反应详情

HATU (27.8 mg, 0.073 mmol) was added to a solution of methyl (2S)-1-((1R,3S,5R)-3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Intermediate 131) (40 mg, 0.061 mmol) and (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (15.90 mg, 0.073 mmol) were dissolved into DMF (0.5 mL) and DIPEA (0.053 mL, 0.31 mmol) and the reaction was stirred at rt for 2 h. The reaction was diluted with methanol and purified by preparative HPLC (MeOH/water with an ammonium acetate buffer) to yield methyl ((1S)-2-((1R,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (3.5 mg) as a light yellow solid. LC-MS retention time 2.785 min; m/z 855.74 (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 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.17 (s, 1H), 8.10 (s, 1H), 7.93 (dd, J=8.5, 3.0 Hz, 2H), 7.77-7.86 (m, 6H), 7.44 (s, 1H), 7.35 (s, 1H), 5.20 (dd, J=8.9, 4.6 Hz, 1H), 5.15 (dd, J=8.8, 5.0 Hz, 1H), 4.66 (d, J=7.8 Hz, 1H), 4.61 (d, J=6.8 Hz, 1H), 3.90-3.99 (m, 2H), 3.68 (s, 6H), 3.64-3.76 (m, 3H), 3.34-3.43 (m, 3H), 2.39-2.61 (m, 4H), 2.12-2.23 (m, 1H), 1.99-2.10 (m, 2H), 1.52-1.67 (m, 2H), 1.41-1.51 (m, 1H), 1.08-1.18 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H), 0.76-0.84 (m, 2H).

1. custompurified by preparative HPLC (MeOH/water with an ammonium acetate buffer)