Diisopropylethylamine → methyl (S)-1-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HATU (464 mg, 1.22 mmol) was added to a solution of (1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (280 mg, 1.02 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (214 mg, 1.22 mmol) and DIEA (1.8 mL, 10 mmol) in DMF (3 mL). The reaction mixture was stirred 2 h at room temperature and then diluted with MeOH (5 mL) and water (5 mL). The volatiles were removed under vacuum and the residue was purified with flash chromatography (sample was dry loaded on silica gel and eluted with 0-100 ethyl acetate/hexanes) to afford methyl (S)-1-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (500 mg, 0.925 mmol, 91% yield) as yellowish oil. LC-MS retention time 0.850 min; m/z 432.97 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 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 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.09 (s, 1H), 5.09 (dd, J=8.9, 4.6 Hz, 1H), 4.47-4.60 (m, 1H), 3.67 (s, 3H), 3.59-3.62 (m, 1H), 2.39-2.49 (m, 1H), 2.29-2.39 (m, 1H), 2.12 (dq, J=13.6, 6.8 Hz, 1H), 1.95-2.06 (m, 1H), 1.11 (dt, J=8.6, 5.5 Hz, 1H), 0.94-1.02 (m, 3H), 0.91 (d, J=6.7 Hz, 3H), 0.76 (br s, 1H).

1. customThe volatiles were removed under vacuum
2. customthe residue was purified with flash chromatography (sample was dry loaded on silica gel and eluted with 0-100 ethyl acetate/hexanes)

ORD record

ord-cf2aa75d742b4f2291a2945ebc3e693b

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09303007B2