KR20090104253A - Method for preparing atorvastatin, intermediate compounds used in the method and their preparation methods - Google Patents

Abstract

PURPOSE: A method for manufacturing an atorvastatin and an intermediate compound used for the same are provided to synthesize the intermediate compound with improved reaction, efficiency, safety, and economic efficiency. CONSTITUTION: A method for manufacturing a compound of the chemical formula 1 or pharmaceutically acceptable salt comprises: a step of reacting a compound of the chemical formula 7 with a compound of the chemical formula 8 to produce a compound of the chemical formula 9, and a step of deprotecting and hydrolyzing the compound of the chemical formula 9.

Description

Method for preparing atorvastatin, intermediate compounds used in the method and their preparation methods

The present invention relates to a process for the preparation of atorvastatin or a pharmaceutically acceptable salt thereof and to novel intermediate compounds used therein and to methods for their preparation.

Drugs that exhibit cholesterol-lowering effects through a mechanism that inhibits the activity of HMG-CoA reducing agent (3-hydroxy-3-methyl-glutaryl coenzyme A reductase) are commonly called 'statins', the first of which is The first-generation compounds developed include the fermentation products simvastatin, lovastatin, pravastatin, and the like. The second-generation compounds, atorvastatin, fluvastatin, Rosuvastatin, pitavastatin, and the like. Since the atorvastatin compound has optical activity, the conventional main method for preparing the compound is a method using a chiral intermediate. Commercially, a manufacturing method of Warner Lambert (WO 98/04543) is known and a chiral intermediate of the formula is reacted with a 1,4-dione compound.

All HMG-CoA reducing agent inhibitors produced synthetically have, in common structural features, an aromatic base structure and the so-called statin side chain represented by the above formula. In particular, the chiral intermediate is the most important intermediate for preparing atorvastatin has been studied in various ways to prepare it (US Patent No. 5,594,153, US Patent No. 5,457,227, International Patent Publication 03/070733, International Patent Publication 03 / 004459, International Patent Publication 94/20492). However, known intermediate compounds of atorvastatin and methods for preparing atorvastatin using them are insufficient in terms of efficiency, stability and economy.

The inventors of the present invention have been researching to develop useful intermediates for preparing atorvastatin in an improved method compared to the prior art, and thus synthesized a novel intermediate compound that satisfies the reactivity, efficiency, safety and economy of the atorvastatin synthesis reaction. The manufacturing method was developed to complete the present invention.

That is, the present invention provides a novel intermediate compound of statin, in particular atorvastatin, and a method for preparing the same, and an object of the present invention is to provide an efficient synthetic method for preparing atorvastatin using the intermediate compound.

The present invention provides a process for preparing atorvastatin or a pharmaceutically acceptable salt thereof. Also provided are useful intermediate compounds for preparing atorvastatin and methods for their preparation.

The present invention is to react the compound of the formula (7) and the compound of the formula (8) to a first step of preparing a compound of the formula (9), and a deprotection reaction and hydrolysis reaction of the compound of the formula (9) prepared in the first step Provided is a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof, comprising a second step.

Wherein R ₁ is hydrogen, an alkyl branched or straight chain having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, phenyl, benzyl or α, α-dimethylbenzyl, and R ₂ and R ₃ are each independently hydrogen, Or oxygen, an alkyl branched or straight chain of 1 to 8 carbon atoms, phenyl or benzyl, or R ₂ and R ₃ together form-(CH ₂ ) _n -where n is 4 or 5.

In addition, the present invention is the first step of preparing a compound of formula 9 by reacting a compound of formula 5 and a compound of formula 6b, and a deprotection reaction and hydrolysis reaction of the compound of formula 9 prepared in the first step It provides a method of preparing a compound of formula (1) or a pharmaceutically acceptable salt thereof, comprising a second step.

[Formula 1]

[Formula 9]

Wherein R ₁ , R ₂ and R ₃ are as defined above.

The present invention also provides compounds of the following formulas (4), (5), (7) and (9).

[Formula 5]

[Formula 7]

[Formula 9]

Wherein R ₁ , R ₂ and R ₃ are as defined above.

In addition, the present invention by reacting the compound of formula 2 and the compound of formula 3 to the first step of preparing a compound of the formula (4), and reducing the compound of formula (4) prepared in the first step of the formula Provided are methods for preparing the compounds.

[Formula 5]

[Formula 4]

Wherein R ₁ , R ₂ and R ₃ are as defined above and R ₄ and R ₅ are each independently hydrogen, an alkyl branched or straight chain of 1 to 8 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, phenyl or benzyl .

In addition, the present invention provides a method for preparing a compound of formula 7 by reacting a compound of formula 5 with a compound of formula 6a.

[Formula 7]

[Formula 5]

Wherein R ₁ , R ₂ and R ₃ are as defined above.

Preferably, in Formulas 2, 3, 4, 5, 7 and 9, R ₁ is t-butyl, and R ₂ and R ₃ are both methyl.

In the above formulas (2), (4), (5), (7) and (9), R ₁ is a carboxy group protecting group and is particularly ester-forming. The carboxyl protecting group is for example methyl, ethyl, propyl, butyl, 9-fluorenylmethyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl , Pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl, 1,3-ditianyl-2-methyl, dicyclopropylmethyl, acetonyl, phen acyl, p-bromophenacyl, α-methyl Phenacyl, p-methoxyphenacyl, decyl, carbamidomethyl, p-azobenzenecarboxamidomethyl, N-phthalimidomethyl or 4-picolinyl, 2-iodo-, 2-bromo- or 2- Chloro-ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 2- (p-nitrophenylsulphenyl) ethyl, 2- (p-toluenesulfonyl ) Ethyl, 2- (2'-pyridyl) ethyl, 2- (p-methoxyphenyl) ethyl, 2- (diphenylphosphino) ethyl, 1-methyl-1-phenylethyl, 2- (4-acetyl 2-nitrophenyl) ethyl or 2-cyanoethyl, i Propyl, tert-butyl, 3-methyl-3-pentyl, 2,4-dimethyl-3-pentyl, 4-chlorobutyl, 5-chloropentyl, cyclopentyl, cyclohexyl, allyl, metalyl, 2-methylbuty- 3-en-2-yl, 3-methylbut-2-enyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamil or α-methylcinnamil, Prop-2-ynyl, phenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl, 2,6-di-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4 -Methoxyphenyl, p- (methylthio) phenyl, pentafluorophenyl, benzyl, α, α-dimethylbenzyl, triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) methyl, 9-an Trilmethyl, 2- (9,10-dioxo) anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2- (trifluoromethyl) -6-chromemonylmethyl, 2,4,6 -Trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl) benzyl, 4-sulfo Benzyl, 4-azidomethock Benzyl, 4- {N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) -3-methylbutyl] amino} benzyl, piperonyl or p-polymer-benzyl, tetra Hydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl, di-tert-butylmethylsilyl or phenyldimethylsilyl, alternatively the carboxyl group is oxazolyl , 2-alkyl-1,3-oxazolinyl, 4-alkyl-5-oxo-1,3-oxazolidinyl or 2,2-bisfluoromethyl-4-alkyl-5-oxo-1,3- It may also be protected in the form of an oxazolidinyl radical.

Preferably, in Formulas 2 to 5, 7 and 9, R ₁ is t-butyl, and R ₂ , R ₃ , R ₄ and R ₅ are all methyl.

The novel intermediate compounds according to the invention and methods for the preparation of atorvastatin or pharmaceutically acceptable salts thereof using the same, allow mass production of atorvastatin or pharmaceutically acceptable salts thereof safely and efficiently at low cost.

Specific schemes representing one embodiment of the process for preparing atorvastatin and pharmaceutically acceptable salts thereof according to the present invention are as follows.

Referring specifically to the above reaction scheme, which is an aspect of the present invention,

In order to prepare the compound of Formula 4, a commercially available compound of Formula 2 and a cheap compound of Formula 3 are subjected to a protection reaction under a reaction solvent and an acid catalyst. As the acid catalyst, at least one selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, para-toluenesulfonic acid, pyridine para-toluenesulfonic acid, and trifluoromethanesulfonic acid, Is 0.05 to 1 molar equivalent, preferably 0.1 to 0.5 molar equivalent of pyridine para-toluenesulfonic acid. Examples of the reaction solvent include aromatic solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran, dioxane, dialkyl ether, t-butyl alkyl ether and dialkoxy ether, methylene chloride, dichloromethane, chloroform and carbon tetrachloride. And at least one selected from the group consisting of halogen solvents such as tetrachlorethylene, chlorobenzene and dichlorobenzene, and methylene chloride is preferably used. In preparing the compound of Formula 4, the reaction temperature is 0 to 80 ° C, preferably 10 to 50 ° C, most preferably room temperature, and when the temperature is lower than 0 ° C, the reactivity is lowered. . The reaction time in the preparation of the compound of formula 4 is 1 to 7 hours, preferably 2 to 5 hours.

In addition, the compound of Formula 5 is prepared through a simple reduction of the compound of Formula 4. Reduction of the nitrile group of the compound of formula 4 can be achieved using reduction systems known in the art (International Patent Publication No. 89/07598, International Patent Publication No. 94/20492, International Patent Publication No. 02/057274). Ho, International Patent Publication No. 05/012246 Ho, Org. Process. Res. Dev ., 1997, 1, 320-324, Tetrahedron Lett ., 1992, 33, 2283-2284). Preferably, it is reduction with hydrogen such as Raney nickel, palladium or rhodium, hydrogenation reagent such as LiAlH ₄ , reduction with tetrahydrofuran-borane. Most preferably, Raney nickel is used.

In addition, the compound of Formula 9 is prepared by the cyclic condensation reaction of the compound of Formula 5 and the compound of Formula 6a by adding an acid under a selected organic solvent using Paal-Knorr synthesis method to prepare a compound of Formula 7, the selected reaction solvent and acid It may be prepared by reacting the compound of Formula 7 and the compound of Formula 8 in the presence of (Path A). Compounds of formula 6a are described in the American Journal of J. Med . Chem ., 1991, 34, 357-366 and US Pat. No. 5,003,081.

The organic solvent may be a hydrocarbon solvent such as hexane, cyclohexane, heptane; Aromatic solvents such as toluene, benzene, xylene; Ethers such as tetrahydrofuran, diethyl ether, dioxane, diisopropyl ether; Alcoholic solvents such as methanol, ethanol, propanol, butanol; At least one selected from the group consisting of polar solvents such as dimethylformamide and N, N-dimethylacetamide is preferably used, preferably an aromatic solvent, most preferably toluene.

The acid added in the preparation of the compound of formula 7 is pivalic acid, trifluoromethylsulfonic acid, methanesulfonic acid, para-toluenesulfonic acid or acetic acid, preferably pivalic acid. Pivalic acid is used in 0.2-1 molar equivalents, preferably in 0.5-0.8 molar equivalents. In order to remove water during the cyclocondensation reaction, it may be performed using a water remover or a water remover. Molecular sieve, anhydrous magnesium sulfate or anhydrous sodium sulfate may be used as the moisture removing agent, and Dean-Stark trap may be used as the moisture removing apparatus. In the present invention, to remove moisture, a Dean-Stark trap ( Dean-Stark traps are preferred.

The reaction temperature in the cyclocondensation reaction is 50 ~ 110 ℃, preferably reflux temperature for the solvent, more preferably 80 ~ 100 ℃. If the reaction temperature is lower than 50 ° C. or higher than 110 ° C., the reaction does not proceed or side reactions are produced, resulting in a marked decrease in yield. The reaction time is about 1 to 48 hours, preferably 5 to 30 hours, more preferably 12 to 20 hours. In this case, the compound of Formula 6a may use 1 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents.

The compound of formula 8 may use 1 to 10 molar equivalents, preferably 1 to 8 molar equivalents, most preferably 2 to 6 molar equivalents. Reaction solvents selected when preparing the compound of formula 9 from the compound of formula 7 and compound 8 are halogen solvents such as methylene chloride, chloroform, carbon tetrachloride; Aromatic solvents such as toluene, benzene, nitrobenzene, xylene; At least one is selected from the group consisting of ether solvents such as tetrahydrofuran, diethyl ether, dioxane, diisopropyl ether, preferably a halogen solvent or an aromatic solvent, most preferably methylene chloride.

As the acid selected in the preparation of the compound of formula 9 from the compound of formula 7 and compound of formula 8, Lewis acid is used. Preferably, aluminum chloride, zinc chloride, trifluoro borane, tribromo borane , Titanium tetrachloride, iron chloride or tin tetrachloride, most preferably aluminum chloride. The aluminum chloride used at this time is used in 1 to 10 molar equivalents, preferably 1 to 8 molar equivalents, most preferably 2 to 6 molar equivalents. The reaction temperature is -78 deg. C to room temperature, preferably -78 to 0 deg. C, most preferably -78 to -40 deg. The reaction time is 10 minutes to 12 hours, preferably 10 minutes to 5 hours.

In addition, the compound of Formula 9 may be prepared by the cyclocondensation reaction of the compound of Formula 5 and the compound of Formula 6b by adding an acid under a selected organic solvent (Path B). The organic solvent may be a hydrocarbon solvent such as hexane, cyclohexane, heptane; Aromatic solvents such as toluene, benzene, xylene; Ethers such as tetrahydrofuran, diethyl ether, dioxane, diisopropyl ether; Alcoholic solvents such as methanol, ethanol, propanol, butanol; At least one selected from the group consisting of polar solvents such as dimethylformamide and N, N-dimethylacetamide is preferably used, preferably an aromatic solvent, most preferably toluene. The acid added is pivalic acid, trifluoromethylsulfonic acid, methanesulfonic acid, para-toluenesulfonic acid or acetic acid, preferably pivalic acid. Pivalic acid is used in 0.2-1 molar equivalents, preferably in 0.5-0.8 molar equivalents. In order to remove water during the cyclocondensation reaction, it may be performed using a water remover or a water remover. Molecular sieve, anhydrous magnesium sulfate or anhydrous sodium sulfate may be used as the water removing agent, and Dean-Stark trap may be used as the water removing device, and in order to remove water in the present invention, Dean stark trap (Dean) It is preferable to use Stark trap. The reaction temperature during the cyclocondensation reaction is 50 ~ 110 ℃, preferably reflux temperature for the solvent, more preferably 80 ~ 100 ℃. If the reaction temperature is lower than 50 ° C. or higher than 110 ° C., the reaction does not proceed or side reactions are produced, resulting in a marked decrease in yield. The reaction time is about 1 to 72 hours, preferably 24 to 56 hours, more preferably 36 to 48 hours. In this case, the compound of Chemical Formula 6b may use 1 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents.

As described above, the compound of formula 6a provides a compound of formula 7 through a condensation reaction with the compound of formula 5, and the obtained compound of formula 7 is reacted with the compound of formula 8 in the presence of a selected reaction solvent and acid The step of preparing the compound of 9 is further carried out. Because the compound of formula 6b having a substituent at the carbon position 3 of 1- (4-fluorophenyl) -5-methyl-2-phenylhexane-1,4-dione as the compound of formula 6a, This leads to long reaction times and vigorous conditions, resulting in increased by-products and lower yields. In the case of the present invention was compared the reactivity according to the presence or absence of the action, using the compound of formula 6a having less steric hindrance can be carried out a ring condensation reaction while overcoming various problems such as reaction time, by-products and reaction yield.

The compound of formula 9 prepared by the above method is a white solid compound with good stability and can be obtained in high purity by crystallization with an organic solvent (99% HPLC purity). Organic solvents used for crystallization include hydrocarbon solvents such as water, hexane, cyclohexane, heptane; Aromatic solvents such as toluene, benzene, xylene; Ethers such as tetrahydrofuran, diethyl ether, dioxane, diisopropyl ether; At least one is selected from the group consisting of alcoholic solvents such as methanol, ethanol, propanol, butanol, preferably ether or alcoholic solvents, most preferably hexane, heptane, diisopropyl ether, methanol, ethanol or these Is a mixed solvent.

Deprotection and hydrolysis reaction of a compound of formula 9 to prepare a compound of formula 1, and to prepare pharmaceutically acceptable salts thereof, methods known in the art are used (International Patent Publication No. 89/07598). International Patent Publication No. 04/106299).

Pharmaceutically acceptable salts include organic and inorganic salts, preferably organic salts such as morpholine, piperazine, trimethylamine, triethylamine, dimethylamine, diethylamine, dipropylamine, diisopropyl Amines, dibenzylamine, dicyclohexylamine, lysine, ornithine, threonine, arginine, metformin, N-benzyl-2-phenylethanamine, 2-amino-2-methyl-1-propanol, 1-phenylethanamine, 1,2-ethanediamine, ammonia, 2-methyl-2-propanamine, phenethylamine or 2- (3,4-dimethoxyphenyl) ethanamine can be used, and the inorganic salts include lithium, sodium Alkali metals such as potassium, cesium, alkaline earth metals such as magnesium, calcium, aluminum, bismuth or iron may be used, but are not limited thereto.

The deprotection reaction of the compound of formula 9 can be prepared by adding an acid to prepare the compound of formula 10, wherein the acid used in the reaction is hydrochloric acid, sulfuric acid, bromic acid, fluoric acid, formic acid, oxalic acid, lactic acid, citric acid, sulfurous acid, phosphoric acid, At least one selected from the group consisting of acetic acid and tartaric acid, most preferably hydrochloric acid may be used. At this time, hydrochloric acid may be used in 1 to 10 molar equivalents, preferably 2 to 7 molar equivalents, most preferably 3 to 5 molar equivalents. Reaction temperature is 0-80 degreeC, Preferably it is 20-50 degreeC, Most preferably, it is room temperature. The reaction time is about 1 to 8 hours, preferably about 3 to 6 hours.

As a solvent used for reaction, For example, Alcoholic solvents, such as methanol, ethanol, a propanol, or butanol; At least one is selected from the group consisting of ether solvents such as tetrahydrofuran, diethyl ether, dioxane, diisopropyl ether and water, preferably a mixture of ether solvent, alcoholic solvent and water is used, more preferably Tetrahydrofuran, a mixture of methanol and water is used.

In addition, the compound of Formula 10 provides a compound of Formula 11 through hydrolysis reaction under basic conditions. Hydrolysis reactions are easily carried out using alcoholic solvents, ether solvents or water as a general reaction. The solvent used for the reaction is an alcoholic solvent, ether solvent or water, preferably a mixture of ether solvent and water, more preferably tetrahydrofuran and water. The base used is at least one selected from the group consisting of lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and potassium hydroxide, most preferably sodium hydroxide can be used. Reaction temperature is 0-80 degreeC, Preferably it is 20-50 degreeC, Most preferably, it is room temperature. The reaction time is about 1 to 8 hours, preferably about 2 to 5 hours.

The compound of Formula 11 may proceed to the calcium salt formation reaction without a separate purification process. After hydrolysis using sodium hydroxide as described above, a compound in the form of sodium salt is obtained, and then selected from the group consisting of calcium carbonate, calcium hydroxide, calcium acetate, calcium sulfate and calcium chloride, to obtain atorvastatin hemicalcium salt on the selected solvent. have. The preferred equivalent of calcium acetate for the calcium salt formation is 0.5 mole.

The solvent used in the reaction may be, for example, an alcoholic solvent such as methanol, ethanol, propanol or butanol; At least one is selected from the group consisting of ether solvents such as tetrahydrofuran, diethyl ether, dioxane, diisopropyl ether and water, preferably a mixture of alcoholic solvent and water is used, more preferably methanol and water Mixtures are used.

 Reaction temperature is 10-80 degreeC, Preferably it is 10-60 degreeC, Reaction time is about 1 to 6 hours, Preferably it is about 1 to 3 hours.

Although the present invention will be described in more detail based on the following examples, the present invention is not limited by the following examples.

Example 1.Preparation of 2-((4R, 6R) -6- (cyanomethyl) -2- (dimethylamino) -1,3-dioxan-4-yl) acetic acid tert-butyl ester

Dissolve (3R, 5R) -tert-butyl 6-cyano-3,5-dihydroxyhexanoate (46 g) and pyridine para-toluene sulfonate (10 g) in methylene chloride (250 mL), Dimethylformamide dimethylacetal (47.7 g) is slowly added dropwise at room temperature for 10 minutes. The reaction mixture is stirred for 3 hours at room temperature (determination of reaction termination using TLC or mass spectrometry). After completion of the reaction, methylene chloride (250 mL) was added to dilute and washed three times with water (250 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 51 g of the target compound as a yellow oil using column chromatography.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32 (m, 2H), 1.48 (s, 9H), 1.53 (m, 6H), 1.74 (m, 2H), 2.28 (s, 6H), 2.31-2.52 (m, 2H), 3.56-3.63 (m, 2H), 3.93-4.03 (m, 2H), 4.10-4.21 (m, 1H); MS (ESI) m / z 285.2 (M + l).

Example 2. Preparation of 2-((4R, 6R) -6- (2-aminoethyl) -2- (dimethylamino) -1,3-dioxan-4-yl) acetic acid tert-butyl ester

2-((4R, 6R) -6- (cyanomethyl) -2- (dimethylamino) -1,3-dioxan-4-yl) in a 500 mL capacity hydrogen reactor (Parr pressure vessel, autoclave) Acetic acid tert-butyl ester (50 g), Raney nickel (15 g), isopropyl alcohol (200 mL) and 28% aqueous ammonia (100 mL) are added in this order. Charge the reactor with hydrogen (50 psi) and stir at room temperature for 15 hours. After completion of the reaction, the mixture was filtered using a celite pad, and the filtrate was concentrated under reduced pressure. The resulting crude product is diluted by addition of ethyl acetate (250 mL) and washed twice with water (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 49 g (96.6%) of the title compound as a yellow oil, which was used in the next step without purification.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (m, 2H), 1.43 (s, 9H), 1.53 (m, 6H), 1.74 (m, 2H), 2.28 (s, 6H), 2.31-2.52 (m, 2H), 3.56-3.63 (m, 2H), 3.93-4.03 (m, 2H), 4.10-4.21 (m, 1H); MS (ESI) m / z 289.2 (M + l).

Example 3. 2-((4R, 6R) -2- (dimethylamino) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl Carbamoyl) -1H-pyrrole-1-yl) ethyl) -1,3-dioxan-4-yl) acetic acid tert-butyl ester

The nitrogen-filled flask was charged with 18 g of 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -4-methyl-3-oxo-N-phenylpentanamide, 400 mL of toluene, triethyl 4.8 mL of amine, 20 g of 2-((4R, 6R) -6- (2-aminoethyl) -2- (dimethylamino) -1,3-dioxan-4-yl) acetic acid tert-butyl ester and pivalic acid 3.5 g was added. The mixture is heated and stirred at reflux for 42 hours to remove water with a Dean-Stark trap. Cool slowly to 20-25 ° C. and wash the organic layer with water (300 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 19.6 g of the target compound as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (m, 2H), 1.41 (s, 9H), 1.52 (m, 6H), 1.72 (m, 2H), 2.29 (s, 6H), 2.26-2.50 (m, 2H), 3.52-3.62 (m, 2H), 3.87-3.97 (m, 2H), 4.09-4.15 (m, 1H), 4.69 (s, 1H), 6.90-7.18 (m, 14H); MS (ESI) m / z 670.0 (M + l).

Example 4. 2-((4R, 6R) -2- (dimethylamino) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl Carbamoyl) -1H-pyrrole-1-yl) ethyl) -1,3-dioxan-4-yl) acetic acid tert-butyl ester

1) The nitrogen-filled flask was 45 g of 1- (4-fluorophenyl) -5-methyl-2-phenyl-1,4-hexanedione, 1.0 L of toluene, 14 mL of triethylamine, 2-((4R, 62 g of 6R) -6- (2-aminoethyl) -2- (dimethylamino) -1,3-dioxan-4-yl) acetic acid tert-butyl ester and 10.2 g of pivalic acid were added. The mixture is heated and stirred at reflux for 14 hours to remove water with a Dean-Stark trap. Cool slowly to 20-25 ° C. and wash with water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 74.2 g of the target compound as a pale yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (m, 2H), 1.43 (s, 9H), 1.53 (m, 6H), 1.74 (m, 2H), 2.28 (s, 6H), 2.31-2.52 (m, 2H), 3.56-3.63 (m, 2H), 3.93-4.03 (m, 2H), 4.10-4.21 (m, 1H), 4.64 (s, 1H), 6.25 (s, 1H), 7.03-7.16 (m, 9H); MS (ESI) m / z 551.3 (M + l).

2) Add 72 g of aluminum chloride and 600 mL of methylene chloride to the reaction part under nitrogen, and stir. 58 mL of phenyl isocyanate is slowly added dropwise to the mixed carbon solution over 40 minutes. The temperature was lowered from -50 to -60 ° C and 2-((4R, 6R) -2- (dimethylamino) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-3- 74 g of phenyl-1H-pyrrole-1-yl) ethyl) -1,3-dioxan-4-yl) acetic acid tert-butyl ester is dissolved in 600 mL of methylene chloride, slowly added dropwise over 30 minutes, followed by stirring for 1 hour. . After completion of the reaction, purified water was added and stirred for 30 minutes, and then slowly raised to room temperature, followed by stirring for 30 minutes. The organic layer was separated and washed three times with water and once with saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The oil obtained was crystallized with isopropyl ether and heptane to obtain 68.2 g of a solid compound.

Example 5. (3R, 5R) -7- (2- (4-Fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl)- Preparation of 3,5-dihydroxyheptanoic acid tert-butyl ester

2-((4R, 6R) -2- (dimethylamino) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbox) Bamoyl) -1H-pyrrole-1-yl) ethyl) -1,3-dioxan-4-yl) acetic acid 68 g of tert-butyl ester was added thereto, and 1 liter of tetrahydrofuran and 1 liter of methanol were added to dissolve it. 200 mL of 1 M aqueous hydrochloric acid is slowly added dropwise at room temperature for 20 minutes. After the reaction was stirred at room temperature for 5 hours, the organic solvent was concentrated under reduced pressure. 2 L of ethyl acetate is added to the obtained crude product and washed twice with 1 L of saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to crystallize the product from isopropyl ether and heptane to give 62 g of a solid compound.

Example 6. (3R, 5R) -7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl) -3 Of 5,5-dihydroxy heptanoic acid sodium salt

(3R, 5R) -7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl) -3 in the reaction section After dissolving 62 g of 5,5-dihydroxyheptanoic acid tert-butyl ester in 500 mL of tetrahydrofuran, 500 mL of purified water and 16 g of sodium hydroxide are added. After stirring the reaction at room temperature for 3 hours, 1 L of ethyl acetate is added for extraction. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to slurry the crude product with heptane to give 55 g of a white solid compound.

Example 7. (3R, 5R) -7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl) -3 Of 5,5-dihydroxy heptanoic acid hemicalcium salt

To 55 g of atorvastatin sodium salt obtained in Example 6 was added 300 mL of methanol and 200 mL of purified water, and heated to 50 ° C., another reaction part was prepared, and 0.5 molar equivalent of calcium acetate was dissolved in 200 mL of water and slowly added dropwise thereto. After the addition was completed, the mixture was filtered after stirring for 2 hours while gradually cooling to 15 ° C. The obtained solid was washed with 1 L of purified water, slurried with 500 mL of diisopropyl ether for 6 hours, filtered, and the obtained solid was dried under vacuum at 50 ° C. to obtain 52 g of a white solid compound atorvastatin hemicalcium salt.

IR (KBr) 3406, 1651, 1600, 1565, 1510, 1441, 1412, 1316, 1222, 1154, 843, 752 cm ⁻¹ ; ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.23 (m, 1H), 1.36 (d, J = 6.5 Hz, 6H), 1.38-1.63 (m, 3H), 1.99 (m, 1H), 2.12 (m, 1H), 3.17-4.05 (m, 7H), 6.96-7.27 (m, 12H), 7.51 (d, J = 7.8 Hz, 2H), 9.85 (s, 1H); MS (ESI) m / z 559.2 (M + l).

Claims (10)

A first step of preparing a compound of Formula 9 by reacting a compound of Formula 7 with a compound of Formula 8; Comprising a second step of the deprotection reaction and hydrolysis reaction of the compound of formula 9 prepared in the first step, A process for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Formula 1

Formula 7

Formula 8

Formula 9

Wherein R ₁ is hydrogen, an alkyl branched or straight chain having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, phenyl, benzyl or α, α-dimethylbenzyl, and R ₂ and R ₃ are each independently hydrogen, Or oxygen, an alkyl branched or straight chain of 1 to 8 carbon atoms, phenyl or benzyl, or R ₂ and R ₃ together form-(CH ₂ ) _n -where n is 4 or 5. 2. The method of claim 1, wherein R _{1 in} formula 7 and formula 9 is t-butyl, and R ₂ and R ₃ are both methyl, or a pharmaceutically acceptable salt thereof. A first step of preparing a compound of Chemical Formula 9 by reacting a compound of Chemical Formula 5 with a compound of Chemical Formula 6b; Comprising a second step of the deprotection reaction and hydrolysis reaction of the compound of formula 9 prepared in the first step, A process for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Formula 1

Formula 5

Formula 6b

Formula 9

Wherein R ₁ , R ₂ and R ₃ are the same as defined in claim 1. 4. A process according to claim 3 wherein R _{1 in} formulas 5 and 9 is t-butyl and R ₂ and R ₃ are both methyl, or a process for preparing a pharmaceutically acceptable salt thereof. A compound of formula Formula 4

Wherein R ₁ , R ₂ and R ₃ are the same as defined in claim 1. A compound of formula Formula 5

Wherein R ₁ , R ₂ and R ₃ are the same as defined in claim 1. A compound of formula Formula 7

Wherein R ₁ , R ₂ and R ₃ are the same as defined in claim 1. A compound of formula Formula 9

Wherein R ₁ , R ₂ and R ₃ are the same as defined in claim 1. A first step of preparing a compound of Formula 4 by reacting a compound of Formula 2 with a compound of Formula 3, A method for preparing the compound of formula 5 by reducing the compound of formula 4 prepared in the first step. Formula 5

Formula 2

Formula 3

Formula 4

Wherein R ₁ , R ₂ and R ₃ are as defined in claim 1, and R ₄ and R ₅ are each independently hydrogen, an alkyl branched or straight chain having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, phenyl Or benzyl. Method for producing a compound of formula 7 characterized in that the reaction of the compound of formula 5 and the compound of formula 6a. Formula 7

Formula 5

Formula 6a

Wherein R ₁ , R ₂ and R ₃ are as defined in claim 1.