June 8, 2009 [Repeated from December 8, 2008]
Here’s an improved synthesis of atorvastatin. Statins are used to reduce the levels of cholesterol and the risk of cardiovascular diseases; they continue to attract considerable interest. F. Wang and co-inventors describe improvements in the stereoselectivity of a reaction used in the original synthesis of the anti-hyperlipoproteinemic agent atorvastatin (Lipitor, 1). The reaction in question is between aldehyde 2 and chiral ester 3 (see figure). By carrying out the reaction in the presence of a chelating solvent, the inventors obtained product 4 that contains a higher R,S/S,S diastereomer ratio than has been achieved previously.
Examples of the chelating solvents are N,N,N’,N’-tetramethylethylenediamine, (EtOCH2)2, (MeOCH2)2, and dioxane. The original process required the presence of Mg2+, but the improvement eliminates this need and simplifies the process.
The aldol reaction of 2 and 3 is carried out in the presence of i-Pr2NLi in (MeOCH2)2 and produces 4 with an R,S/S,S ratio of 95:5, compared with 86:14 when the original procedure is used. In the next step, 4 is hydrolyzed with MeOH–H2O, and crude byproduct alcohol 5 is filtered off and recovered in 90% yield for recycling. The diastereomers of carboxylic acid 6 are then resolved by using (R)-PhCHMeNH2 to obtain the (R)-amine salt of 7 with 97.8% ee; recrystallization increases the diastereoselectivity to >99% ee.
In the last stage of the process, amine salt of 7 is converted to β-ketoester 8 by reaction with the magnesium salt of di-tert-butyl malonate in the presence of 1,1’-carbonyldiimidazole. Ketoester 8 can then be used to prepare 1, but the inventors give no details. The patent does describe the preparation of the aldehyde 2 by acid hydrolysis of an acetal that is obtained by a method reported in Butler, D.F., et al. U.S. Patent 5,003,080, March 26, 1991. (Apotex Pharmachem [Brantford, ON]. U.S. Patent 7,429,613, Sept 30 2008; Keith Turner)
View patent information from CAS.
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