KR20050100267A - Process for preparation of simvastatin - Google Patents

Abstract

The present invention relates to a method for preparing simvastatin represented by the following Chemical Formula 1, wherein a lactone compound represented by the following Chemical Formula 2 and an acid derivative compound represented by the following Chemical Formula 3 are reacted under an appropriate solvent without an activator such as a metal halide. To prepare simvastatin of the formula (1) in a simple and economical yet high purity and high yield.

[Formula 1]

[Formula 2]

[Formula 3]

Description

Process for preparation of Simvastatin

The present invention relates to a method for preparing simvastatin and intermediates thereof for use in the treatment of hyperactive hypercholesterolemia.

Simvastatin represented by the following Chemical Formula 1 is known as a compound that inhibits the biosynthesis of cholesterol by inhibiting the activity of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and a method for preparing the same Research has been conducted in various ways.

[Formula 1]

HMG-CoA reductase catalyzes the formation of mevalonic acid (an initial intermediate of cholesterol biosynthesis). The chemical name of simvastatin is 6 (R)-[2- [8 '(S) -2' ', 2' '-dimethylbutyloxy-2' (S), 6 (R ')-dimethyl-1', 2 ' , 6 ', 7', 8 ', 8a' (R) -hexahydronaphthyl-1 '(S) ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H- Pyran-2-one (CAS reg. No. 79902-63-9).

Known general production methods related to the present invention relating to the preparation of this compound are hydrolysis reaction, lactonation reaction, protection reaction, acylation reaction and deprotection reaction using lovastatin (4) as starting materials as shown in Scheme 1. Simvastatin can be synthesized via

Scheme 1

 U.S. Patent No. 4,444,784 (Korean Patent Publication, No. 1985-0000669) contains compounds which are acylated using dimethylaminopyridine as an activator and pyridine as base and solvent as shown in Scheme 2 below. The synthesis method of 7) was reported.

Scheme 2

However, this method requires a high temperature, a long reaction condition, an excess of acyl chloride (3), and has a disadvantage in that a by-product is generated by removing a t-butyldimethyl protecting group during the reaction.

US Pat. No. 4,845,237 reported a process using dimethylaminopyridine and alkali bromide as activators to inhibit the production of by-products as shown in Scheme 3 below in the acylation step.

Scheme 3

However, the lithium bromide used at this time is highly hygroscopic, so a pretreatment process that requires drying for a long time (3 days) under high temperature (135 ° C.) and vacuum before use is necessary. If the lithium bromide absorbed with water is used, the reaction yield This lowers and produces a large amount of by-products.

In addition, the Republic of Korea Patent Publication No. 2001-0114047 reported an acylation reaction that can be replaced with a less hygroscopic alkali metal iodide in order to improve the problem of using the highly hygroscopic alkali metal bromide of the patent.

However, sodium iodide, which is used as an activator in this method, has less hygroscopicity than lithium bromide, but has a hydrophilic property, so it must be dried before use, which is difficult in mass production.

As a result, these conventional manufacturing methods require high temperature and long reaction conditions, and the process is cumbersome due to the use of raw materials having high hygroscopicity, and thus, there is a difficulty in industrial production.

Therefore, in the present invention, to solve the problem of the acylation reaction of the prior art, the acylation method that excludes the use of lithium bromide or sodium iodide, which is used as an activator in the acylation reaction in the conventional method, and does not use the activator at all. The development of high purity and high yield of acylated compounds was developed under conditions that ensure ease of operation in industrial mass production and no difficulty in mass production in terms of reaction time and reaction temperature.

As a result, to provide a new method for preparing simvastatin of the formula (1).

The method for preparing simvastatin of Chemical Formula 1 according to the present invention for achieving the above technical problem is by adding an aromatic hydrocarbon and pyridine without an activator to the lactone compound represented by the following Chemical Formula 2 and the acyl halide derivative represented by the following Chemical Formula 3 It characterized in that it comprises an acylation reaction step of preparing a compound represented by the formula (7).

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 7]

Scheme of the preparation method of simvastatin according to the present invention can be represented by the following scheme 4.

Scheme 4

Hereinafter, the present invention will be described in detail.

The present invention can be divided into an acylation step and a deprotection step, as shown in Scheme 4, and the lactone compound of Formula 2 and the deprotection step of Scheme 4 can be synthesized by a known method.

In the present invention, the acylation reaction is carried out by adding a solvent and a base to the lactone compound of Formula 2 and warming it to 40 to 80 ° C., followed by adding an acid derivative of Formula 3 to the reaction solution to perform acylation.

The solvent used in the acylation step is an aromatic hydrocarbon such as benzene, toluene, xylene, and the like, preferably benzene, and the amount used is 6 to 7 liters per mole of the lactone compound of Formula 2, and more preferably. Use 6.5 liters.

In addition, pyridine is preferred as a base used to neutralize the hydrochloric acid generated in the acylation step and to activate the reaction, and the amount thereof is used in an amount of 1 to 4 liters per mole of the lactone compound of Formula 2, more preferably 2 to Use 2.5 liters. When the amount of pyridine used is less than 1 liter, the yield is lowered. When the amount of pyridine is used at 4 liters or more, the reaction occurs suddenly, making it difficult to control the reaction temperature. By-products are generated, and the yield is lowered. It is most preferable because the reaction temperature is easy to control and the yield is the highest.

In the present invention, the use of the aromatic organic solvent decreases the concentration of pyridine, so that the reaction proceeds rapidly, thereby preventing the formation of by-products, and the reaction temperature is easily controlled.

In addition, the acid derivative is preferably an acyl halide such as 2,2-dimethylbutyryl chloride, and in general, 3.5 to 6 liters per mole of the lactone compound represented by the formula (2), preferably 4 to 4.5 liters. use.

The reaction temperature of the acylation step is 60 to 120 ℃, preferably 85 to 95 ℃ and the reaction time is 6 to 36 hours, preferably 22 to 24 hours.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention or its field is not limited thereto.

Example 1

 6 (R)-[2- [8 '(S) -2' ', 2' '-dimethylbutyloxy-2' (S), 6 (R ')-dimethyl-1', 2 ', 6',

7 ', 8', 8a '(R) -hexahydronaphthyl-1' (S)]-4 (R)-(dimethyl-tert-butylsiloxy) -3,4,5,6-tetrahydro- Preparation of 2H-pyran-2-one (Formula 7)

6 (R)-[2- [8 '(S) -hydroxy-dimethylbutyloxy-2' (S), 6 (R ')-dimethyl-1', 2 ', 6', 7 'under nitrogen stream. , 8 ', 8a' (R) -hexahydronaphthyl-1 '(S)]-4 (R)-(dimethyl-tert-butylsiloxy) -3,4,5,6-tetrahydro-2H- 45 g of benzene and 15 ml of pyridine are added to 3 g (6.9 mmol) of pyran-2-one and warmed up to 60 ° C.

28 ml of 2,2-dimethylbutyryl chloride was added dropwise to the reaction solution for 15 minutes, and the mixture was stirred for 23 hours at an internal temperature of 90 ° C.

Cool the reaction solution to room temperature, add 60 ml of ethyl acetate, add 48 g of ice and 48 ml of concentrated hydrochloric acid at once, and stir for 20 minutes. The reaction mixture is filtered through diatomaceous earth and the organic layer is separated, and then the separated organic layer is washed with 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.49 g of the superposed compound. (Yield: 95%)

Example 2

 6 (R)-[2- [8 '(S) -2' ', 2' '-dimethylbutyloxy-2' (S), 6 (R ')-dimethyl-1', 2 ', 6',

7 ', 8', 8a '(R) -hexahydronaphthyl-1' (S) ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2- Preparation of On (Formula 1)

6 (R)-[2- [8 '(S) -2' ', 2' '-dimethylbutyloxy-2' (S), 6 (R ')-dimethyl- obtained in Example 1 above under a nitrogen stream. 1 ', 2', 6 ', 7', 8 ', 8a' (R) -hexahydronaphthyl-1 '(S)]-4 (R)-(dimethyl-tert-butylsiloxy) -3, To 4.5 g (8.45 mmol) of 4,5,6-tetrahydro-2H-pyran-2-one, 30 ml of tetrahydrofuran, 1.65 g of acetic acid, and 5.44 g of tetrabutylammonium fluoride trihydrate were added sequentially and stirred at room temperature for 23 hours. do. 10 ml of purified water, 10 ml of ethyl acetate, and 60 ml of normal hexane were added to the reaction mixture, which was stirred for 30 minutes at room temperature, and then left to separate an organic layer.

The separated organic layer was washed with 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated brine, dehydrated with anhydrous magnesium sulfate, dried and distilled under reduced pressure.

The concentrated residue was recrystallized from 24 ml of cyclohexane to give 2.3 g of the supernatant compound (Formula 1). (Yield: 79%)

As a result, it is possible to synthesize high purity and high yield simvastatin without using an acylation reaction activator which is difficult to handle in the acylation reaction, which is the most important in the preparation of simvastatin.

Claims (6)

In the method for preparing simvastatin of the formula (1), An acylation reaction step of preparing a compound represented by Chemical Formula 7 by adding an aromatic hydrocarbon and pyridine to an lactone compound represented by Chemical Formula 2 and an acyl halide derivative represented by Chemical Formula 3 without an activator; Simvastatin manufacturing method comprising a. [Formula 1] [Formula 2] [Formula 3] [Formula 7] The method of claim 1, The aromatic hydrocarbon is a method for producing simvastatin, characterized in that any one selected from benzene, toluene, xylene or mixed. The method of claim 1, The aromatic hydrocarbon is used 6 to 7 liters per mole of the lactone compound of Formula 2, The pyridine is used in an amount of 1 to 4 liters based on 1 mole of the lactone compound of Formula 2, The acyl halide derivative of Chemical Formula 3 is a method for preparing simvastatin, using 3.5 to 6 liters per mole of the lactone compound of Chemical Formula 2. The method of claim 3, wherein The pyridine is used in the method for producing simvastatin, characterized in that 2 to 2.5 liters per mole of the lactone compound of Formula 2. The method of claim 3, wherein The acyl halide derivative of Chemical Formula 3 is used for the preparation of simvastatin, using 4 to 4.5 liters per mole of the lactone compound of Chemical Formula 2. The method of claim 5, Method for preparing simvastatin characterized in that the acylation reaction is carried out for 22 to 24 hours at a reaction temperature of 85 to 95 ℃.