Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-09-04
2004-06-29
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S119000
Reexamination Certificate
active
06756507
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of sodium salts of statins, namely Compactin, Lovastatin and Pravastatin having the Formula Ia:
BACKGROUND OF THE INVENTION
The “statins” are a family of compounds that are usually inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. As HMG-CoA reductase inhibitors, the statins are able to reduce plasma cholesterol levels in various mammalian species, including humans and are therefore effective in the treatment of hypercholesterolaemia.
Of all the statins known only two are produced directly by fermentation. These are Lovastatin (also called mevinolin or monacolin-K) and Compactin (also called mevastatin or ML-236B). Other statins are produced either chemically or enzymatically derived from Lovastatin or Compactin. One of these is Pravastatin, which has found favour recently as a more potent HMG-CoA reductase inhibitor than Lovastatin or Compactin and is disclosed in U.S. Pat. No. 4,346,227.
Preparation of sodium salts of these compounds has been described in U.S. Pat. Nos. 4,448,979; 4,346,227; and 4,447,626. The methods employ use of alkali, acid, solvents, ion exchange chromatography followed by freeze drying operation using either the lactone or methyl ester form of Pravastatin as the raw material.
Further, U.S. Pat. No. 4,432,996 describes a method for the preparation of sodium salts of compactin. This method employs compactin lactone form as the starting material and involves sodium salt formation using sodium hydroxide and its subsequent isolation by taking to dryness ‘in vacuo’.
The isolation method reported till now comprises complete removal of the solvent by either freeze drying or dryness under vacuum. In addition, the process involves an elaborate extraction procedure for the work up and is uneconomical at commercial manufacturing scale because of large number of steps. This operation is time consuming and also involves capital intensive equipment at industrial scale.
The recent commercial introduction of chemically synthesized HMG-CoA reductase inhibitors has provided a need for development of high yielding processes for production of fermentation-based statins. The techniques to improve the processes include, but are not limited to, improving the producer microorganisms, scale up of the process, improving the culture medium or simplifying downstream recovery process.
DESCRIPTION OF THE INVENTION
It is an object of the present invention to solve the problems associated with the prior art and to provide a simplified and efficient method for the preparation of sodium salts of these statins using conditions which are convenient to operate on commercial scale.
The present invention specifically describes a process for the preparation and isolation of sodium salts of statins of Formula Ia. The process comprises contacting a solution of the hydroxy acid form of the statins of Formula Ib
with sodium 2-ethylhexanoate and recovering the corresponding sodium salts of the statins from a solution thereof.
According to the present invention, the starting material is hydroxy acid form of the statins or is generated in situ from the lactone form or other ester or salts of the statins. Sodium 2-ethylhexanoate is prepared by the methods known in the literature.
Solvents which may be used are generally selected depending upon the solubility of the hydroxy acid form of the statins and preferably are water-immiscible organic solvents. These include chlorinated hydrocarbons such as chloroform, dichloromethane, dichloroethane etc., aromatic hydrocarbons, such as benzene, toluene, xylene, ketones such as methyl ethyl ketone, methyl isobutyl ketone or esters such as ethyl acetate, butyl acetate, isopropyl acetate or isobutyl acetate or mixtures thereof. The preferred solvent being ethyl acetate from economics point of view.
Methods known in the art may be used with the process of this invention to enhance any aspect of this process. For example, slurry may be cooled prior to filtration or a miscible “anti-solvent” can be advantageously used to complete crystallization. Preferably, the anti-solvent is selected from a group of solvents, like acetone and acetonitrile, most preferred being acetone or water immiscible solvents like ether and hexane.
The following examples illustrate the present invention and are not intended to be limiting the scope of the invention.
REFERENCES:
patent: 4346227 (1982-08-01), Terahara et al.
patent: 4432996 (1984-02-01), Gullo et al.
patent: 4447626 (1984-05-01), Terahara et al.
patent: 4448979 (1984-05-01), Terahara et al.
patent: 5559241 (1996-09-01), Corsi et al.
patent: WO 98/56750 (1998-12-01), None
Kumar M. Lakshmi
Kumar Parveen
Narula Pardeep
Raman Srinivasan
Deshmukh Jayadeep R.
Killos Paul J.
Ranbaxy Laboratories Limited
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