Reaction Steps
Carbonyldiimidazole (CDI) (0.19 g, 1.2 mmol) was added to a solution of 3-indole propionic acid (0.22 g, 1.2 mmol) in dry THF (10 ml) under an argon atmosphere. The reaction mixture was stirred for 0.5 h at room temperature, then dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime (0.23 g, 1.2 mmol, prepared according to the procedure of Tsukamoto et. al. Chem. Pharma. Bull. 1995, 43, 842-852) was added. The reaction mixture was stirred for 4 h at room temperature and then for 8 h at 45° C. The reaction mixture was cooled to room temperature, dichloromethane (80 ml) was added and the mixture was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (30 ml). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography in a Combi-Flash Companion system (Isco, Inc) (HP 12-gold silica column, CH2Cl2/MeOH/NH4OH 90/10/1) followed by further flash chromatography in a Combi-Flash Companion system (Isco, Inc) (HP 12-gold silica column, CH2Cl2/MeOH/NH4OH 120/10/1). The residue was triturated in ether to give AF733 (104 mg), obtained as a white solid. 1H NMR (CDCl3, 300 MHz) δ 8.17 (br s, 1H, NH-indole), 7.60 (d, J=7.73 Hz, 1H, CHC arom), 7.35 (d, J=7.98 Hz, 1H, CHC arom), 7.19 (app t, J=7.76 Hz, 1H, CHCH arom), 7.12 (app t, J=7.43 Hz, 1H, CHCH arom), 7.04 (d, J=2.11 Hz, 1H, CHNH arom), 5.56 (q, J=6.3 Hz, 1H, CHCH3), 3.18 (t, J=7.37 Hz, 2H, CH2), 2.83 (t, J=7.41 Hz, 2H, COCH2), 2.40 (ABq, J=18.6 Hz, 2H, CH2), 2.5-2.3 (m, 4H), 2.28 (s, 3H, NCH3), 1.74 (2m, 3H), 1.5 (m, 1H), 1.43 (d, J=6.36 Hz, 3H, CH3—CH) ppm; 13C NMR (CDCl3, 300 MHz) δ 173.4 (C), 171.0 (C), 136.5 (C), 127.3 (C), 122.2 (CH), 122.1 (CH), 119.5 (CH), 118.8 (CH), 114.5 (C), 111.4 (CH), 78.7 (C), 72.5 (CH), 52.5 (CH2), 52.2 (CH2), 46.1 (CH3), 40.0 (CH2), 37.4 (CH2), 34.4 (CH2), 33.7 (CH2), 20.9 (CH2), 19.5 (CH3) ppm.
