Propiolic Acid → tert-Butyl ((S)-1-(((S)-3,3-dimethyl-1-oxo-1-((2S,4S)-4-propiolamido-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)butan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of propiolic acid (0.06 mL, 0.90 mmol) in DMF (2 mL) at 0° C. was added HATU (123 mg, 0.32 mmol) followed by tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-amino-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (100 mg, 0.18 mmol) and DIEA (0.06 mL, 0.36 mmol). The reaction mixture was stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 90% EtOAc/hexane) to afford the title compound as a white solid (76 mg, 70%). 1H NMR (CDCl3) δ 8.60 (d, J=6.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.25 (m, 1H), 7.16-6.98 (m, 3H), 5.23-5.08 (m, 1H), 4.73 (d, J=8.8 Hz, 1H), 4.63-4.48 (m, 1H), 4.32 (d, J=8.6 Hz, 1H), 3.96 (dd, J=10.9, 5.0 Hz, 1H), 3.75 (d, J=11.0 Hz, 1H), 2.80-2.70 (m, 5H), 2.43 (d, J=13.9 Hz, 1H), 2.18 (ddd, J=14.0, 8.9, 6.4 Hz, 1H), 2.06-1.94 (m, 1H), 1.91-1.80 (m, 4H), 1.46 (s, 10H), 1.30-1.25 (m, 3H), 0.76 (s, 9H); MS(ESI+) m/z 610.4 (M+H)+.

1. customThe organic layer was separated
2. washwashed with aq. NaHCO3 solution
3. dry with materialdried over MgSO4
4. concentrationconcentrated in vacuo
5. customThe residue was purified by flash column chromatography (eluting with 90% EtOAc/hexane)

ORDレコード

ord-23f5e9d6c8ad4e8da92f9df666047c72

出典データセット

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09345740B2