title: An improved kilogram-scale preparation of atorvastatin calcium.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000 Russian Federation.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Novozhilov
authors.affiliation: The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000 Russian Federation.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Dorogov
authors.affiliation: The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000 Russian Federation.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Blumina
authors.affiliation: The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000 Russian Federation.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Smirnov
authors.affiliation: Institute of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof, 198504 Russian Federation.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
keywords: Atorvastatin; Ester hydrolysis; Ethyl acetate solubility; Hemi-calcium salt; Ketal deprotection