Lactonization process

Details Lactonization process Lactonization process

2000-10-23

2002-04-30

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

06380401

ABSTRACT:

FIELD OF THE INVENTION
The present invention involves a lactonization process which is useful for making 3-hydroxy lactone-containing products, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.
BACKGROUND OF THE INVENTION
It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering arrnamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. With the introduction of lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938), the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain comparatively large reductions in plasma cholesterol with very few adverse effects.
In addition to the HMG-CoA reductase inhibitors which are natural fermentation products, mevastatin and lovastatin, there are now a variety of semi-synthetic and totally synthetic analogs thereof, including simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin (PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin (LESCOL®; see U.S. Pat. No. 5,354,772), atorvastatin (LIPITOR®; see U.S. Pat. No. 5,273,995), cerivastatin (also known as rivastatin; see U.S. Pat. No. 5,177,080) and nisvastatin (also known as NK-104, see U.S. Pat. Nos. 5,284,953, 5,356,896 and 5,856,336). The hemi-calcium salt of nisvastatin is described and claimed in U.S. Pat. No. 5,856,336, while the structural formulas of the other noted HMG-CoA reductase inhibitors, as well as additional examples of HMG-CoA reductase inhibitors, are described at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (Feb. 5 1996). The HMG-CoA reductase inhibitors described above belong to a structural class of compounds which contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding open-ring 3,5-dihydroxy acid, as depicted below in the Scheme, and are commonly referred to as “statins.”
The lactonized forms of the statins are metabolized to the active open-ring 3,5-dihydroxy acid form in the body. Lovastatin and simvastatin are marketed worldwide in their lactonized form. However, the preparation of the naturally occurring compounds and their semi-synthetic analogs leads to a mixture of the lactone and the open-ring 3,5-dihydroxy acid forms. Therefore, it is important to employ a high yielding and efficient method for lactonizing the open-ring form or a salt thereof.
Since lactonization is an equilibrium reaction, as illustrated in the Scheme below, some means of shifting the equilibrium to the “right,” i.e., towards formation of the lactone, is required to achieve product in high yield and high purity.
In previous published procedures for making 3-hydroxy lactone-containing HMG-CoA reductase inhibitors, this equilibrium reaction was driven toward lactone formation by either (1) heating the dihydroxy acid in a neutral solvent with continuous removal of the water by-product, see U.S. Pat. No. 4,444,784 , or by (2) removing the lactone product by adding water in order to crystallize out the lactone product, see U.S. Pat. No. 4,916,239.
When applying the technique of water removal to drive the equilibrium toward the desired lactone product, higher temperatures are required which promote an undesirable esterification reaction between the 3-hydroxy group of the 3-hydroxylactone with the precursor free acid to produce a dimeric impurity. As an example, the dimer of simvastatin is shown below. Reduction of the dimer impurity content in the final product is difficult, since standard purification methods such as re-crystallization, which requires heating, tend to promote further dimer formation.
Applying the approach of adding water to the reaction mixture to drive the equilibrium toward the lactone product mitigates the dimer impurity problem, but two other problems occur with this procedure. One problem is that the addition of water to effect crystallization of the product and drive the equilibrium toward the lactone side provides insufficient force to take the reaction to completion, resulting in contamination of the final product with unconverted starting material. This requires an additional purification step to produce a high purity product. A second problem is that when a water-miscible protic solvent such as acetic acid is used for the lactonization as is taught in U.S. Pat. No. 4,916,239, an esterification reaction between the solvent and the 3-hydroxy group of the 3-hydroxylactone occurs to produce 3-O-acylated lactone and corresponding 3-O-acylated open-ring 5-hydroxy acid side-product impurities which are not effectively removed, even after a subsequent purification step.
The instant invention provides a novel single-pot lactonization/purification process that can be used to produce 3-hydroxy lactone containing products, including statins, that avoids the aforementioned problems and provides a higher quality lactone product having a lower amount of total impurity than previously possible on a commercial scale. Particularly, all 3-O-acylated lactone and 3-O-acylated open-ring sideproduct impurities are eliminated. In addition, when the procedure is performed at sufficiently cold temperatures, the amount of dimer impurity in the final product measured by analytical HPLC as an area percentage is 0.1 area % or less. Therefore, the instant process eliminates the need for a separate purification step. The novel process described herein also results in a better yield and greater throughput in a single step.
SUMMARY OF THE INVENTION
One object of this invention is to provide an improved lactonization and purification process for making 3-hydroxy lactone-containing products in high yield using strong mineral acid to effect the lactonization and precipitation of the final product.
A second object is to employ the instant process for the preparation of 3-hydroxy lactone-containing HMG-CoA reductase inhibitors of the statin class.
A third object is to employ the process using a water-miscible, polar, 15 aprotic solvent thereby eliminating the formation of any 3-O-acylated lactone or 3-O-acylated open-ring side-product impurities.
A fourth object is to employ the process at sufficiently cold temperatures in order to decrease any dimer side-product impurity that forms to 0.20 area % or less, as quantified by analytical HPLC.
A fifth object is to employ the instant process under conditions so as to reduce the level of any single impurity that is present in the final product to 0.1 area % or less, as quantified by analytical HPLC.
A sixth object is to provide a process that can be adapted to be efficiently run on a large, factory scale.
A seventh object is to provide a commercial scale composition comprised of a 3-hydroxy lactone-containing product, for example a statin, and specific, reduced levels of chemical impurities that are present in the product.
Additional objects will be evident from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
This invention is concerned with a novel process that can be performed in one pot for preparing a 3-hydroxy lactone-containing product from its corresponding open-ring 3,5-dihydroxy acid or a salt thereof.
The novel process for preparing a 3-hydroxy lactone-containing product from a salt of its corresponding open-ring 3,5-dihydroxy acid comprises the steps of:
(i) adding a strong mineral acid to a stirring suspension of the salt of a 3,5-dihydroxy acid-containing compound in a water-miscible organic solvent in an amount sufficient to protonate the salt and form the corresponding 3,5-dihydroxy acid;
(ii) adding additional strong mineral acid to the stirring solution of the 3,5-dihydroxy acid in an amount sufficient to lactonize the 3,5

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