Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-01-22
2003-08-05
Solola, Taofiq (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06603022
ABSTRACT:
BACKGROUND OF THE INVENTION
Certain hexahydronaphthalene derivatives are known as potent inhibitors of the enzyme HMG-CoA reductase, the rate-controlling enzyme in the biosynthetic pathway for formation of cholesterol in the human body. Well-known examples of these compounds are Mevastatin (U.S. Pat. No. 3,983,140), Lovastatin (U.S. Pat. No. 4,231,938), Pravastatin (U.S. Pat. No. 4,346,227) and Simvastatin (U.S. Pat. No. 4,444,784). All of these compounds are important pharmaceuticals and are widely used in hypercholesterolaemic treatments.
Mevastatin (also known as Compactin), Lovastatin (i.e., Mevinolin) and Pravastatin are natural fermentation products which possess a 2-methylbutyrate side chain at C-8 of their hexahydronaphthalene ring system. It has been reported that compounds possessing a C-8 2,2-dimethylbutyrate side chain (e.g., Simvastatin) are better inhibitors of HMG-CoA reductase than their 2-methylbutyrate counterparts. For example, Simvastatin has been shown to be approximately twice as potent as Pravastatin and Lovastatin, while Mevastatin is the least powerful. Thus 2,2-dimethylbutyrate derivatives show greater promise for the treatment of, for example, artherosclerosis, hyperlipemia, familial hypercholesterolemia and similar disorders. However, these derivatives, including Simvastatin, are not naturally occurring and thus have to be produced synthetically. As a result, the introduction on the market of the more potent HMG-CoA reductase inhibitor Simvastatin has prompted the need for efficient, high yielding processes for manufacturing it.
Several processes for the preparation of Simvastatin from Lovastatin have been reported. For example, 2,2-dimethylbutyrate derivatives and processes for their preparation are disclosed in U.S. Pat No. 4,444,784 and EPO patent No. 33538. However, the route described is both tedious and cumbersome and gives very poor overall yields. U.S. Pat. No. 4,444,784 discloses a synthetic route whereby an additional &agr;-methyl group is introduced on the C-8 acyl side chain of Lovastatin or analogues thereof. This process involves indirect methylation of the C-8 side chain through several chemical steps: deesterification of the whole 2-methylbutyrate side chain, protection of the pyranone ring 4-hydroxy group with a tert-butyldimethylsilyl protective group, reesterification of the protected lactone with 2,2-dimethylbutyric acid, and deprotection of the pyranone ring hydroxy group. This procedure involves multiple chemical reactions with a low overall yield.
Another route, based on direct methylation of the C-8 acyl side chain of Lovastatin and its analogues, is disclosed in U.S. Pat. No. 4,582,915. Direct methylation of the 2-methylbutyrate side chain of Lovastatin is achieved, after conversion to an alkali metal salt, using a methylhalide in the presence of a strong base (metal alkylamide). The process suffers from poor conversion coupled with many side reactions which complicate both isolation and purification of the final product, Simvastatin.
The problems of low yields and poor quality of the final product have been addressed in a process disclosed in U.S. Pat. No. 4,820,850. This procedure comprises: (i) treatment of Lovastatin with butylamine to achieve ring-opening of the lactone, followed by the protection of the hydroxyl-groups therein with tert-butyldimethylsilyl chloride; (ii) treatment of the obtained protected intermediate with an alkalimetal amide followed by contact with alkylhalide to add an alkyl group to the 2-position of the butyrate side chain; (iii) removal of the silyl protective groups by an acid, preferably hydrofluoric acid; (iv) treatment with dilute base to hydrolyse the alkylamide; and (v) heating of the resulting carboxylate salt in a hydrocarbon solvent to reform the lactone. However, the process involves a large number of steps, hence affecting the overall yield. Furthermore, the process utilizes a highly expensive silylating agent to protect the hydroxyl groups thus rendering the route cost ineffective.
Another direct methylation process is described in U.S. Pat. No. 5,393,893, where a Lovastatin-C
3
-C
7
-alkyl amide, cycloalkylamide or aralkylamide is prepared. The hydroxyl-groups are then protected with a phenylboronic acid and the resulting intermediate is further reacted with an alkylhalide in the presence of a base to introduce the alkyl moiety on the C-8 butyrate side chain. Similarly as in the above-referenced patent, the subsequent steps leading to Simvastatin involve the removal of the protective groups, hydrolysis of the alkylamide and relactonization to form Simvastatin.
The above two synthetic routes, which involve the step of direct methylation, differ from each other in the nature of the OH-protective group used in forming the reaction intermediates. These protected intermediates are generally characterized by a silicon- or boron-containing protecting group. These processes all suffer from severe disadvantages such as excessive steps including those involved with the insertion and removal of protecting groups, and the relative lack of stability of the protected intermediates under the reaction conditions utilized in the synthetic sequence, in particular the strongly alkaline conditions used in the methylation step. As a result, undesirable amounts of by-products are formed during the synthesis, thereby requiring additional isolation and purification steps before a product of desired pharmaceutical quality can be obtained, and adversely affecting the cost and overall yield of the synthetic route. Furthermore, the protecting agents used are economically undesirable.
The problems associated with the cumbersome hydroxyl protection/deprotection strategy have been addressed in a process disclosed in U.S. Pat. Nos. 5,763,653 and 5,763,646. The process involves the synthesis of Simvastatin using Lovastatin or mevinolinic acid in salt form as the starting material. U.S. Pat. No. 5,763,653 describes a method for preparing Simvastatin from a Lovastatin amide intermediate prepared by treating Lovastatin or the salt form of mevinolinic acid with a primary amine such as cyclopropyl or butyl amine, without requiring the afore-mentioned hydroxyl protection/deprotection sequence. However, the use of a primary amine to effect the pyranone ring opening results in the formation of a primary Lovastatin amide intermediate which may in turn undergo undesired side reactions due to the presence of its amide hydrogen atom. For example, the amide hydrogen atom can react with the lithium amide base used in the &agr;-methylation step, thereby necessitating a higher equivalent of the lithium amide base. Furthermore, undesired side reactions may occur with the methylating agent (e.g., methyl iodide), thereby lowering the overall yield.
Thus there remains a need for efficient and high-yielding processes for the preparation of Simvastatin and 2-alkyl-2-methylbutyrate analogues thereof.
SUMMARY OF THE INVENTION
The present invention discloses a new process for the preparation of compounds of formula I (e.g., 2-alkyl-2-methylbutyryloxy derivatives of Lovastatin, Mevastatin and related compounds).
wherein R is hydrogen, hydroxyl or substituted or unsubstituted lower alkyl; and R′ is substituted or unsubstituted lower alkyl
In a preferred embodiment, the present invention provides a new process for the preparation of Simvastatin of formula II.
The method does not require the protection-deprotection sequence of the hydroxy groups generated from the lactone ring opening and thus does not necessitate the use of rather expensive silyl or other protecting agents. In addition, the method addresses the problems associated with primary statin amides as intermediates, particularly side-reactions (and thus lower yields) due to the primary amide hydrogen atom. Accordingly, the invention provides a highly effective method for the synthesis of Simvastatin and 2-alkyl-2-methylbutyrate Lovastatin and Mevastatin analogues by increasing the overall yield and purity of the final product, and by minimizing the cost of production of Sim
Acharya Poornaprajna
Mathew Joy
Sambasivam Ganesh
Sridharan Madhavan
Biocon India Limited
Choate Hall & Stewart
Pasternak Sam
Solola Taofiq
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