Process for producing simvastatin

Details Process for producing simvastatin Process for producing simvastatin

2002-08-20

2003-06-10

Owens, Amelia (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06576775

ABSTRACT:

This is a Nationalization of PCT/KR00/00283, Mar. 30, 2000 and published in the English.
FIELD OF THE INVENTION
The present invention relates to a process for producing Simvastatin compound. This compound has the following formula I:
and is useful in inhibiting the biosynthesis of cholesterol.
It is known that Simvastatin compound is a suppressor of HMG CoA reductase and a medicament useful for the treatment of hypercholesterolemia. Several processes for producing said compound are disclosed. One is disclosed in U.S. Pat. No. 4,444,784 (corresponding to Korean Publication Patent No. 85-669) with the following reaction mechanism:
DESCRIPTION OF THE PRIOR ART
The said process described in U.S. Pat. No. 4,444,784 is generally performed in the presence of an excess acylchloride (II) under the condition of high temperature and a long reaction time. In addition, said process has the following disadvantages: i) lower yield of acylated substance; ii) production of by-product due to removal of t-butyldimethylsilyloxy radical; and iii) difficulty of separating the resulting substance, ester (IV), from residual alcohol (III) and acylchloride (II). The residual substances may inhibit the crystallization of the resulting substance.
A process for reforming the above-mentioned process is described in U.S. Pat. No. 4,845,237. Its reaction mechanism is as follows:
This process reduces the production of by-product and increases the yield of resulting substances by activating acylchloride (II) through the addition of alkalic metal and 4-dialkylaminopyridine. However, this process is also troublesome in that acylchloride (II) should be prepared from carboxylic acid (V), and the LiBr involved in activation of acylchloride is a substance the treatment of which is very difficult. Using LiBr requires that it be dried at 135 °C. for 3 days under a vacuum condition. When the dried LiBr is added to acylchloride, it should be treated using plastic container because it is very water-absorbent. If the wetted LiBr is added, the yield is lowered and by-product is produced. Therefore, the process becomes complicated and difficult.
Accordingly, we have researched and developed a new process, which acylchloride (II), and without the use of LiBr.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for producing Simvastatin comprising the steps of acylating of 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-butylmethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-on with carboxylic acid compound (VI), and hydroxylating of acylated compound. The said carboxylic acid compound has the following formula (VI):
wherein, R is methyl, ethyl, propyl, n-butyl, t-butyl, or phenyl.
In the present invention, carboxylic acid (VI) used for acylation is activated by trialkylphosphine and halogen compounds, and is directly used without separation, which allows for the simplification of the process. This reaction mechanism is as follows:
wherein, R is methyl, ethyl, propyl, n-butyl, t-butyl, or phenyl, R1 is a halogen compounds, such as hexachloroethane, carbon tetrachloride, carbon tetrabromide, or hexachloroacetone. When activated carboxylic acid (VI), which is not separated or purified, reacts with alchol (III), a higher yield of acylated substance (IV) is obtained.
The formula (III) compound of the invention is easily prepared by those skilled in the art. It is preferable that PR
3
of the initial compound (VI) is triphenylphosphine. The halogen compound is preferably hexachloroethane. It may be used in amount of from 1.0 to 4.0 equivalent, preferably from 3.0 to 3.6 equivalent. Temperature is from 0 °C. to 110 °C., preferably 83° C.
The solvent is used alone or in combination with inert solvents, including acetonitrile, dichioromethane, dichloroethane, cyclohexane, and toluene, most preferably dichioroethane.
It is to be understood that the examples which follow, are intended to illustrate and not limit the scope of the invention.
EXAMPLES


REFERENCES:
patent: 5393893 (1995-02-01), Kubela et al.
patent: 0511867 (1992-04-01), None

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