1227752-00-2Relevant academic research and scientific papers
Trifluoroacetic acid in 2,2,2-trifluoroethanol facilitates SNAr reactions of heterocycles with arylamines
Carbain, Benoit,Coxon, Christopher R.,Lebraud, Honorine,Elliott, Kristopher J.,Matheson, Christopher J.,Meschini, Elisa,Roberts, Amy R.,Turner, David M.,Wong, Christopher,Cano, Celine,Griffin, Roger J.,Hardcastle, Ian R.,Golding, Bernard T.
supporting information, p. 2311 - 2317 (2014/03/21)
Small-molecule drug discovery requires reliable synthetic methods for attaching amino compounds to heterocyclic scaffolds. Trifluoroacetic acid-2,2,2-trifluoroethanol (TFA-TFE) is as an effective combination for achieving SNAr reactions between
Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2- trifluoroethoxysulfonates
Wong, Christopher,Griffin, Roger J.,Hardcastle, Ian R.,Northen, Julian S.,Wang, Lan-Zhen,Golding, Bernard T.
experimental part, p. 2457 - 2464 (2010/07/09)
The attenuated SN2 reactivity of the 2,2,2-trifluoroethyl group has been exploited for the synthesis of a series of 6-cyclohexylmethoxy-2- arylaminopurines in which a sulfonamide moiety was attached to the aryl ring via a methylene group. These were required as potential inhibitors of serine-threonine kinases of interest for the treatment of cancer. 3-Nitrophenylmethanesulfonyl chloride was converted into the corresponding 2,2,2-trifluoroethoxysulfonyl ester by reaction with 2,2,2-trifluoroethanol in the presence of triethylamine/4-dimethylaminopyridine. Catalytic hydrogenation of the nitro group employing 2,2,2-trifluoroethanol as solvent gave 2,2,2-trifluoroethyl 3-aminophenylmethanesulfonate, which was reacted with 6-cyclohexylmethoxy-2-fluoropurine in 2,2,2-trifluoroethanol/trifluoroacetic acid to afford 2,2,2-trifluoroethyl 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino) phenylmethanesulfonate. 3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino) phenylmethanesulfonamides were synthesised by microwave heating of the trifluoroethoxysulfonate with an amine and 1,8-diazabicycloundec-7-ene in tetrahydrofuran. The mechanism of this process was shown to involve an intermediate sulfene by a deuterium-labelling experiment. 3-(6- Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide derivatives were assayed as inhibitors of human cyclin-dependent kinase 2. Previous structure-activity studies demonstrated that relocating the sulfonamide group of O6-cyclohexylmethoxy-2-(4′-sulfamoylanilino)purine from the 4- to the 3-position on the 2-arylamino ring resulted in a 40-fold reduction in potency against CDK2. In the present study, no further loss of activity was observed on introducing a methylene group between the sulfonamide and the aryl ring, 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide proving equipotent with O6-cyclohexylmethoxy-2-(3′-sulfamoylanilino) purine (IC50 = 0.21 μM). N-Alkylation of the sulfonamide reduced CDK-2 inhibitory activity, while a substituted benzyl or 3-phenylpropyl group on the sulfonamide resulted in a loss of potency compared with 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide. The dimethylaminopropyl derivative, 1-[3-(6-cyclohexylmethoxy-9H-purin-2-ylamino) phenyl]-N-(3-dimethylaminopropyl)methanesulfonamide was only 2-fold less potent than 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide, suggesting an interaction between the basic dimethylamino group and the kinase. The presence of alicyclic groups on the pendant sulfonamide showed IC 50 values in the 0.5-1.5 μM range. N-(4-tert-Butylphenyl)-1-[3-(6- cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methanesulfonamide was markedly less active (IC50 = 34 μM), suggesting a steric effect within the ATP-binding domain.
