RSC Adv.2016 6(66):61458-61467

An optimized approach in the synthesis of Imatinib intermediates and analogues

Maria Kinigopoulou,a Maria Filippidou,a Marina Gogou,a Aimilia Giannousi,a Paraskevi Fouka,a Nikoleta Ntemou,a Dimitrios Alivertis,b Christos Georgis,a Alexis Brentas,a Vasiliki Polychronidou,a Pinelopi Voulgari,a Vassiliki Theodorou*a and Konstantinos Skobridis*a

aDepartment of Chemistry, University of Ioannina, Ioannina, Greece bDepartment of Biological Applications and Technology, University of Ioannina, Ioannina, Greece

 

Abstract

We revisited the classical synthetic procedure for Imatinib synthesis providing an improved and optimized approach in the preparation of a series of new Imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity  and has the potential to be used for the synthesis of many analogues. Τhe formation of the desired guanidine salt 4, one of the key steps to the Imatinib synthesis, was proceeded almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam’s catalyst. In addition, the application of this optimized approach can be extended in the synthesis of Nilotinib and its analogues intermediates.

 

Supplement

Tyrosine kinase inhibitors currently represent the most important class of anticancer drugs, based on the concept of targeted therapy. Imatinib (Glivec or Gleevec, Novartis) is the first clinically approved tyrosine kinase ATP-competitive inhibitor, established as a model for a revolutionized treatment of cancer. It is a specific inhibitor of Bcr-Abl kinase, which was used as a front-line therapy for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). However, secondary drug resistance is a main complication, caused by point mutations of Abl, after an initial positive response to Imatinib. To overcome this problem, second generation of Bcr-Abl tyrosine kinase inhibitors are required. Extensive efforts have been devoted to the design and development of potent and more selective kinase inhibitors. Thus, a great number of structurally diverse compounds, such as Nilotinib, a derivative of Imatinib, Sorafenib, Dasatinib, have been developed.

Given the great potential of kinase inhibitors, they have attracted considerable interest in the reinvestigation of their synthesis and the optimum reaction conditions to construct them. Imatinib, the leading kinase inhibitor, provides an excellent model system to investigate how changes in chemical structure impact biological activity. The original synthetic procedure to it, first reported by Zimmermann et al. (1-2), was completed via several steps (Scheme 1).

 

 

scheme1

Scheme 1 J. Zimmermann approach.

 

In the present study, the investigations were focused on the construction of a series of new analogues, making variations on the A, C and D blocks (Fig.1) and providing a modified synthetic protocol (Scheme 2).

 

fig1

Fig. 1 Structural modifications of designed Imatinib analogues.

scheme2

Scheme 2 Optimized synthetic protocol for the preparation of Imatinib analogues.

 

Keeping the original route to Imatinib, all the steps were reinvestigated, aiming to develop better reaction conditions for the synthesis of Imatinib and its structurally related analogues (3,4). The new Imatinib analogues were obtained in a five-step synthesis, in very high overall yields (58-63%) and high analytical purity (> 99.5%).

The described synthetic approach was employed for the synthesis of a wide range of compounds, as potential kinase inhibitors. The modifications mainly concern (i) the pyridyl-pyrimidine key structure by varying the number and the position of nitrogens and (ii) the replacement of N-methylpiperazinyl group by, in general, withdrawing substituents in various places of the phenyl group (Fig. 1).

Moreover, a new series of analogues were prepared, replacing the NH group of the 2-aminopyrimidine ring with the alternative binding group NHCO (5), following the same protocol (Scheme 3) and providing a platform for further drug development.

 

scheme3

Scheme 3 Synthesis of new Imatinib analogues.

 

Following the described advantageous route, the investigations were extended into the scope of Nilotinib analogues (Scheme 4).

 

 

scheme4

Scheme 4 Synthesis of Nilotinib analogues

 

References

(1) J. Zimmermann, E. Buchdunger, H. Mett, T. Meyer, N. B. Lydon and P. Traxler, 1996, Phenylamino-pyrimidine (PAP) – derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors Bioorg. Med. Chem. Lett., 6, 1221-1226

(2) J. Zimmermann, E. Buchdunger, H. Mett, T. Meyer, N. B. Lydon and P. Traxler, 1997, Potent and selective inhibitors of the Abl-kinase: phenylamino-pyrimidine (PAP) derivatives, Med. Chem. Lett., 7, 187-192

(3) K. Skobridis, M. Kinigopoulou, V. Theodorou, E. Giannousi, A. Russell, R. Chauhan, R. Sala, N. Brownlow, S. Kiriakidis, I. Domin, A. G. Tzakos and N. J. Dibb, 2010, Novel Imatinib Derivatives with Altered Specificity between Bcr–Abl and FMS, KIT, and PDGF Receptors, ChemMedChem, 130-139

(4) K. Arvaniti, A. Papadioti, M. Kinigopoulou, V. Theodorou, K. Skobridis, G. Tsiotis, 2014, Changes Induced by Imatinib and Novel Imatinib Derivatives in K562 Human Chronic Myeloid Leukemia Cells Proteome, 2, 363-381

(5) V Theodorou, M Gogou, A Giannoussi, K Skobridis, 2014, Insights into the N, N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: an alternative N-monoacylation reaction, 4, 11-23

 

Acknowledgements

This research project has been co-nanced by the European Union (European Regional Development Fund—ERDF) and Greek national funds through the Operational Program–THESSALY-MAINLAND GREECE AND EPIRUS-2007-2013 of theNational Strategic Reference Framework (NSRF 2007-2013). We thank the NMR Center and the Mass Spectrometry Unit of the University of Ioannina for taking the 1H/13C-NMR and HRMS spectra.

 

Contact

Konstantinos Skobridis

Professor of Organic Chemistry

Department of Chemistry, University of Ioannina, Greece

GR-45110 Ioannina, kskobrid@cc.uoi.gr

 

 

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