JP2009114121A - Method for producing simvastatin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing high-purity simvastatin in high yield by a simple and commercially advantageous method. <P>SOLUTION: The method for producing the simvastatin includes reacting a compound represented by general formula (3) (wherein, R is a 1-4C alkyl group) with an acid in a nonprotonic polar solvent and a hydrocarbon solvent in the presence of water. Preferably, the simvastatin is produced by subjecting the simvastatin obtained by converting a triol acid into an acetonide, acylating the resultant acetonide, and subjecting the acylated product to deacetonidation and lactonization, to crystallization by using an aromatic hydrocarbon-based solvent and an aliphatic hydrocarbon-based solvent, and/or crystallization by using a ketone-based solvent or a mixed solvent of a nitrogen-containing solvent with water. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing simvastatin known as a therapeutic agent for hyperlipidemia.

As a method for producing simvastatin, for example, the following methods are known.
(I) A method comprising deprotection of 2-methylbutyrate side chain of lovastatin, selective silylation of hydroxy group, acylation at 8-position, and deprotection of 4-hydroxy group. (Patent Document 1)
(II) A method in which the α-carbon of the methylbutyrate side chain of lovastatin is directly alkylated using a metal alkylamide and methyl halide. (Patent Document 2)
(III) A method of directly methylating a monoalkylamide of lovastatin. (Patent Document 3)
(IV) General formula (1);

A method comprising the ketalization of triol acid represented by the formula, acylation at the 8-position, and hydrolysis and lactonization of the ketal. (Patent Document 4)
US4444784 US4582915 US4820850 WO00 / 34264

  Regarding the method (I), the reaction selectivity in the steps after the selective silylation is not sufficiently high, and the total yield is not sufficiently high.

  Regarding the method (II), in order to efficiently convert the starting material, it is necessary to repeatedly add the amide base methyl halide. In addition, many impurities are generated during the methylation and hydrolysis steps, and the method (III) above is not suitable for industrial production because the reaction must be performed at an ultra-low temperature.

  Furthermore, although the method (IV) is a simple method, there is room for improvement in the purity of the obtained simvastatin.

  As a result of intensive studies in view of the above problems, the present inventors have found that the following formula (4);

The process which can produce the simvastatin represented by high quality with a high yield was discovered.

  That is, the present invention provides the following formula (3) in the presence of water in an aprotic polar solvent and a hydrocarbon solvent:

It relates to a method for producing simvastatin represented by the above formula (4), wherein an acid is allowed to act on the compound represented by the formula (wherein R represents an alkyl group having 1 to 4 carbon atoms).

  According to the present invention, high-quality simvastatin can be produced in high yield on an industrial scale.

All the steps in the present invention can be represented by the following steps (a) to (c) and the isolation purification method (d):
(A) a step of converting triolic acid (1) into an acetonide form (2);
(B) converting the acetonide form (2) into the acyl form (3);
(C) converting the acyl form (3) to simvastatin (4);
(D) A step of isolating and purifying simvastatin (4).

  These will be described in detail below in order.

1. Step (a)
In step (a), the following formula (1);

Is reacted with 2,2-dialkoxypropane in the presence of an acid to give the following formula (2):

The acetonide body (2) represented by these is manufactured.

  In the formula (2), R represents an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and tert-butyl group. A methyl group is preferred. The 2,2-dialkoxypropane is not particularly limited, and examples thereof include dimethoxypropane, diethoxypropane, dipropoxypropane, and dibutoxypropane.

  The compound represented by the formula (1) can be obtained, for example, by the method described in WO02 / 020453.

  Reaction (a) of the present invention is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, alcohol solvents, ether solvents, ester solvents, aromatic hydrocarbon solvents, ketone solvents, and nitrogen-containing solvents. Organic solvents, such as a solvent, are mentioned.

  Although it does not restrict | limit especially as an alcohol solvent, For example, methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol etc. can be mentioned.

  The ether solvent is not particularly limited, and examples thereof include tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and methyl tert-butyl ether.

  Although it does not restrict | limit especially as an ester solvent, Preferably it is C2-C8, More preferably, it is C3-C6 ester, Specifically, for example, methyl acetate, ethyl acetate, n-propyl acetate, Examples include isopropyl acetate, n-butyl acetate, and tert-butyl acetate.

  Although it does not restrict | limit especially as an aromatic hydrocarbon type solvent, Preferably it is C6-C12, More preferably, it is C6-C10, More preferably, it is C6-C8 aromatic hydrocarbon, Specifically, Examples include benzene, toluene, xylene, chlorobenzene and the like.

  Although it does not specifically limit as a ketone solvent, Acetone, methyl ethyl ketone, etc. are mentioned.

  The nitrogen-containing solvent is not particularly limited, and examples thereof include nitrile solvents such as acetonitrile and propionitrile, and amide solvents such as N, N-dimethylamide.

  Needless to say, the reaction solvents may be used alone or in combination of two or more.

  Although it does not specifically limit as reaction temperature, Usually, -20-100 degreeC is preferable and 0-50 degreeC is more preferable.

  The acid used in the reaction of the present invention (a) is not particularly limited. For example, hydrogen halides such as hydrogen chloride and hydrogen bromide; mineral acids such as sulfuric acid and phosphoric acid; methanesulfonic acid, ethanesulfonic acid and propane Sulfonic acids such as sulfonic acid, butanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 1-phenylethanesulfonic acid; formic acid, acetic acid, propanoic acid, 2-methylpropanoic acid, pivalic acid, butanoic acid 2-methylbutanoic acid, 2,2-dimethylbutanoic acid, pentanoic acid, 2-methylpentanoic acid, 2,2-dimethylpentanoic acid, hexanoic acid, 2-methylhexanoic acid, 2,2-dimethylhexanoic acid, Examples thereof include aliphatic carboxylic acids such as heptanoic acid and 2-methylheptanoic acid, and aromatic carboxylic acids such as benzoic acid. These may be used alone or in combination of two or more.

  Although the usage-amount of an acid is not specifically limited, Generally 0.01-10 mol% is preferable with respect to triol acid (1), More preferably, it is 0.1-5 mol%.

  In order to obtain a product from the reaction solution, a general post-treatment may be performed. For example, the reaction liquid after completion | finish of reaction is neutralized by processing with a base, After adding water, the method of extracting a product to an organic layer is mentioned.

  Although it does not specifically limit as said base, An inorganic base or an organic base is mentioned.

  Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and the like. Preferred are alkali metal carbonates and alkali metal hydrogen carbonates, and more preferred are alkali metal hydrogen carbonates.

  Examples of the organic base include primary amines such as methylamine, ethylamine, propylamine, butylamine and dimethylaniline, secondary amines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine and dicyclohexylamine, trimethylamine, There can be mentioned tertiary amines such as triethylamine, tripropylamine, tributylamine, triamylamine, ethyldiisopropylamine, pyridine, lutidine, imidazole and 4-dimethylaminopyridine.

  Although it does not specifically limit as a processing method using a base, A base may be once dissolved in an organic solvent and water, and may be added directly. In addition, the usage-amount of a base will not be specifically limited if it is the quantity which can neutralize an acid component.

  After treatment with a base, washing with water or the like may be performed as necessary. Thereafter, when the reaction solvent and the extraction solvent are distilled off by an operation such as heating under reduced pressure, the desired product is obtained. Although it does not specifically limit as temperature conditions which distill off a solvent, Usually, -20-100 degreeC is preferable, More preferably, it is -10-60 degreeC, More preferably, it is 0-40 degreeC. The target product thus obtained is almost pure, but it may be further purified by a general technique such as fractional distillation, column chromatography, etc.

  In addition, this reaction is usually carried out under an inert gas, but dissolved oxygen in the reaction solution and the solution in the subsequent step may be further removed.

2. Step (b)
In step (b) of the present invention, 2,2-dimethylbutanoic acid chloride is allowed to act on the acetonide compound (2) in the presence of a base to acylate the hydroxyl group at the 8-position, and the following formula (3):

Is produced. In the formula (3), R is the same as described above.

  The 2,2-dimethylbutanoic acid chloride used in the step (b) of the present invention can be procured from a reagent manufacturer or the like, but 2,2-dimethylbutanoic acid can be separately chlorinated and used. Hereinafter, a method for chlorinating 2,2-dimethylbutanoic acid will be described.

  Chlorination of 2,2-dimethylbutanoic acid can be performed by a general method known in the literature. For example, 2,2-dimethylbutanoic acid can be achieved by reacting thionyl chloride and a basic compound.

  The amount of thionyl chloride used in the above reaction can be suitably carried out usually at a 1-fold molar amount or more.

  In the above reaction, the basic compound to be used is not particularly limited, but preferred examples include organic bases, amide group-containing compounds, and quaternary ammonium halides.

  Specific examples of the organic base include those described above.

  Specific examples of the amide group-containing compound include, but are not limited to, dimethylformamide, dimethylacetamide, tetramethylurea, N-methylpyrrolidone, and hexamethylphosphoric triamide.

  Specific examples of the quaternary ammonium halide include tetramethylammonium chloride, tetraethylammonium chloride, tetra-n-butylammonium chloride, benzyltrimethylammonium chloride, benzyltri-n-butylammonium chloride, tetramethylammonium bromide, and tetraethyl bromide. Examples include ammonium, tetra-n-butylammonium bromide, benzyltrimethylammonium bromide, and benzyltri-n-butylammonium bromide, but are not limited thereto.

  In the above reaction, the amount of the basic compound used is not particularly limited, but is 0.01 mol% to 5 mol% with respect to 2,2-dimethylbutanoic acid.

  The above reaction can be carried out in the absence of a solvent depending on the basic compound to be used, but a solvent may be appropriately used as long as the reaction is not adversely affected.

  As reaction temperature, -20-120 degreeC is preferable, More preferably, it is 0-80 degreeC, More preferably, it is 10-60 degreeC.

  As a method for obtaining 2,2-dimethylbutanoic acid chloride from this reaction solution, concentration or distillation can be mentioned.

  The distillation or rectification of 2,2-dimethylbutanoic acid chloride is preferably performed under reduced pressure. The target product thus obtained is almost pure and may be reacted with the acetonide form (2) as it is. However, purification is performed by a general method such as column chromatography to further increase the purity. May be.

  Next, a method for acylating the hydroxyl group at the 8-position of the acetonide compound (2) using 2,2-dimethylbutanoic acid chloride in the presence of a base will be described.

  As the acetonide body (2), one obtained by the method of the aforementioned step (a) may be used, or one prepared separately may be used.

  The amount of 2,2-dimethylbutanoic acid chloride used is usually 1 mol or more with respect to the acetonide form (2).

  This reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it essentially does not adversely affect the reaction, and examples thereof include organic solvents such as ether solvents, ester solvents, and aromatic hydrocarbon solvents. Specific examples include those described above. Needless to say, the reaction solvents may be used alone or in combination of two or more.

  The above-mentioned bases can be used regardless of inorganic bases and organic bases, but organic bases are preferable, and tertiary amines are particularly preferable.

  These may be used alone or in combination of two or more.

  Although the usage-amount of a base is not specifically limited, Usually, it is 0.05-50 times mole amount with respect to an acetonide body (2), Preferably it is 0.1-20 times mole amount.

  Regarding the reaction temperature, it can be suitably carried out usually at 20 to 130 ° C.

  Although it does not specifically limit regarding reaction time, Usually, it is 100 hours or less, Preferably it is 48 hours or less.

  In order to obtain a product from the reaction solution, a general post-treatment may be performed. For example, water can be added to the reaction solution after completion of the reaction, and an extraction operation can be performed using a general extraction solvent such as toluene, ethyl acetate, diethyl ether, hexane or the like. The obtained organic layer can be appropriately washed with water, acidic water and / or basic water.

  As the acid for washing the organic layer with acidic water, any organic acid or inorganic acid can be used. Specifically, mineral acids such as hydrochloric acid and sulfuric acid, citric acid, formic acid, acetic acid, etc. And alkylsulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.

  The base when the organic layer is washed with basic water is not particularly limited, and examples thereof include alkali metal or alkaline earth metal hydroxides, and organic bases such as secondary amines and tertiary amines. it can. Examples of the alkali metal hydroxide, secondary amine, and tertiary amine include those described above. Examples of the alkaline earth metal hydroxide include magnesium hydroxide and calcium hydroxide, but are not limited thereto.

  The inorganic base is preferably used as an aqueous solution from the viewpoint of operability and the like. Usually, for example, an aqueous solution of alkali metal hydroxide of 0.01 to 20 mol / L, preferably 0.1 to 10 mol / L is used. Is preferred. These bases can be added while sequentially added at a rate that maintains the system at an appropriate pH. In view of the stability of the product and the like, it is preferably carried out in the range of pH 7-13.

  In addition, after the washing under the above basic condition, the base remaining in the system can be removed to the aqueous layer side by washing with water under acidic conditions. The pH at this time is not particularly limited, but considering the stability of the acyl body (3) under strongly acidic conditions, pH 1 to 6 is preferable.

  In order to obtain the target acyl body (3) from the obtained extract, the reaction solvent and the extraction solvent may be removed by an operation such as heating under reduced pressure. The temperature at which the solvent is distilled off is usually 0 to 100 ° C, preferably 10 to 60 ° C.

  The target product thus obtained is almost pure, but it may be further purified by a general technique such as fractional distillation, column chromatography, etc.

  Also, in the step (b) of the present invention, as described in the step (a), it is preferably carried out in the presence of an inert gas.

3. Step (c)
In the step (c) of the present invention, the acyl compound (3) is treated in the presence of an acid to give the following formula (4):

It is the process of converting into simvastatin represented by these.

  As the acyl body (3) used in this step, one produced by the above-described method may be used, or one obtained separately may be used.

  The acid to be used is not particularly limited, and examples thereof include hydrogen halides such as hydrogen chloride and hydrogen bromide, mineral acids such as sulfuric acid and phosphoric acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. it can.

  Although the usage-amount of the said acid is not specifically limited, Generally 0.01-5 times mole amount is preferable with respect to an acyl body (3).

  Step (c) of the present invention is carried out in the presence of water in an aprotic polar solvent and a hydrocarbon solvent.

  Usually, the amount of water used is suitably about 1 to 50 times the molar amount of the acyl compound (3).

  The aprotic polar solvent is not particularly limited, and includes the above ether solvents; ester solvents; ketone solvents; sulfur-containing solvents such as dimethyl sulfoxide; acetonitrile, dimethylformamide, diethylacetamide, dimethylbutyramide and the like. Mention may be made of nitrogenous solvents. Although it does not specifically limit as said hydrocarbon solvent, For example, aliphatic hydrocarbon solvents, such as the above-mentioned aromatic hydrocarbon solvent; Hexane, heptane, etc. can be mentioned. These may be used alone or in combination of two or more.

  The mixing ratio of the aprotic polar solvent and the hydrocarbon solvent is not particularly limited, but the lower limit of the ratio of the aprotic polar solvent to the total of the aprotic polar solvent and the hydrocarbon solvent is preferably 20 wt% or more. More preferably, it is 30 wt% or more. The upper limit is 100 wt%, preferably 80 wt% or less, more preferably 60 wt% or less.

  This reaction can be suitably carried out usually at -20 to 60 ° C.

  In addition, since the lactonization in this step is a transesterification reaction, the equilibrium between the raw material and the product may be tilted toward the product side by appropriately distilling off the methanol produced as a by-product from the reaction by an operation such as concentration. This can increase the reaction yield.

  After the reaction, a general post-treatment may be performed. For example, a method of adding water to the reaction solution for extraction, a method of subjecting the reaction solution to a concentration step, and the like can be mentioned. The reaction solution may be used as it is, or may be subjected to an extraction or concentration step after being treated with a base to neutralize the acid.

  In the step (c) of the present invention, when the acid is neutralized using a base after the reaction, the base to be used can be any inorganic base or organic base, and specific examples thereof include those described above. It is done.

  The amount of the base used is preferably 1 mol or more with respect to the acid used in the reaction.

  Although the method in the case of performing concentration operation is not specifically limited, Usually, it implements under reduced pressure.

  Regarding the post-treatment operation from the above reaction, maximization of yield and impurity control can be advantageously performed by appropriately combining the operations described.

  Also, in the step (c) of the present invention, it is preferable to carry out in the presence of an inert gas as described in the reaction (a).

4). Isolation / purification step (d)
Next, a method for isolating and purifying simvastatin (4) will be described.

  Simvastatin (4) obtained by steps (a) to (c) of the present invention usually contains dimer (5) as an impurity.

  In order to obtain the high-purity simvastatin (4) by removing the impurities, it is preferable to perform crystallization using an organic solvent. Specifically, it is preferable to perform crystallization using an aromatic hydrocarbon solvent and an aliphatic hydrocarbon solvent, and / or crystallization using a ketone solvent or a nitrogen-containing solvent, and water. In addition, this method can be used effectively also when refine | purifying the simvastatin obtained by methods other than process (a)-(c).

  Although it does not specifically limit as an organic solvent used for crystallization, For example, C5-C12 aromatic hydrocarbon solvent which may have a substituent, C5-C5 which may have a substituent. Examples thereof include hydrocarbon solvents such as 12 aliphatic hydrocarbon solvents and aprotic water-soluble solvents.

  Although it does not specifically limit according to the said aromatic hydrocarbon solvent, For example, benzene, toluene, xylene etc. can be mentioned.

  Although it does not specifically limit as said aliphatic hydrocarbon solvent, For example, a pentane, hexane, heptane, octane, nonane, a decane etc. can be mentioned.

  Examples of the aprotic water-soluble solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, ketone solvents such as acetone and methyl ethyl ketone, and nitrogen-containing solvents such as acetonitrile, dimethylformamide, diethylacetamide, and dimethylbutylamide. I can list them.

  In the crystallization, simvastatin (4) can be an extract or a concentrate obtained by the method of steps (a) to (c) of the present invention. The crystallization method is not particularly limited, and a poor solvent addition crystallization method, a cooling crystallization method, a concentrated crystallization method, a solvent substitution crystallization method, and the like can be used. Needless to say, these crystallization methods can be used in appropriate combination.

  In crystallization, seed crystals may be added as necessary.

  In the crystallization, a solution of simvastatin (4) may be treated in advance using an adsorbent such as activated carbon.

  The crystallization concentration is not particularly limited, but the weight of simvastatin (4) with respect to the solvent capacity is generally preferably 0.5 to 30 wt / v%, more preferably 2 to 20 wt / v%.

  Although the crystallization temperature is not particularly limited, 0 to 60 ° C. is preferable and 0 to 40 ° C. is more preferable in consideration of the stability of simvastatin (4) and the quality of the obtained crystal.

  The method of crystallization using a ketone solvent or nitrogen-containing solvent and water is, for example, by dissolving simvastatin (4) obtained by the above method in a ketone solvent or nitrogen-containing solvent and adding water. The cooling crystallization method, the concentration crystallization method, the solvent substitution crystallization method, and the like can be appropriately combined. In crystallization, seed crystals can be added as necessary. Examples of the ketone solvent or the nitrogen-containing solvent include those described above.

  The volume ratio of water to the water-soluble aprotic solvent is generally preferably 0.5 to 1.5. However, the volume ratio may be appropriately changed in consideration of the purification effect of simvastatin (4) and the physical properties of the crystals obtained. it can.

  Regarding the crystallization temperature, it is generally preferable to carry out at an upper limit of 40 ° C. in consideration of the thermal stability of simvastatin (4). The lower limit is not lower than the solidification temperature of the system, but is usually 0 ° C. or higher, more preferably 5 ° C. or higher.

  The crystallization concentration is not particularly limited, but the weight of simvastatin (4) with respect to the solvent capacity is generally preferably 1 to 40 wt / v%, more preferably 5 to 20 wt / v%.

  In addition, the isolation and purification method of the present invention is preferably carried out in the presence of an inert gas as described in the reaction (a).

  The crystals of simvastatin (4) obtained in the present invention can be collected using a general solid-liquid separation method such as centrifugation, pressure filtration, and vacuum filtration. The obtained crystal can be obtained as a dry crystal by, for example, drying under reduced pressure, if necessary.

  According to the production method of the present invention, high-quality simvastatin (4) crystals can be obtained in high yield.

  Hereinafter, the present invention will be described in detail with reference to examples. Of course, these examples do not limit the present invention in any way.

(Example 1)
2,2-dimethyl-6 (R)-(2-8 (S) -hydroxy-2 (S), 6 (R) -dimethyl-1,2,6,7,8,8a (R) -hexahydro Naphthyl-1 (S)) ethyl) -4 (R)-(methyloxycarbonyl) methyl-1,3-dioxane (2) (hereinafter abbreviated as acetonide form) A nitrogen-substituted flask was charged with triol acid ( 12.0 g of 1) (purity: 96.3%) and 120 g of toluene were added and dissolved under stirring. To this was added 2,2-dimethylbutanoic acid (0.3 g), dimethoxypropane (16.6 g), and p-toluenesulfonic acid monohydrate (0.17 g), and the mixture was stirred at room temperature. After adding pyridine, the mixture was washed with 5% aqueous sodium bicarbonate and water, and then concentrated with a rotary evaporator to obtain a toluene solution containing 13.9 g of the title compound (yield 100%).

(Example 2)
Production Method of 2,2-Dimethylbutyryl Chloride 2,2-Dimethylbutanoic acid (19 g) and triethylamine were charged into a nitrogen-substituted flask, and then thionyl chloride (21. 2) was stirred with attention to heat generation at room temperature. 4 g) was added slowly. After completion of the reaction, the reaction solution was distilled under reduced pressure to obtain the title compound.

Example 3
2,2-dimethyl-6 (R)-(2- (8 (S)-(2,2-dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl-1,2,6,7 , 8,8a (R) -hexahydronaphthyl-1 (S)) ethyl) -4 (R)-(methyloxycarbonyl) methyl-1,3-dioxane (3) (hereinafter abbreviated as acyl form) law nitrogen-purged flask, toluene solution containing acetonide body (2) 13.8 g, was placed pyridine 28.0 g, and 4-dimethylaminopyridine 0.87 g. To this, 9.5 g of 2,2-dimethylbutanoic acid chloride prepared by the method of Example 2 was added, followed by stirring at 110 ° C. After cooling to near room temperature, it was washed with an aqueous sodium hydroxide solution. After adding toluene, the organic layer was washed with dilute sulfuric acid and water, and concentrated with a rotary evaporator to obtain a toluene solution containing 17.2 of the acyl compound (3) (yield 99.0%).

(Example 4)
Manufacturing method of simvastatin (4) A toluene solution containing 1.2 g of acyl (3), 10 g of acetonitrile, 0.3 g of water, and 0.06 g of methanesulfonic acid were placed in a flask purged with nitrogen, and then at room temperature. Stir. After completion of the reaction, 0.06 g of pyridine was added and the solution was partially concentrated under reduced pressure. Toluene was added to the concentrate, washed with water, and concentrated under reduced pressure to obtain a concentrate containing 0.9 g of the title compound (yield: 90%).

(Example 5)
Manufacturing method of simvastatin (4) To a flask purged with nitrogen was added a toluene solution containing 10.0 g of simvastatin (4) (dimer: 0.85%) and 0.5 g of activated carbon, and then suspended. The mixture was stirred at room temperature for 30 minutes. After the activated carbon was filtered with a Kiriyama funnel, the filtrate was partially concentrated with a rotary evaporator. Subsequently, heptane was added with stirring (inoculated with seed crystals of simvastatin on the way), then cooled and stirred for 30 minutes in an ice bath. After filtering the slurry with a Kiriyama funnel, the wet cake was dried while heating under reduced pressure to obtain 9.6 g of simvastatin (4) crystals (yield: 94.5%). When analyzed by HPLC, the purity was 97.5 wt% and the dimer content was 0.36%.

(Example 6)
After 1.8 g (purity: 91.1 wt%) of separately obtained simvastatin (4) was added to the flask purged with nitrogen and dissolved in 5.5 g of acetone, 6.5 g of water was slowly added to this solution in an ice bath. Added. The obtained slurry was stirred for 2 hours, then filtered through a Kiriyama funnel, and the resulting wet cake was dried while heating under reduced pressure to obtain 1.6 g of simvastatin (4) crystals (yield: 88). %). When analyzed by HPLC, the purity was 99.5 wt% and the dimer content was 0.35%.

Claims (6)

In the presence of water in an aprotic polar organic solvent and a hydrocarbon organic solvent, the following formula (3):
(Wherein R represents an alkyl group having 1 to 4 carbon atoms) an acid is allowed to act on the compound represented by the following formula (4);
The manufacturing method of simvastatin represented by these. The compound represented by the formula (3) is represented by the following formula (2);
The production method according to claim 1, wherein the acetonide compound represented by the formula (wherein R is the same as above) and 2,2-dimethylbutanoic acid chloride are reacted in the presence of a base. The compound represented by the formula (2) is represented by the following formula (1);
The production method according to claim 2, which is obtained by reacting a compound represented by the formula (2) with 2,2-dialkoxypropane in the presence of an acid.   The manufacturing method according to claim 1, wherein the obtained simvastatin represented by the formula (4) is subjected to a crystallization step.   The method according to claim 4, wherein crystallization is performed using an aromatic hydrocarbon solvent and an aliphatic hydrocarbon solvent.   5. The production method according to claim 4, wherein crystallization is performed using a ketone solvent or a nitrogen-containing solvent and water.