1,4-Dihydropyridines et Pyrimidines

Notre travail couvre des méthodologies de synthèse pour accéder à de nombreuses 1,4-dihydropyridines, qui sont utilisées comme antagonistes du calcium, aux pyridines correspondantes, ainsi qu’aux pyrimidines analogues (composes de Biginelli).

Des réactions multi-composants sont impliquées dans ces synthèses.



La Nifedipine, un médicament introduit aux USA en 1982, appartient à la classe des bloquants des canaux calciques, aussi appelés antagonistes du calcium. Les applications cliniques de ce groupe de medicaments couvent l’angine de poitrine, l’hypertension et les arythmies ventriculaire et supraventriculaire.
Link: Article de Medicinenet au sujet de la Nifedipine

Le métabolisme de la Nifedipine et des 1,4-dihydropyridines analogues implique une étape d’oxydation qui est catalysée, dans le foie, par un cytochrome P-450. Cette réaction peut-être reproduite en milieu abiotique et est le sujet de nombreuses publications.

  • 1,3-Dicarbonyl Compound as Third Component (Hantzsch Pyridine Synthesis). J.J. Vanden Eynde, A. Mayence. Science of Synthesis. Multicomponent Reactions 1. Chapter 1.2.1.2. 67 (2014) – 32 pages. Georg Thieme Verlag KG, Stuttgart, Germany Chemistry (2014).
  • Batch and Continuous Flow Preparation of Hantzsch 1,4-Dihydropyridines under Microwave Heating and Simultaneous Real-time Monitoring by Raman Spectroscopy. An Exploratory Study. S. Christiaens, X. Vantyghem, M. Radoiu, J.J. Vanden Eynde. Molecules,19,9986 (2014).
  • Ionic Liquid Phase Organic Synthesis (IoLiPOS) Methodology Applied to the Preparation of New 3,4-Dihydropyrimidine-2(1H)-ones Bearing Bioisostere Group in N-3 Position. J.C. Legeay, J.J. Vanden Eynde, J.P. Bazureau. Tetrahedron, 64, 5328 (2008)
  • Sequential Synthesis of a New Analogue of Amlodipine Bearing a Short Amino Polyethyleneglycol Chain. J.C. Legeay, J.J. Vanden Eynde, J.P. Bazureau. Tetrahedron, 63, 12081 (2007)
  • A Three-component Condensation Protocol Based on Ionic Liquid Phase Bound Acetoacetate for the Synthesis of Biginelli 3,4-Dihydropyrimidine-2(1H)-ones. J.C. Legeay, J.J. Vanden Eynde, L. Toupet, J.P. Bazureau. Arkivoc, Part (iii), 13 (2007)
  • A New Approach to N-3 Functionalized 3,4-Dihydropyrimidine-2(1H)-ones With 1,2,4- Oxadiazole Group as Amide Isostere via Ionic Liquid Phase Technology. J.C. Legeay, J.J. Vanden Eynde, J.P. Bazureau. Tetrahedron Lett.,48, 1063 (2007)
  • Liquid-phase Synthesis of Polyhydroquinoline Using Task-specific Ionic Liquid Technology. J.C. Legeay, J.Y. Goujon, J.J. Vanden Eynde, L. Toupet, J.P. Bazureau. J. Comb. Chem., 8, 829 (2006)
  • Ionic Liquid Phase Technology Supported the Three Component Synthesis of Hantzsch 1,4-Dihydropyridines and Biginelli 3,4-Dihydropyrimidin-2(1H)-ones under Microwave Dielectric Heating. J.-C. LEGEAY, J.J. VANDEN EYNDE, J.P. BAZUREAU. Tetrahedron, (2005).
  • New Pyridine-containing Non-cyclic and Macrocyclic Schiff Bases: Synthesis and Interferon-inducing Activity. R. LOZYTSKA, D. KRYZHANOVSKY, A. MAZEPA, V. GORUDNIUK, V. KUZ’MIN, V. LOZITSKY, A. FEDCHUCK, S. RYBALKO, S. DIADIUM, J.J. VANDEN EYNDE Arkivoc, Part (xiv), 118 (2004)
  • Ionic Liquid Phase Organic Synthesis (IoLiPOS) Methodology Applied to the Three Component Preparation of 2-Thioxo Tetrahydropyrimidin-4(1H)-ones under Microwave Dielectric Heating. H. HAKKOU, J.J. VANDEN EYNDE, J. HAMELIN, J.P. BAZUREAU. Tetrahedron, 60, 3745 (2004).
  • Syntheses and Aromatization of Hantzsch 1,4-Dihydropyridines under Microwave Irradiation. An Overview. J.J. VANDEN EYNDE, A. MAYENCE. Molecules, 8, 381 (2003)
  • Polymer-assisted Synthesis of Ethyl 2-Amino-4,6-diarylpyrimidine-5-carboxylates. J.J. VANDEN EYNDE, N. LABUCHE, Y. VAN HAVERBEKE, L. TIETZE. Arkivoc, Part xv, 22 (2003)
  • Insoluble versus Soluble Polymer-assisted Synthesis. A First Approach for the Preparation of a Biginelli Compound. J.J. VANDEN EYNDE, O. WATTE. Arkivoc, Part iv, 93 (2003)
  • Hydrogen Transfer from Hantzsch 1,4-Dihydropyridines to Carbon-carbon Double Bonds under Microwave Irradiation. S. TORCHY, G. CORDONNIER, D. BARBRY, J.J. VANDEN EYNDE. Molecules, 7, 528 (2002).
  • The Analysis of Structure-anticancer and Antiviral Activity relationships for Macrocyclic pyridinophanes and their Analogues on the Basis of 4D QSAR Models V.E. KUZMIN, A.G. ARTEMENKO, V.P. LOZITSKY, E.N. MURATOV, A.S. FEDTCHOUK, N.S. DYACHENKO, L.N. NOSACH, T.L. GRIDINA, L.I. SHITIKOVA, L.M. MUDRIK, V.A. CHELOMBITKO, A.I. ZHELTVAY, J.J. VANDEN EYNDE. Acta Biochimica Polonica, 49, 157 (2002)
  • Anticancer and Antiviral Properties of Macrocyclic Pyridinophanes and their Derivatives. A.S. FEDCHUK, V.P. LOZITSKY, N.S. DYACHENKO, L.N. NOSACH, O. Yu POVNITSA, V.L. ZHOVNOVATAYA, J.J. VANDEN EYNDE, R.N. LOZITSKAYA, G.L. KAMALOV, D. KRYZHANOVSKY, V.E. KUZMIN, E. SASVILLE. Experimental Oncology, 23, 193 (2001)
  • New Methodologies for the Preparation of Drugs and their Metabolites. Application to 1,4-dihydropyridines Structurally Related to Calcium Channel Modulators of the Nifedipine®-type. J.J. VANDEN EYNDE, A. MAYENCE. Intern. J. Med. Biol. Environm., 28, 89 (2000)
  • En Route to Macrocyclic Pyridinophanes as Anticancer Drugs. Synthetic Ways to the Building Blocks. J.J. VANDEN EYNDE, A. MAYENCE. Experimental Oncology, 22 suppl. 2, 4 (2000)
  • Evidence for a Robinson-like Annulation during the Reaction Between a N-(1-chloroalkyl)pyridinium Chloride and a N-Substituted Enaminoester. J.J. VANDEN EYNDE, A. MAYENCE, O.N. KATAEVA, I.A. LITVINOV, E. ANDERS. Arkivoc, Part i, 73 (2000)
  • Chemistry of N-(1-Haloalkyl)heteroarylium Salts. E. ANDERS, K. WERMANN, J.J. VANDEN EYNDE, Advances in Heterocyclic Chemistry, 77, 183 (2000)
  • Microwave-mediated Derivatization of Poly(styrene-co-allyl alcohol), a Key Step for the Soluble Polymer-assisted Synthesis of Heterocycles. J.J. VANDEN EYNDE, D. RUTOT. Tetrahedron, 55, 2687 (1999)
  • Synthesis and Aromatization of Dihydropyrimidines Structurally Related to Hantzsch Calcium Channel Modulators. J.J. VANDEN EYNDE, N. AUDIART, V. CANONNE, S. MICHEL, Y. VAN HAVERBEKE, C.O.KAPPE. Heterocycles, 45, 1967 (1997)
  • Microwave-mediated Domino Reactions in Dry Medium. Preparation of Dihydropyridinones and Pyridinones Structurally related to Hantzsch Esters. J.J. VANDEN EYNDE, N. LABUCHE, Y. VAN HAVERBEKE. Synth. Commun., 27, 3683 (1997)
  • Old Reagents, New Results : Aromatization of Hantzsch 1,4-Dihydropyridines with Manganese Dioxide and 2,3- Dichloro-5,6-dicyano-1,4- benzoquinone. J.J. VANDEN EYNDE, F. DELFOSSE, A. MAYENCE, Y. VAN HAVERBEKE. Tetrahedron, 51, 6511 (1995)
  • Bentonite K10 Clay, an Efficient Catalyst for the Formation of Nitrogen Derivatives. J.J. VANDEN EYNDE, A. MAYENCE, P. LOR, Y. VAN HAVERBEKE. Bull. Soc. Chim. Belg., 104, 387 (1995)
  • Potassium Permanganate, a Versatile Reagent for the Aromatization of Hantzsch 1,4-Dihydropyridines. J.J. VANDEN EYNDE, R. D'ORAZIO, Y. VAN HAVERBEKE. Tetrahedron, 50, 2479 (1994)
  • An Unusual Aromatization of 4-Antipyryl Hantzsch-type 1,4-Dihydropyridines. J.J. VANDEN EYNDE, A. MAYENCE, A. MAQUESTIAU, E. ANDERS. Heterocycles, 37, 815 (1994)
  • Rate-determining Effects in the Formation of Hantzsch 1,4-Dihydropyridines from N-(1-Haloalkyl)azinium Halides and Methyl 3-Amino-2-butenoate. J.J. VANDEN EYNDE, A. MAYENCE, A. MAQUESTIAU, E. ANDERS. Chem. Ber., 126, 1251 (1993)
  • Novel Syntheses of Heterocy­cles with N-(1-Haloalkyl)azinium Halides. Part 5. Preparation of N-Substituted 1,4-Dihydropyridines. J.J. VANDEN EYNDE, A. MAYENCE, A. MAQUESTIAU, E. ANDERS. Synth. Commun., 22, 3291 (1992)
  • Novel Syntheses of Heterocycles with N-(1-Haloalkyl)azinium Halides. Part 2. Preparation of N-Unsubstituted 1,4-Dihydropyridines. J.J. VANDEN EYNDE, P. D'ORAZIO, A. MAYENCE, A. MAQUESTIAU, E. ANDERS. Tetrahedron, 48, 1263 (1992)
  • A Novel Application of the Oxidizing Properties of Pyridinium Chloro-chromate: Aromatization of Hantzsch 1,4-Dihydropyridi­nes. J.J. VANDEN EYNDE, A. MAYENCE, A. MAQUESTIAU. Tetrahedron, 48, 463 (1992)
  • Ultrasound-promoted Aromatization of Hantzsch 1,4-Dihydropy­ridines by Clay-supported Cupric Nitrate. A. MAQUESTIAU, A. MAYENCE, J.J. VANDEN EYNDE. Tetrahedron Lett., 32, 3939 (1991)