Compound 18
7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
From: Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain
Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.
To a solution of ethyl 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate 17 (74 mg, 0.1 mmol) in THF (0.2 mL) and H2O (0.2 mL) was added MeOH (20 μL) and lithium hydroxide monohydrate (LiOH, 26 mg, 1.08 mmol) and the reaction was allowed to stir overnight. The reaction was acidified with 1M HCl and extracted with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated. A portion of crude product (68.2 mg) was directly used in the next transformation and the remainder was purified by reverse-phase chromatography using 5 to 100% acetonitrile in H2O with 0.1% TFA, affording pure product 18 as a white powder (12 mg) that was used in characterization and testing. Spectral data: 1H NMR (300 MHz, CDCl3) δ ppm 2.12 (s, 3H), 2.26 (tt, J = 7.40, 6.47 Hz, 2H), 3.36 (t, J = 7.40 Hz, 2H), 3.87 (s, 3H), 4.11 (t, J = 6.47 Hz, 2H), 5.02 (s, 2H), 6.65 (d, J = 6.0 Hz, 1H), 7.07 (dd, J = 9.0, 3.0 Hz, 1H) 7.14 (s, 1H), 7.15 (s, 1H), 7.32-7.39 (dd, J = 8.0, 7.6 Hz, 1H), 7.40 - 7.42 (m, 2H), 7.43-7.48 (m, 2H), 7.49-7.52 (m, 2H), 7.68 (q, J = 3.0 Hz, 1H), 7.79-7.84 (m, 1H), 8.32-8.39 (m, 1H), 10.48 (s, 1H); 13C NMR (600 MHz, CDCl3) δ ppm 10.31, 23.55, 27.14, 32.81, 62.42, 66.91, 100.01 103.84, 104.57, 113.53, 119.26, 119.97, 120.04, 121.00, 121.08, 121.10, 121.67, 121.87, 123.12, 125.09, 125.40, 125.70, 126.57, 127.57, 127.78, 134.17, 135.57, 136.28, 139.85, 145.91,156.00, 154.75, 161.45, 190.42, 203.92; MS-ESI (m/z): [M + H]+ calcd for C35H30BrN3O5, 652.14; found 652.0.
- PubChemID:
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316894729
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