KR20040107647A - Process for preparing intermediate of simvastatin - Google Patents

Abstract

PURPOSE: A process for preparing an intermediate of simvastatin is provided, thereby stably carrying out hydrolysis of lovastatin under the strong basic condition by using a mixed solvent and cheaply and industrially preparing the intermediate of simvastatin which is useful as a HMG-CoA reductase inhibitor. CONSTITUTION: The process for preparing an intermediate of simvastatin, 6(R)-(2-(8'(S)-hydroxy-2'(S), 6'(R)-dimethyl-1',2',6',7',8',8'a(R)- hexahydronaphthyl-1'(S))-ethyl)- 4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one of the formula(I), comprises the steps of: hydrolyzing lovastatin of the formula(III) in the presence of inorganic base in a mixed alcohol solvent of tetrahydrofuran and alcohol selected from primary, secondary or tertiary alcohol solvent to prepare triol acid of the formula(II); and acidifying or lactonizing the triol acid of the formula(II), wherein the primary alcohol solvent is normal propanol or normal butanol; the secondary alcohol solvent is isopropanol or isobutanol; and tertiary alcohol solvent is t-butanol.

Description

Process for preparing intermediate compound of simvastatin {Process for preparing intermediate of simvastatin}

The present invention relates to a method for preparing an intermediate compound of simvastatin useful as a therapeutic agent for hypercholesterolemia, and specifically, 6 (R)-[2- (8 '(S) -hydroxy-2' of the following structural formula (I). (S), 6 '(R) -Dimethyl-1', 2 ', 6', 7 ', 8', 8'a (R) -hexahydronaphthyl-1 '(S))-ethyl] -4 A method for producing (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (diol lactone).

Simvastatin is an HMG-CoA reductase inhibitor and a substance that inhibits the biosynthesis of cholesterol and is known as a drug for hypercholesterolemia.

As a starting material for preparing simvastatin, lovastatin of the following structural formula (III) which can be prepared through a fermentation process using a microorganism strain belonging to the genus Aspergillus (US Pat. No. 4,444,784) can be used.

To date, it is known that the preparation technique for the diol lactone of the structural formula (I), which is an intermediate useful for preparing the final target substance simvastatin, is prepared through the same process as in Scheme 1 below.

U.S. Patent No. 4,444,784 discloses a method of hydrolyzing lovastatin of formula (III) with lithium hydroxide to obtain triol acid of formula (II) and lactonizing to obtain diol lactone of formula (I).

However, the above-mentioned conventional method is carried out under a long time (12 to 56 hours), high temperature (100 to 130 ° C.) and pressurized conditions in an excess water solvent (75 times compared to lovastatin) during the preparation of the structural formula (II) (hydrolysis reaction). It has disadvantages that must be made, and by-products are generated and yield is low (81%), which is an inefficient production method.

In a further improved method, according to Korean Patent Publication No. 10-2001-0040760 (priority claim Japanese Patent No. 98-531865), lovastatin of formula (III) is used in excess of secondary or 3 in an inert atmosphere such as nitrogen gas. A method of obtaining a diol lactone of the structural formula (I) by hydrolyzing with an inorganic base using a secondary alcohol solvent (12-40 times compared to lovastatin) to obtain a triol acid of the structural formula (II), and performing lactolation reaction.

However, this method is also an unsuitable production method due to the severe reaction conditions of long time (1 to 60 hours) and high temperature (60 to 100 ° C.) depending on the alcohol solvent, resulting in by-products and low yield and purity.

The present inventors intend to complete the improved manufacturing method of the diolactone intermediate through the uninterrupted experiment to solve the above problems.

Accordingly, the present invention is to provide a novel method for preparing a commercially and economically advantageous diol lactone intermediate of the formula (I) by improving the yield and purity of the hydrolysis reaction, which is a general problem derived from the preparation of simvastatin.

In order to achieve the above object, the present invention performs hydrolysis by reacting lovastatin of formula (III) in at least one alcohol mixed solvent selected from tetrahydrofuran and a primary, secondary or tertiary alcohol solvent in the presence of an inorganic base. Thereby, the first step of producing a triol acid of the structural formula (II) in high purity; The triol acid was acidified and lactonated to give 6 (R)-[2- (8 '(S) -hydroxy-2' (S), 6 '(R) -dimethyl-, which is a diol lactone of formula (I). 1 ', 2', 6 ', 7', 8 ', 8'a (R) -hexahydronaphthyl-1' (S))-ethyl] -4 (R) -hydroxy-3,4,5 Provided is a method for preparing a simvastatin intermediate comprising a second step of continuously preparing 6-tetrahydro-2H-pyran-2-one.

The present invention will be described in more detail as follows.

In the first step, lovastatin of formula (III) can be hydrolyzed by treatment with an inorganic base in a mixed solvent selected from tetrahydrofuran and primary, secondary or tertiary alcohols to obtain trioleic acid of formula (II).

In this step, the alcohol solvent may be a primary, secondary or tertiary alcohol, preferably an alcohol solvent having 3 to 6 carbon atoms is suitable, and is not particularly limited, but normal propanol, normal butanol, isopropanol, isobutanol, t-butanol and the like are preferable, and normal propanol and isopropanol are more preferable.

The amount of the mixed solvent used in this step is 3 to 5 times, preferably 4 times compared to lovastatin, the ratio of the mixed solvent and the ratio of tetrahydrofuran is preferably 0.5 to 1.5: 1, the ratio of 1: 1 It is more preferable to use as.

In this step, the reaction temperature is preferably carried out at 60 to 100 ℃, preferably 70 to 90 ℃, the reaction time is suitable to react for 10 minutes to 5 hours, preferably 1 to 3 hours.

In this step, the inorganic base is not particularly limited, but most preferably alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like and alkali metal alkoxides such as potassium t-butoxide, sodium isopropoxide and the like, most preferably Is potassium hydroxide, and the inorganic base is preferably 5 to 10 molar equivalents, preferably 6 to 8 molar equivalents, relative to the amount of lovastatin.

The second step is an acid such as sulfuric acid, phosphoric acid, methanesulfonic acid, and the like, in order to lactonate the compound of formula (II) obtained in the first step, and inert such as toluene, xylene, etc. The solvent can be added to reflux stirring for 30 minutes to 3 hours, preferably 1 hour, to obtain the desired compound of formula II.

Typically triol acid of formula (II) is not isolated and can be obtained by lactonation in the form of a concentrate of the acidified reaction mixture to obtain diol lactone of formula (I), which is carried out by conventional methods. It is possible to confirm the production of the resulting triol acid of formula (II) and diol lactone final structure of formula (I) by qualitatively and quantitatively measuring by high performance liquid chromatography to calculate the yield and purity. In the reaction, the purity of triol acid was more than 97%, which was superior to that of 85 to 92% of the triol acid purity provided by the conventional method. As a result, the purity of the diol lactone of the final separated and purified formula (I) was The yield was more than 98.5%, the yield was also more than 97%, which was much better than the 80 to 85% yield of the conventional method.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only intended to present preferred embodiments of the present invention, and the scope of the present invention is not limited thereby. The present invention includes not only the following embodiments but also various modifications and modifications within the scope without departing from the scope of the technical idea of the present invention.

Reference example. High performance liquid chromatography analysis conditions

Compounds of the present invention were determined qualitatively and quantitatively by high performance liquid chromatography under the following conditions.

Organization: SCL-10A, Shimadzu Corporation

Column: Xterra RP18, 250 mm x 4.6 mm, 5 μm

Eluent: acetonitrile / phosphate buffer (pH 3) = 6: 4

Flow rate: 1.5ml / min

Input amount: 10µl

Detection: 238 nm (UV detector)

Temperature: 40 ℃

Comparative Example 1. Method for preparing diolactone of structural formula (I) (based on US Pat. No. 4,444,784)

8.0 g of lovastatin and 8.31 g of lithium hydroxide monohydrate were dissolved in 600 ml of purified water, and the mixture was stirred under reflux for 56 hours under nitrogen. The reaction was cooled to 0 ° C. and neutralized with 20 mL hydrochloric acid, then extracted four times with 200 mL ether, washed with saturated brine, then dried, filtered and concentrated using forget-me-not. 200 ml of toluene was added to the concentrate, and the mixture was refluxed for 2 hours, concentrated under reduced pressure, and crystallized by addition of hexane to give 5.15 g (yield: 81%) of white crystals.

Comparative Example 2. Method for Producing Diolactone of Structural Formula (I) (Korean Patent Publication No. 10-2001-0040760

To a solution of 7.92 g of KOH in 300 mL of t-butanol was added 8.09 g of lovastatin and the mixture was stirred for 30 minutes under argon gas. The temperature was then raised and the mixture was refluxed with stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added, acidified with phosphoric acid (pH 3.5) and extracted with ethyl acetate. The extract was concentrated under reduced pressure to give a brown oil. The brown oil was dissolved in 200 ml of isopropyl acetate, 65 μl of methanesulfonic acid was added, and then the solution was concentrated to about 1/5 volume under reduced pressure. The obtained residue was washed with saturated aqueous sodium hydrogen carbonate solution, cooled to -20 ° C and stirred. The resulting slurry was filtered and dried in vacuo to give 5.76 g (yield: 90%) of white crystals.

Example 1 Preparation of Diolactone of Structural Formula (I) 1

200 g of tetrahydrofuran and 200 g of normal propanol were mixed, 100 g of lovastatin and 100 g of potassium hydroxide were added, and the reaction temperature was raised to reflux and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, 500 g of purified water was added thereto, followed by acidification with 160 g of hydrochloric acid. Toluene 600g and phosphoric acid 5g were added to the residue obtained by extraction with 500 g of ethyl acetate and concentrated under reduced pressure, followed by stirring under reflux for 1 hour. 600 g of hexane was added to the residue obtained by concentration under reduced pressure, and crystallization was performed. The resulting solid was filtered and dried at 50 ° C. to give 78 g of a white title compound (yield: 98.5%; HPLC purity: 99.2%).

Example 2 Preparation of Diolactone of Structural Formula (I) 2

Except for using 200 g of tetrahydrofuran and 200 g of isopropanol, 79 g of a white title compound (yield: 99.7%; HPLC purity: 98.7%) were obtained in the same manner as in Example 1.

Example 3 Preparation of Diolactone of Structural Formula (I) 3

Except for using 200 g of tetrahydrofuran and 200 g of normal butanol, 77 g of a white title compound (yield: 97.2%; HPLC purity: 98.5%) was obtained in the same manner as in Example 1.

Example 4 Preparation of Diolactone of Structural Formula (I) 4

Except that 200 g of tetrahydrofuran, 100 g of normal butanol and 100 kg of isopropanol were used, the same procedure as in Example 1 was carried out, and 77 g of a white title compound (yield: 97.2%; HPLC purity: 98.0%) was obtained.

Experimental Example 1. Purity and yield confirmation experiment

The method of Example 1 and the methods of Comparative Examples 1 and 2 were compared with each other to measure the reaction time and the amount of step products, respectively, and are shown in Table 1 below.

Comparative Example 1 Comparative Example 2 Example 1 Reaction time 2 hours 56 hours 2 hours 4 hours 2 hours Trioleic acid 2.3% 85.5% 81.2% 89.5% 97.4% Dior lactone 0.0% 2.4% 0.5% 2.5% 2.0% Unidentified Impurities 0.55 11.6% 3.3% 7.8% 0.6% Lovastatin 97.2% 0.5% 15% 0.2% 0.0% Separation Yield and Purity of Final Diol Lactone 81% 90% (95.1%) 98.5%

As can be seen in Table 1, the production method according to the present invention has a significantly higher separation yield (98.5-99.7%) of the final diol lactone in terms of yield compared to Comparative Examples 1 and 2, triol acid through the first step It was also found that the purity (98.5-99.7%, measured by HPLC in the reaction) of the triol acid and diol lactone products in the preparation of was also significantly improved compared to the purity by conventional methods.

In the production method of the present invention, hydrolysis is performed more stably under a strong base by using a mixed solvent, thereby preparing triol acid of formula (II) in high purity and high yield and lactonizing the structural formula (I), which is an intermediate of simvastatin. It is possible to provide an improved manufacturing method that can economically and industrially usefully synthesize diol lactone of a).

Claims (8)

A lovastatin of formula (III) is reacted with tetrahydrofuran and an alcohol mixed solvent selected from primary, secondary or tertiary alcohol solvents in the presence of an inorganic base to prepare a triol acid of formula (II) step; The triol acid was acidified and lactoneized to give 6 (R)-[2- (8 '(S) -hydroxy-2' (S), 6 '(R) -dimethyl-1', 2 ', 6', 7 ', 8', 8'a (R) -hexahydronaphthyl-1 '(S))-ethyl] -4 (R) -hydroxy-3,4,5,6- A method for producing a simvastatin intermediate comprising a second step process of preparing a tetrahydro-2H-pyran-2-one diolactone body. The method according to claim 1, wherein the primary alcohol solvent of the first step is normal propanol or normal butanol. The method according to claim 1, wherein the secondary alcohol solvent of the first step is isopropanol or isobutanol. The method according to claim 1, wherein the tertiary alcohol solvent of the first step is t-butanol. The method according to claim 1, wherein the use ratio of tetrahydrofuran and the mixed solvent in the first step is 1: 0.5 to 1.5. The method according to claim 5, wherein the use ratio of tetrahydrofuran and the mixed solvent of the first step is 1: 1. The method according to claim 1, wherein the inorganic base of the first step is lithium hydroxide, sodium hydroxide or potassium hydroxide. The method of claim 1, wherein the reaction time of the first step is 1 hour to 3 hours.