Lactonization process

Details Lactonization process Lactonization process

2002-03-11

2003-05-13

Solola, Taofiq (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06562984

ABSTRACT:

Antihypercholesterolemic compounds lovastatin and simvastatin are widely used in medicine for the lowering of levels of blood cholesterol. These compounds are derivatives of mevinic acid and have the following structural formula (1):
wherein when R═H, the compound is lovastatin and wherein when R═CH
3
, the compound is simvastatin.
The chemical structure of both compounds includes the presence of a cyclic lactone moiety (4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one group) in the molecule. Accordingly, their chemical structure as expressed by the formula (1) may be simplified by the common formula (A),
wherein Q represents the corresponding remaining part of the molecule of lovastatin or simvastatin.
Lovastatin is typically produced by a process that involves fermentation of various microorganisms while simvastatin is produced via a semi-synthetic or synthetic method as is known in the art. The fermentation methods for preparing lovastatin and/or simvastatin usually lead to the formation of a dihydroxyacid form (B) or a salt thereof
wherein X=hydrogen, metal cation, or ammonia cation, instead of or in addition to the desired lactone form (A).
Ammonium salts of the dihydroxyacid form are often used as intermediates in production methods as these salts are nicely crystalline. Acid and lactone forms may also be formed in the mixture. Whenever this occurs, it is necessary to convert the intermediate dihydroxyacid form (B) (or, accordingly, a salt thereof) into the desired lactone form (A).
Hereafter, the dihydroxyacid form (B) of compounds of formula (1) may be denoted as the “statin acid” or, if appropriate, “lovastatin acid” or “simvastatin acid” of formula (2).
Wherein R and X are as hereinabove defined.
Lactonization is a process wherein a hydroxy acid loses one molecule of water to form an intramolecular ester—a lactone. This reaction is generally catalyzed by an acid; the necessary acidity arises either through the ambient acidity of the substrate itself or by an addition of a stronger acid, i.e. a lactonization agent, to enhance lactonization.
Lactonization is an equilibrium process characterized, in the case of statins, by the following equation:
In order to obtain a high yield of the lactone product, some means is typically employed to shift the equilibrium to the lactone side of the equation. The common means of shifting the equilibrium to the lactone side (from (B) to (A)) is the removal of a reaction product from the reaction mixture.
One known way of removal of the reaction product during lactonization of a statin acid is the physical removal of produced water from the reaction mixture, e.g. by means of azeotropic distillation. In this arrangement, the statin acid and/or ammonium salt thereof is heated in a suitable solvent (toluene, butyl acetate, ethyl acetate, cyclohexane) to boiling, whereby the azeotropic mixture of the solvent and water having a lower boiling point distills off first and the reaction equilibrium is thus shifted to the formation of the lactone. The speed of water and, optionally, ammonia removal may be increased by passing a stream of inert gas through the hot reaction mixture. The ambient acidity of the statin acid is believed to be responsible for the lactonization reaction at these high temperatures. This process has been disclosed e.g. in U.S. Pat. Nos. 4,444,784, 4,582,915, 4,820,850, WO 98-12188 and many others.
An alternate known possibility, described in U.S. Pat. No. 5,393,893, is to perform the lactonization in a two-phase system of an organic solvent, in which the lactone is soluble, and an aqueous acid, whereby the formed water is displaced from the organic layer containing the lactone, to the aqueous layer.
Both alternatives have the disadvantage that elevated temperatures and long reaction times are necessary to be applied for completing the reaction. Statins are sensitive to heating and so the use of such elevated temperatures gives rise to the risk of impurities being formed. One of the most common impurities arises from dimerization of the starting material. For instance, simvastatin of pharmaceutically acceptable quality (e.g. the quality of Ph.Eur. monograph) should contain only less than 0.2% of such dimer.
Another known method is based on the removal of the lactone itself from the reaction medium. In this arrangement, the statin acid or its salt is dissolved in a water-miscible solvent under presence of an acidic catalyst and water is added to the reaction mixture after certain reaction period, as an antisolvent. The lactone is not soluble in water and separates from the solution, thus shifting the equilibrium in the solution to allow formation of the next lactone. This method has been disclosed in EP 351918/U.S. Pat. Nos. 4,916,239 and in 5,159,104. The reaction does not require elevated temperatures so that the potential for forming impurities, particularly dimers, is lower. However, the selection of the water-miscible solvent and the proper amounts and timings of added water is crucial since fast or premature addition of water can lead to serious problems in isolation of the product; i.e., impurities of similar structure present in the starting statin acid may accordingly separate from the solution and decrease the purity of the obtained lactone.
In addition, many of the above lactonization methods of the prior art require relatively long reaction times, typically longer than one hour, for obtaining an acceptable degree of conversion. This, together with the necessary subsequent work-up, makes the prior art methods somewhat complicated to carry out and economically less desirable.
It would be desirable to provide a process for carrying out lactonization that could be done simply in a short amount of time and that ideally would not require a high risk of impurity or dimer formation.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that a lactonization agent can be used that is hydrated by the water produced by the lactonization reaction to form an insoluble hydrated lactonization agent. Because the hydrated complex is insoluble in the reaction medium, the produced water is effectively removed from the reaction and the equilibrium is shifted towards the lactone side. Accordingly, a first aspect of the present invention relates to a process, which comprises subjecting a compound of formula (2):
wherein R is a hydrogen atom or a lower alkyl group, and X is a hydrogen atom, a metal cation or an ammonia cation,
to a lactonization reaction in a solvent in the presence of a lactonization agent to form a compound of formula (1):
wherein R has the same meaning as above in formula (2) and wherein water released in the lactonization reaction complexes with said lactonization agent to form an insoluble hydrated complex lactonization agent. Preferably R is methyl, which corresponds to simvastatin in formula (1).
Optionally, the process also comprises the steps of removal of the hydrated complex after the reaction from the reaction mixture and isolation of the compound (1) from the reaction medium, preferably without the aid of an antisolvent.
This lactonization of the statin can proceed at ambient temperature (no heating need), is simple and short and is easily operable in industrial scale. Furthermore, the process does not require any special techniques or operations for shifting the equilibrium during the reaction.
DETAILED DESCRIPTION OF THE INVENTION
The starting acid form of simvastatin or lovastatin may be employed in a crude or purified state. A preferred precursor is the ammonium salt of lovastatin or simvastatin acid as this compound may be isolated from reaction mixtures of preceding reaction steps by methods known per se, in a stable crystalline form. Also this salt form may be used in the crude or purified state.
The reaction solvent employed in the process of the invention is generally inert, preferably water immiscible, and one in which the lactone form is sufficiently soluble. The solvent is not a good solvent for the hydrated complex. Preferably the solvent is a good solvent

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