Pioglitazone hydrochloride (1) is an antidiabetic agent for the treatment of noninsulin dependent diabetes mellitus (NIDDM). It decreases hyperglycaemia and acts by increasing insulin sensitivity.

Reduction of
(E)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene}thiazolidene-2,4-dione with sodium borohydride and cobalt(II) complex in dimethyldioxyme and a subsequent conversion of a free base with HCl afforded pioglitazone hydrochloride in high yield (about 95%) and purity (above 99%).

The scale-up was performed taking into account the results of a laboratory study on the optimization of a key process of the synthesis, i.e. the reduction of the double bond in benzylidenethiazolidenedione [1,2].

A summary of the small plant scale synthetic procedure will be given. More details are available through the polish patent application No. P-376857 [3].

[1] A. Leś, W. Pucko, W. Szelejewski, "Optimisation of the reduction of 5-benzylidenethiazolidine-2,4-dione derivative supported by the reaction response surface analysis: synthesis of pioglitazone hydrochloride", Organic Process Research & Development, 8 (2004) 157-162.
[2]. A. Leś, W. Szelejewski, "Optymalizacja wybranych etapów syntez substancji farmaceutycznych", Przemysł Chemiczny, 84/5 (2005) 314-319
[3]. W. Pucko, J. Roszczyński, J. Winiarski, P. Baran, W. Szelejewski, A. Leś, M. Ławecka, "Sposób wytwarzania chlorowodorku pioglitazonu o wysokiej czystości farmaceutycznej", polskie zgłoszenie patentowe nr P-376857, dn. 01.09.2005.