Efficient and regioselective one-step synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivatives

Abstract

Two facile and efficient one-step procedures for the regioselective synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines have been developed, via reactions of 3,5-diamino-1,2,4-triazole with variously substituted 1-aryl-1,3-butanediones and 1-aryl-2-buten-1-ones, respectively. The excellent yield and/or regioselectivity shown by the reactions decreased when ethyl 5-amino-1,2,4-triazole-3-carboxylate was used. [1,2,4]Triazolo[1,5-a]pyrimidine being a privileged scaffold, the procedures herein reported may be useful for the preparation of biologically active compounds. In this study, the preparation of a set of compounds based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold led to the identification of compound 20 endowed with a very promising ability to inhibit influenza virus RNA polymerase PA-PB1 subunit heterodimerization.

1,2,4-Triazolo[1,5-a]pyrimidines as a Novel Class of Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity

“…The synthesis of the 2-amino-1,2,4-triazolo[1,5-a]pyrimidine derivatives 12b-g, 13c-g, 14b-g, 15g, 16hh and 17h was accomplished starting with the preparation of the 2-amino synthons 12-16, as shown in Scheme 1. Synthons 12 [31] and 13 [31] were synthesized via reaction of 3,5-diaminotriazole with 1-phenylbutane-1,3-dione and 1-phenylbut-2-en-1-one, respectively [31]. Synthons 14 [32] and 15 [33] were prepared through a more efficient procedure than that already published, entailing the reaction of 3,5-diamino-1,2,4-triazole with the appropriate β-diketone in glacial acetic acid at reflux.…”

“…with a 10-fold weaker potency than that demonstrated against the RNase H. As outlined in Scheme 2, the synthesis of 2-carboxyamide-1,2,4-triazolo[1,5-a]pyrimidine derivatives 18g and 19g was accomplished starting from the carboxylic acid synthons 18 [31] and 19 [31], synthesized as already described in the literature [31] by reacting ethyl 5-amino-1,2,4-triazole-3-carboxylate [34] with 1-phenylbutane-1,3-dione and 1-phenylbut-2-en-1-one, respectively, and then hydrolysing the ethyl esters groups under basic conditions. Thus, coupling reaction between their corresponding carbonyl chlorides with 3,4-dimethoxyaniline performed in dry DCM in the presence of DIPEA, led to intermediates 18f and 19f, which after the O-demethylation furnished the target compounds 18g and 19g, respectively.…”

“…Thus, coupling reaction between their corresponding carbonyl chlorides with 3,4-dimethoxyaniline performed in dry DCM in the presence of DIPEA, led to intermediates 18f and 19f, which after the O-demethylation furnished the target compounds 18g and 19g, respectively. As outlined in Scheme 2, the synthesis of 2-carboxyamide-1,2,4-triazolo[1,5-a]pyrimidine derivatives 18g and 19g was accomplished starting from the carboxylic acid synthons 18 [31] and 19 [31], synthesized as already described in the literature [31] by reacting ethyl 5-amino-1,2,4-triazole-3carboxylate [34] with 1-phenylbutane-1,3-dione and 1-phenylbut-2-en-1-one, respectively, and then hydrolysing the ethyl esters groups under basic conditions. Thus, coupling reaction between their…”

“…Butyl-N-(5-methyl-7-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)benzamide (12b). The title compound was prepared starting from 12[31] through Method A (24 h) by using 4-butylbenzoyl chloride, and purified by flash chromatography eluting with CHCl 3 /MeOH (99:1), in 25% yield as white solid; mp 157-158• C. 1 H-NMR (DMSO-d 6 ,400 MHz): δ 0.85 (t, J = 7.3 Hz, 3H, CH 2 CH 3 ), 1.20-1.35 (m, 2H, CH 2 CH 3 ), 1.50-1.60 (m, 2H, CH 2 CH 2 CH 3 ), 2.55-2.70 (m, 5H, CCH 2 and CH 3 ), 7.30 (d, J = 8.1 Hz, 2H, aromatic CH), 7.45 (s, 1H, H-6), 7.55-7.65 (m, 3H, aromatic CH), 7.90 (d, J = 8.1 Hz, 2H, aromatic CH), 8.15-8.25 (m, 2H, aromatic CH), 11.20 (s, 1H, NHCO); 13 C-NMR (DMSO-d 6 , 101 MHz): δ 14.1, 22.1, 24.9, 33.1, 35.0, 110.1, 128.5, 128.6, 129.0, 129.8, 130.1, 131.3, 131.8, 145.8, 147.3, 155.1, 160.3, 164.8, 165.1.2-Fluoro-N-(5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)benzamide (12c). The title compound was prepared starting from 12 [31] through Method A (2h) by using 2-fluorobenzoyl chloride, and purified by crystallization by cyclohexane/EtOAc, in 9% yield as white solid; mp 292-302 • C. 1 H-NMR (DMSO-d 6 , 400 MHz): δ 2.75 (s, 3H, CH 3 ), 7.25-7.35 (m, 2H, aromatic CH), 7.45 (s, 1H, H-6), 7.50-7.60 (m, 5H, aromatic CH), 8.10-8.15 (m, 2H, aromatic CH), 11.45 (s, 1H, NHCO).…”

Potent and broad-spectrum cycloheptathiophene-3-carboxamide compounds that target the PA-PB1 interaction of influenza virus RNA polymerase and possess a high barrier to drug resistance

“…Since these interactions are essential for viral replication and their binding interfaces are highly conserved among IAV and IBV strains (Pérez and Donis, 1995;Ghanem et al, 2007;Stevaert and Naesens, 2016), the disruption of such interactions represents an attractive strategy for the development of anti-influenza drugs with broad activity (Loregian et al, 2002;Loregian and Palù, 2005;Palù and Loregian, 2013;Loregian et al, 2014;Stevaert and Naesens, 2016;Massari et al, 2016). The feasibility and the effectiveness of such an approach have been demonstrated by the increasing number of PA-PB1 dissociative inhibitors developed in the last decade (Wunderlich et al, 2009;Wunderlich et al, 2011;Muratore et al, 2012a;Muratore et al, 2012b;Fukuoka et al, 2012;Massari et al, 2013;Kessler et al, 2013;Lepri et al, 2014;Pagano et al, 2014;Tintori et al, 2014;Massari et al, 2015;Trist et al, 2016;Yuan et al, 2016;Desantis et al, 2017;Watanabe et al, 2017;Massari et al, 2017;Zhang et al, 2018;D'Agostino et al, 2018).…”