Reaction Steps
tert-Butyl N-[2-(2-{3-(aminocarbonyl)-2-[(aminocarbonyl)amino]thien-5-yl}phenoxy)ethyl]-N-benzylcarbamate (0.16 g) was dissolved in DCM (3 ml); thioanisole (0.5 g) and trifluoroacetic acid (1 ml) were added. The mixture was stirred for 30 min, then water (5 ml) was added and the mixture extracted with DCM. The DCM was added to a SCX cation exchange column and eluted with 30% methanol-DCM to remove the thioanisole, then with methanolic ammonia-DCM mixtures. The solvent was evaporated and the residue recrystallised from methanol affording the title compound as a white solid (0.04 g). MS (ES) 411 (M+H)+. 1H NMR (DMSO-D6) 2.9 (t, 2H), 3.8 (s, 2H), 4.1 (t, 2H), 6.9 (s, 2H), 7.0 (t, 1H), 7.05 (d, 1H), 7.15-7.35 (m, 8H), 7.6 (d, 1H), 7.65 (s, 1H), 7.8 (s, 1H), 10.9 (s, 1H). b) tert-Butyl N-[2-(2-{3-(aminocarbonyl)-2-[(aminocarbonyl)amino]thien-5-yl}phenoxy)ethyl]-N-benzylcarbamate This was prepared from tert-butyl N-benzyl-N-[2-(2-bromophenoxy)ethyl]carbamate in a similar manner to Example 1 (a), except that the DCM layer was chromatographed twice on silica in DCM-methanol mixtures affording the title compound as a resinous solid. MS (ES) 511 (M+H)+. 1H NMR (DMSO-D6) 1.35 (s, 9H), 3.6 (t, 2H), 4.2 (t, 2H), 4.5 (s, 2H), 6.5 (s 2H), 6.9-7.4 (m, 10H), 7.5 (d, 1H), 7.6 (s, 1H), 10.9 (s, 1H) c) tert-Butyl N-benzyl-N-[2-(2-bromo henoxy)ethyl]carbamate A solution of di-t-butyl dicarbonate (0.96 g) in DCM (4 ml) was added over 5 min to a stirred solution of N-benzyl-N-[2-(2-bromophenoxy)ethyl]amine (1.3 g) in DCM (16 ml) and the mixture was stirred for 1.5 h, then concentrated to 6 ml, and diluted with isohexane (12 ml). The solution was chromatographed on silica in isohexane-DCM mixtures affording the title compound as a colourless oil (0.9 g). MS (ES) 350 (M+H-56)+. 1H NMR (DMSO-D6, 100° C.) 1.4 (s, 9H), 3.5 (t, 2H), 4.15 (t, 2H), 4.55 (s, 2H), 6.9 (t, 1H), 7.1 (d, 1H), 7.2-7.35 (m, 6H), 7.55 (d, 1H). d) N-Benzyl-N-[2-(2-bromophenoxy)ethyl]amine This was prepared from benzylamine and 1-bromo-2-(2-chloroethoxy)benzene by the method of Example 1 (b). The material obtained after chromatography on silica in DCM-methanolic ammonia mixtures was stirred in DCM and a solid removed by filtration. Evaporation of the mother liquors afforded the title compound as an oil. 1H NMR (DMSO-D6) 2.9 (t, 2H), 3.2-3.3 (bs, 1H), 3.8 (s, 2H), 4.1 (t, 2H), 6.9 (t, 1H), 7.1 (d, 1H), 7.2-7.35 (m, 6H), 7.55 (d, 1H).
