反应详情

To a stirred suspension of 49 (300 mg, 0.578 mmol, scheme 15) and DIPEA (303 μl, 1.74 mmol) in DMSO (5 ml) under nitrogen at rt was added 5-(2-chloroethyl)-1H-tetrazole (137 mg, 1.03 mmol), and the reaction mixture was stirred at rt for 1 h, heated at 60° C. overnight, then at rt. More 5-(2-chloroethyl)-1H-tetrazole (300 mg, 2.27 mmol) was added and the reaction mixture was heated at 60-65° C. for 24 h, then rt. The reaction mixture was diluted with water, and sonicated. The solid was collected by filtration, rinsed with water and air-dried. The crude material was purified three times by Biotage (Snap 25 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 5/95 to 25/75 over 20 CV, then 25/75 to 50/50 over 20 CV; Silia Sep HP 12 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 10/90 to 30/70 over 20 CV, then 30/70 to 40/60 over 20 CV; Snap 30 g KP-C18-HS (reverse phase): MeOH/water (millipore): 20/80 to 95/05 over 40 CV), to afford the desired product 512 (14 mg, 0.02 mmol, 3.9% yield) as a beige sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): one NH is missing, 8.74 (s, 1H), 8.54 (bd, J=1.6 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (dd, J=9.0, 1.4 Hz, 1H), 6.64 (dd, J=5.4, 0.7 Hz, 1H), 6.60 (bd, J=2.5 Hz, 1H), 3.55 (s, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.59-2.32 (m, 9H), 0.72-0.58 (m, 2H), 0.50-0.37 (m, 2H). MS (m/z): 615.7 (M+H).

1. temperatureheated at 60° C. overnight
2. customat rt
3. temperaturethe reaction mixture was heated at 60-65° C. for 24 h
4. customrt
5. customsonicated
6. filtrationThe solid was collected by filtration
7. washrinsed with water
8. customair-dried
9. customThe crude material was purified three times by Biotage (Snap 25 g cartridge