反应详情

Intermediate 67e (86 mg, 0.13 mmol) and DIPEA (49 mg, 65 μL) were suspended in DCM (5 mL) and methanesulfonyl chloride (19 mg, 13 μL, 0.16 mmol) was added, and the reaction was stirred at room temp. After 30 min, H2O (5 mL) and DCM (5 mL) was added, stirred, and passed through a phase separator cartridge and the organics concentrated in vacuo. The resulting residue was then suspended in dimethylamine solution (2M in THF, 2.5 mL) in a microwave vial, sealed with a crimped septum and stirred at 60° C. The reaction was then cooled, concentrated in vacuo, subjected to FCC, eluting with 0-7% 2M NH3 in MeOH/DCM, then purified further by HPLC (Gemini C18, 10-98% MeCN in H2O, 0.1% HCO2H, 20 min gradient, 18 mL/min) and the combined fractions freeze dried to afford the title compound (22 mg, 24%). LCMS (Method 5): Rt 3.55 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.2 Hz), 1.27 (9H, s), 1.46-1.54 (2H, m), 1.61-1.73 (2H, m), 1.75-1.87 (2H, m), 1.89-1.97 (2H, m), 1.99-2.10 (1H, m), 2.17 (6H, s), 2.15-2.22 (2H, m), 2.87-2.95 (1H, m), 3.13-3.20 (1H, dt, J=12.0, 4.5 Hz), 3.32 (2H, m, obscured by water), 3.98 (2H, t, J=6.2 Hz), 4.83 (1H, q, J=7.9 Hz), 5.53 (1H, t, J=4.1 Hz), 6.37 (1H, s), 6.54-6.56 (1H, m), 6.57-6.61 (1H, dd, J=7.4, 2.4 Hz), 7.18-7.23 (1H, dd, J=2.3, 9.9 Hz), 7.24-7.32 (2H, m), 7.35-7.40 (3H, m), 7.64 (1H, dd, J=0.8, 9.8 Hz), 7.70-7.72 (1H, m), 7.73 (1H, d, J=7.5 Hz), 8.22 (0.25H, s), 8.35 (1H, s).

1. stirringstirred
2. concentrationthe organics concentrated in vacuo
3. customsealed with a crimped septum
4. stirringstirred at 60° C
5. temperatureThe reaction was then cooled
6. concentrationconcentrated in vacuo
7. washeluting with 0-7% 2M NH3 in MeOH/DCM
8. custompurified further by HPLC (Gemini C18, 10-98% MeCN in H2O, 0.1% HCO2H, 20 min gradient, 18 mL/min)
9. customthe combined fractions freeze dried