KR100322630B1 - Processes for Producing Simvastatin and its Intermediate - Google Patents

Abstract

The present invention relates to a carboxylic acid compound represented by the following formula (VI), wherein 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) -t-butyldimethylsilyloxy-3,4,5,6 The present invention relates to a method for preparing a simvastatin intermediate compound represented by the following formula (I '), characterized by acylating -tetrahydro-2H-pyran-2-one. To a process for preparing simvastatin compounds known as:

(VI)

Wherein R is methyl, ethyl, propyl, n-butyl, t-butyl or phenyl and X is halogen.

Description

Process for Producing Simvastatin and Intermediate Compounds thereof {Processes for Producing Simvastatin and its Intermediate}

The present invention relates to a process for preparing a compound of formula (I ′):

The present invention also relates to a method for preparing a simvastatin compound represented by the following formula (I):

Simvastatin is an inhibitor of HMG CoA reductase and is well known as an antihypercholesterolemia compound, which is useful for inhibiting cholesterol biosynthesis.

There are several known methods in the preparation of simvastatin compounds, as described in US Pat. No. 4,444,784 (Korean Patent Publication No. 85-669).

The process generally requires high temperature, long reaction conditions and an excess of acyl chloride (II) required for the reaction. In addition, there is a disadvantage that the yield of acylated material obtained under this condition is low. In addition, under these conditions, t-butyldimethylsilyloxy radicals are removed, resulting in a by-product. Excess starting material alcohol (III) and unconsumed acylchloride (II) remain, which leads to difficulty in separating the reactants and thus poor ester (I ') yield. This impurity may interfere with the crystallization of the final material.

An improved method of this is described in US Pat. No. 4,845,237. This is represented by the reaction scheme as follows.

The method has the advantage of activating acyl chloride (II) by adding alkali metal and 4-dialkylaminopyridine to reduce reaction by-products and increase yield. However, this method has the disadvantage of having to use acyl chloride (II) synthesized from carboxylic acid (V) and difficulty in handling LiBr necessary for activating acyl chloride. In order to use LiBr, it has to be dried for 3 days at high temperature (135 ° C.) under vacuum, and has a very strong hygroscopicity, so that the water absorption is completely reduced by using a plastic container. When moisture-absorbed LiBr is used, the reaction yield is lowered and by-products are produced. Therefore, the process is cumbersome and difficult to produce on an industrial scale.

Therefore, the present inventors have studied the acylation reaction in a simpler way.

A method for producing a good yield was developed without using acyl chloride (II) separately and using carboxylic acid (V) directly and without using LiBr, which is difficult to handle.

The present invention relates to a carboxylic acid compound represented by the following general formula (VI), wherein the compound represented by the following general formula (III) (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)-((t-butyldimethylsilyl (Oxy) -3,4,5,6-tetrahydro-2H-pyran-2-one) provides a process for preparing simvastatin intermediate compounds of formula (I '):

In the above formula,

R is methyl, ethyl, propyl, n-butyl, t-butyl or phenyl,

X is halogen.

In addition, the present invention provides a carboxylic acid compound represented by the following formula (VI) 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)-((t-butyldimethylsilyl) oxy) -3,4 A method for preparing a simvastatin compound of formula (I) by acylating with 5,6-tetrahydro-2H-pyran-2-one to produce a compound of formula (I ′) and hydroxylating the product. It is about:

In the above formula,

R is methyl, ethyl, propyl, n-butyl, t-butyl or phenyl,

X is halogen.

The present invention activates the carboxylic acid (V) used for acylation by using trialkylphosphine or triphenylphosphine and halogen compounds having 1 to 2 carbon atoms, and immediately using them without separating them. I can do it. Schematic of this is as follows.

Wherein R is methyl, ethyl, propyl, n-butyl, t-butyl or phenyl and R1 is a halogen compound, for example hexachloroethane, carbon tetrachloride, carbon tetrabromide or hexachloroacetone. When the activated carboxylic acid (VI) is reacted with alcohol (III) without purification or separation, the desired acylating substance (I ') can be obtained in high yield. Schematic of this is as follows.

The compound of formula (III) used in the present invention can be easily prepared according to known techniques. PR ₃ is preferably triphenylphosphine with respect to the starting compound (III), and halogen compound R1 is preferably hexachloroethane, and the amount thereof used is 1.0 to 4.0 equivalents, preferably 3.0 equivalents and 3.6 equivalents, respectively. The reaction temperature at this time is 0-110 degreeC, Preferably it is 83 degreeC.

As the solvent of the reaction, an inert solvent, for example, an organic solvent such as acetonitrile, dichloromethane, dichloroethane, cyclohexane, toluene may be used alone or in combination, but is preferably used in consideration of reaction temperature and by-products. Is dichloroethane.

The following examples illustrate the preparation of the invention. However, these examples are intended to explain the present invention in more detail and should not be understood as limiting the scope of the present invention.

Example 1

6 (R)-[2- (8 '(S)-((2,2-dimethylbutyryl) oxy) -2' (S), 6 '(R) -dimethyl-1', 2 ', 6' , 7 ', 8', 8'a (R) -hexahydronaphthyl-1 '(S)) ethyl] -4 (R)-((t-butyldimethylsilyl) oxy) -3,4,5, Preparation of 6-tetrahydro-2H-pyran-2-one

Dissolve 18.1 g of triphenylphosphine in 100 ml of dichloroethane and add hexachloroethane.

Add 19.6 g. Stir at 20 ° C. for 1 hour and add 8.0 g of 2,2-dimethylbutyl acid.

Stir for 45 minutes. 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)-((t-butyldimethylsilyl) oxy-3,4,5,6-tetrahydro-2H-pyran 10.0 g of 2-one was added and refluxed for 20 hours, when the reaction was monitored by HPLC, the starting material was converted to 99% or more, the area ratio of the desired material (I) was 96-97%, and the amount of unsaturated lactone produced as a by-product was 1 It is very small, about 2%, cooled to 10 ° C., 100 ml of 2% hydrochloric acid is added, stirred, and the organic layer is separated, and the reaction solution is concentrated and 100 ml of cyclohexane is added to form triphenyloxide as crystals. The mixture was cooled to 2 hours, stirred for 2 hours, filtered and washed with cooled cyclohexane to obtain the title compound which was used directly in the next reaction.

Example 2

6 (R)-[2- (8 '(S)-((-2,2-dimethylbutyryl) oxy) -2' (S), 6 '(R) -dimethyl-1', 2 ', 6 ', 7', 8 ', 8'a (R) -hexahydronaphthyl-1' (S) ethyl] -4 (R)-((t-butyldimethylsilyl) oxy-3,4,5,6 Preparation of Tetrahydro-2H-pyran-2-one

Dissolve 18.1 g of triphenylphosphine in 50 ml of dichloroethane and add 19.6 g of hexachloroethane. Stir at 20 ° C. for 1 hour. This solution was added dropwise to a solution of 8.0 g of 2,2-dimethylbutyl acid dissolved in 50 ml of dichloroethane and stirred for 1 hour. 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)-((t-butyldimethylsilyl) oxy) -3,4,5,6-tetrahydro-2H 10.0 g of pyran-2-one was added and refluxed for 20 hours. After cooling to 10 ° C., 100 ml of 2% hydrochloric acid was added and stirred, and the organic layer was separated. The reaction solution was concentrated and 100 ml of cyclohexane was added to form triphenyloxide as crystals. It was cooled to 10 ° C., stirred for 2 hours, filtered and washed with cooled cyclohexane to obtain the desired title compound which was used directly in the next reaction.

Example 3

Preparation of Simvastatin

6 (R)-[2- (8 '(S)-(4-butyl-2,2-dimethyloxy) -2' (S), 6 '(R) -dimethyl-1', 2 ', 6' , 7 ', 8', 8'a (R) -hexahydronaphthyl-1 '(S)) ethyl] -4 (R) -t-butyldimethylsilyloxy-3,4,5,6-tetrahydro To 19.7 g of -2H-pyran-2-one, 175 ml of acetonitrile and 8.8 ml of 40% hydrogen fluoride were added and stirred at 30 ° C. for 3 hours. After the reaction, the mixture was cooled to 10 ° C., 200 ml of distilled water and 500 ml of ethyl acetate were added, and the organic layer was separated. The separated solution is washed with 200 ml of 5% sodium bicarbonate and concentrated. 20 ml of toluene and 400 ml of cyclohexane were added to the concentrate to crystallize. Once the crystals are formed, they are stirred for 1 hour at 10 ° C. and filtered to obtain 13.9 g of pure simvastatan.

As can be seen from the above results, it is evident that the present invention is industrially useful by obtaining an acylated substance (I ') with high yield (97%) without using LiBr, which is difficult to handle.

Claims (5)

The compound of formula VI is added to 6 (R)-[2- (8 '(S) in at least one inert organic solvent selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, cyclohexane, toluene and mixtures thereof. ) -Hydroxy-2 '(S), 6' (R) -dimethyl-1 ', 2', 6 ', 7', 8 ', 8'a (R) -hexahydronaphthyl-1' (S ))ethyl]- Of a compound of formula (I ′) characterized by acylation with 4 (R)-((t-butyldimethylsilyl) oxy) -3,4,5,6-tetrahydro-2H-pyran-2-one Manufacturing method: (VI) In the above formula, R is phenyl, X is halogen. The compound of formula (VI) is triphenylphosphine hexachloroethane. A method for producing a halogenated compound by reacting with a halogen compound selected from the group consisting of carbon tetrachloride, carbon tetrabromide and hexachloroacetone, and then reacting it with a carboxylic acid compound of formula (V). (V) The method of claim 1, wherein the halogen compound is hexachloroethane. The method of claim 2, wherein the halogen compound is used in an amount of 1.0 to 4.0 equivalents. The method of claim 1 wherein the inert organic solvent is dichloroethane.