Nitrogen → (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A solution of (S)-tert-butyl 2-(6-(4-bromophenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (674 mg, 1.53 mmol, for its preparation, see PCT Publication No. WO 2008/021927)), (S)-tert-butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (518 mg, 1.98 mmol), copper(I) iodide (29.0 mg, 0.152 mmol) and triethylamine (0.64 mL, 4.6 mmol) in DMF (15 mL) was degassed under vacuum for 10 min and backfilled with N2. Pd(Ph3P)4 (176 mg, 0.152 mmol) was then added and the reaction was sealed and heated at 50° C. for 16 h. The reaction mixture was concentrated to remove the volatiles and the residue was dissolved into a minimal amount of MeOH and then partitioned between EtOAc and water. The layers were separated and the organic layer was concentrated and purified on a BIOTAGE® (300 g silica gel, eluted with 20 to 100% EtOAc/DCM) to yield (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (305 mg) and a mixture of this product with (2S,2′S)-tert-butyl 2,2′-(5,5′-(buta-1,3-diyne-1,4-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate. The mixture was further purified by preparative HPLC (acetonitrile/water/0.1% TFA) to provide a TFA salt of (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (100 mg) and a TFA salt of (2S,2′S)-tert-butyl 2,2′-(5,5′-(buta-1,3-diyne-1,4-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate (128 mg) as white solid.

Provenance & Evidence