Process for lactonization to produce highly pure simvastatin

Details Process for lactonization to produce highly pure simvastatin Process for lactonization to produce highly pure simvastatin

2003-06-23

2004-11-30

Solola, Taofiq (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06825362

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not Applicable
FIELD OF THE INVENTION
A process for lactonization to produce highly pure simvastatin of Formula I
BACKGROUND OF THE INVENTION
This invention relates to a process for lactonization to produce highly pure 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 product as it would avoid accumulation of impurities during prolonged usage and would reduce the possible side effects during medical treatment.
In most of the synthetic methods known to manufacture simvastatin (Formula I) shown below, the compound of Formula IIA also shown below, is the common intermediate, which is cyclized to obtain simvastatin and thus lactonization constitutes an essential step of the synthesis.
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 in formation of increased amounts of dimer (Formula III).
This dimer impurity is difficult to separate from the desired lactone even with repeated crystallization. Efforts to minimise the formation of the dimer have led to the use of high dilution during lactonization reaction. Nevertheless, this technique results in lower efficiency and is disadvantageous at commercial scale.
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. However, the purity of the final product obtained by this procedure is not more than 99%. Furthermore, in this patent, there is no reference to the level of dimeric impurity produced in the process.
The aim of the present invention is to obtain highly pure simvastatin that contains dimeric impurity less than 0.1%. 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 STATEMENT OF THE INVENTION
According to this invention, there is provided a process for lactonization to produce highly pure simvastatin of Formula I
which comprises lactonization of a compound of the Formula II,
where Z is H or NH
4
in a mixture of acetonitrile and glacial acetic acid under anhydrous conditions at a temperature of 65-70° C. and wherein the dimer impurity of Formula III formed is less than 0.1 and thereafter adding water to the reaction mixture thereby causing simvastatin of Formula I to precipitate from the reaction mixture.
In this process in Formula II above, preferably Z is NH
4
.
The process further comprises adding water to the reaction mixture, thereby causing simvastatin of Formula I to precipitate from the reaction mixture.


REFERENCES:
patent: 6573385 (2003-06-01), Sambasivam et al.
patent: 6649775 (2003-11-01), Lee et al.

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