WO2011105649A1

WO2011105649A1 - New method for manufacturing pitavastatin hemicalcium using new intermediate

Info

Publication number: WO2011105649A1
Application number: PCT/KR2010/001302
Authority: WO
Inventors: 조동옥; 김승기; 조현숙
Original assignee: (주)메디켐코리아
Priority date: 2010-02-24
Filing date: 2010-03-03
Publication date: 2011-09-01
Also published as: KR101134021B1; KR20110097058A

Abstract

The present invention is useful as a HMG-Co A reductase inhibitor and relates to a new method for manufacturing pitavastatin hemicalcium which is used as a treatment for hyperlipidemia. More specifically, a new method for manufacturing pitavastatin hemicalcium using a new intermediate is disclosed. The present invention has the following advantages: the usage of the new intermediate for manufacturing pitavastatin provides a more effective method for manufacturing pitavastatin; an alcohol protecting group, which is one of the new intermediates, easily protects dialcohol within one to two hours under acid catalyst and mild reaction conditions; the deprotection reaction of dialcohol is completed within thirty minutes to one hour under very mild reaction conditions of 0 to 25 degrees celsius, which reduces the formation of isomers to the extent possible. Also, the present invention is able to obtain a high yield of high purity pitavastatin hemicalcium despite consecutively executing a hydrolytic reaction and a pitavastatin hemicalcium reaction, without an isolation reaction after the deprotection reaction.

Description

Novel Process for Preparing Pitavastatin Hemicalcium Using New Intermediates

The present invention is useful as a HMG-Co A reductase inhibitor, and relates to a novel method for preparing pitavastatin hemicalcium used as a therapeutic agent for hyperlipidemia. In particular, the present invention relates to a novel process for the preparation of pitavastatin hemicalcium and its crystalline forms using the novel intermediates.

Pitavastatin hemicalcium represented by Formula 1 is low density lipoprotein (LDL) in the bloodstream of a patient at risk of developing cardiovascular disease, which is sold by Nissan Chemical industry under the trade name LIVALO. Drugs that are low in concentration and useful for hyperlipidemia (Ref. Cardiovasc Drug Rev 2003; 21: 199-215. J Clin Pract 2005; 59: 239-252).

Formula 1

The pitavastatin hemicalcium of Formula 1 is Japanese Patent No. 207224 (1987), Japanese Patent No. 15585 (1988), Japanese Patent No. 193606 (1988), Japanese Patent No. 93/01551, International Patent No. 95 / 11898, U.S. Pat.No.5856336, U.S. Pat.No.4739073, European Patent No.11402, Korean Patent No.1996-0000852, Paper Bioorganic & Medical Chemistry Letters 9 (1999) 2977 ~ 2982, Paper Bioorg. Med. Chem 9 (2001) 2727-2743 and the like are summarized in the following Reaction Scheme 1.

Scheme 1

Scheme 1 is a diethylcyanomethyl phosphate compound after the benzyl alcohol compound of formula (2) is synthesized by converting the benzyl alcohol group to benzaldehyde group by oxidation reaction under dimethyl sulfoxide (DMSO) and oxidizing agent And the Emmons-Honer coupling reaction, and then synthesized into a propenal compound of Formula (4) by reduction with diisobutyl aluminum hydride (DIBAH), a powerful reducing agent. Propane compound of formula (4) was subjected to beta-keto-δ-hydroxyester (β-keto-δ) by aldol condensation with ethyl acetate under a strong base of n-butyllithium (n-BuLi). -hydroxy ethyl ester) is synthesized by racemic formula (5). The racemic compound of Formula (5) is reduced with sodium borohydride (NaBH ₄ ), a powerful reducing agent, to synthesize Enantiomer (Formula (6)), followed by hydrolysis and calcium reaction. Pitavastatin hemicalcium of Formula 1 was synthesized.

Scheme 1 of the synthesis process of pitavastatin has the disadvantage that isomers are simultaneously synthesized in the synthesis of formula (4), formula (5) and formula (6), and also isobutyl aluminum hydride, n-butyl lithium, It is disadvantageous in that industrially disadvantageous reducing agents and bases, such as sodium borohydride, which are very sensitive to contact with moisture and air, have a risk of explosion, must be used.

Looking at the reaction scheme 1 in more detail as follows.

first ; Benzaldehyde of formula (3) of Scheme 1 is trans-propenal of formula (4) through an emons-Honner coupling reaction using dithycyanomethyl phosphonate In the case of synthesizing (trans-Propenal), isomers of Z-form as impurities are generated at the same time, and the removal of the resulting isomeric compound (Z-propenal) is not easy.

second ; In addition to the disadvantage of having to perform the purification process to remove the isomers, the synthesis of β-keto-δ-hydroxy ester of formula (5) is very resistant to moisture and air. The disadvantage of using a highly explosive base of n-butyllithium (n-BuLi). In addition, when the aldehyde group of the Z-propenal compound, which is an impurity of the formula (4), is converted to a secondary alcohol, a disadvantage is that a mixture of racemic substances having different stereochemical properties is produced. This has the disadvantage of having a very low purity up to the racemic mixture produced when synthesizing the formula (5) to the E-form, G-form mixture produced during the synthesis of the formula (4).

third ; After selectively reducing the β-keto group of the formula (5) to synthesize the formula (6), the formula (6) of (R, R), (S, S) of the stereochemical structure different from each other A major disadvantage is that it is produced as a mixture of enantiomers.

As an improved method of Scheme 1, a preparation method represented by Scheme 2 was proposed.

Scheme 2

Reaction Scheme 2 synthesizes Formula (D), performs a coupling reaction with Formula (G), deprotects the protecting group of the diol, and then synthesizes Formula (J), which is a lactone compound. The lactone of formula (J) is hydrolyzed to synthesize pitavastatin.

Scheme 2 is an improved method of preparing pitavastatin compared to Scheme 1, but has the following disadvantages.

first ; In the case of synthesizing the formula (H) through the coupling reaction of the formula (G) and the formula (D), a considerable amount of isomers of the formula (I) are produced, and the impurities of the formula (I) which are very difficult to separate and purify There is a disadvantage in that the isomer of) must be separated and purified.

second ; In the synthesis of Formula (H) to Formula (J), the protecting group of the diol should be deprotected. In the deprotection reaction, a strong acid, trifluoroacetic acid (TFA), must be used, and a very long reaction time of 24 hours or more is required. It is a disadvantage, and the disadvantage is that an isomer (Z-form) is generated due to a long reaction time.

third ; In order to synthesize the above formula (J), after deprotection with a strong reaction with a strong acid for 24 hours, the lactone compound of the formula (J) should be synthesized again. However, at this time, a considerable amount of isomers (Z-form) are generated, and also has a problem in that the yield is reduced because a process for removing the isomers must be performed.

As described above, the existing methods such as Scheme 1 and Scheme 2 have to go through a very complicated purification process to remove the isomer and the purity due to the isomer that is inevitably generated during the reaction. It may be a cause of lowering of purity.

An object of the present invention is to provide a method for preparing pitavastatin, which supplements the above-mentioned disadvantages, and is an industrially useful method for preparing pitavastatin.

The method of producing pitavastatin, which the inventors have systematically and intensively researched for a long time, is an industrially very useful manufacturing process. This not only uses industrially useful raw materials and reagents for the production of pitavastatin, but also simplifies the production of pitavastatin and is suitable for mass production. have.

The present invention for achieving the object as described above, characterized in that composed of a total of seven steps as represented by the following Scheme 3 for the production of pitavastatin hemicalcium.

Scheme 3

The present invention provides a novel method for preparing pitavastatin hemicalcium, which is useful as an HMG-Co A reductase inhibitor, and is used as a therapeutic agent for hyperlipidemia. By providing a novel method for preparing pitavastatin hemicalcium, it not only uses industrially useful raw materials and reagents, but also simplifies the production of pitavastatin, making it suitable for mass production and enabling mass production. .

1 is an X-ray powder diffractogram of pitavastatin hemicalcium.

Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings.

The present inventors have systematically and persistently studied the manufacturing method of pitavastatin hemicalcium, and not only greatly simplified the manufacturing process but also completed the manufacturing method of pitavastatin which can be industrially mass-produced.

One of the features of the present invention provides an efficient process for the preparation of pitavastatin using a novel intermediate for preparing pitavastatin, and the alcohol protecting group in the novel intermediate is 1 to 2 hours under mild reaction conditions under acid catalyst. In addition to easily protecting the dial within the alcohol, the reaction was completed within 30 minutes to 1 hour under very mild reaction conditions of 0 to 25 ° C. during the deprotection of the dialcohol, thus reducing the formation of isomers as much as possible. This can be said to be an advantage.

In addition, the present invention is an advantage of the present invention that high purity pitavastatin hemicalcium can be obtained in high yield even after the deprotection reaction is carried out without hydrolysis and pitavastatin hemicalcium reaction without isolation reaction. This can be called.

The present invention consists of a total of seven steps as represented by Scheme 3 below for the preparation of pitavastatin hemicalcium.

Scheme 3

Hereinafter, the present invention will be described in more detail step by step.

The novel method for preparing pitavastatin hemicalcium using the new intermediate according to the present invention consists of a total of seven step processes, which will be described separately below.

First step: synthesis of tert-butyl2-((4R, 6S) -6- (hydroxymethyl) -2-alkoxy-1,3-dioxan-4-yl) acetate (Formula (9))

Tert-butyl2-((4R, 6S) -6-formyl-2-alkoxy-1,3-dioxane- constituting the side chain of pitavastatin (Formula 1) of Scheme 3 Tert-butyl2-((4R, 6S) -6 (hydroxymethyl) -2-alkoxy-1,3-dioxane-4 as a precursor to synthesize 4-yl) acetate (Formula 10) -Yl) acetate (Formula 9).

Starting material (3R, 5S) -tert-butyl-3,5,6-trihydroxyhexanoate (Formula 8) was converted to tetrahydrofuran (THF), dichloromethane, acetonitrile, dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), acetone or a solvent consisting of two or more mixtures thereof, and then from a group consisting of triethylamine, trimethylamine, pyridine, N, N-dimethylaniline or a mixture of two or more thereof After adding the selected base catalyst, the primary alcohol group at position 6 is protected by reacting with acetyl chloride under conditions of a reaction temperature in the range of -10 to 25 ° C.

The reaction solution obtained above is washed with purified water and saturated brine, and magnesium sulfate is added to remove residual moisture, followed by filtration.

The filtrate is cooled to -10 to 25 DEG C, preferably 0 to 5 DEG C, and then again made of tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone or a solvent composed of two or more thereof. After dissolving in, an acid catalyst selected from the group consisting of sulfuric acid, acetic acid, para-toluenesulfonic acid, methanesulfonic acid or a mixture of two or more thereof is added, followed by stirring for 10 to 30 minutes, followed by triethyl orthoformate. , Trimethyl orthoformate, triphenyl orthoformate and any one compound selected from the group consisting of, and then stirred for 30 minutes to 2 hours while maintaining the temperature 3, 5 times Protect secondary alcohols in position.

Thereafter, the acid catalyst in the reaction solution was removed by neutralization, and then tert-butyl2-((4R, 6S) -6- (hydroxymethyl) -2-methoxy-1,3-dioxan-4-yl Acetate (Formula 9) can be obtained in the form of a racemate in high yield of at least 95%.

Subsequently, the racemate of formula (9) is dissolved in a solvent consisting of tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone or a mixture of two or more thereof. Potassium carbonate or sodium bicarbonate under a catalyst of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), potassium bromide (KBr) or lithium bromide (LiBr) in a separate reaction vessel After adding a weak base catalyst such as (NaHCO ₃ ) and stirring, cooling to -5 to 5 ° C., and then slowly adding the solution of formula (9) dropwise, further adding NaOCl and NaHCO ₃ , and then at room temperature Stir for 4-10 hours. Deprotection of the primary alcohol group at position 6 under the weak base by stirring to give tert-butyl2-((4R, 6S) -6- (hydroxymethyl) -2- in a yield of at least 97% as a yellow oil. Alkoxy-1,3-dioxan-4-yl) acetate (Formula (9)) is synthesized.

In the present invention, a trialkylorthoformate represented by CH (OR) ₃ is selected and used as a protecting agent for the dihydroxy group.

Second Step: Synthesis of tert-Butyl2-((4R, 6S) -5-formyl-2-methoxy-1,3-dioxan-4-yl) acetate (Formula 10)

The primary alcohol group of formula (9) obtained in the first step is manganese dioxide (MnO ₂ ), hydrogen peroxide (H ₂ O ₂ ), peracetic acid (CH ₃ CO ₃ H), sodium hypochlorite (NaOCl) or these Converting the primary alcohol group to an aldehyde group through an oxidation reaction using an oxidizing agent selected from the group consisting of two or more mixtures. Tertiary-butyl2-((4R, 6S) -6-formyl-2-methoxy-1,3-dioxan-4-yl by aldehyde oxidation of the primary alcohol group at position 6 of formula (9) Acetate (Formula 10) is synthesized.

The oxidation reaction is carried out using a selected solvent using an oxidizing agent under a single or mixed catalyst, oxidizing the hydroxymethyl group of the terminal group to an aldehyde group under mild reaction conditions ranging from 0 ° C to room temperature, preferably 0 to 25 ° C. Formula (10) can be obtained in high yield (90% or more). As a catalyst, TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) can be used alone or as a mixed catalyst with KBr (potassium bromide), and a mixed catalyst is more effective. In the oxidation reaction, a solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, dimethylsulfoxide, diethyl ether, benzene, dichloromethane, acetonitrile, acetone or a mixture of two or more thereof can be used. In more detail, in a reaction vessel under a base of sodium bicarbonate (NaHCO 3), 0.005% of TEMPO catalyst by weight and 0.005% of KBr by weight were added to dichloromethane and suspended at 0 ° C., followed by the above formula (9). The solution dissolved in dichloromethane is added dropwise, and stirred at room temperature.

Third Step: Synthesis of 3- (Bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline (Formula 12)

Tert-butyl2-((4R, 6S) constituting the side chain in a quinoline structure constituting the skeleton structure of pitavastatin (Formula (1)) -6-formyl-2-alkoxy-1,3-dioxan-4-yl) acetate (Formula 10).

Methyl alcohol group of (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) methanol (Formula 11) as a starting material was converted to a halide to give 3- (bromomethyl) -2- Synthesis of cyclopropyl-4- (4-fluorophenyl) quinoline (Formula 12).

The halide agent for converting to a halide is selected from the group consisting of bromine (Br ₂ ), chlorine (Cl ₂ ), pentachloropostin (PCl ₅ ), tribromophosphine (PBr ₃ ) or mixtures of two or more thereof The halide agent is 0 in a solvent selected from the group consisting of toluene, benzene, xylene, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, diethyl ether, dichloromethane, acetonitrile, acetone or mixtures of two or more thereof. Under a mild reaction temperature of 25 ° C., a compound having a halogen group represented by Formula 12 was introduced. In more detail, after dissolving the formula (11) in a mixed solvent of toluene / dichloromethane at room temperature, the halogenating agent is added. After the reaction was cooled to 0 ° C., sodium bicarbonate was slowly added dropwise to complete the reaction.

*

Fourth Step: Synthesis of Triphenyl (2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide salt (Formula 13)

Formula (12) using trialkylphosphine or triarylphosphine compound represented by P (R ₁ ) ₃ triphenyl (2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3- Monomethyl) -phosphonium) bromide (Formula 13).

The halide compound of formula (12) is dissolved in a solvent selected from the group consisting of benzene, toluene, xylene, dimethyl sulfoxide, dimethylformamide or a mixture of two or more thereof, and then trialkylphosphine or triarylphosphine After addition, the mixture was heated for 1 to 5 hours to obtain triphenyl (2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13). .

In more detail, the above formula (12) and trialkylphosphine or triarylphosphine are added to toluene, stirred at room temperature for 30 minutes, and then heated for 3 hours. When the reaction is complete, the above formula (13) is produced in the reaction solution, and the step is performed by cooling to room temperature and then filtering.

Fifth step: tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl)- Synthesis step of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

The formula (13) and the formula (10) is potassium carbonate (K ₂ CO ₃ ), sodium bicarbonate (NaHCO ₃ ), potassium tert-butoxide (t-BuOK), potassium hydroxide (KOH), sodium hydroxide ( Tertiary-butyl2-(() through a coupling reaction under an inorganic base such as NaOH) or a base selected from the group consisting of organic bases such as aniline, substituted aniline, pyridine, substituted pyridine and the like, or a mixture of two or more thereof. 4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) -2-methoxy-1,3-dioxane- 4-yl) acetate (Formula 14) is synthesized. As the reaction solvent, a solvent selected from the group consisting of benzene, toluene, xylene, dimethyl sulfoxide, dimethylformamide or a mixture of two or more thereof may be used, and after dissolving the reactants with the reaction solvent, 50 to 150 ° C The compound of formula (14) is obtained by coupling to a coupling reaction. In more detail, after dissolving the formula (13), the formula (10) and sodium carbonate in a dimethyl sulfoxide solvent, the mixture is heated and stirred at 70 ° C. for about 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent. The reaction solution was dissolved in toluene, washed with purified water, and residual moisture was removed with magnesium sulfate. The insoluble matter was removed by filtration, and toluene was concentrated under reduced pressure, and then separated by chromatography to obtain tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4) as a white solid. -(4-fluorophenyl) quinolin-3-yl) vinyl) -2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14) is obtained.

Sixth Step: (E, 3R, 5S) -tert-butyl7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhep-6 Synthesis step of tenoate (Formula 15)

(E, 3R, 5S) -tert-butyl 7 as an acid catalyst of the 2-methoxydioxane group of the formula (14) through a deprotection process under dilute acid diluted hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid and the like in purified water -(2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhep-6-tenoate (Formula 15).

The formula (14) was added to a dilute acid solution in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone or a mixture of two or more thereof, followed by degassing within 1 hour under a mild reaction temperature of 0 to 25 ° C. Perform the gelatinization reaction. In more detail, after dissolving the formula (14) in which the dihydroxy group is protected in a solvent of methanol, 2N hydrochloric acid is added under a reaction temperature of 0 to 5 ° C, and then stirred for 10 to 30 minutes to quantitatively formulate the formula (14). Manufacture. The formula (15) in which the diol is deprotected may be carried out in an isolated or continuous process, but in isolation, the isolation process is advantageous.

Step 7: Synthesis of Pitavastatin (1)

Hydrolysis of the formula (15) is a process for producing pitavastatin acid of the formula (1).

(E, 3R, 5S) -tert-butyl7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhepte of formula (15) -6-noate was hydrolyzed in an aqueous solution using an inorganic base such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide and the like to prepare a pitavastatin metal salt represented by Formula 1, followed by pitavastatin in a continuous reaction. Hemicalcium is obtained.

The process can be performed in isolation or in a continuous process. The continuous process is followed by hydrolysis in aqueous solution, followed by continuous addition of calcium chloride (CaCl ₂ ) and calcium acetate (Ca (OAc) ₂ ) calcium agents to obtain pitavastatin hemicalcium. New crystals are prepared. Since the difference in yield or purity of the isolation process or the continuous process is small in the pitavastatin hemicalcium manufacturing process, the continuous process is advantageous.

In more detail, (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5 of formula (15) Sodium hydroxide, hydroxide in dihydroxyhepte-6-noate in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone, acetonitrile or a mixture of two or more thereof under a mild reaction temperature of 0 to 25 ° C. By using an inorganic base such as potassium, potassium tert-butoxide, etc., hydrolysis is carried out in an aqueous solution for 1 to 2 hours to prepare pitavastatin acid represented by Chemical Formula 1. The pitavastatin acid of Formula 1 may be prepared by pitavastatin hemicalcium in an isolated or continuous process, and the isolation process is advantageous in terms of yield. However, the difference between the isolation process and the continuous process does not lead to a difference in purity. Calcium chloride (CaCl ₂ ) or calcium acetate (Ca (OAc) ₂ ) was added to the phytavastatin sodium salt reaction solution produced by hydrolysis, and the mixture was stirred at 0 to 25 ° C. for 5 to 8 hours to obtain high yield (more than 91%). ), A new crystalline form of pitavastatin hemicalcium is prepared in high purity (99.6% HPLC Area%) as follows.

Table 1 below shows the following X-ray powder diffraction expressed in terms of relative intensity having a relative intensity of> 20% measured on a diffracter (Bruker D8 advance) by CuKα irradiation after 2θ, d-spacing and grinding for 2 minutes. Aspects are characterized by pitavastatin hemicalcium and its hydrates.

Table 1

2θ	d-value	Relative strength after grinding for 2 minutes (> 20%)
3.854	22.90762	100
5.412	16.31713	69.7
7.741	11.31156	49.9
11.297	7.82632	46.7
15.457	5.72801	35.2
17.807	4.97705	46.2
19.323	4.58979	54.5

1 is an X-ray powder diffractogram of pitavastatin hemicalcium.

Moisture in pitavastatin hemicalcium obtained according to the present invention is absorbed in the compound of Formula 1, and the compound of Formula 1 and 1 to 3 water molecules are hydrated. exist.

The water absorbed by the pitavastatin hemicalcium may be removed by drying for about 10 hours in a dryer of 50 to 60 ℃. The pitavastatin hemicalcium hydrate was confirmed by drying the pitavastatin hemicalcium crystals in a drier at 60 ° C. for 10 hours to remove the moisture, followed by a water meter (Karl-Fisher) and a thermogravimetric analysis (TGA). ) Can be confirmed by measurement.

In Scheme 3, R represents hydrogen, methyl, ethyl, C ₁ ~ C ₆ alkyl group or C ₆ ~ C ₁₈ aryl group, R ₁ is C ₁ ~ C ₆ alkyl group or alkoxy group, phenyl group, substituted phenyl group, non- The substituted phenyl group is represented and X represents a halogen atom.

In addition, each of the compounds represented by Chemical Formula (9), Chemical Formula (10) and Chemical Formula (14) synthesized as a reaction intermediate in the course of carrying out a series of preparation processes according to Scheme 3 are novel intermediate compounds. It is useful for the synthesis of pitavastatin according to the invention.

According to the present invention, in the method for preparing pitavastatin represented by Chemical Formula 1, the following effects are obtained.

first ; By separating the processes from the first to the seventh step, it is possible to obtain a high yield of pitavastatin hemicalcium through high-purity intermediates (more than 99.6% high performance liquid chromatography (HPLC) area%).

second ; Synthesis of a dihydroxy group protected optically active diol intermediate in the initial stage of the reaction to prepare pitavastatin through a coupling reaction with a quinoline derivative, there is an effect of obtaining a high purity optical activity and stereochemical compounds.

third ; By using trialkylorthoformate as a protecting agent for the dihydroxy group, four of the seven steps are quantitatively quantitatively prepared within 30 minutes to 3 hours at reaction temperature conditions below room temperature, which is industrially very easy. The effect obtained is obtained.

fourth ; By using trialkyl orthoformate as the protecting agent of the dihydroxy group, the protection reaction can be performed even at 0 ° C to room temperature, and the deprotection reaction and the hydrolysis reaction can be carried out continuously, as well as the pitavastatin salt. It can be carried out by the continuous reaction of pitavastatin hemicalcium without separation to obtain the effect of obtaining the desired pitavastatin hemicalcium in high yield and high purity (99.6% or more high performance liquid chromatography area%).

As described above, the manufacturing method of the present invention has a relatively simple manufacturing process, mild reaction conditions, and high production yield and purity, so that phytavastatin hemicalcium, which is an effective drug for treating hyperlipidemia, can be applied as an industrial production method. Very suitable.

The present invention will be described in more detail based on the following examples, which should not be construed as limiting the invention thereto.

Example 1 Preparation of Tert-Butyl 2-((4R, 6S) -6- (hydroxymethyl) -2-methoxy-1,3-dioxan-4-yl) acetate (Formula (9))

30 g (0.136 mol (mol)) of (3R, 5S) -tert-butyl 3,5,6-trihydroxyhexanoate was added to a reaction vessel filled with nitrogen and dissolved in 270 ml of tetrahydrofuran. After cooling the reaction vessel to 0 ° C., 6.3 ml (0.136 mol) of triethylamine was added, followed by stirring for 10 minutes. After diluting 10.6 ml (0.149 mol) of acetyl chloride with 20 ml of tetrahydrofuran, the mixture was slowly added for 30 minutes and stirred at 30 minutes for 1 hour while maintaining the temperature. After confirming that the reaction was completed through thin layer chromatography (TLC), the reaction solvent was removed by concentration under reduced pressure. The concentrated solution was added to 300 ml of ethyl acetate and dissolved, and 200 ml of purified water was added to wash the reaction twice. The organic solvent was separated and then washed with brine, and residual moisture was removed with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and dissolved in 270 ml of tetrahydrofuran. After filling with nitrogen, it was cooled to 0 ° C and 0.1 g of methanesulfonic acid was added. After stirring for 10 minutes while maintaining the temperature, 17.9 ml (0.163 mol) of trimethylorthoformate was added over 30 minutes. The reaction solution was stirred for 1 hour while maintaining the temperature. After neutralizing the reaction solution with triethylamine, the reaction solvent was concentrated under reduced pressure. The concentrated solution was dissolved in methanol, cooled to 0 ° C., and a solution obtained by dissolving 5.4 g (0.136 mol) of sodium hydroxide in 50 mL of purified water was slowly added to the reaction solution, followed by stirring for 20 minutes. 450 ml of dichloromethane and 100 ml of purified water were added to the reaction solution, and the layers were separated. The organic layer was washed again with 300 ml of purified water and brine sequentially, and the residual solvent was removed with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 33.5 g (93.2%) of the title Epimer as colorless oil.

Proton Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR (CDCl ₃ )) Data: δ 1.32 (s, 9H), δ 1.5 ~ 1.8 (m, 2H), δ 2.2 ~ 2.5 (m, 2H), δ 3.32 (s, 3H), δ 3.5-3.9 (m, 3H), δ 4.41 (m, 1H), 5.89 (s, 1H).

Example 2 Preparation of Tert-Butyl 2-((4R, 6S) -5-formyl-2-methoxy-1,3-dioxan-4-yl) acetate (Formula 10)

In a two-necked reaction vessel filled with nitrogen, 45.2 g (0.538 mol) of sodium bicarbonate (NaHCO ₃ ), 4.8 g (0.04 mol) of potassium bromide (KBr), and 100 mg of TEMPO were added and suspended in 300 ml of dichloromethane. The reaction was cooled to 0 ° C. and then stirred for 30 minutes. 50 g (0.19) of tert-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2-methoxy-1,3-dioxan-4-yl) acetate in a separate nitrogen-filled reaction vessel Mole) was dissolved in 200 ml of dichloromethane and added to the reaction solution.

80 ml of 10% sodium hypochlorite (NaOCl) was slowly added while maintaining the temperature at 0 ° C, followed by stirring for 20 minutes. 48.3 g (.0576 mol) of sodium bicarbonate was further added to the reaction solution, followed by further stirring for 20 minutes. After adding 27 ml of 10% sodium hypochlorite, the mixture was heated to room temperature and stirred for 4 hours.

The reaction solution was filtered under a filter filled with celite, and then the filtrate was washed with 10% sodium thiosulfate (Na ₂ S ₂ O ₃ ) solution. The filtrate was removed with residual water with magnesium sulfate (MgSO ₄ ) and then filtered and concentrated to give 44.8 g (90.3%) of the title compound as a pale yellow oil.

Proton Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR (CDCl ₃ )) Data: δ 1.38 (s, 9H), δ 1.8 ~ 2.6 (m, 4H), δ 4.4 ~ 4.7 (m, 2H), δ 3.33 (s, 3H), δ 5.88 (s, 1H), δ 9.48 (s, 1H).

Example 3: Preparation of 3- (Bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline (Formula 12)

Dissolve 50 g (0.170 mole) of (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) methanol in a mixed solvent of 340 ml of toluene and 170 ml of dichloromethane in a three-necked reaction vessel filled with nitrogen. I was.

32.8 mL (0.348 mol) of phosphorus tribromide (PBr ₃ ) was slowly added to the reaction mixture at room temperature, followed by stirring for 2 hours. After cooling the reaction solution to 0 ° C., the cooled sodium bicarbonate solution was slowly added, followed by extraction twice with 400 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 53.3 g (87.8%) of the title compound as a white solid.

Proton Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR (CDCl ₃ )) Data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.4 ~ 7.3 (m, 5H), δ 7.23 (d, 1H) , δ 5.66 (s, 2H), δ 2.75 ~ 2.70 (m, 1H), δ 1.2 ~ 1.1 (m, 2H), δ 1.07 ~ 1.03 (m, 2H).

Example 4 Preparation of Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13)

30 g (0.0845 mole) of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline and 23.3 g (0.0887 mole) of PPh ₃ were added to a reaction vessel filled with nitrogen and toluene 420 at room temperature. Dissolved in ml. The temperature was slowly raised to reflux for 3 hours. After the reaction was completed, the resulting solid was filtered by cooling to room temperature. The filtrate was dried to give 50.4 g (96.4%) of the title compound as a white solid.

Proton Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR (CDCl ₃ )) Data: δ 7.8 ~ 7.9 (m, 5H), δ 7.6 ~ 7.7 (m, 8H), δ 7.4 ~ 7.2 (m, 10H), δ 5.21 ( bs, 2H), δ 2.0-1.99 (m, 1H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

Example 5 Preparation of Triethyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13)

30 g (0.0845 mole) of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline and 9.6 g (0.0887 mole) of triethylphosphine were added to a reaction vessel filled with nitrogen. The solution was dissolved in 420 ml of toluene at room temperature. The temperature was slowly raised to reflux for 3 hours. After the reaction was completed, the resulting solid was filtered by cooling to room temperature. The filtrate was dried to give 42 g of the title compound as a white solid.

Proton nuclear magnetic resonance spectroscopy ( ¹ H NMR (CDCl ₃ )) data: δ 7.8 ~ 7.9 (m, 5H), δ 7.6 ~ 7.7 (m, 8H), δ 7.4 ~ 7.2 (m, 10H), δ 2.61 (bs, 2H), δ 1.3-1.4 (m, 6H), δ 0.91-0.93 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

Example 6 Preparation of Triethoxy ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13)

30 g (0.0845 mol) of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline, 14.8 g of potassium ethoxide (P (OEt) ₃ ) in a reaction vessel filled with nitrogen 0.0887 mol) was dissolved in 420 ml of toluene at room temperature. The temperature was slowly raised to reflux for 3 hours. After the reaction was completed, the resulting solid was filtered by cooling to room temperature. The filtrate was dried to give 29.3 g of the title compound as a white solid.

Proton Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR (CDCl ₃ )) Data: δ 7.8 ~ 7.9 (m, 5H), δ 7.6 ~ 7.7 (m, 8H), δ 7.4 ~ 7.2 (m, 10H), δ 3.4 ~ 3.6 (m, 6H) δ 2.63 (bs, 2H), δ 0.90 to 1.1 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

Example 7: tertiary t-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) Preparation of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide 46g (0.074mol), potassium carbonate 30.8g (0.223 mol) was added and dissolved in 460 ml of dimethyl sulfoxide. The reaction was heated to reflux at 70 ° C. for 4 hours.

After the reaction was cooled to room temperature, 460 ml of purified water was added, followed by extraction twice with 350 ml of toluene. The organic layer was washed twice with 500 ml of purified water twice, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product as a solid.

The crude product was separated by chromatography to give 29.6 g (76.7%) of the title compound as a white solid.

Proton nuclear magnetic resonance spectroscopy ( ¹ H NMR (CDCl ₃ )) data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H) , δ 6.54 (d, 1H), δ 5.99 (s, 1H), δ 5.49 (dd, 1H), δ 4.3 ~ 4.5 (m, 2H), δ 3.26 (s, 3H), δ 2.5 ~ 2.2 (m, 2H), δ 1.7-1.5 (m, 3H), δ 1.3-1.4 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

Example 8 tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl)- Preparation of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide 46g (0.074mol), sodium bicarbonate 18.7 g (0.223 mol) was added and dissolved in 460 ml of dimethyl sulfoxide. The reaction was heated to reflux at 70 ° C. for 9 hours.

After the reaction was cooled to room temperature, 460 ml of purified water was added, followed by extraction twice with 350 ml of toluene. The organic layer was washed twice with 500 ml of purified water, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product as a solid.

The crude product was separated by chromatography to give 17.9 g (46.5%) of the title compound as a white solid.

Example 9: tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl)- Preparation of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide 46g (0.074mol), dimethylaminopyridine 27.2 g (0.223 mol) of DMAP) were added and dissolved in 460 ml of dimethyl sulfoxide. The reaction was heated to reflux at 70 ° C. for 6 hours.

After the reaction was cooled to room temperature, 460 ml of purified water was added, followed by extraction twice with 350 ml of toluene. The organic layer was washed twice with 500 ml of purified water, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product as a solid.

The crude product was separated by chromatography to give 21.2 g (55.0%) of the title compound as a white solid.

Example 10 (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhepte-6 Preparation of Noate (Formula 15)

T-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) with 99.4% purity in the reactor) 20 g of -2-methoxy-1,3-dioxan-4-yl) acetate were added and dissolved in 140 ml of methanol. 28 mL of 2N hydrochloric acid was added to the reaction, followed by stirring for 30 minutes to 1 hour. When the reaction was completed, 100 ml of purified water and 200 ml of dichloromethane were added to the reaction solution. After re-extracting the aqueous layer with dichloromethane, all the organic layers were combined and washed successively with 150 ml of purified water and saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure. The concentrated solution was dissolved in dichloromethane, cooled to 0 ° C. and hexane was added slowly to give 17.7 g (96.4%; purity 99.6% high performance liquid chromatography area%) of the title compound as a white solid.

Proton nuclear magnetic resonance spectroscopy ( ¹ H NMR (CDCl ₃ )) data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H) , δ 6.54 (d, 1H), δ 5.49 (dd, 1H), δ 4.3 ~ 4.5 (m, 2H), δ 2.5 ~ 2.2 (m, 2H), δ 1.7 ~ 1.5 (m, 3H), δ 1.3 ~ 1.4 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

Example 11 (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhepte-6 Preparation of Noate (Formula 15)

Tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) of 99.4% purity in the reactor 20 g of) -2-methoxy-1,3-dioxan-4-yl) acetate was added and dissolved in 140 ml of methanol. 28 mL of 2N hydrochloric acid was added to the reaction, followed by stirring for 30 minutes to 1 hour. When the reaction was completed, 100 ml of purified water and 200 ml of dichloromethane were added to the reaction solution. After re-extracting the aqueous layer with dichloromethane, all the organic layers were combined and washed successively with 150 mL of purified water and saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure. The concentrated solution proceeded to the next reaction immediately without any further reaction.

Example 12: (E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhep-6-tenoic sodium salt (Formula 1) Manufacturing

The concentrated compound obtained in Example 11 was dissolved in 140 ml of methanol at room temperature. A solution of 2.3 g (0.057 mol) of sodium hydroxide dissolved in 20 ml of purified water was slowly added. The reaction was completed by stirring at room temperature for 2 hours. The following reaction proceeded without further purification.

Example 13 Preparation of Pitavastatin Hemicalcium

A solution of 4.2 g (0.037 mol) of calcium chloride (CaCl ₂ ) dissolved in 10 ml of purified water was slowly added to the reaction product of Example 12 cooled to 0 ° C. After stirring for 30 minutes, the insolubles were filtered off, and then the filtrate was raised to room temperature and stirred for 8 hours.

After the reaction was cooled to 0 ° C., 280 ml of purified water was slowly added to precipitate crystals.

The crystals were filtered and dried in vacuo to yield 12.3 g of pitavastatin hemicalcium as a white solid.

Proton nuclear magnetic resonance spectroscopy ( ¹ H NMR (DMSO-d6)) data: δ 11.2 (s, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H ), δ 6.64 (d, 1H), δ 6.25 (dd, 1H), δ 3.91 (m, 2H), δ 3.56 (m, 1H), δ 2.5 to 2.2 (m, 2H), δ 1.6 to 1.5 (m , 3H), δ 0.6-0.3 (m, 4H).

Example 14 Preparation of Pitavastatin Hemicalcium

A solution in which 5.8 g (0.037 mol) of calcium acetate (Ca (OAc) ₂ ) was dissolved in 10 mL of purified water was slowly added to the reaction product of Example 12 cooled to 0 ° C. After stirring for 30 minutes, the insolubles were filtered off, and then the filtrate was raised to room temperature and stirred for 8 hours.

The crystals were filtered and dried in vacuo to yield 12.7 g of pitavastatin hemicalcium as a white solid.

As described above, the present invention has no unnecessary manufacturing process in order to introduce a specific functional group in the production of Pitavastatin hemicalcium, and the present invention has a short reaction time under relatively mild reaction conditions in all seven steps. Thus, pitavastatin can be obtained in high yield, and can be used to prepare novel pitavastatin which is industrially effective.

Although the present invention has been described in detail only with respect to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the technical scope of the present invention, and such modifications and modifications are within the scope of the appended claims.

Claims

In the preparation of pitavastatin hemicalcium,

i) trialkylorthoport, wherein (3R, 5S) -tert-butyl-3,5,6-trihydroxy hexanoate represented by formula (8) in Scheme 4 is represented by CH (OR) 3 under an acid catalyst Protected reaction with mate, t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2-alkoxy-1,3-dioxane-4- represented by the formula (9) in Scheme 4 below. (1) a first step of preparing acetate;

Scheme 4

In Scheme 4, R is hydrogen, methyl, ethyl, C 1 ~ C 6 alkyl group, C 6 ~ C 12 phenyl group, substituted or unsubstituted aryl group,

ii) tert-butyl-((4R, 6S) -6 (hydroxymethyl) -2-alkoxy-1,3-dioxan-4-yl) acetate represented by the formula (9) in Scheme 5 Manganese dioxide (MnO 2 ), hydrogen peroxide (H 2 O 2 ), as oxidant in the presence of, 2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), potassium bromide (KBr) or lithium bromide (LiBr), Tert-butyl2 represented by the following formula (10) by oxidizing with an oxidizing agent selected from the group consisting of peracetic acid (CH 3 CO 3 H), sodium hypochlorite (NaOCl) or a mixture of two or more thereof A second step of preparing-((4R, 6S) -5-formyl-2-alkoxy-1,3-dioxan-4-yl) acetate;

Scheme 5

In Scheme 5, R is hydrogen, methyl, ethyl, C 1 ~ C 6 alkyl group, C 6 ~ C 12 phenyl group, substituted or unsubstituted aryl group,

iii) Bromine (Br 2 ) and phosphorus bromide (PBr 3 ) as a halogenating agent of (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) methanol represented by the formula (11) 3- (halomethyl) -2-cyclopropyl-4 represented by the following formula (12) using a halogenating agent selected from the group consisting of chlorine (Cl 2 ) and phosphorus chloride (PCl 5 ) A third step of preparing-(4-fluorophenyl) quinoline;

Scheme 6

In Scheme 6, X is a halogen atom,

iv) 3- (halomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline represented by the general formula (12) of Scheme 7 below with a trialkyl represented by the general formula (13) A fourth step of preparing 2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromid salt;

Scheme 7

In Scheme 7, R1 is a C 1 ~ C 6 alkyl group, an alkoxy group, a C 6 ~ C 12 phenyl group, a phenoxy group, a substituted or unsubstituted aryl group, X is a halogen atom,

v) trialkyl (2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide salt represented by the formula (13) Coupling reaction with tert-butyl2-((4R, 6S) -6-formyl-2-alkoxy-1,3-dioxan-4-yl) acetate represented by the formula (10) Tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) represented by (14) A fifth step of preparing) -2-alkoxy-1,3-dioxan-4-yl) acetate;

Scheme 8

In Scheme 8, R and R1 are C 1 to C 6 alkyl group, alkoxy group, C 6 to C 12 phenyl group, phenoxy group, substituted or unsubstituted aryl group, X is a halogen atom,

vi) tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl)) represented by formula (14) in Scheme 9 below. Deprotection reaction of quinolin-3-yl) vinyl) -2-alkoxy-1,3-dioxan-4-yl) acetate with aqueous solution of sulfuric acid, hydrochloric acid, acetic acid or methanesulfonic acid diluted with purified water or organic solvent (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5 represented by Chemical Formula (15) A sixth step of preparing dihydroxyhepte-6-noate;

Scheme 9

In Scheme 9, R and R1 are C 1 ~ C 6 Alkyl group, alkoxy group, C 6 ~ C 12 phenyl group, phenoxy group, substituted or unsubstituted aryl group,

vii) (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3 represented by formula (15) in Scheme 10 below A hydrolyzate using a hydrolyzing agent selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, lithium hydroxide or a mixture of two or more thereof, as a hydrolysis agent of, 5-dihydroxyhepte-6-noate After the decomposition reaction, a seventh step of preparing pitavastatin hemicalcium represented by Chemical Formula (1) in a continuous reaction using calcium chloride or calcium acetate as the calcium agent;

Scheme 10

Method for producing pitavastatin hemicalcium, characterized in that comprises a.
The method of claim 1,

The protection reaction is a solvent selected from the group consisting of tetrahydrofuran (THF), dimethyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), benzene, dichloromethane, acetonitrile, acetone or mixtures of two or more thereof. Method for producing pitavastatin hemicalcium, characterized in that carried out under the conditions using.
The method of claim 1,

The protection reaction is carried out under the conditions using an acid catalyst selected from the group consisting of sulfuric acid, hydrochloric acid, acetic acid, methanesulfonic acid, para-toluenesulfonic acid or a mixture of two or more thereof, phytavastatin hemicalcium Way.
The method of claim 1,

The oxidation reaction is KBK, LiBr and TEMPO mixed catalyst as a catalyst in a dichloromethane solvent, and the oxidizing agent is carried out under the conditions using MnO 2 , NaOCl, H 2 O 2 , CH 3 O 3 H, m-CPBA The manufacturing method of pitavastatin hemicalcium which is used.
The method of claim 1,

The coupling reaction is tetrahydrofuran (THF), dimethyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), benzene, toluene, xylene, dichloromethane, acetonitrile, acetone or a mixture of two or more thereof. Method for producing pitavastatin hemicalcium, characterized in that carried out under conditions using a solvent selected from the group consisting of a base selected from the group consisting of NaHCO 3 , NaH, K 2 CO 3 .
The method of claim 1,

The deprotection reaction is a solvent selected from the group consisting of methanol, acetone, acetonitrile, DMSO, DMF, THF or a mixture of two or more thereof as a solvent and sulfuric acid, hydrochloric acid, acetic acid, methanesulfonic acid, para-toluene as a deprotection agent. A process for producing pitavastatin hemicalcium, characterized in that it is carried out under conditions using a dilute acid selected from the group consisting of sulfonic acid or a mixture of two or more thereof.
The method of claim 1,

After the hydrolysis reaction, the method of producing pitavastatin hemicalcium, characterized in that the pitavastatin hemicalcium is carried out in a continuous reaction.
The method of claim 1,

Method for producing pitavastatin hemicalcium, characterized in that carried out in a continuous reaction using calcium chloride or calcium acetate as the calcium agent.
Tert-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2-alkoxy-1,3-dioxan-4-yl) acetate represented by the following formula (9):

[Formula 9]

R in Formula 9 is H, C 1 ~ C 6 Alkyl, C 6 ~ C 12 phenyl group, a substituted or unsubstituted aryl group.
Tert-butyl2-((4R, 6S) -5-formyl-2-alkoxy-1,3-dioxan-4-yl) acetate represented by the following formula (10):

[Formula 10]

R in Formula 10 is H, C 1 ~ C 6 Alkyl, C 6 ~ C 12 phenyl group, a substituted or unsubstituted aryl group.
Tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) ) -2-alkoxy-1,3-dioxan-4-yl) acetate:

[Formula 14]

In Formula 14, R is H, C 1 ~ C 6 alkyl, C 6 ~ C 12 phenyl group, substituted or unsubstituted aryl group.
X-ray powder diffraction pattern shown in Table 2 below, expressed in terms of relative intensity having a relative intensity of> 20% measured on a diffracter (Bruker D8 advance) by 2K, d-spacing and 2 min grinding. Having pitavastatin hemicalcium and its hydrates:

TABLE 2 2θ d-value Relative strength after grinding for 2 minutes (> 20%) 3.854 22.90762 100 5.412 16.31713 69.7 7.741 11.31156 49.9 11.297 7.82632 46.7 15.457 5.72801 35.2 17.807 4.97705 46.2 19.323 4.58979 54.5