KR20080078127A - Atorvastatin intermediates and method for producing the same - Google Patents

Abstract

A method for preparing an intermediate of atorvastatin is provided to produce the atorvastatin intermediate with high purity and high efficiency. To prepare [6-(2-amino-ethyl)-2-R-[1,3,2]dioxaborinan-4-yl]-acetic acid t-butyl ester represented by a formula(1), a boronic acid derivative is reacted with 6-cyano-3,5-dihydroxy-hexanoic acid t-butyl ester. To prepare an atorvastatin intermediate represented by a formula(2), the compound of the formula(1) is used as an intermediate. In the formulae(1) and (2), R is alkyl having at least 3 carbon atoms, phenyl ethyl or substituted phenyl ethyl.

Description

Atorvastatin intermediates and method for producing the same

The present invention relates to a compound of the general formula (1) which can be used as an important intermediate for preparing atorvastatin, a compound of the general formula (3), and a novel method for producing the same, with high purity and high efficiency.

Where

R is a C3 or more alkyl group, phenylethyl or substituted phenylethyl group.

[R- (R ', R' ')]-2- (4-fluorophenyl) -3,5-dihydroxy-5- (1-methylethyl) -3-phenyl] -4- [ (Phenylamino) carbonyl] -1H-pyrrole-1-heptanoylacid hemipotassium (hereinafter referred to as atorvastatin) is a substance described in U.S. Pat. Known as a useful drug that works on cholesterol.

   In US Pat. No. 5,003,080, which is incorporated herein by reference, compound (4R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate of formula 4 is 4-fluorine. A process for preparing atorvastatin by reacting with -α- [2-methyl-1-oxopropyl] γ-oxo-N-β-diphenylbenzenebutanamide to produce lactone, followed by deprotection and hydrolysis. In US Pat. No. 5,216,174, hydroxyphenylamino-2-isopropylcarbonyl-3-phenyl-4- (4-fluorophenyl) -1,4-dioxobutane is used to prepare atorvastatin. The reaction of R-6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetic acid is described.

Where

R is a hydroxy or t-butyl group.

   Many experiments have been conducted to prepare atorvastatin with high purity and high efficiency, in particular, the compound of formula 4 (4R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4 Many studies have been conducted to efficiently prepare acetates. US Pat. No. 5,155,251 provides a process for preparing (3R) -4-cyano-3-hydroxy butyric acid from (S) -3-hydroxy butyrolactone. In addition, Korean Patent KR 10-0308524 describes a method of preparing (S) -3-hydroxybutyrolactone by reacting amylopectin with an enzyme and then performing an oxidation reaction, an esterification reaction, and a cyclization reaction. . Japanese Patent JP Hei 6-65,226 and JP Hei 4-69,355 describe a method for preparing 3,5,6-trihydroxy hexanoic acid ester derivatives from 4-chloroacetic acid ester and maleic acid, respectively. US 5,278,313 discloses the preparation of (4R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate from 4-chloro-3-hydroxy butyric acid. The method is described.

   The methods for preparing (4R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate described above use 1,3-diol to acetone and toluenesulphonic acid. Or to protect 2,2-dimethoxy-propane in the form of acetonide using toluenesulphonic acid under dimethylformamide conditions, and then to prepare atorvastatin of Formula 3 or an optically pure substance in the acetonide protecting group. It is difficult to obtain.

   US Pat. No. 6,867,306 describes a process for preparing the boronate compound of formula (5). The industrially available phenylboronic acid is refluxed with 1,3-diol under toluene conditions to produce an optically pure intermediate, but the manufacturing cost is high and is not suitable for industrial use.

Where

R is a methyl group or 3-nitro group.

   In addition, many methods are known for protecting 1,3-diol, and the benzylidene acetal form obtained by reacting benzaldehyde with zinc chloride or toluenesulphonic acid is not useful because it is not easily deprotected. The silyl protecting group of the formula (6) can be easily obtained under the conditions of acetonitrile, triethylamine and hydroxybenzotriazole under di-t-butylsilyl-dichloride but is industrially applied due to the disadvantage of being easily hydrolyzed. There is a difficulty.

Where

R is a di-t-butyl group.

Boronic acid derivatives used as protecting groups include J. Chem. Soc., Perkin Trans. I 1863 (1981) is phenyl, tolyl, nitrophenyl boronic acid, etc., as mentioned for the preparation of phenylboronate, and the efficacy of other derivatives as protecting groups has not been studied.

The present invention aims to provide an important intermediate for preparing atorvastatin. It is also an object of the present invention to provide a method for preparing an important intermediate for preparing atorvastatin.

The compound according to the present invention is a compound having the structure of Formula 1 below [6- (2-amino-ethyl) -2-R- [1,3,2] dioxaborinane-4-yl] -acetic acid t-butyl ester.

The preparation method according to the present invention is a compound of formula 1 [6- (2-amino-ethyl) -2-R- [1,3,2] dioxaborinane-4-yl] -acetic acid t- A method for producing a butyl ester is characterized by reacting a boronic acid derivative with 6-cyano-3,5-dihydroxy-hexanoic acid t-butyl ester.

(Formula 1)

Where

R is at least 3 carbon atoms, preferably 3 to 12 alkyl groups, phenylethyl or substituted phenylethyl groups.

In addition, another compound according to the present invention is characterized in that the boronate compound having a structure of formula (2).

The preparation method according to the present invention is a method for preparing the atorvastatin intermediate of the following formula (2), characterized in that to prepare a boronate compound of the formula (1) as an intermediate.

(Formula 2)

Where

R is at least 3 carbon atoms, preferably 3 to 12 alkyl groups, phenylethyl or substituted phenylethyl groups.

(Formula 1)

Where

R is at least 3 carbon atoms, preferably 3 to 12 alkyl groups, phenylethyl or substituted phenylethyl groups.

In the following, various boronic acids are prepared to look at the efficacy of boronate as a selective protecting group for 1,3-diol.

We have found J. Org. Chem. 45, 384 to 389 (1980), Bioorganic & Medicinal Chemistry , Vol 2, No 1, 35 to 48 (1994) and the like to prepare a variety of boronic acid in the same manner as in Scheme 1 below.

 Vinyl derivatives used in the above reaction formula are acetylene, styrene derivatives, and the like. Diburoboborane dimethyl sulfide is refluxed for 10 to 15 hours using 1.0 to 1.1 equivalents, and then suitable organic solvents such as ethyl acetate and methylene chloride are used. Extraction using the same and then concentrated to obtain various types of boronic acid (1) of Scheme 1.

The obtained boronic acid (1) of Scheme 1 is reacted with the 1,3-diol compound (2) of Scheme 2 to obtain the boronate compound (3) of Scheme 2. Boronic acid (1) of Scheme 1 is preferably used 1.5-2.5 equivalents, but preferably 2.0 equivalents. Dichloromethane, carbon tetrachloride, acetonitrile, benzene, toluene, xylene, and the like may be used as the solvent for the reaction, but toluene is most preferred. The reaction may be performed at 40 to 130 ° C. for 10 to 40 hours, but is most preferably performed at 90 to 120 ° C. for 10 to 15 hours. The cyano group of the compound boronate (3) of Scheme 2 is subjected to a reduction reaction to obtain the compound of formula VI.

The 1,3-diol compound (2) of Scheme 2 used in the reaction was prepared by the following Scheme 3. Compound 4-cyano-3-hydroxybutyric acid ethyl ester (4) of Scheme 3 was reacted with acetate (5), a compound of Scheme 3, to prepare β-ketoest (6). Acetate (5) was reacted with a base such as lithium diisopropylamide or butyl lithium at -40 to -70 ° C. in tetrahydrofuran to generate anions, followed by reaction with compound (4) of Scheme 3. Acetate (5) used at this time is methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate, t-butyl acetate, isopropyl acetate and the like. Of these, t-butyl acetate is most preferred. β-ketoest (6) was reduced with sodium borohydride or the like in a tetrahydrofuran solvent to obtain 1,3-diol compound (7).

Consideration of the preparation of atorvastatin using the boronate of Chemical Formula 1, a compound proposed in the present invention, was carried out as in Scheme 4.

(Formula 2)

Where

R is at least 3 carbon atoms, preferably 3 to 12 alkyl groups, phenylethyl or substituted phenylethyl groups. Preferably, R is 3 to 12 carbons.

The compound of formula 2 above is a compound 2- [2- (4-fluoro-phenyl) -2-oxo-1- in Scheme 4, which is an important substance for preparing atorvastatin, which has been suggested and industrially supplied in many studies. Phenyl-ethyl] -4-methyl-3-oxo-pentanoic acid phenylamide (8) can be readily prepared by Paar-Knorr reaction with a boronate compound which is a compound of formula (1). As the reaction solvent, acetonitrile, methylene chloride, tetrahydrofuran, benzene, toluene, xylene and the like can be used, but toluene or xylene is preferable. In addition, the use of an appropriate acid catalyst is useful because two molecules of dehydration must occur. Although methanesulfonic acid, benzene sulfonic acid, and toluene sulfonic acid can be used, toluene sulfonic acid is preferable. The reaction depends on the solvent used for 20 to 50 hours in the 40 to 130 ℃ range, but preferably 25 to 35 hours in the 90 to 130 ℃ range.

The boronate compound (9) of Scheme 4 can produce atorvastatin with high purity through an appropriate hydrolysis reaction. After dissolving compound (9) of Scheme 4 in ethyl acetate or dichloromethane, an appropriate base, preferably sodium hydroxide, can be added to react for 2 to 5 hours to hydrolyze. After the reaction is completed, the reaction solution is acidified with hydrochloric acid. Calcium hydroxide was added to the acidified reaction solution to prepare atorvastatin calcium as a target compound.

Through the following examples will be described in more detail the present invention.

Example 1 Preparation of Phenylethylboronic Acid

3 ml (26 mmol) of styrene was added to the reactor, and 26 ml (26 mmol) of dibromoborane dimethyl sulfide in a 1 M dichloromethane solution was added thereto, followed by reflux for 13 hours. After the reaction was completed, 10 ml of water was added thereto, stirred for 10 minutes, and 50 ml of ethyl acetate was added for extraction. The separated organic layer was concentrated, 50 ml of n-hexane was added and stirred at 5-10 ° C. for 2 hours, and the precipitated solid was filtered and dried to yield 2.25 g (58%) of the title compound.

Example 2. Preparation of 6-cyano-5-hydroxy-3-oxo-hexanoic acid t-butylester

150 ml of tetrahydrofuran and 24 g of diisopropylamine were added to the reactor and cooled to -10 ° C. 170 ml of n-butyllithium was slowly added while maintaining the temperature, followed by stirring for 30 minutes. The temperature was cooled to -40 ~ -35 ℃, 45ml t-butyl acetate was slowly added and stirred for 1 hour while maintaining the temperature. 12 g of 4-cyano-3-hydroxybutyric acid ethyl ester was slowly added to the reactor at the same temperature and reacted at -20 to -15 ° C for 2 hours. After the reaction was completed, 200 ml of water was added thereto, stirred for 30 minutes, extracted with 300 ml of ethyl acetate, and the organic layer was concentrated in vacuo to give a pale yellow oily compound. The oily compound obtained was used for next step without any further separation.

Example 3. Preparation of 6-cyano-3,5-dihydroxy-hexanoic acid t-butylester

To an oily compound of 6-cyano-5-hydroxy-3-oxo-hexanoic acid t-butylester obtained in Example 2 was added 200 ml of tetrahydrofuran and cooled to -80 ° C, followed by sodium borohydride 5 g. Was added slowly and stirred at the same temperature for 6 hours. After the reaction was completed, the mixture was neutralized with acetic acid, and extracted with 100 ml of water and 200 ml of ethyl acetate. The obtained organic layer was concentrated to give a yellow oily compound. The compound obtained was used in the next step without further separation.

Example 4 Preparation of (6-Cyanomethyl-2-phenethyl- [1,3,2] dioxaborinane-4-yl) -acetic acid t-butylester

The 6-cyano-3,5-dihydroxy-hexanoic acid t-butyl ester obtained in Example 3 was diluted with 100 ml toluene, 5.2 g of phenylethylboronic acid was added, and then azotropic distillation was performed for 5 hours. Water was removed. When the reaction was completed, toluene was removed and 100 ml of diethyl ether was added to obtain 10 g of the target compound.

¹ H NMR (CDCl ₃ , 300 MHz): 1.1 (2H, t), 1.35 (9H, s), 1.58 (2H, d), 2.43 (2H, d), 2.60 (2H, d). 2.65 (2H, t), 3.2 (1H, t), 3.9 (1H, m), 7.2 (5H, m)

Example 5 Preparation of (6-Cyanomethyl-2-propyl- [1,3,2] dioxaborinane-4-yl) -acetic acid t-butylester

The 6-cyano-3,5-dihydroxy-hexanoic acid t-butyl ester obtained in Example 3 was diluted with 100 ml toluene, 3 g of propylboronic acid was added, and then azotropic distillation was performed for 5 hours. Was removed. After the reaction was completed, toluene was removed and 100 ml of diethyl ether was added to obtain 7 g of the target compound.

¹ H NMR (CDCl ₃ , 300 MHz): 0.6 (2H, t), 0.9 (3H, t), 1.3 (9H, s), 1.6 (2H, t), 2.4 (2H, d), 2.6 (2H, d ), 3.2 (1H, m), 3.9 (1H, m)

Example 6 Preparation of [6- (2-Amino-ethyl) -2-phenethyl- [1,3,2] dioxaborinane-4-yl] -acetic acid t-butylester

10 g of the boronate compound of Example 4 was added to the reactor, 100 ml of ammonia-saturated methanol was added, 10 g of Ra nickel was added thereto, and the reaction was performed with hydrogen. After the reaction was conducted for 8 hours under 5 kg pressure, the residue was filtered and the filtrate was concentrated to give 10 g of the target compound.

¹ H NMR (CDCl ₃ , 300 MHz): 1.1 (2H, t), 1.4 (9H, s), 1.6 (2H, d), 1.7 (2H, m), 2.60 (2H, d). 2.65 (2H, t), 3.2 (1H, t), 3.9 (1H, m), 7.2 (5H, m)

Example 7 Preparation of [6- (2-Amino-ethyl) -2-propyl- [1,3,2] dioxaborinanan-4-yl] -acetic acid t-butylester

10 g of the boronate compound of Example 5 was added to the reactor, 100 ml of ammonia-saturated methanol was added, 10 g of Ra nickel was added thereto, and the reaction was performed with hydrogen. After the reaction was performed for 8 hours under 5 kg pressure, the residue was filtered and the filtrate was concentrated to give 7 g of the target compound.

¹ H NMR (CDCl ₃ , 300 MHz): 0.6 (2H, t), 0.9 (3H, t), 1.4 (9H, s), 1.5 (2H, t), 1.6 (2H, m), 1.7 (2H, m ), 2.4 (2H, d), 2.6 (2H, d), 3.2 (1H, m), 3.9 (1H, m)

Example 8. (6- {2- [2- (4-Fluoro-phenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -ethyl} -2-phenethyl Preparation of-[1,3,2] dioxaborinane-4-yl) -acetic acid t-butyl ester

10 g of 2- [2- (4-fluoro-phenyl) -2-oxo-1-phenyl-ethyl] -4-methyl-3-oxo-pentanoic acid phenylamide and [6- (2-amino-ethyl) 8.5 g of) -2-phenethyl- [1,3,2] dioxaborinane-4-yl] -acetic acid t-butylester was added thereto, 150 ml of toluene was added, and then a catalytic amount of toluene sulfonic acid was added. The reaction solution was added to the reflux temperature and azotropic to remove the water produced during the reflux. The solvent was completely removed after refluxing for 30 hours while continuously dehydrating. 100 ml of ethyl acetate and 100 ml of water were added to the concentrated oily compound, stirred for 30 minutes, the organic layer was separated, concentrated, and 100 ml of n-Hexane was added to obtain 15 g of the target compound.

¹ H NMR (CDCl ₃ , 300 MHz): 0.9 (2H, t), 1.2 (2H, m), 1.4 (9H, s), 1.5 (6H, d), 1.6 (2H, m), 2.3 (2H, dd ), 2.6 (2H, t), 3.6 (1H, m), 3.7 (1H, m), 3.9 (1H, m), 4.2 (2H, m), 7.2 (19H, m)

Example 9. (6- {2- [2- (4-Fluoro-phenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -ethyl} -2-propyl- Preparation of [1,3,2] dioxaborinane-4-yl) -acetic acid t-butyl ester

10 g of 2- [2- (4-fluoro-phenyl) -2-oxo-1-phenyl-ethyl] -4-methyl-3-oxo-pentanoic acid phenylamide and [6- (2-amino-ethyl) 6 g of) -2-propyl- [1,3,2] dioxaborinane-4-yl] -acetic acid t-butylester was added thereto, 150 ml of toluene was added, and the amount of toluene sulfonic acid was added. The reaction solution was added to the reflux temperature and azotropic to remove the water produced during the reflux. The solvent was completely removed after refluxing for 30 hours while continuously dehydrating. 100 ml of ethyl acetate and 100 ml of water were added to the concentrated oily compound, stirred for 30 minutes, the organic layer was separated, concentrated, and 100 ml of n-Hexane was added to obtain 10 g of the target compound.

¹ H NMR (CDCl ₃ , 300 MHz): 0.6 (2H, t), 0.9 (3H, t), 1.2 (2H, m), 1.4 (9H, s), 1.5 (6H, d), 1.55 (2H, m ), 1.6 (2H, m), 2.3 (2H, dd), 2.6 (2H, t), 3.6 (1H, m), 3.7 (1H, m), 3.9 (1H, m), 4.2 (2H, m) , 7.2 (14H, m)

Example 7 Preparation of Atovastatin Calcium

(6- {2- [2- (4-Fluoro-phenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -ethyl} -2-phenethyl- [1, 15 g of 3,2] dioxaborinane-4-yl) -acetic acid t-butyl ester was added to the reactor, and 150 ml of ethyl acetate was completely dissolved. 50 ml of 1N NaOH was slowly added dropwise for 30 minutes, followed by stirring for 3 hours. When stirring is completed, the pH is adjusted to 1-2 using 1N HCl and stirred for 30 minutes, and then the organic layer is separated. Potassium acetate was added to the organic layer, stirred for 2 hours, and the fish solid was filtered to obtain 7 g of the target compound.

The present invention is a method capable of producing atorvastatin with high purity by using the compounds of formulas (1) and (2), which is an intermediate, has an excellent industrial utility value.

Claims (4)

As a method of preparing the compound [6- (2-amino-ethyl) -2-R- [1,3,2] dioxaborinane-4-yl] -acetic acid t-butylester of Formula 1, A process for preparing boronate, comprising reacting a boronic acid derivative with 6-cyano-3,5-dihydroxy-hexanoic acid t-butylester: (Formula 1)

Where R is a C3 or more alkyl group, phenylethyl or substituted phenylethyl group. As a method of preparing the atorvastatin intermediate of the formula (2), Method for producing an atorvastatin intermediate, characterized in that to prepare a boronate compound of formula (1) as an intermediate. (Formula 2)

Where R is a C3 or more alkyl group, phenylethyl and substituted phenylethyl group. (Formula 1)

Where R is a C3 or more alkyl group, phenylethyl or substituted phenylethyl group. [6- (2-amino-ethyl) -2-R- [1,3,2] dioxaborinane-4-yl] -acetic acid t-butyl ester, which is a compound having the structure of Formula 1. (Formula 1)

Where R is a C3 or more alkyl group, phenylethyl or substituted phenylethyl group. A boronate compound having the structure of formula (2). (Formula 2)

Where R is a C3 or more alkyl group, phenylethyl or substituted phenylethyl group.