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]pyrimidin-7(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.
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Hamby JM, Connolly CJC, Schroeder MC, Winters RT, Showalter HDH, Panek RL, Major TC, Olsewski B, Ryan MJ, Dahring T, Lu GH, Keiser J, Amar A, Shen C, Kraker AJ, Slintak V, Nelson JM, Fry DW, Bradford L, Hallak H, Doherty AM (1997) Structure–activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J Med Chem 40: 2296–2303. doi:10.1021/jm970367n
Klutchko SR, Hamby JM, Boschelli DH, Wu Z, Kraker AJ, Amar AM, Hartl BG, Shen C, Klohs WD, Steinkampf RW, Driscoll DL, Nelson JM, Elliott WL, Roberts BJ, Stoner CL, Vincent PW, Dykes DJ, Panek RL, Lu GH, Major TC, Dahring TK, Hallak H, Bradford LA, Showalter HD, Doherty AM (1998) 2-Substituted aminopyrido[2,3-d]pyrimidin-7(8H)-ones. structure-activity relationships against selected tyrosine kinases and in vitro and in vivo anticancer activity. J Med Chem 41: 3276–3292. doi:10.1021/jm9802259
Boschelli DH, Wu Z, Klutchko SR, Showalter HD, Hamby JM, Lu GH, Major TC, Dahring TK, Batley B, Panek RL, Keiser J, Hartl BG, Kraker AJ, Klohs WD, Roberts BJ, Patmore S, Elliott WL, Steinkampf R, Bradford LA, Hallak H, Doherty AM (1998) Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8H-pyrido[2,3-d]pyrimidines: identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors. J Med Chem 41: 4365–4377. doi:10.1021/jm980398y
Dorsey JF, Jove R, Kraker AJ, Wu J (2000) The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells. Cancer Res 60: 3127–3131
Wisniewski D, Lambek CL, Liu C, Strife A, Veach DR, Nagar B, Young MA, Schindler T, Bornmann WG, Bertino JR, Kuriyan J, Clarkson B (2002) Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Res 62: 4244–4255
Huang M, Dorsey JF, Epling-Burnette PK, Nimmanapalli R, Landowski TH, Mora LB, Niu G, Sinibaldi D, Bai F, Kraker A, Yu H, Moscinski L, Wei S, Djeu J, Dalton WS, Bhalla K, Loughran TP, Wu J, Jove R (2002) Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. Oncogene 21: 8804–8816
Huron DR, Gorre ME, Kraker AJ, Sawyers CL, Rosen N, Moasser MM (2003) A novel pyridopyrimidine inhibitor of abl kinase is a picomolar inhibitor of Bcr-abl-driven K562 cells and is effective against STI571-resistant Bcr-abl mutants. Clin Cancer Res 9: 1267–1273
Wolff NC, Veach DR, Tong WP, Bornmann WG, Clarkson B, Ilaria RL Jr (2005) PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia. Blood 105: 3995–4003
Martínez-Teipel B, Teixidó J, Pascual R, Mora M, Pujolà J, Fujimoto T, Borrell JI, Michelotti EL (2005) 2-Methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles: versatile starting materials for the synthesis of libraries with diverse heterocyclic scaffolds. J Comb Chem 7:436–448. doi:10.1021/cc049828y
Victory P, Nomen R, Colomina O, Garriga M, Crespo A (1985) New synthesis of pyrido[2,3-d]pyrimidines. 1. Reaction of 6-alkoxy-5-cyano-3,4-dihydro-2-pyridones with guanidine and cyanamide. Heterocycles 23: 1135–1141
Borrell JI, Teixidó J, Matallana JL, Martínez-Teipel B, Colominas C, Costa M, Balcells M, Schuler E, Castillo MJ (2001) Synthesis and biological activity of 7-oxo substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF) and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). J Med Chem 44: 2366–2369. doi:10.1021/jm990411u
Borrell JI, Teixidó J, Martínez-Teipel B, Serra B, Matallana JL, Costa M, Batllori X (1996) An unequivocal synthesis of 4-amino-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-diones and 2-amino-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4, 7-diones. Collect Czech Chem Commun 61: 901–909
Mont N, Teixidó J, Kappe CO, Borrell JI (2003) A one-pot microwave-assisted synthesis of pyrido[2,3-d]pyrimidines. Mol Divers 7: 153–159. doi:10.1023/B:MODI.0000006808.10647.f8
Berzosa X, Bellatriu X, Teixidó J, Borrell JI (2010) An unusual Michael addition of 3,3-dimethoxypropanenitrile to 2-aryl acrylates: a convenient route to 4-unsubstituted 5,6-dihydropyrido [2,3-d]pyrimidines. J Org Chem 75: 487–490. doi:10.1021/jo902345r
Perez-Pi I, Berzosa X, Galve I, Teixido J, Borrell JI (2010) Dehydrogenation of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones: a convenient last step for a synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones. Heterocycles 82: 581–591
Goswami S, Hazra A, Jana S (2009) One-pot two-step solvent-free rapid and clean synthesis of 2-(substituted amino)pyrimidines by microwave irradiation. Bull Chem Soc Jpn 82: 1175–1181
Liu JJ, Luk KC (2006) 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones. US patent 7098332(B2), August 29, 2006 (CAN 141:71554)
Ha HH, Kim JS, Kim BM (2008) Novel heterocycle-substituted pyrimidines as inhibitors of NF-κB transcription regulation related to TNF-α cytokine release. Bioorg Med Chem Lett 18: 653–656. doi:10.1016/j.bmcl.2007.11.064
El Ashry ESH, El Kilany Y, Rashed N, Assafir H (1999) Dimroth rearrangement: translocation of heteroatoms in heterocyclic rings and its role in ring transformations of heterocycles. Adv Heterocycl Chem 75: 79–165
El Ashry ESH, Nadeem S, Raza Shah M, El Kilany Y (2010) Recent advances in the dimroth rearrangement: a valuable tool for the synthesis of heterocycles. Adv Heterocycl Chem 101: 161–228
Shishoo CJ, Jain KS (1993) Reaction of nitriles under acidic conditions Part VII. Study on the reaction of α-aminonitriles with cyanamides to synthesize 2,4-diaminothieno[2,3-d]pyrimidines. J Heterocycl Chem 30: 435–440
Victory P, Crespo A, Garriga M, Nomen R (1988) New synthesis of pyrido[2,3-d]pyrimidines. III. Nucleophilic substitution on 4-amino-2-halo- and 2-amino-4-halo-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H-ones. J Heterocycl Chem 25: 245–247
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Galve, I., Puig de la Bellacasa, R., Sánchez-García, D. et al. Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3-d]pyrimidine-7(8H)-ones from arylguanidines. Mol Divers 16, 639–649 (2012). https://doi.org/10.1007/s11030-012-9398-6
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DOI: https://doi.org/10.1007/s11030-012-9398-6