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 F_2a 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_2α, 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 F_2a, IF 932, 2012.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/28124 must be provided.

1. The comparison of the stability indicating  two HPLC methods and their application for the determination of bosentan in coated tablets 
2. What modern crystallography can add to pharmaceutical research?
3. Antiproliferative and cytotoxic effect of vitamin D₃ and its derivatives on the selected cells with a higher proliferative potential
4. A novel convergent synthesis of the prostaglandin F_2α analogues
5. Comparative permeation studies of tacalcitol through the human skin from brand product versus generic product
6. Vitamin D analogs enhance the activity of imatinib mesylate in human non-small cell lung cancer model
7. Colon cancer treatment with the use of vitamin D analogs and irinotecan 
8. Experimental and theoretical charge density studies on a model analogue of vitamin D
9. Synthetic Technologies of Pharmaceutical Substances
10. The influence of (24R)-1,24- dihydroxyvitamin D₃ on the anticancer activity of 5-fluorouracil in human colon cancer model
11. The use of the hyphenated LC-MS/MS technique for the characterisation of impurity profile of Quetiapine during drug development
12. A novel synthesis of 19-nor analogs of vitamin D
13. The influence of novel analogs of vitamin D₃ on the antiproliferative activity of cisplatin or doxorubicin on human promyelocytic leukaemia cell line HL-60 
14. Isolation, structural elucidation and characterization of impurities in latanoprost
15. New rosiglitazone salts
16. New calcipotriol analogs, their toxicity and antitumor activity in vivo in comparison to the affinity with VDR and DBP
17. High-yielded method of synthesis of voriconazole.
18. Polimorphism of Active Pharmaceutical Ingredients
19. ANTITUMOR EFFECT OF CISPLATIN OR FLUOROURACIL IN COMBINED TREATMENT WITH (24R)-1,24-DIHYDROXYVITA- MIN D₃
20. COMBINATION OF: IMATINIB, PRI-2191 AND CYTOSTATICS - THE ANTIPROLIFERATIVE EFFECTS ON HL-60 LEUKEMIA CELL LINE
21. ANTIPROLIFERATIVE ACTIVITY IN VITRO OF DIASTEREOMERIC ANALOGUES OF VITAMIN D3 AGAINST NORMAL AND CANCER CELL LINES