Cesium carbonate → 1-{3-[3-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-ol

Participants

Reaction Conditions

Reaction Steps

To a degassed solution of 1-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol (0.100 g, 0.21 mmol) in toluene (3 ml) at rt under nitrogen was added Pd(OAc)2 (1 mg, 4.45 μmop and BINAP (5 mg, 8.03 μmol). Nitrogen was bubbled through the mixture for 10 min before a degassed solution of 1-biphenyl-2-ylmethyl-piperazine (64 mg, 0.25 mmol) in toluene (1 ml) was introduced. After 5 min Cs2CO3 (1.39 g, 4.27 mmol) was added. During all additions nitrogen was continuously bubbled through the reaction. Once the additions were completed the reaction vessel was sealed and then heated to 95° C. where it was maintained for 1d. After this time, the reaction was cooled to rt and additional Pd(OAc)2 (1 mg, 4.45 □mol) and BINAP (5 mg, 8.03 □mol) were added. The reaction was then returned to 95° C. where it was maintained for 3 d. The suspension was then cooled to rt, filtered through Celite® and the collected solids were washed with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure and the crude product was purified by preparative HPLC twice. The purified product was partitioned between a saturated solution of NaHCO3 and dichloromethane and the organic phase was separated. The aqueous layer was extracted with additional dichloromethane and then the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-{3-[3-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-ol (10 mg, 7%). HPLC-MS 642 [M+1]+, 322.

Provenance & Evidence