Reaction Steps
HATU (203 mg, 0.533 mmol) was added to a stirred solution of (1R,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (225 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (93 mg, 0.53 mmol) in DMF (3 mL) and DIPEA (0.37 mL, 2.1 mmol) and the reaction was stirred at rt for 3 hr. The crude reaction was concentrated under a stream of nitrogen and the residue was dissolved into MeOH and purified by preparative HPLC (MeOH/water with an ammonium acetate buffer) to yield (1R,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg) as a yellow solid. LC-MS retention time 4.053 min; m/z 790.25 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.28 (s, 2 H), 8.13 (d, J=8.8 Hz, 1 H), 8.08 (d, J=8.8 Hz, 1 H), 7.94-8.02 (m, 4 H), 7.76-7.92 (m, 3 H), 7.85 (dd, J=8.7, 1.6 Hz, 1 H), 7.29 (br. s., 5 H), 5.21 (d, J=12.1 Hz 1 H), 5.16 (dd, J=9.2, 6.9 Hz, 1 H), 4.97 (t, J=8.2 Hz, 1 H), 4.57 (d, J=6.5 Hz, 1 H), 3.78-3.87 (m, 1 H), 3.68 (s, 3 H), 3.64-3.77 (m, 2 H), 2.66-2.77 (m, 2 H), 2.40-2.56 (m, 2 H), 2.14-2.25 (m, 1 H), 2.05-2.14 (m, 1 H), 1.87 (d, J=6.5 Hz, 1 H), 1.06-1.16 (m, 1 H), 1.02 (d, J=6.8 Hz, 3 H), 0.94 (d, J=6.8 Hz, 3 H), 0.87-0.99 (m, 2 H), 0.74-0.82 (m, 1 H).
