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A previously reported condensation reaction of ambiphilic 2‐(1H‐pyrazol‐5‐yl)phenols with various o‐chloro‐substituted nitroaromatic synthons to provide medicinally important tetracyclic pyrazolo[1,5‐d][1,4]oxazepines was extended to more readily available and convenient‐to‐use 1,2‐dihaloazines. Although 4,5‐dichloropyridazin‐3(2H)‐ones and 2,3‐dichloropyrazine are popular bis(electrophilic) partners in various SNAr‐type condensations and also were efficiently used in the reaction reported herein, the facility with which various 3‐bromo‐2‐chloropyridines underwent the same cyclization was unexpected. These reactions are presumed to occur as sequential intermolecular SNAr/Smiles rearrangement/intramolecular SNAr tandem reactions and provide a rare example of the transition‐metal‐free substitution of a bromine atom at the 3‐position of a pyridine ring.

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.