Reaction Steps
Previously reported 1-tert-butoxycarbonylamino-{2-[biphenyl-4-yl-(3-methyl-3H-imidazol-4-ylmethyl)-amino]}-ethane (compound 9a in reference 31b) (30 mg, 0.0739 mmol) was deprotected by stirring in a 1:1 mixture of TFA-CH2Cl2 (1 mL) for 30 minutes. After removal of all solvent in vacuo, the residue (23 mg, 0.0739 mmol) was sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl chloride, but with 5 equiv of DIPEA. Generally, the appropriate sulfonyl chloride (1.2 equiv) was added to a solution of the amine (1 equiv) and DIPEA (2 equiv) in anhydrous CH3CN (0.1 M) at 0° C. The reaction was warmed to room temperature and stirred for 16 h, at which time the solvent was evaporated. The residue was re-dissolved in CH2Cl2, washed with 5% NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. After the usual work-up, the residue was purified by silica gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to afford 1-methyl-1H-imidazole-4-sulfonic acid benzyl-[2-(biphenyl-4-ylamino)-ethyl]-amide as a colorless film (30 mg, 91%) Next, the secondary aniline of 1-methyl-1H-imidazole-4-sulfonic acid benzyl-[2-(biphenyl-4-ylamino)-ethyl]-amide (30 mg, 0.067 mmol, 1 equiv) was alkylated with the HCl salt of 5-chloromethyl-1-methyl-1H-imidazole. The secondary aniline (1 equiv) was dissolved in DMF (0.07 M), then the reaction was cooled to 0° C. After 15 min, NaH (3 eq.) was added in one portion. After a further 15 min, 5-chloromethyl-1-methyl-1H-imidazole.HCl (1.1 eq) was added. The reaction was allowed to stir at 0° C. from 2-3 h, when TLC indicated the reaction was complete or had stalled. Upon quenching the reaction with brine (approximately 1 mL), the reaction was diluted with water and extracted with EtOAc (×3). The EtOAc extractions were combined, and washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. After the usual work-up, the crude material was dry-loaded onto silica gel and purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to give 11 as a glassy film (24 mg, 65%): δH (500 MHz, CDCl3) 3.16 (m, 2H, (Bn)NCH2CH2N), 3.33 (m, 2H, (Bn)NCH2CH2N), 3.44 (s, 3H, CH3 (Im)), 3.75 (s, 3H, CH3 (Im)), 4.27 (s, 2H, CH2Ph), 4.38 (s, 2H, CH2Im), 6.56 (d, J=9.0 Hz, 2H, 2 CH (Ar)), 6.79 (s, 1H, CH (Im)), 7.34-7.51 (m, 15H, 10 CH (Ph), 3 CH (Im), 2 CH (Ar)); δC (125 MHz, CDCl3) δ1.9, 34.2, 44.9, 45.4, 50.0, 54.5, 113.5, 124.6, 126.4, 126.5, 128.1, 128.3 (2), 128.9, 129.0, 129.2, 129.4, 130.5, 136.8, 138.8, 139.3, 139.9, 141.1, 147.2; HRMS (ES+) calcd for [C30H32N6O2S+H] 541.2380. found 541.2386; HPLC (I) tR=13.01 min (100%), (II) tR=20.24 min (100%).
