Certain mevalonate derivatives are known to inhibit the activity of HMG-CoA reductase, the rate-controlling enzyme in the biosynthetic pathway for cholesterol. They are mevastatin (also called compactin), lovastatin (also known as mevinolin or monacolin K) and analogs of these compounds such as pravastatin and simvastatin.
Mevastatin and lovastatin are natural fermentation products which possess a 2-methylbutyrate side chain in the 8-position of their hexahydronaphthalene ring system. It was proven by others that products having a 2,2-dimethylbutyrate side chain in this position are more active inhibitors of HMG-CoA reductase than analogs with a 2-methylbutyrate side chain.
There are basically three known routes to introduce the additional .alpha.-methyl group to the 8-acyl side chain of lovastatin or mevastatin and their analogs.
In U.S. Pat. No. 4,444,784, a process for preparation of 8-acyloxy derivatives of lovastatin is disclosed which involves several distinct chemical steps: de-esterification of the 2-methylbutyrate side chain, relactonization of the de-esterified mevinic acid, dimethyl butylsilyl protection of the hydroxy group in the pyranone ring, re-esterification with 2,2-dialkylbutyric acid and de-protection of the hydroxy group of the pyranone ring. All these different steps result in a low overall yield.
U.S. Pat. No. 4,582,915 to Merck discloses a process to prepare lovastatin analogs with a 2,2-dimethylbutyrate side chain. One component of the process is a direct alkylation of the methylbutyrate side chain using a metal alkylamide and methylhalide. Such process however presents at the commercial scale some disadvantages, including product contamination by a significant concentration of unconverted starting material and a relatively high concentration of by-products, reducing the purity of the final product and rendering it almost unsuitable for use in human health care.
The problem of low yields and poor quality of the final product have been addressed in a process disclosed in Canadian Patent No. 1,287,063 and U.S. Pat. No. 4,820,850 to Merck. However, this process also has several disadvantages: in the first step, it uses low boiling amines which are unsafe to handle on an industrial scale, the silyl intermediate is an oil and therefore it is difficult to isolate for purification and characterization purposes; the de-protection of hydroxy groups is done with hydrofluoric acid which is highly corrosive and the hydrolysis of the amide is made under basic conditions leading to the metal salt of the mevinic acid which needs an additional step of lactonization.
We describe a process that will eliminate such disadvantages at an industrial scale and will be a cheaper, safer and quicker route to 2,2-dimethylbutyrate derivatives of lovastatin.
USPTO Backgrounds
USPTO Backgrounds