KR20120125190A - Process for the preparation of t-butyl 2-4R,6S-6-formyl-2,2-dimethyl-1,3-dioxane-4-ylacetate - Google Patents

Abstract

PURPOSE: A manufacturing method of t-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl)acetate is provided to easily manufacturing a large amount of t-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl)acetate of solid phase with high and constant purity by using polymer-supported TEMPO. CONSTITUTION: A manufacturing method of t-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl)acetate indicated in chemical formula 1 comprises a step of oxidizing t-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate indicated in chemical formula 2 by using a polymer-supported TEMPO indicated in chemical formula 3. In chemical formulas, P is an organic/inorganic polymer support, m is 0 or 1. The polymer is polystyrene, polyacrylate, polymethacrylate, polyacrylamide, polyvinylether, polyether, polynorbonene, polyethylene glycol or silica.

Description

Process for the preparation of t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate 4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxane-4-yl) acetate}

The present invention relates to a process for the preparation of t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate. More specifically, the present invention provides t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxane- having optical activity, which is a key intermediate of various HMG-CoA reduction inhibitors. 4-yl) acetate can be commercially mass-produced in solids of high purity and constant purity.

Generally, drugs that exhibit cholesterol-lowering effects through a mechanism of action that inhibits the activity of HMG-CoA reductant (3-hydroxy-3-methyl-glutaryl coenzyme A reductase) are called "statins", the first of which is developed. First generation statins include simvastatin, lovastatin, pravastatin, which are microbial fermentation products, and atorvastatin, fluvastatin, Rosuvastatin, pitavastatin, and the like.

T-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate having optical activity is a chiral intermediate having the structure It is a very useful key intermediate in the manufacture of HMG-CoA reduction inhibitors rosuvastatin, fluvastatin, pitavastatin and the like.

[Formula 1]

The compound of Formula 1 is conventionally obtained from t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate Known as Swern oxidation or TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl) oxyl, (2,2,6,6-tetramethylpiperidin-1-yl) It has been reported that it can be synthesized by oxidation using oxyl).

[Formula 2]

For example, according to US Pat. No. 4,970,313, t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxane-4- in Formula 2 1) The compound of Formula 1 is prepared by reacting acetate, oxalyl chloride and dimethyl sulfoxide (DMSO) in a methylene chloride solvent.

However, the above production method is difficult to deal with by using toxic and expensive oxalyl chloride. In addition, there is a disadvantage that it is not easy to apply in economic and industrial aspects because the cryogenic reaction of -78 ^o C has to proceed, and it is not easy to control the temperature by exotherm during the reaction, which is 75 ~ 90% (GC analysis value). There is a problem that the compound of formula 1, which is low in purity and inconsistent, is obtained as a liquid. In addition, there is a problem of low purity when storing the product.

Meanwhile, according to US Patent No. 7,161,004, t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) of Chemical Formula 2 There is disclosed a method for preparing the compound of Formula 1 using TEMPO, NaOCl and KBr from acetate, but this production method also has a problem that the product is further oxidized to carboxylic acid because the temperature control is not easy due to rapid exotherm However, there is still an economic burden for commercial application. In addition, since the product is obtained in a liquid state as shown in the picture of Figure 1, it is difficult to purify the commercial mass production, it is difficult to produce a compound having a certain purity, there is a problem that is not stable to heat and poor storage. .

In addition, when preparing pitavastatin and the like using the compound of Chemical Formula 1 prepared by a known method, as described in US Pat. No. 7,312,329, the substance produced after reacting the compound of Chemical Formula 1 There is a problem that requires a very complicated and long purification process. This is considered to be because the compound of formula 1 is obtained in a liquid state by a known method, which is unstable, resulting in lower chemical purity during storage or reaction, resulting in more impurities.

Therefore, there is an urgent need for the development of a method for preparing the compound of Formula 1, which is a key intermediate in the preparation of statin-based drugs among HMG-CoA reduction inhibitors, in a high purity and a constant purity solid state.

The present inventors have studied diligently to overcome the technical problems caused by commercial mass production of the compounds of Formula 1, which are the key intermediates of various HMG-CoA reduction inhibitors, and as a result, the compounds of Formula 1 using polymer-supported TEMPO It has been found that the present invention can be prepared in a solid state of high purity and constant purity, and completed the present invention.

Accordingly, an object of the present invention is to provide a method for preparing the compound of Formula 1 in a solid state of high purity and constant purity.

Another object of the present invention is to provide a method of economically and effectively preparing the compound of Formula 1.

Still another object of the present invention is to provide a method for preparing the pitavastatin intermediate of Formula 15 in high purity and high yield using the compound of Formula 1 in the solid state.

It is yet another object of the present invention to provide a method for preparing high purity pitavastatin on a commercial scale.

The present invention provides t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of Formula 2 T-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl of formula 1 comprising the step of oxidizing with a polymer supported TEMPO The present invention relates to a method for producing acetate.

[Formula 1]

[Formula 2]

(3)

Where

P is an organic-inorganic polymer support,

m is 0 or 1;

In one specific embodiment of the invention, the invention is

(i) t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of formula (2) is dissolved in the reaction solvent. Then adding a base;

(ii) adding an auxiliary oxidant to the resulting mixed solution, and then slowly adding the oxidant; And

(iii) t-butyl 2-((4R, 6S) -6- of formula 1 comprising adding and dropping a solution obtained by dissolving a polymer-supported TEMPO of formula 3 in a reaction solvent to the resulting mixed solution; It relates to a method for preparing formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate.

[Formula 1]

[Formula 2]

(3)

Where

P is an organic-inorganic polymer support,

m is 0 or 1;

Hereinafter, a method for preparing the compound of Formula 1 according to the present invention will be described in more detail.

The compound of Formula 2 may be prepared by a known method or may be purchased commercially.

The polymer-supported TEMPO of Formula 3 is a compound in which at least one TEMPO moiety is bonded to the organic-inorganic polymer support, wherein the polymer is polystyrene, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl ether, Organic polymers such as polyether, polynorbornene and polyethylene glycol and inorganic polymers such as silica.

Specifically, the polymer-supported TEMPO of Chemical Formula 3 may be a compound of Formula 4 (PIPO-TEMPO), a compound of Formula 5 (PHDM-TEMPO), a compound of Formula 6 (silica-TEMPO), of Formulas 7-13 Compounds and the like can be used, but are not limited thereto.

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Chemical Formula 9]

[Formula 10]

[Formula 11]

[Chemical Formula 12]

[Chemical Formula 13]

Where

R ₁ is a C ₁ -C ₁₂ alkyl group, more preferably 1,1,3,3-tetramethylbutyl,

n is an integer of 3 to 200.

As used herein, an alkyl group of C ₁ -C ₁₂ refers to a straight or branched hydrocarbon having 1 to 12 carbon atoms, and includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, and the like. It is not limited.

The polymer-supported TEMPO can be prepared by a known method or commercially available.

The amount of the polymer-supported TEMPO is preferably in the range of 0.001 to 0.04 equivalents relative to the compound of formula (2).

In the oxidation reaction, sodium hypochlorite (NaOCl), oxone (oxone), Dess-Martin reagent, etc. may be used as the oxidizing agent, and sodium hypochlorite (NaOCl) is most preferably used.

As the auxiliary oxidizing agent, an alkali metal halide, an alkaline earth metal halide, or the like may be used, and sodium bromide (NaBr) is most preferably used.

The base may be an carbonate, hydroxide, hydride, alkoxide or alkyl compound of an alkali metal, a carbonate, hydroxide, hydride, alkoxide or an alkyl compound of an alkaline earth metal, sodium hydrogen carbonate (NaHCO ₃ ) Most preferably. It is preferable to proceed with the reaction by adjusting the pH of the mixed solution to 8.5 to 9.5 using the base.

The reaction solvents include aliphatic or aromatic hydrocarbons such as hexane, benzene and toluene, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, dimethyl ether Ethers such as diisopropyl ether and tetrahydrofuran, alcohols such as methanol, ethanol, propanol, isopropanol and butanol, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and the like can be used, These can be used individually or in mixture. Most preferably toluene is used.

The reaction temperature is preferably in the range of -20 to 5 ^o C, more preferably in the range of -15 to -5 ^o C.

The compound of Chemical Formula 1 prepared according to the present invention can be recovered in a solid state simply and easily according to a conventional recovery method, which can be further purified by recrystallization. Most preferably, the recrystallization uses heptane.

According to the preparation method of the present invention, it is possible to prepare a compound of formula 1 which is a solid of high purity (above 97%, GC analysis value) within a short reaction time by controlling rapid exotherm using a polymer-supported TEMPO (FIG. 2). Reference).

On the other hand, the present invention

(a) t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of Formula 2 Oxidation reaction using polymer-supported TEMPO to obtain t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate Making; And

(b) combining t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate with the compound of formula It relates to a method for preparing the pitavastatin intermediate of the formula (15) comprising the step of.

[Formula 1]

[Formula 2]

(3)

[Formula 14]

[Formula 15]

Where

P is an organic-inorganic polymer support,

m is 0 or 1;

Hereinafter, a method for preparing the pitavastatin intermediate according to the present invention will be described in more detail.

Step (a) is the same as the preparation method of the compound of Formula 1 described above, so the description is omitted to avoid duplication.

The coupling reaction in step (b) is preferably carried out under basic conditions in a solvent. As the base, carbonates, hydroxides, hydrides, alkoxides or alkyl compounds of alkali metals, carbonates, hydroxides, hydrides, alkoxides or alkyl compounds of alkaline earth metals may be used, and potassium carbonate (K ₂ CO ₃ Is most preferred.

Dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, etc. can be used as said solvent, These can be used individually or in mixture. Most preferably dimethyl sulfoxide is used.

The reaction temperature is preferably in the range from 50 to 90 ^° C., more preferably in the range from 60 to 80 ^° C.

When the coupling reaction is performed using the compound of Chemical Formula 1 obtained in step (a), the pitavastatin intermediate of Chemical Formula 15 can be prepared in high purity and high yield without complex and long purification process.

On the other hand, the present invention

(a) t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of Formula 2 Oxidation reaction using polymer-supported TEMPO to obtain t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate Making;

(b) combining t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate with the compound of formula To obtain a pitavastatin intermediate of Formula 15; And

(c) removing the diol protecting group of the pitavastatin intermediate of Formula 15 and removing the t-butyl group.

[Formula 1]

[Formula 2]

(3)

[Formula 14]

[Formula 15]

[Chemical Formula 16]

Where

P is an organic-inorganic polymer support,

m is 0 or 1;

Hereinafter, a method of preparing pitavastatin according to the present invention will be described in more detail.

Steps (a) and (b) are the same as the method for preparing the compound of Formula 1 and the method for preparing the compound of Formula 15, and thus, description thereof is omitted.

In step (c), the diol protecting group may be removed by treatment with an acid according to a known method, followed by treatment with a base to remove the t-butyl group.

According to the production method of the present invention, it is possible to easily mass-produce the compound of Chemical Formula 1 using solid TEMPO of high purity and constant purity using a polymer-supported TEMPO. In addition, the prepared compound of Formula 1 has excellent stability and can be easily increased in purity by recrystallization, and used in the next reaction without further purification process to easily and easily obtain high purity of the pitavastatin intermediate of Formula 15. And high yields.

1 is a photograph of a compound of formula 1 prepared according to a known method.
2 is a photograph of a compound of formula 1 prepared according to the method of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it is obvious to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1 Preparation of a Compound of Formula 1 Using PIPO-TEMPO

Of Formula 2 t-Butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate (335 g, 1.3 mol) in toluene solvent (6.7 L ), Cooled to -15 ^o C and added sodium hydrogen carbonate (NaHCO ₃ , 487 g, 5.8 mol). Sodium bromide (NaBr, 131g, 1.3mol) was added at a time, paying attention to the exotherm, and sodium hypochlorite (NaOCl, 798ml, 1.42mol) was slowly added thereto while maintaining the temperature below -10 ^° C.

In the resulting mixed solution, a solution obtained by dissolving compound PIPO-TEMPO (R ₁ = 1,1,3,3-tetramethylbutyl) (0.001 equivalent, 0.838 g, 0.0013 mol) in Formula 4 in toluene solvent (300 ml) was prepared. -5 ^o C or less, and maintaining the mixture was stirred for 30 min and then slowly added dropwise, maintaining the below -5 ^o C. Upon completion of the reaction, Na ₂ S ₂ O ₃ (1.5L) was added thereto, stirred at room temperature for 20 minutes to terminate the reaction, and the layers were separated to recover an organic layer. The aqueous layer was further washed twice with toluene solvent (1 L), and the recovered organic layer was filtered by anhydrous treatment with Na ₂ SO ₄ . The obtained organic layer was concentrated under reduced pressure to give a solid product (233 g), and then recrystallized from heptane to give the title compound (157 g, yield: 49%, very pale yellow-white solid, GC purity: 98% or more).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.21 (s, 9H), 1.37 (s, 3H), 1.45 (s, 12H), 1.22-1.61 (m, 2H), 2.38 (dd, J ₁ = 24.7 , J ₂ = 7.1 Hz), 4.03-4.14 (m, 3H), 4.29 (m, 1H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 14.2, 21.7, 22.6, 24.5, 27.5, 33.3, 37.2, 60.5, 61.1, 61.8, 74.9, 93.3, 164.4, 172.4;

Mass [M + Na] ⁺ : 367

Melting Point: 56 ~ 60 ^o C.

Example 2 Using PHDM-TEMPO Preparation of Compound of Formula 1

Of Formula 2 t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate (10 g, 0.04 mol) in toluene solvent (200 ml) After dissolving in, it was cooled to -15 ^o C and sodium hydrogencarbonate (NaHCO ₃ , 14.5 g, 0.17 mol) was added. Sodium bromide (NaBr, 3.9g, 0.04mol) was added at a time, paying attention to the exotherm, and sodium hypochlorite (NaOCl, 24ml, 0.04mol) was slowly added while maintaining -10 ^° C or less.

To the resulting mixed solution, a solution obtained by dissolving the compound PHDM-TEMPO (0.001 equivalent, 0.023 g, 0.04 mmol) of the formula (5) in toluene solvent (10 ml) was slowly added dropwise while keeping it at -5 ^o C or less, and then -5 ^o Stir for 30 minutes while maintaining C or less. Upon completion of the reaction, Na ₂ S ₂ O ₃ (50ml) was added thereto, stirred at room temperature for 20 minutes to terminate the reaction, and the layers were separated to recover an organic layer. The aqueous layer was further washed twice with toluene solvent (30 ml), and the recovered organic layer was filtered by anhydrous treatment with Na ₂ SO ₄ . The obtained organic layer was concentrated under reduced pressure to give a solid product (7.5 g), and then recrystallized from heptane to give the title compound (5.0 g, yield: 50%, very pale yellow-white solid, GC purity: 98% or more).

Example 3 Preparation of Compound of Formula 1 Using Silica-TEMPO

Of Formula 2 t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate (2 g, 0.008 mol) in toluene solvent (80 ml) After dissolving in, it was cooled to -15 ^° C. and sodium hydrogencarbonate (NaHCO ₃ , 3.0 g, 0.035 mol) was added. Sodium bromide (NaBr, 0.78g, 0.008mol) was added at a time while paying attention to the exotherm, and sodium hypochlorite (NaOCl, 6.3ml, 0.012mol) was slowly added while maintaining -10 ^° C or less.

To the resulting mixed solution, a solution of the compound of Formula 6, silica - TEMPO (0.04 equivalents, 0.615 g, 0.3 mmol) dissolved in toluene solvent (40 ml) was slowly added dropwise with -5 ^o C or lower, and then -5 ^o Stir for 2.5 hours keeping C below. Upon completion of the reaction, Na ₂ S ₂ O ₃ (50ml) was added thereto, stirred at room temperature for 20 minutes to terminate the reaction, and the layers were separated to recover an organic layer. The aqueous layer was further washed twice with toluene solvent (10 ml), and the recovered organic layer was filtered by anhydrous treatment with Na ₂ SO ₄ . The organic layer obtained was concentrated under reduced pressure to give the title compound (1.5 g, yield: 83%, very pale yellow-white solid, GC purity: 97% or more).

Example 4 Preparation of Pitavastatin Intermediate of Formula 15

The compound of Formula 14 (30 g, 48.5 mmol) and the compound of Formula 1 obtained in Example 1 (15.04 g, 58.2 mmol) were dissolved in DMSO (90 ml) and stirred for 10 minutes at room temperature, followed by K ₂ CO ₃ (13.41 g, 97.02 mmol) was added and stirred at 70 ^° C. for 2 hours. After confirming the completion of the reaction, 2-propanol (270ml) was added thereto, H ₂ O (180ml) was added thereto, and the mixture was heated and dissolved at reflux at 80 ^° C. for 20 minutes. Then, the reaction solution was slowly cooled to form crystals, stirred for 30 minutes at room temperature, the precipitate was separated by filtration under reduced pressure, and dried under reduced pressure at about 60 ^° C. to give the title compound (19.66 g, yield: 78%, White crystals, HPLC purity: 99.8%).

Melting Point: 113.8 ~ 114.6 ^o C.

Example 5 Preparation of Pitavastatin

Pitavastatin intermediate (1 g, 1.93 mmol) obtained in Example 4 was added to acetonitrile (7 ml), and 1N HCl (1.9 ml) was slowly added over 30 minutes while maintaining 35 to 40 ^° C. Then, the mixture was stirred at 40 ^° C. for 3 hours. After confirming the completion of the reaction, the reaction mixture was cooled to room temperature (25 ^° C), 3N NaOH (1.9 ml) was added thereto, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, sodium chloride (1 g) was added and stirred at -5 ^o C for 1 hour, followed by additional sodium chloride (0.5 g) and 1N HCl (1.9 ml), adjusted to pH 3.4-4 and stirred for 10 minutes. . Then, acetonitrile (13 ml) was added thereto, separated from the water layer, and dried under reduced pressure. Distilled water (50ml) was added to the obtained compound, and CaCl ₂ -2H ₂ O (1.7g) dissolved in distilled water (10ml) was slowly added at room temperature, followed by stirring for 45 minutes to precipitate a solid compound. The precipitated solid compound was filtered and washed with water (60 ml) to yield 0.6 g (yield: 58%, white solid, purity: 99.0%) of pitavastatin calcium salt.

Claims (20)

T-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of formula (2) T-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate of Formula 1 comprising the step of oxidizing with TEMPO Manufacturing Method:
[Formula 1]

(2)

(3)

In this formula,
P is an organic-inorganic polymer support,
m is 0 or 1; (i) t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of formula (2) is dissolved in the reaction solvent. Then adding a base;
(ii) adding an auxiliary oxidant to the resulting mixed solution, and then slowly adding the oxidant; And
(iii) t-butyl 2-((4R, 6S) -6- of formula 1 comprising adding and dropping a solution obtained by dissolving a polymer-supported TEMPO of formula 3 in a reaction solvent to the resulting mixed solution; Formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate
[Formula 1]

(2)

(3)

In this formula,
P is an organic-inorganic polymer support,
m is 0 or 1; The method according to claim 1 or 2, wherein the polymer is polystyrene, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl ether, polyether, polynorbornene, polyethylene glycol or silica. . The method according to claim 1 or 2, wherein the polymer-supported TEMPO is a compound of formula 4 (PIPO-TEMPO), a compound of formula 5 (PHDM-TEMPO), a compound of formula 6 (silica-TEMPO) and the formula A method for producing a compound, characterized in that it is selected from the group consisting of 7 to 13 compounds:
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Formula 10]

(11)

[Chemical Formula 12]

[Chemical Formula 13]

In this formula,
R ₁ is an alkyl group of C ₁ -C ₁₂ ,
n is an integer of 3 to 200. The method according to claim 1 or 2, wherein the polymer-supported TEMPO is a compound of formula (4) (PIPO-TEMPO), a compound of formula (5) (PHDM-TEMPO) or a compound of formula (6) (silica-TEMPO) Manufacturing Method
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

In this formula,
R ₁ is 1,1,3,3-tetramethylbutyl,
n is an integer of 3 to 200. The process according to claim 1 or 2, wherein the polymer-supported TEMPO is used in the range of 0.001 to 0.04 equivalents relative to the compound of formula (2). The process according to claim 2, wherein the oxidizing agent is sodium hypochlorite (NaOCl). 3. A process according to claim 2 wherein the auxiliary oxidant is sodium bromide (NaBr). The process according to claim 2, wherein the base is sodium hydrogen carbonate (NaHCO ₃ ). The method according to claim 2, wherein the reaction is performed by adjusting the pH of the mixed solution to 8.5 to 9.5 using a base. The production process according to claim 2, wherein the reaction solvent is toluene. The process according to claim 2, wherein the reaction temperature is in the range of -15 to -5 ^° C. 3. The t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate of claim 1 is in a solid state. Production method characterized in that. The process of claim 13, wherein the t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate of formula 1 is purified by recrystallization. Manufacturing method characterized in that it further comprises. 15. The process of claim 14, wherein the recrystallization is performed using heptane. (a) t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of Formula 2 Oxidation reaction using polymer-supported TEMPO to obtain t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate Making; And
(b) combining t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate with the compound of formula Method of preparing a pitavastatin intermediate of Formula 15 comprising the step of:
[Formula 1]

(2)

(3)

[Chemical Formula 14]

[Chemical Formula 15]

In this formula,
P is an organic-inorganic polymer support,
m is 0 or 1; The process according to claim 16, wherein the coupling reaction in step (b) is carried out under basic conditions in a solvent. 18. The process according to claim 17, wherein the base is potassium carbonate (K ₂ CO ₃ ). 18. The process according to claim 17, wherein the solvent is dimethyl sulfoxide. (a) t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate of Formula 2 Oxidation reaction using polymer-supported TEMPO to obtain t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate Making;
(b) combining t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate with the compound of formula To obtain a pitavastatin intermediate of Formula 15; And
(c) a process for preparing pitavastatin of formula 16 comprising removing the diol protecting group of the pitavastatin intermediate of formula 15 and removing the t-butyl group:
[Formula 1]

(2)

(3)

[Chemical Formula 14]

[Chemical Formula 15]

[Chemical Formula 16]

In this formula,
P is an organic-inorganic polymer support,
m is 0 or 1;

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