 mL of dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, and distilled under a reduced pressure to obtain a foamy residue. The residue was recrystallized using 40 mL of a mixture of hexane and dichloromethane (1/1, v/v) to obtain 2.3 g of the title compound as a pale yellow solid (yield: 82 %.)

m.p.: 122-124 ⁰C; 1H-NMR (CDCl₃, ppm) δ 8.01-7.97 (d, IH), 7.83-7.80 (d, IH), 7.75-7.73 (d, IH), 7.60-7.58 (t, IH), 7.42-7.40 (t, IH), 7.33-7.25 (m, 5H), 7.18-7.15 (m, 2H), 4.76 (s, 2H), 2.52-2.47 (m, IH), 1.40-1.35 (m, 2H), 1.11-1.05 (m, 2H); and IR (KBr, cm⁴) 3051, 1600, 1511, 1492, 1459, 1218.

Example 2. Preparation of N- [5- [[(benzothiazoϊ-2-yl)thio] methyl] -4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl]-iV-methyl methanesulfonamide 4.4 g (26 mmol) of 2-mercaptobenzothiazole was dissolved in 80 mL of N,N-dimethylformamide, and 1.1 g (26 mmol) of 60 % sodium hydride was added thereto at 0 ⁰C, followed by stirring for 30 minutes. To the resulting mixture was added 10 g (24 mmol) of N-[5-bromomethyl-4-(4-fluorophenyl)-6- isopropylpyrimidin-2-yl]-N-methyl methanesulfonamide. The resulting mixture was stirred at room temperature for 2 hours, 300 mL of water was added thereto, and then the resulting mixture was extracted with 300 mL of ethyl acetate. The organic layer was separated, washed with 400 mL of purified water, dried over anhydrous sodium sulfate, and distilled under a reduced pressure to obtain a foamy residue. The residue was recrystallized with 110 mL of a mixture of hexane and dichloromethane (10/1, v/v) to obtain 10.6 g of the title compound as a white solid (yield: 88 %.)

m.p.: 132-135 ⁰C;

¹H-NMR (CDCl₃, ppm) δ 7.86-7.70 (m, 4H)₅ 7.43(t, IH), 7.32 (t, IH), 7.15-7.08 (m,

2H), 4.64 (s, 2H), 3.57 (s, 3H), 3.52 (s, 3H), 3.47(m, IH), 1.35 (d, 6H); and

IR (KBr, cm^"1) 2970, 1553, 1509, 1379, 1215, 1161, 966.

Example 3. Preparation of 3-[[(benzothiazol-2-yl)sulfonyl]methyl]-2- cyclopropyl-4-(4-fluorophenyl)quinoline

18.9 g (41.7 mmol) of 3-[[(benzothiazol-2-yl)thio]methyl]-2-cycloproρyl-4- (4-fluorophenyl)quinoline obtained in Example 1 was dissolved in a mixture of 50 mL of water and 200 mL of acetic acid, and then 13.1 g (83.3 mmol) of potassium permanganate was added thereto dropwise at 0 ⁰C. The resulting mixture was stirred at room temperature for 24 hours, cooled to 0 ⁰C, and 30 % hydrogen peroxide was added thereto dropwise until the color of the solution was disappear. The resulting solution was extracted with 200 mL of dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, and distilled under a reduced pressure to obtain a foamy residue. The residue was recrystallized with 100 mL of a mixture of hexane and dichloromethane (1/1, v/v) to obtain 15.5 g of the title compound as a white solid (yield: 76 %.)

m.p.: 159-161⁰C;

¹H-NMR (CDCl₃, ppm) δ 8.15-8.13 (d, IH), 8.00-7.97 (d, 2H), 7.67-7.63 (m, 3H), 7.33-7.31 (t, IH), 7.19-7.15 (m, 3H), 6.96-6.93 (m, 2H), 5.20 (s, 2H), 2.51-2.59 (m, IH), 1.30 (br, 2H)₅1.04-1.01 (m, 2H); and

IR(KBr, cm -^"1¹) 3074, 1603, 1513, 1491, 1469, 1332, 1225.

Example 4. Preparation of Λ'-JS-tJφenzothiazol-Z-y^sulfonylJmethyl]- 4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-Λ'^r-methyI methanesuIfonamide

8.8 g (18 mmol) of N-[5-[[(benzothiazol-2-yl)mio]methyl]-4-(4- fluoropheny i)-6-isopropy lpyrimidin-2-y 1] -N-methyl methanesulfonamide obtained in Example 2 was dissolved in 150 mL of dichloromethane, and 9 g (40 mmol) of m-chloroperoxybenzoic acid was added thereto. The resulting mixture was stirred at room temperature for 12 hours, and 5.5 g (44 mmol) of anhydrous sodium sulfite in 500 mL of water was added thereto. The resulting mixture was extracted with

100 mL of dichloromethane. The organic layer was separated, washed with 300 mL of brine, dried over anhydrous sodium sulfate, and distilled under a reduced pressure to obtain a foamy residue. The residue was recrystallized with 80 mL of a mixture of hexane and dichloromethane (1/1, v/v) to obtain 8.3 g of the title compound as a white solid (yield: 89 %.)

m.p.: 189-19O ⁰C;

¹H-NMR (CDCl₃, ppm) δ 8.10-8.00 (m, 2H), 7.66-7.62 (m, 2H), 7.26-7.23 (m, 2H), 6.83-6.78 (m, 2H), 5.06 (s, 2H), 3.59 (m, IH), 3.55 (s, 3H), 3.48 (s, 3H), 1.37 (d, 6H); and IR (KBr, cm^"1) 2977, 1606, 1551, 1338, 1227, 1155, 961.

Example 5. Preparation of tert-bntyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4- fluorophenyl)qumoIin-3-yl]-3,5-0-isopropylidene-3,5-dihydroxy-6-heptenoate

3 g (6.3 mmol) of 3-[[(benzothiazol-2-yl)sulfonyl]methyl]-2-cyclopropyl-4- (4-fluorophenyl)quinoline obtained in Example 3 and 2.1 g (8.2 mmol) of tert-butyl (3R,5S)-6-oxo-3,5-O-isopropylidene-3,5-dihydroxyhexanoate were dissolved in 63 mL of tetrahydrofuran and then cooled to -30 ⁰C. To the resulting mixture was added 1.2 g (10.7 mmol) of potassium tert-bυtoxide dropwise followed by stirring for 30 minutes. After the reaction temperature was increased to room temperature, the reaction mixture was stirred for an hour, and then 20 mL of sat. ammonium chloride was added thereto. The resulting mixture was distilled under a reduced pressure to remove tetrahydrofuran, and extracted twice with 30 mL of ethyl acetate. The organic layer was separated, washed with 20 mL of water, dried over anhydrous sodium sulfate, and distilled under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 10/1) to obtain 2.83 g of the title compound as a foam (yield: 86 %.)

¹H-NMR (CDCl₃, ppm) δ 7.94 (d, IH), 7.58 (dd, IH)₅ 7.36-7.14 (m, 6H), 6.56 (dd, IH)₅ 5.57 (dd, IH)₅ 4.38-4.32 (m, IH), 4.30-4.24 (m, IH), 2.54 (dd₅ IH), 2.44 (m, IH)₅ 2.34 (dd, IH)₅ 1.46 (s, 12H), 1.41-1.35 (m, 4H), 1.37 (s, 3H), 1.32-1.26 (m, 2H), 1.04 (dd, 2H).

Example 6. Preparation of tert-butyl (3R,5S,6E)-7-[2-cycIopropyl-4-(4- fluorophenyl)quinolin-3-yl]-3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate

126 g (0.27 mol) of 3-[[(benzothiazol-2-yl)sulfonyl]methyl]-2-cycloproρyl-

4-(4-fluorophenyl)quinoline obtained in Example 3 and 89 g (0.35 mol) of tert-butyl (3R,5S)-6-oxo-3,5-O-isopropylidene-3,5-dihydroxyhexanoate were dissolved in 1.26 L of tetrahydrofuran and then cooled to -30 ⁰C. To the resulting mixture was added 50.6 g (0.45 mol) of potassium tert-butoxide dropwise followed by stirring for an hour, and 750 rnL of 20% ammonium chloride was added thereto. The resulting mixture was distilled under a reduced pressure to remove tetrahydrofuran, and then extracted twice with 500 mL of tert-butyl methyl ether. The organic layer was separated, washed with 500 mL of water and 500 mL of brine, and then distilled under a reduced pressure. The residue was recrystallized with a mixture of 750 mL of acetonitrile and 375 mL of water to obtain 105.5 g of the title compound as a white solid (yield: 77 %.) m.p.: 108-110 ⁰C; and ¹H-NMR result of the product was the same as that obtained in Example 5.-

Example 7. Preparation of tert-butyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl]-3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate

2 g (4.2 mmol) of 3-[[(benzothiazol-2-yl)sulfonyl]methyl]-2-cyclopropyl- 4-(4-fluorophenyl)quinoline obtained in Example 3 and 1.3 g (5.0 mmol) of tert-butyl (3R,5S)-6-oxo-3,5-O-isopropylidene-3,5-dihydroxyhexanoate were dissolved in 35 mL of tetrahydrofuran, and 0.25 g (6.3 mmol) of 60 % sodium hydride was added thereto at 0 ⁰C, followed by stirring for 30 minutes. The resulting solution was stirred at room temperature for 12 hours, 50 mL of water was added thereto, and then the resulting mixture was extracted with 60 mL of ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and distilled under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 10/1) to obtain 1.3 g of the title compound as a foam (yield: 59 %.)

¹H-NMR result of the product was the same as that obtained in Example 5.

Example 8. Preparation of ethyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-3,5-O-isopropylidene-3,5-dihy droxy-6-haptenoate

5 g (9.4 mmol) of N-[[[5-(benzothiazol-2-yl)sulfonyl]methyl]-4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methyl methanesulfonamide obtained in Example 4 and 2.8 g (12.2 mmol) of ethyl (3R,5S)-6-oxo-3,5-0-isopropylidene- 3,5-dihydroxyhexanoate were dissolved in 50 mL of tetrahydrofuran and then cooled to -30 ⁰C. To the resulting solution was added 1.8 g (15.9 mmol) of potassium tert-butoxide followed by stirring, and 20 mL of sat. ammonium chloride was added thereto. The resulting mixture was extracted with 50 mL of tert-butyl methyl ether. The organic layer was separated, washed with 20 mL of water, dried over anhydrous sodium sulfate, and distilled under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 15/1) to obtain 4.3 g of the title compound as a white solid (yield: 83%.)

¹H-NMR (CDCl₃, ppm) δ 7.66 (m, 2H), 7.11 (m, 2H), 6.53 (dd, IH), 5.47 (dd, IH), 4.10 (q, 2H), 3.56 (s, 3H), 3.50 (s, 3H), 3.39 (m, IH), 2.45 (dd, IH), 2.31 (dd, IH), 1.56 (dd, IH), 1.50 (s, 3H), 1.41 (s, 3H), 1.29 (t, 3H), 1.25 (dd, 6H).

Example 9. Preparation of ethyl (3R,5S,6E)-7-[4-(4-fluorophenyI)-6-isopropyI- 2-[methyl(methylsulfonyI)aniino]pyrimidin-5-yl]-3,5-O-isopropylidene-3,5-dihy droxy-6-haptenoate

3 g (5.6 mmol) of N-[[[5-(benzothiazol-2-yl)sulfonyl]methyl]-4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methyl methanesulfonamide obtained in Example 4 and 1.5 g (6.7 mmol) of ethyl (3R,5S)-6-oxo-3,5-(9-isopropylidene- 3,5-dihydroxyhexanoate were dissolved in 45 mL of tetrahydrofuran, and 0.34 g (8.4 mmol) of 60 % sodium hydride was added thereto at 0 ⁰C, followed by stirring for 30 minutes. The resulting solution was further stirred at room temperature for 12 hours, 60 mL of water was added thereto, and then the resulting mixture was extracted with 80 mL of ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and distilled under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 15/1) to obtain 1.8 g of the title compound as a foam (yield: 58 %.)

¹H-NMR result of the product was the same as that obtained in Example 8. Example 10. Preparation of pitavastatin calcium

tert-bvLtyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]- 3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate 2.0 g (3.9 mmol) obtained in Examples 5 to 7 was dissolved in 14 mL of acetonitrile, 6.4 niL of 2 N aqueous HCl was added thereto and then stirred at 30 ⁰C for 2 hours. To the reaction mixture was added 8.4 mL of 2 N aqueous sodium hydroxide followed by stirring at 35 ⁰C for 2 hours. After cooling to room temperature, 1 N aqueous HCl was added thereto to neutralize to pH 4.8 and the resulting solution was extracted with 30 mL of ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, distilled under a reduced pressure, and then 40 mL of toluene was added thereto. The resulting mixture was refluxed for 3 hours, cooled to room temperature, and then 20 mL of ethyl acetate was added thereto. The resulting mixture was washed with sat. sodium hydrogen carbonate and then dried over anhydrous sodium sulfate followed by distilled under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 5/1) to obtain 1.42 g of (4R,6S)-6-[(E)-2-[cycloproρyl-4-(4-fluoroρhenyl)quinolin- 3-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one of formula (14a).

The lactone compound of formula (14a) was dissolved in 10 mL of tetrahydrofuran, and 10 mL of water and 3.6 mL of 1 N aqueous sodium hydroxide were added thereto followed by stirring at room temperature for an hour. The reaction mixture was distilled under a reduced temperature to reduce its volume to 1/2 and then washed with 20 mL of tert-butyl methyl ether. The aqueous layer was separated, and 40 mL of water was added thereto. To the resulting mixture, 0.32 g (2.15 mmol) of calcium chloride dihydrate dissolved in 5 mL of water was added dropwise with stirring vigorously, followed by stirring overnight. The resulting precipitate was isolated by filtering, washed with 30 mL of water, and then dried at 40 ⁰C under a reduced pressure to obtain 1.28 g of pravastatin calcium as a white solid (yield: 75 %.)

m.p.: 225-235 ⁰C (decomposition, condensed at 200 ⁰C); moisture content: 4.2 % (Karl-Fischer titrator);

M_D ^{20 =} +23.2 (c=l. O₅ acetonitrile/water=l/l);

¹H-NMR (DMSO-d₆, ppm) δ 7.86 (d, IH), 7.62 (m. IH), 7.42-7.25 (m, 6H), 6.49 (d,

IH), 5.61 (dd, IH), 4.12 (m, IH), 3.51 (m, IH), 2.52 (m, IH), 2.15-1.77 (m, 2H),

1.53-1.04 (m, 6H); and

IR(KBr, cm^"1) 3452, 3000, 1604, 1520, 1245, 970.

Example 11: Preparation of pitavastatin calcium

2.0 g (3.9 mmol) of tert-huty\ (3R,5S,6E)-7-[2-cycloρroρyl-4-(4- fluorophenyl)quinolin-3-yl]-3,5-(9-isopropylidene-3,5-dihydroxy-6-heptenoate obtained in Examples 5 to 7 was dissolved in 14 mL of acetonitrile, 6.4 mL of 2 N aqueous HCl was added thereto and then stirred at 30 ⁰C for 2 hours. To the reaction mixture was added 8.4 mL of 2 N aqueous sodium hydroxide followed by stirring at 35 ⁰C for 2 hours. The resulting mixture was distilled under a reduced pressure, and 10 mL of water was added thereto, followed by washing with 30 mL of tert~buty\ methyl ether. The resulting precipitate was removed by filtering, and 40 mL of water and 0.32 g (2.15 mmol) of calcium chloride dihydrate dissolved in 5 mL of water was added sequentially to the remaining solution with stirring vigorously, followed by stirring at room temperature overnight. The resulting precipitate was isolated by filtering, washed with 30 mL of water, and then dried at 40 ⁰C under a reduced pressure to obtain 1.5 g of pravastatin calcium as a white solid which was the same as that obtained in Example 10 (yield: 88 %.)

Example 12: Preparation of rosuvastatin calcium

3.0 g (5.5 mmol) of (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidm-5 -yl] -3 , 5 -O-isopropylidene-3 ,5 -dihydrox y-6-haptenoate obtained in Examples 8 to 9 was dissolved in 20 mL of acetonitrile, and 6.1 mL of 1 N aqueous HCl was added thereto followed by stirring at 25 ⁰C for 2 hours. To the resulting mixture was added 5.9 mL of 2 N aqueous sodium hydroxide, followed by stirring at 35 ⁰C for 2 hours. After cooling to room temperature, 1 N aqueous HCl was added thereto to neutralize to pH 4.8, and the resulting solution was extracted with 50 mL of ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, distilled under a reduced pressure, and then 40 mL of toluene was added thereto. The resulting mixture was refluxed for 5 hours, cooled to room temperature, and then 20 mL of ethyl acetate was added thereto. The resulting mixture was washed with sat. sodium carbonate and then dried over anhydrous sodium sulfate followed by distilled under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 10/1) to obtain 2.22 g of N-(4-(4-fluorophenyl)-5-{(E)-2- [(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethenyl}-6-isopropylpyrimidin -2-yl)-N-methyl methanesulfonamide of formula (14b).

The lactone compound of formula (14b) was dissolved in 20 mL of tetrahydrofuran, 15 mL of water and 5.6 mL of 1 N aqueous sodium hydroxide were added thereto followed by stirring at room temperature for 2 hours. The reaction mixture was distilled under a reduced temperature to reduce its volume to 1/2 and then washed with 20 mL of tert-butyl methyl ether. To the residue was added 40 mL of water and 0.41 g (2.78 mmol) of calcium chloride dihydrate dissolved in 8 mL of water dropwise at 40 ⁰C with stirring vigorously, and then the resulting mixture was further stirred overnight. The resulting precipitate was isolated by filtering, the solid was washed with 45 mL of water, and then dried at 40 ⁰C under a reduced pressure to obtain 2.12 g of rosuvastatin calcium as a white solid (yield: 76 %.)

m.p.: 150-160 ⁰C (decomposition); moisture content: 2.0 % (Karl-Fischer titrator);

[α]_D ²⁰ = +15.0 (C=LO, 50 % methanol);

¹H-NMR (DMSO-d₆₅ ppm) δ 7.70 (dd, 2H)₅ 7.13 (t, 2H), 6.59 (dd, IH), 5.54 (dd,

IH), 4.35 (m, IH), 4.01 (m, IH), 3.53 (s, 3H), 3.51 (s, 3H), 3.44 (m, IH), 2.45 (dd,

IH), 2.41-2.20 (m, 2H), 1.70-1.37 (m, 2H), 1.27 (dd, 6H); and IR (KBr, cm-¹) 3418, 2967, 1605, 1547, 1381, 1154, 963.

Example 13: Preparation of rosuvastatin calcium

3.0 g (5.5 mmol) of ethyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-

[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-3,5-O-isopropylidene-3,5-dihydrox y-6-haptenoate obtained in Examples 8 to 9 was dissolved in 20 mL of acetonitrile, 6.1 mL of 1 N aqueous HCl was added thereto and then stirred at 30 ⁰C for 2 hours. To the resulting mixture was added 5.9 mL of 2 N aqueous sodium hydroxide followed by stirring at 35 ⁰C for 2 hours. The resulting solution was distilled under a reduced pressure, 50 mL of water was added thereto, washed with 20 mL of tert-butyl methyl ether, and then the resulting precipitate was removed by filtering. To the remaining solution was added 0.41 g (2.78 mmol) of calcium chloride dihydrate dissolved in 8 mL of water with stirring vigorously, followed by stirring at room temperature overnight. The resulting precipitate was isolated by filtering, washed with 45 mL of water, and then dried at 40 ⁰C under a reduced pressure to obtain 2.4 g of rosuvastatin calcium as a white solid which was the same as that obtained in Example 12 (yield: 86 %.)

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A method for preparing a statin compound of formula (1) or a pharmaceutically acceptable salt thereof, comprising the steps of: a) subjecting a benzothiazolyl sulfone compound of formula (3) to a reaction with an aldehyde of formula (4) at a temperature ranging from -50 ⁰C to room temperature in the presence of sodium hydride or potassium tert-butoxide in tetrahydrofuran to obtain a vinyl compound of formula (2); and b) removing the hydroxy and carboxy protective groups of the vinyl compound of formula (2) by hydrolysis in the presence of an acid or a base in a water-miscible organic solvent or a mixture thereof with water:

O^ O

O (4) wherein, R is methyl, ethyl, or tert-butyϊ, and Q is the substituent group of formula (6) or (7):

2. The method of claim I₅ wherein the pharmaceutically acceptable salt is sodium salt, potassium salt, or calcium salt.

3. The method of claim 1, wherein Q is the substituent group of formula (6).

4. The method of claim I₅ wherein Q is the substituent group of formula (7).

5. The method of claim 1, wherein the amount of the base used is 1.0 to 2.0 mole equivalents based on the benzothiazolyl sulfone compound of formula (3).

6. The method of claim I₅ wherein the hydroxy protective group is removed by treating the vinyl compound of formula (2) with dilute HCl in a water-miscible solvent or a mixture thereof with water.

7. The method of claim I₅ wherein the carboxy protective group is removed by treating the vinyl compound of formula (2) with sodium hydroxide in a water-miscible solvent or a mixture thereof with water.

8. A benzothiazolyl sulfone compound of formula (3):

wherein, Q has the same meaning as defined in claim 1.