Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3- d ]pyrimidine-7(8 H )-ones from arylguanidines
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Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3-d]pyrimidine-7(8H )-ones from arylguanidines Iñaki Galve · Raimon Puig de la Bellacasa · David Sánchez-García · Xavier Batllori · Jordi Teixidó · José I. Borrell
Received: 20 April 2012 / Accepted: 24 September 2012 / Published online: 10 October 2012 © Springer Science+Business Media Dordrecht 2012
Abstract A practical protocol was developed for the synthesis of 2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H )-ones from α,β-unsaturated esters, malononitrile, and an aryl substituted guanidine via the corresponding 3-aryl-3,4,5,6- tetrahydropyrido[2,3-d]pyrimidin7(8H )-ones. Such compounds are formed upon treatment of 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles with an aryl substituted guanidine in 1,4-dioxane and are converted to the desired 4-aminopyridopyrimidines with NaOMe/MeOH through a Dimroth rearrangement. The overall yields of this three-step protocol are, generally speaking, higher than the multicomponent reaction, previously developed by our group, between an α,β-unsaturated ester, malononitrile, and an aryl substituted guanidine. Keywords Pyrido[2,3-d]pyrimidin-7(8H )-ones · Arylguanidines · 3-Aryl-3,4,5,6-tetrahydropyrido[2,3d]pyrimidin-7(8H )-ones · Dimroth rearrangement
Introduction Pyrido[2,3-d]pyrimidin-7(8H )-ones are a kind of bicyclic heterocyclic compounds for which very interesting inhibitory activities have been described in the field of protein kinase inhibitors. Thus, compounds of general structure 1 have shown IC50 in the range µM to nM in front of PDFGR, Electronic supplementary material The online version of this article (doi:10.1007/s11030-012-9398-6) contains supplementary material, which is available to authorized users. I. Galve · R. Puig de la Bellacasa · D. Sánchez-García · X. Batllori · J. Teixidó · J. I. Borrell (B) Grup d’Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain e-mail: [email protected]
FGFR, EGFR, and c-Scr particularly when R4 is an aryl group [1–8]. These compounds are usually obtained through a multistep strategy in which the pyridine ring is constructed by condensation of a nitrile 2 (bearing the desired substituent R1 ) onto a preformed pyrimidine aldehyde 3 bearing substituent R5 and a methylthio group which can be later substituted by the NHR4 substituent using an amine 4 (Scheme 1). Through the years our group has been interested in the development of synthetic methodologies for the synthesis of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H )-ones with up to four diversity centers starting from α, β-unsaturated esters (5) (Scheme 2). Thus, using the so-called cyclic strategy, the 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitriles (7) are obtained by reaction of an α, β-unsaturated ester (5) and malononitrile (6, G = CN) in NaOMe/MeOH [9]. Treatment of pyridones 7 with guanidine systems (9, R4 = H, alkyl) affords 4-aminopyrido[2,3-d]pyrimidines (10, R3 = NH2 ) [10]. An acycli
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