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Pharmaceutical  technologies  – why do they have to be innovative

Janusz Obukowicz 1Wiesław Szelejewski Andrzej Kutner 2

1. Instytut Farmaceutyczny (PRI), Rydygiera 8, Warszawa 01-793, Poland
2. Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland


An overview will be given of the syntheses of pharmaceutical substances, using representative examples selected from the syntheses completed at the Institute, over the last two decades. The discussion will start from a one step convergent synthesis of antihypertensive dihydropyridin and methods of their isolation and purification, used in middle eighties to get a pharmaceutical substance that meets the purity requirements of that time. Convergent synthesis of a PDE-5 inhibitor will be presented to prove an innovative synthesis that might be competitive with the innovator’s process. Linear synthesis of a class IB anti-arrythmic will demonstrate an innovative one step reductive amination, leading efficiently to target molecule. The same linear synthesis was used to construct a molecule of tyrosine kinase inhibitor and obtain the final product in a patent non-infringing polymorphic form. A contribution of the Institute to the technology of anticancer oxazaphosphorinane will also be discussed. New phase-transfer catalytic process was used efficiently to synthesize a selective aromatase inhibitor. Recent convergent strategies for the preparation of vitamin D active metabolites and analogs and also of antiglaucoma analogs of prostaglandin F2a will be discussed in some more details. The retro-synthetic analysis of prostaglandins from this group resulted in a design of the new advanced intermediate that was lately proved to be useful in a synthesis of not only of a lead analog from this group but also of other two analogs used in a therapy. The concept will be discussed how to approach a problem of diastereomeric purity for a synthetic multi-chiral pharmaceuticals to comply with current very strict regulations in this matter. The advantage of using chiral pool of natural products as raw materials for syntheses will be demonstrated on examples of side-chains of prostaglandin analogs.        

All the syntheses discussed were developed in a way required for pharmaceutical substances and this is why they could have been implemented at the Institute and manufactured on an industrial scale for the European pharmaceutical market. Most of the inventive steps have been protected by national or international patents and the technologies were awarded with distinctive national and international prizes.  Past and present challenges faced in syntheses of pharmaceuticals will be outlines and successful approaches will be presented that were developed over the years at the Institute.          

1. W. Szelejewski, A. Kutner, Innovation in drug development, Przem. Chem., 2012, in press.

2. J. Martynow, J. Jóźwik, W. Szelejewski, O. Achmatowicz, A. Kutner, K. Wiśniewski, J. Winiarski, O. Zegrocka-Stendel, P. Gołębiewski, Sposób wytwarzania pochodnych 13,14-dihydro-PGF, P-374461, 2005; WO 2006/112742, 2006.

3. I. Dams, M. Chodyński, A. Kutner, M. Krupa, A. Pietraszek, P. Cmoch, M. Zezula,  Process for the preparation of 13,14-en-15-ol analogs of prostaglandin F2a, IF 932, 2012.


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Related papers

Presentation: Invited oral at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Janusz Obukowicz
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-04-17 11:49
Revised:   2012-04-17 13:34