Process for lactonization to produce simvastatin

Details Process for lactonization to produce simvastatin Process for lactonization to produce simvastatin

2003-05-19

2004-09-28

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

06797831

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not Applicable.
BACKGROUND OF INVENTION
This invention relates to a process for lactonization to produce simvastatin.
Lovastatin, simvastatin, pravastatin, atorvastatin and mevastatin are well known potent antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. This class of compounds, referred to generally as statins, are produced either by natural fermentation process or through semi-synthetic and totally synthetic means thereof. Two of the most popular compounds in this therapeutic category are simvastatin and atorvastatin. The former is one of the most prescribed drugs in the treatment of primary hypercholesterolemia with minimum side effects and well established safety profile. The use of highly pure simvastatin is exceedingly desirable in preparation of a pharmaceutical form as it would avoid accumulation of impurities during prolonged usage and would reduce the possible side effects during medical treatment.
1. Field of the Invention
A process for lactonization to produce simvastatin of Formula I
2. Description of Related Art
In most of the synthetic methods known to manufacture simvastatin (Formula I) shown below,
hydroxyacid ammonium salt (Formula IIA) also shown below is the common intermediate,
which is cyclized to obtain simvastatin and thus lactonization constitutes an essential step of the process. It is of considerable importance to employ an efficient method for the lactonization that can produce simvastatin of high purity in good yield.
The process disclosed in the U.S. Pat. No. 4,820,850 involves heating of hydroxyacid ammonium salt in toluene at 100° C. under a purge of nitrogen. The lactonization completion requires 6-8 hours refluxing and results information of increased amounts of dimer (Formula III).
This dimer impurity is difficult to separate from the desired lactone even with repeated crystallization. The presence of dimer lowers the purity of the simvastatin product.
U.S. Pat. No. 4,916,239 describes another process where the lactonization reaction has been carried out by treating hydroxyacid ammonium salt in a mixture of acetic acid and water, and in the presence of a strong acid catalyst. This process requires gradual addition of water in several lots to effect crystallization of the lactonized product from the reaction medium to shift the equilibrium to the lactone side and this drives the lactonization to completion. This process is not amenable to industrial scale due to effluent generation and low purity of simvastatin product even though dimer content obtained is reported to be less than 0.2%.
U.S. Pat. No. 5,917,058 provides an alternate process to lactonize hydroxyacid or its salt by treatment with acetic acid under anhydrous conditions. The reaction is to be carried out essentially for a period of 5-7 hours and extensive water washing of the product is required to remove traces of acetic acid.
The aim of the present invention is to provide a highly efficient method for lactonization to produce simvastatin of greater than 99% purity in high yield. An example where simvastatin of greater than 99.5% purity has been achieved is cited in WO 99/42601 wherein the product was purified by successive crystallizations from aqueous acetone and from ethyl acetate.
BRIEF SUMMARY OF THE INVENTION
According to this invention, there is provided a process for lactonization to produce simvastatin, Formula I
which comprises heating a compound namely acid or ammonium salt of compound of Formula II
where Z is H or NH
4
in an organic solvent selected from xylenes, ethylbenzene and mixtures thereof at a temperature of 130 to 140° C.
The lactonization reaction (heating) is completed in 20-40 minutes.
The organic solvent is preferably xylenes and Z is NH
4
.


REFERENCES:
patent: 4820850 (1989-04-01), Verhoeven et al.
patent: 4916239 (1990-04-01), Treiber
patent: 5917058 (1999-06-01), Kumar et al.

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