173600-03-8Relevant articles and documents
Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution
Alam, Ryan M.,Keating, John J.
, p. 1939 - 1951 (2021/08/23)
The indazole scaffold represents a promising pharmacophore, commonly incorporated in a variety of therapeutic drugs. Although indazole-containing drugs are frequently marketed as the corresponding N-alkyl 1H- or 2H-indazole derivative, the efficient synthesis and isolation of the desired N-1 or N-2 alkylindazole regioisomer can often be challenging and adversely affect product yield. Thus, as part of a broader study focusing on the synthesis of bioactive indazole derivatives, we aimed to develop a regioselective protocol for the synthesis of N-1 alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for N-1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we observed > 99% N-1 regioselectivity for 3-carboxymethyl, 3-tert-butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on N-1/N-2 regioisomeric distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate electrophiles, while maintaining a high degree of N-1 regioselectivity.
Efficient two-step sequence for the synthesis of 2,5-disubstituted furan derivatives from functionalized nitroalkanes: Successive Amberlyst A21- and Amberlyst 15-catalyzed processes
Palmieri, Alessandro,Gabrielli, Serena,Ballini, Roberto
supporting information; experimental part, p. 6165 - 6167 (2010/10/20)
The nitroaldol reaction of ketal-functionalized nitroalkanes with α-oxoaldehydes, promoted by Amberlyst A21, followed by acidic treatment (Amberlyst 15) of the obtained nitroalkanol, leads to the formation of 2,5-disubstituted furans in good yields. The p
Development of potent serotonin-3 (5-HT3) receptor antagonists. II. Structure-activity relationships of N-(1-benzyl-4-methylhexahydro-1H-1,4- diazepin-6-yl)carboxamides
Harada,Morie,Hirokawa,Terauchi,Fujiwara,Yoshida,Kato
, p. 1912 - 1930 (2007/10/03)
Our studies on 4-amino-5-chloro-2-ethoxybenzamides led to the discovery that the N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)benzamide 9 and the 1- benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 10 are potent serotonin-3 (5-HT3) receptor antagonists. Structure-activity relationship (SAR) studies on the influence of the aromatic nucleus of 9 and 10 upon inhibition of the von Bezold-Jarisch reflex in rats are described. Heteroaromatic rings such as pyrrole, thiophene, furan, pyridine, pyridaziae, 1,2-benzisoxazole, indole, quinoline, and isoquinoline rings showed weak 5-HT3 receptor antagonistic activity. Within this series, use of the 1H-indazole ring as an aromatic moiety led to a substantial increase of the activity; the 1H- indazolylcarboxamides 54, 57, 97, and 102 showed potent 5-HT3 receptor antagonistic activity. The optimal compound identified via extensive SAR studies was N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole- 3-carboxamide (54), whose effect was superior to that of the corresponding benzamide 10 and essentially equipotent to those of ondansetron (1) and granisetron (4).
