KR100503022B1 - A highly efficient synthetic process for the preparation of simvastatin and new intermediates therefor - Google Patents

Abstract

The present invention relates to a novel method of preparing simvastatin, known as a therapeutic agent for hyperlipidemia, and to novel intermediates used therein.

Description

A new method for preparing simvastatin and synthetic intermediates used therein {A HIGHLY EFFICIENT SYNTHETIC PROCESS FOR THE PREPARATION OF SIMVASTATIN AND NEW INTERMEDIATES THEREFOR}

The present invention relates to a novel method for preparing simvastatin, known as a therapeutic agent for hyperlipidemia, and to a novel intermediate used therein and a method for producing the same.

Conventional methods for the preparation of simvastatin, as disclosed in U.S. Patent No. 4,444,784, hydrolyze the lactone ring and the 2-methylbutyl group using lovastatin as a starting material, form a new lactone ring, and then lactone ring The first method is to prepare a simvastatin by protecting the hydroxy group of with a tert-butyldimethylsilyl group, then esterifying with dimethylbutyl chloride, and removing the tert-butyldimethylsilyl group from the protected hydroxy group. 1).

Scheme 1

Wherein TBDMS is a tert-butyldimethylsilyl group.

Journal of Organic Chemistry 56, 4929 (1991) also describes the use of butylamine to further aminoaminolyse the lactone ring to amides, and then protect the two hydroxy groups with tert-butyldimethylsilyl groups, followed by n-butyllithium and iodine After methylation using methane, the protecting group is removed with methanesulfonic acid, hydrolysis of the amide with sodium hydroxide, hydrochloric acid and ammonia water treatment, and the lactone ring is re-formed in toluene to prepare simvastatin. Published (see Scheme 2 below).

Scheme 2

Wherein TBDMS is a tert-butyldimethylsilyl group.

However, when simvastatin is prepared according to US Pat. No. 4,444,784, by-products are produced in the removal and relactoneization of lactone rings and 2-methylbutyl groups, resulting in very low overall yields of 48%. In addition, according to the Journal of Organic Chemistry 56, 4929 (1991), the preparation of simvastatin is not only expensive n-butyllithium, but also highly ignitable, and the process is very complicated. And, there is a problem in that the economy is poor because it is manufactured through a multi-step process.

Accordingly, the present inventors have completed the present invention by finding that the yield is high and the production of by-products is low when simvastatin is prepared through a new intermediate, as a result of the study to solve the problems of the prior art.

It is therefore an object of the present invention to provide intermediates useful for the preparation of simvastatin.

It is also an object of the present invention to provide a method for producing the intermediate.

It is also an object of the present invention to provide a method for preparing simvastatin from the intermediate.

The present invention provides a new economical process for preparing simvastatin (Scheme 3 below) and also provides compounds of formulas (1) and (2) as useful novel compounds for use therein.

Scheme 3

[Formula 1]

[Formula 2]

In the above formula, R is a trialkylsilyl group which may be represented by R ¹ R ² R ³ Si, R ¹ , R ² , R ³ each represent a straight or branched alkyl group having 1 to 5 carbon atoms, R ¹ , R ² and R ³ may be the same or different from each other.

Representative examples include tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl and the like.

The novel intermediates of the present invention, the compounds of formulas (1) and (2) can be obtained simply from the compounds of formula (3) obtained from the hydrolysis of lovastatin, and can be very useful for the synthesis of simvastatin.

[Formula 3]

The method provides a new method of preparing simvastatin.

In order to prepare simvastatin according to the present method, a trialkylsilyl chloride represented by R ¹ R ² R ³ Si-Cl in a suitable inert solvent, such as the compound of Formula 3, obtained by hydrolyzing lovastatin in a conventional manner, is represented in Scheme 3. And reacting in the presence of a suitable catalyst to prepare the compound of Formula 1, wherein the compound of Formula 1 is prepared in a suitable inert solvent with 2,2-dimethylbutyric acid or a reactive derivative of 2,2-dimethylbutyric acid. The compound of formula 2 is prepared by reaction in the presence or without a catalyst, and finally, the compound of formula 2 is reacted with a suitable deprotecting agent to remove trialkylsilyl groups and form a lactone ring to complete the process of synthesizing simvastatin. .

Solvents that can be used when preparing the compound of formula 1 from the compound of formula 3 according to the present invention include ether species such as tetrahydrofuran, dioxane, and the like, amide species such as dimethylacetamide and diethylacetamide, and dimethyl sulfoxide. Any inert solvent that does not directly affect the reaction, such as sulfoxide species such as seeds, can be used. The reaction can be suitably carried out at a temperature of usually from 0 degree to the boiling point of the solvent.

In this case, the trialkylsilyl chloride used may be generally used in the amount of 3.0 to 6.0 equivalents based on the compound of the formula (3), preferably 3.3 to 4.5 equivalents for optimal results. In this case, it is generally preferable to remove by-product hydrogen chloride using a base such as imidazole, and the reaction can be carried out without difficulty using various tertiary alkylamines in addition to imidazole.

Any solvent that does not affect the reaction may be used as a solvent that may be used when preparing the compound of Formula 2 from the compound of Formula 1. Possible solvents include ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethyl sulfoxide, and the like. 2,2-dimethylbutyric acid may be used in the reaction as it is with an acylating agent such as DCC, used as a halide such as chloride or bromide, or as another reactive derivative. At this time, as an active derivative, an active mixed acid anhydride, an active amide, an active thioester, an active phosphoric acid or a thiophosphoric acid ester, or the like can be used.

In this case, 2,2-dimethylbutyric acid or an active derivative thereof is preferably used in a ratio of 1.0 to 5.0 equivalents based on the compound of Formula 2, and more preferably 1.0 to 2.0 equivalents relative to the compound of Formula 2. It is good to use as.

The temperature of the reaction may be conveniently determined between 0 degrees and the boiling point of the solvent, and the reaction may be performed. Preferably, the reaction is performed in a range of room temperature to 60 degrees.

The compound of formula 2 may be usefully used to prepare simvastatin by removing all the trialkylsilyl groups as a protecting group through a deprotection process and performing a lactonation process.

In order to prepare simvastatin from the compound of formula (2), simvastatin is prepared by first reacting the compound of formula (2) with a desilylating agent capable of removing the silyl group in a suitable solvent to remove all of the silyl groups and then to form the lactone ring again. do.

The desilylating agent for removing the silyl group may be suitably used a fluoride salt such as quaternary ammonium fluoride or an inorganic acid such as hydrochloric acid or sulfuric acid. Lactones can be formed in the presence of an acid catalyst by the method disclosed in patent 4,444,784.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to these examples.

Example 1 tris (tert-butyldimethylsilyl) triol acid (compound of formula 1)

45 g of dimethylformamide was added to 5 g of triol acid (compound of Formula 3) to dissolve it. 3.52 g (3.5 equivalents) of imidazole and 7.5 g (3.5 equivalents) of TBDMS-Cl were added thereto and reacted at 55-60 ° C. for 16 hours. After the reaction was completed, the mixture was cooled, diluted with hexane, and washed with water. After drying over anhydrous magnesium sulfate and distillation under reduced pressure, the solvent was removed to obtain 9.56 g (95%) of the target substance in the oil phase.

¹ H-NMR (CDCl ₃ , 300 MHz) 0.12 (d, J = 3.3 Hz, 12H), 0.26 (s, 6H), 0.88 (d, J = 5.1 Hz, 3H), 0.89 (m, 27H), 1.19 ( d, J = 7.8Hz, 3H), 1.20-2.5 (m, 14H), 3.80 (bs, 1H), 4.18 (m, 2H), 5.53 (bs, 1H), 5.79 (m, 1H), 5.97 (d , J = 6.6 Hz, 1H)

Example 2: 2,2-dimethylbutyryl-tris (tert-butyldimethylsilyl) triol acid (compound of formula 2)

20 ml of dichloromethane was dissolved in 3.4 g (4.0 equiv) of 2,2-dimethylbutyric acid, followed by addition of 7.7 g (4.0 equiv) of triphenylphosphine. After the reaction mixture was cooled to 0 ° C., 5.2 g of N-bromosuccinimide was added, followed by stirring at room temperature for 30 minutes. 5.0 g of the compound of Formula 1 was added to the reaction mixture at 0 ° C., and 3.6 g of N, N-dimethylaniline was added thereto, followed by stirring at room temperature for 10 hours. 5% diluted hydrochloric acid, water, and saturated aqueous sodium hydrogen carbonate solution are washed in order to separate the organic layer and distilled under reduced pressure to remove the solvent. Add 60 ml of hexane, stir at 0 ° C. for 30 minutes, filter, and concentrate the filtrate to give 5.0 g (88%) of an oily compound.

¹ H-NMR (CDCl ₃ , 300 MHz) 0.15 (d, J = 3.5 Hz, 12H), 0.23 (s, 6H), 0.79 (t, J = 6.9 Hz, 3H), 0.88 (d, J = 5.5 Hz, 3H), 0.91 (m, 27H), 1.08 (d, J = 7.5 Hz, 3H), 1.12 (s, 3H), 1.13 (s, 3H), 1.2-2.5 (m, 14H), 2.56 (d, J = 4.0 Hz, 2H), 4.30 (m, 1H), 4.58 (m, 1H), 5.24 (m, 1H), 5.54 (m, 1H), 5.56 (dd, J = 5.1 Hz, 1H), 6.0 (d , J = 10Hz, 1H)

Example 3: Synthesis of Simvastatin

3.0 g of an oily compound of formula 2 were added to a mixture of 24 ml of tetrahydrofuran and 1.0 ml of 1,4-dioxane. After the reaction was cooled to 0 ° C., 0.86 ml of concentrated hydrochloric acid was added thereto, followed by stirring for 6 hours to complete the reaction. Triethylamine was added to the reaction solution to adjust the pH to 1.5. The concentrated residue was dissolved in 20 ml of ethyl acetate, and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous magnesium sulfate, distilled under reduced pressure, and the solvent was removed to obtain the target product as a white cake. The cake was dissolved in 17.5 ml of dichloromethane and stirred with 35 mg of paratoluenesulfonic acid at room temperature for 1 hour. The reaction mixture was concentrated by distillation under reduced pressure, 7.5 ml of ethyl acetate was added, and the mixture was heated to 40 ° C.-60 ° C. to completely dissolve it. At the same time, 30 ml of hexane was slowly added thereto, and then cooled to room temperature, stirred for 1 hour, cooled to 0 ° C., and further stirred for 2 hours to produce a white precipitate. The filtrate was dried, dissolved in 25 ml of methanol, a small amount of activated carbon was added, stirred for 30 minutes, and filtered through a celite filter. 25 ml of water was added dropwise to the filtrate and stirred at 0 ° C. for 2 hours to form a white precipitate. This precipitate was filtered off and dried in vacuo at 40 ° C. for 16 hours to obtain 1.37 g (85%) of simvastatin.

When simvastatin is prepared by using the compound of Formula 1 as an intermediate in the present invention, there is an advantage in that the yield is high and the generation of by-products is less than that of the conventional preparation method.

Claims (5)

A compound of formula 1 [Formula 1] In the above formula, R is a trialkylsilyl group which may be represented by R ¹ R ² R ³ Si, R ¹ , R ² , R ³ each independently represent a straight or branched alkyl group having 1 to 5 carbon atoms, R ¹ , R ² and R ³ may be the same as each other or may be different from each other. A compound of formula [Formula 2] In the above formula, R is a trialkylsilyl group which may be represented by R ¹ R ² R ³ Si, R ¹ , R ² , R ³ each independently represent a straight or branched alkyl group having 1 to 5 carbon atoms, R ¹ , R ² and R ³ may be the same as each other or may be different from each other. To prepare a compound of formula 1 from the compound of formula 3, and then to prepare a compound of formula 2 using a compound of formula 1, and then using the compound of formula 2 to synthesize a simvastatin represented by the formula (4) Simvastatin production method. [Formula 3] [Formula 1] [Formula 2] [Formula 4] In Formula 1 and Formula 2, R is a trialkylsilyl group represented by R ¹ R ² R ³ Si, and R ¹ , R ² , and R ³ are each independently a linear or branched alkyl group having 1 to 5 carbon atoms. R ¹ , R ² , and R ³ may be the same as or different from each other. The compound of formula 1 according to claim 1, wherein R ¹ R ² R ³ Si is one of tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl. The compound of formula 2 according to claim 2, wherein R ¹ R ² R ³ Si is one of tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl.