Sodium Bicarbonate → N,N'-(4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))bis(1,3-thiazol-2-amine)

Participants

Reaction Conditions

Reaction Steps

A mixture of (S)-3-methyl-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(thiazol-2-ylamino)butan-1-one (275 mg, 0.527 mmol), (S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one (250 mg, 0.527 mmol), NaHCO3 (133 mg, 1.582 mmol) and Pd(Ph3P)4 (60.9 mg, 0.053 mmol) in DME (3 mL) and Water (1 mL) was degassed by passing a stream of N2 through the mixture. The vessel was sealed and the reaction was heated at 80° C. overnight. The reaction mixture was diluted with H2O and extracted with EtOAc containing ca. 5% MeOH (×3). The combined org layers were concentrated, dissolved in MeOH and loaded onto an MCX cartridge. The cartridge was washed with MeOH and then NH3 in MeOH (2M). The appropriate fractions were concentrated in vacuo and the residue was purified by prep HPLC (CH3CN—H2O—NH4OAc). The material was purified by column chromatography (biotage) eluting with 0 to 20% MeOH in EtOAc. Further purification by prep HPLC (CH3CN—H2O—NH4OAc) followed by lyophilization afforded the title compound as a colorless solid (6.9 mg, 2%). 1HNMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 11.75 (s, 2H), 7.75-7.80 (m, 4H), 7.68-7.71 (m, 4H), 7.49 (s, 2H), 6.99 (d, J=3.7 Hz, 2H), 6.57 (d, J=3.7 Hz, 2H), 5.34-5.36 (m, 1H), 5.07 (app dd, J=3.7, 7.0 Hz, 2H), 4.42 (t, J=8.4 Hz, 2H), 3.98-4.05 (m, 2H), 3.79-3.85 (m, 2H), 3.44-3.56 (m, 1H), 1.97-2.21 (m, 8H), 1.01 and 0.95 (d, J=7.0 Hz, 6H, rotamers, 1:3 ratio), 0.99 and 0.92 (d, J=7.0 Hz, 6H, rotamers, 1:3 ratio). LCMS: Anal. Calcd. for C42H48N10O2S2: 788; found: 789 (M+H)+.

Provenance & Evidence