Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-29
2002-10-29
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S252000
Reexamination Certificate
active
06472542
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel process for alkylating the alpha carbon of the 2-methylbutyrate secondary chain of lovastatin and intermediate products of the novel process, wherein the process gives a product in a high yield and in pharmaceutical purity.
BACKGROUND OF THE INVENTION
In recent years, cardiopathy has increasingly become a medical problem. This problem is associated with several factors such as diet, stress and the sedentary lifestyle of the population. One of the most important risk factors associated with coronary heart disease is the incidence of elevated cholesterol levels in plasma. Elevated cholesterol levels in plasma may cause, among other things, obstruction in the arteries and circulatory problems. See Reynolds, J. Martindale, (1993),
The Extra Pharmacopoeia
, 30
th
Edition, The Pharmaceutical Press. Cholesterol accumulation is due to both exogenous factors, such as diet, and endogenous factors, such as cholesterol production by the organism. Presently, unlike exogenous factors, cholesterol production by the organism can only be controlled by drugs that inhibit cholesterol biosynthesis.
Compounds represented by the structure (I), such as lovastatin (Ia, where R=CH
3
) and mevastatin (Ib, where R═H), can be produced by fermentation and are well known anti-hypercholesterolaemic agents. See Republic of South Africa Patent No. 884924, to Verhoeven, T. R. and Askin, D. They act by blocking the endogenous synthesis of cholesterol through the competitive inhibition of the 3-hydroxy-3-methylglutaryl A reductase enzyme (HMG-CoA reductase).
Among several products that are prepared by semi-synthetic routes and which possess a 2,2-dimethylbutyrate secondary chain, there are compounds represented by structure (II), such as simvastatin (where R═CH
3
). The chemical name for simvastatin is [1S-[1&agr;, 3&agr;, 7&bgr;, 8&bgr; (2S*, 4S*), 8a&bgr;]]-2-2-dimethylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester. Its molecular weight is 418.57 a.m.u. Simvastatin is a very active anti-hypercholesterolaemic agent that limits the biosynthesis of cholesterol by inhibiting the HMG-CoA reductase enzyme and it is widely used in the treatment of arteriosclerosis. Products such as simvastatin are considered more potent inhibitors of HMG-CoA reductase than are their analogues with a 2-methylbutyrate chain in their structure.
Compounds represented by structure (II) have been obtained by various routes, such as those described in U.S. Pat. Nos. 4,820,850, to Verhoeven et al., 6,271,398 B1, to Van Dalen F. et. al. and 6,294,680 B1, to Vries et al., and in European Patent No. 299,656 B1, to Verhoeven et al., wherein: (1) the lactone is hydrolyzed, (2) the OH groups of the lactone are protected, (3) the 2-methylbutyrate chain is methylated to form the 2,2-dimethylbutyrate chain, and (4) protection is removed from the lactone OH groups. However, this route is very time and labor intensive and it gives very low product yields.
Another route to alkylate the alpha carbon of the 2-methyl butyrate chain uses a metal alkyl amide and methyl iodide without hydrolyzing the lactone and without protecting the OH groups of the lactone, as described in U.S. Pat. No. 4,582,915 and in European Patent No. 137,445, both to Sletzinger et al. This procedure however presents several operative disadvantages that make it useless for production. For example, to enhance the methylation reaction, it is necessary to carry out repeated additions of the amide base and the methyl halide thereby resulting in increased impurity formation because different sites of the molecule are methylated. The yields are low and the purity of final product is under the permissible limit for use as pharmaceutical active ingredient.
In U.S. Pat. No. 4,820,850, direct methylation of the alpha carbon of the 2-methylbutyrate chain may provide a higher percentage of methylation from a single addition of the amide base and alkyl halide. However, this procedure presents some disadvantages: the protection reaction of the hydroxyl groups of the lactone using tert-butyidimethylsilyl chloride as a silylating agent is accompanied by an undesirable formation of acid. Therefore, it is essential to neutralize the acid by using a base, such as imidazole. The employment of this kind of protecting agent increases the cost of the process. Accordingly, this product is very expensive. Furthermore, this method includes an additional step to deprotect the alcohols, which is carried out in the presence of an acid, such as hydrofluoric, methanesulfonic or others, and contributes to product degradation and increased impurity formation.
In U.S. Pat. No. 6,307,066, a boronic acid is reacted with lovastatin to form a lovastatin boronate, and then the methylation of the 2-methylbutyrloxy group of lovastatin boronate provides simvastatin boronate. However, U.S. Pat. No. 6,307,066 discloses no lactone hydrolysis and no hexadimethyidisilazane protecting agent for lactone OH groups. Further, the methylation of lovastatin is quenched with aqueous acid, thereby necessitating neutralization using, for example, N
a
HSO
3
. Still further, in Example 1 the yield of lovastatin phenylboronate from lovastatin is low (37%).
In arriving at the method of the present invention, the present inventors have sought to avoid the above-mentioned problems. As a result, they have discovered a novel process for alkylating, preferably methylating, the alpha carbon of the 2-methylbutyrate secondary chain of lovastatin, which gives a product, such as simvastatin, in a higher yield than has been attained heretofore and in a purity acceptable for pharmaceutical use.
SUMMARY OF THE INVENTION
The present invention provides a process for methylating the alpha carbon of the 2-methylbutyrate secondary chain of lovastatin to prepare simvastatin in improved yields and in a purity desired for pharmaceutical use. In addition, the present invention provides a process for the alkylation of the alpha carbon of the 2-methylbutyrate secondary chain of lovastatin to provide compounds similar to simvastatin in improved yields. The present invention also provides intermediate and final products of the alkylation, preferably methylation, process. According to the present invention, the process for making simvastatin from lovastatin comprises forming an amide of lovastatin, thereby opening the lactone ring of the lovastatin; protecting the free hydroxyl groups of the lovastatin amide with hexamethyldisilazane (HMDS) to form a novel and unobvious protected lovastatin amide represented by structural formula (IV), given below; methylating or alkylating the &agr;-carbon of the 2-methylbutyrate secondary chain of the protected lovastatin amide to form protected simvastatin amide and removing the protecting groups therefrom by quenching the methylation reaction with water to form simvastatin amide, represented by structural formula (V), given below; hydrolyzing the simvastatin amide to form simvastatin acid; forming a simvastatin ammonium salt in an intermediate purification step; lactonizing the salt to form simvastatin; and purifying the thus formed crude simvastatin to a high degree of purity.
In an embodiment of the present invention, a protecting agent for the lactone hydroxyl groups of lovastatin is selected so as to result in a reaction that does not produce acid. Therefore, a base, such as imidazole, is not required to neutralize the acidity of the reaction medium. This surprising result is achieved by using HMDS as a protecting agent. Another advantage of using HMDS as a protecting agent is that the removal of the protecting agent after the methylation reaction is carried out simply, for example, by water quenching, thereby eliminating a neutralization step in the removal of the protecting group and any additional steps that might be required to remove the neutralizing agent.
In another embodiment of the present invention, the lactonization reaction may
Galeazzi Edvige
Garcia Gustavo A.
Lara Fernando
Lopez Gema
Martinez Orestes
FERMIC S.A. de C.V.
Hollander Law Firm, P.L.C.
Owens Amelia
LandOfFree
Method for alkylating the alpha carbon of the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for alkylating the alpha carbon of the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for alkylating the alpha carbon of the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2987985