Process of lactonization in the preparation of statins

Details Process of lactonization in the preparation of statins Process of lactonization in the preparation of statins

2002-07-23

2003-11-18

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06649775

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for lactonizing mevinic acid or analog thereof. More particularly, the present invention relates to a process for preparing lovastatin and simvastatin in a high yield which comprises (1) performing a lactonization of mevinic acid and analog thereof compounds in the presence of a dehydrating agent without an acid catalyst under nitrogen sweep; and then (2) making crystals at a high temperature.
BACKGROUND
Hypercholesterolemia is known as to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat these diseases. They seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
Presently, lovastatin and simvastatin, analog of lovastatin, are commercially available as highly active therapeutic agents for anti-hypercholesterolemia. They suppress HMG-CoA reductase, by which the cholesterol biosynthesis is inhibited. These compounds so-called statins are reported to exist in a dihydroxylic acid form with an open circular structure as depicted in Formula 2 and in a lactone form as depicted in Formula 1.
Wherein Z is hydrogen, ammonium or metal cation, R is a radical of Formula 3 and R
1
is H or CH
3
.
Statins are known to be active in a dihydroxylic acid form physiologically, but usually administered in a lactone form for patients. Therefore, it is necessary to develop an efficient method to perform a lactonization in a high yield. Since the lactonization is an equilibriated process, specific means should be utilized to transfer the equilibrium toward lactones as shown in Reaction Formula 1 in order to produce lactonized products in a high yield.
dihydroxylic acid (or its ammonium salt)←→lactone+H
2
O (+NH
3
)  <Reaction Formula 1>
In U.S. Pat. No. 4,820,850, azeotropic distillation or nitrogen sweep were exploited to remove by-products of the reaction (water or ammonia) from reacted mixtures so that the lactonization became almost completed. However, there are several disadvantages in this method.
Precisely, hydroxylic acid substrate works as an acid catalyst and thus reduces a reaction velocity, depending upon the substrate consumed so as to take a longer time period for the reaction and to increase by-products generated. Under such a reaction condition, 3-hydroxylactone, a product is reacted with free acids during the extended period. As a result, heterodimers produced through the esterification between 3-hydroxy group of 3-hydroxylactone and the free acids is increased in the amount as depicted in Formula 1
a
.
Wherein, R and R
1
are defined as described above.
In case that this kind of heterodimers are present, the total yield and the purity of lactone products are decreased. Therefore, the reacted product is diluted in a high degree before use in order to minimize the formation of heterodimers. However, this is also disadvantageous for the efficiency of the reaction.
Furthermore, Korean patent publication No. 97-11286 discloses another process for preparing lactones. It involves treating the free hydroxylic acid or ammonium or metal salt derivatives of mevinic acid or analog thereof in a water miscible organic solvent (especially acetic acid medium) which exhibits a sufficient solubility difference between the hydroxylic acid and lactone, and a strong acid catalyst. After the free hydroxylic acid-lactone equilibrium is established, water is added in an amount sufficient to effect complete crystallization of the lactone from the reaction medium. However, in this method strong acids such as methanesulfonic acid, chloric acid, sulfuric acid, trifluoroacetic acid and the like should be utilized in 1.2~1.5 M and strong bases also should be added in a large amount to neutralize the solution. Therefore, this is not unuseful for industrial application in a large scale as well as very harmful environmentally. Besides, extra water should be supplemented in order to complete the lactonization, but this induces a crystallization again onto the existing crystal, and the obtained crystals of lactone become non-homogeneous. In addition, there are some other problems. Moreover, since the resulting product is not filtrated thoroughly, the procedure for the reaction and the work-up takes a very long time approximately 9~12 hours, which reduces the productive efficiency.
In order to improve the conventional method described above, U.S. Pat. No. 5,917,058 has illustrated the process for the preparing lactones, in which dihydroxy groups of statins or analog thereof, especially in an ammonium salt, are reacted with acetic acid medium without adding an acidic catalyst and without removing water or ammonia at 35~40° C., and then insoluble solvent such as water, hexane, cyclohexane and the like is added to make lactones. However, in this method acetic acid as a solvent is utilized in 3~7-fold larger amount than that of the reactant and should be neutralized with bases, which the neutral salt (ammonium acetate) is produced and remained in the final lactone compounds. Therefore, another process is required to recrystallize and the process for the preparing lactones becomes inconvenient and uneconomical. The lactone compound and its neutral salts exist in a mixed state and are not filtrated properly, which makes the process inefficient. In addition, extra contaminant, which is formed from the 3-hydroxy group of lactone ring through dehydration, can be observed in an acidic condition under heated state since only acetic acid is used as a solvent. The contaminant will not removed easily by recrystalization and decreases the purity and the yield of lactone compounds.
As demonstrated above, it is necessary to develop new process for preparing lactone compounds in a high purity. Precisely, since lactone compounds are prepared in an equilibriated reaction from mevinic acid or analog thereof, the by-product (water and ammonia) should be removed so as to complete the reaction. As a result, the lactone compound can be obtained in a high yield and through this procedure the produced heterodimers are reduced in the amount.
DISCLOSURE OF INVENTION
The inventors of the present invention have been studied in this field in order to overcome the foregoing and other disadvantages in the conventional methods described above. Consequently, the inventors developed a new process for the lactonization in the preparation of statins so as to solve the existing problems and completed the present invention successfully.
Therefore, the object of the present invention is to provide a process for preparing lactone compounds, which is convenient and economical as well as decreases the content of heterodimers remarkably.
The present invention relates to a process for lactonizing mevinic acid or analog thereof. More particularly, the present invention relates to a process for preparing a compound of Formula 1 which comprises (1) step of performing a lactonization of Formula 2 in the presence of a dehydrating agent and without an acid catalyst under nitrogen sweep; and then (2) step of making lactone product in crystals.
Wherein, Z is hydrogen, ammonium or metal cation, R is a radical as depicted in Formula 3 and R
1
is H or CH
3
.
Hereinafter, the present invention will be illustrated more clearly.
In the present invention, the dehydrating agent can be one selected among a group comprising magnesium sulfate, sodium sulfate, calcium chloride, molecular sieve and like. Preferably, magnesium sulfate can be used. The dehydrating agent completes the reaction by removing water generated in the equilibriated reaction. As a result, it reduces contaminants of by-products with shortening the period of the reaction time. Therefore, it affects outstandingly to enhance the yield of lactone compounds.
By using the dehydrating agent in the present invention, the time period for the reaction can be reduced to 2~4 hours and preferably to about 3 hours. As a reference, in conventional meth

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