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An Improved Kilogram-Scale Preparation of Atorvastatin Calcium

An Improved Kilogram-Scale Preparation of Atorvastatin Calcium

Yuri V Novozhilov, Mikhail V Dorogov, Maria V Blumina, Alexey V Smirnov, Mikhail Krasavin

Chem Cent J. 2015 Feb 13;9:7.

PMID: 25705254

Abstract:

Background:
If 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.
Results:
We 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.
Conclusion:
The 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP344423989	Atorvastatin Calcium		344423-98-9	Price

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