An improved kilogram-scale preparation of atorvastatin calcium

Abstract

BackgroundIf literature protocols are followed, conversion of an advanced ketal ester intermediate (available in kilogram quantities via a published Paal-Knorr synthesis) to cholesterol-lowering drug atorvastatin calcium is hampered by several process issues, particularly at the final stage where the hemi-calcium salt is obtained.ResultsWe developed a high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities by introducing the following key improvements: i. isolating the pure product of the ketal deprotection step as crystalline solid, and ii. using a convenient ethyl acetate extraction procedure to isolate the pure atorvastatin calcium at the ester hydrolysis and counter-ion exchange step.ConclusionThe convenient and operationally simple conversion of an advanced intermediate of atorvastatin to the clinically used hemi-calcium salt form of the drug that is superior to the methods obtainable from the literature is now available to facilitate the production of atorvastatin calcium on industrial scale.Graphical abstractStepwise ketal and tert-butyl ester group hydrolysis and a modified work-up protocol lead to a more convenient preparation of API-grade atorvastatin calcium.Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-015-0082-7) contains supplementary material, which is available to authorized users.

Synthesis of Heterocycles in Contemporary Medicinal Chemistry

“…Interestingly, initial indications suggested that Yb(OTf) 3 3 in EtOH at 40 C provided the crude enaminone 203, which was taken directly into the next step where it was subjected to a high-speed vibration milling at 20 Hz for 1 h together with 204, 1 mol% Yb(OTf) 3 , and AgNO 3 (1 equiv.). Acetonide-protected atorvastatin tert-butyl ester 177 was then isolated at 40% yield and was readily converted to atorvastatin lactone 156 at 94% yield, using HCl in MeOH at room temperature for 3 h. A detailed description of an improved kilogram-scale synthesis of atorvastatin calcium 186 was reported by Novozhilov and coworkers [124]. Their route started from the acetonide-protected tert-butyl ester of atorvastatin 177 on a 7-kg scale.…”

Covalent modification of biological targets with natural products through Paal–Knorr pyrrole formation

“…One example is in the commercial ton-quantity preparation of an anti-cholesterolemic drug, atorvastatin (Lipitor), as illustrated by the condensation of diketone 8 and amine 9 to afford pyrrole 10 (Scheme 3). 16 …”

Recent Progress in the Synthesis of Super-Statins

“…A detailed description of an improved kilogram-scale synthesis of atorvastatin calcium 186 was reported by Novozhilov and coworkers [124]. Their route started from the acetonide-protected tert-butyl ester of atorvastatin 177 on a 7-kg scale.…”