Compound 63
((8R,9S,10S)-9-(2',3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-((1-methyl-1H-imidazol-2-yl)sulfonyl)-1,6-diazabicyclo[6.2.0]decan-10-yl)methanol
From: Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme
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Compound data: 1H NMR
Compound data: 13C NMR
Compound data: COSY
Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.
A solution of intermediate 71 (37 mg, 0.0755 mmol) was dissolved in THF (5 mL), added 2 mL MeOH, 50 µL of AcOH (~10 drops), and 20 mg 20% Pd(OH)2/C, and stirred vigorously overnight (16 h) under an atmosphere of H2 gas from a balloon. The heterogeneous solution was added MeOH (20 mL) and filtered through a syringe filter (0.2 Micron), evaporated to a residue under vacuum for purification by HPLC. Purification was performed on a C18 21.2 × 250 mm column (5 μm particle size, 100 Å pore size, Kromasil), using a gradient of 10 to 70% MeCN/water over 50 min, and solvents containing 0.1% TFA. Fractions containing the title compound 63 were combined and freeze-dried to produce a white powder (33.4 mg, 0.055 mmol, 73% yield). High resolution mass, calculated for C27H34N4O3S [M+H]+ = 495.2424, found 495.2421, Δ = −0.7 ppm. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H*), 7.51 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 1.1 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 7.6, 1.7 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 1.1 Hz, 1H), 7.01 (dd, J = 7.5, 1.8 Hz, 1H), 4.81 (td, J = 9.8, 2.8 Hz, 2H), 4.41 (td, J = 9.9, 6.4, 3.8 Hz, 1H), 4.02 – 3.84 (m, 4H), 3.83 (s, 3H), 3.83 – 3.76 (m, 2H), 3.61 – 3.49 (m, 2H), 3.29 (ddd, J = 15.6, 8.3, 3.2 Hz, 1H), 2.29 (s, 3H), 2.10 (s, 3H), 2.08 – 1.98 (m, 1H), 1.98 – 1.82 (m, 2H), 1.77 (ddd, J = 14.0, 9.7, 3.7 Hz, 1H). *TFA salt 13C NMR (101 MHz, DMSO-d6) δ 158.23 (q, J = 34.4 Hz*), 141.72, 141.57, 140.99, 136.89, 134.02, 133.33, 129.42 (2C), 128.88, 127.66, 127.41 (2C), 127.30 (2C), 126.32, 125.35, 116.26 (q, J = 294.0 Hz*), 74.06, 70.57, 58.97, 54.32, 50.56, 48.76, 34.33, 26.76, 22.84, 20.29, 16.68. *TFA salt.
