[CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:6]2[CH2:5][C:4]3([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[S:3][CH:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=12,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (573 mg, 3.08 mmol) was dissolved in dry dichloromethane (2 ml) under an argon atmosphere. Distilled triethylamine (644 μl, 4.62 mmol) was added and the resulting solution was cooled to 0° C. A solution of p-fluorobenzenesulfonyl chloride (600 mg, 3.08 mmol) in dry dichloromethane (2 ml) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 1 h of stirring, dichloromethane (50 ml) was added and the resulted solution was washed with water (2×10 ml). The organic phase was dried with anhydrous magnesium sulfate, filtered and evaporated to give the crude mixture as an oil. The crude product was purified by flash chromatography (silica, CH2Cl2/MeOH/NH4OH 93/7/1) to provide AF716 (496 mg, 98.8% chemical purity) as an off-white powder. 1H NMR (CDCl3, 300 MHz) δ 7.89-7.85 (m, 2H, two CHCSO2), 7.27-7.19 (m, 2H, CHCF), 5.02 (q, J=6.12 Hz, 1H, CH—CH3), 3.66 (d, J=11.37 Hz, 1H, CHHNS), 3.48 (d, J=11.37 Hz, 1H, CHHNS), 2.72-2.50 (m, 2H, CH2NCH3), 2.25 (s, 3H, NCH3), 2.16-2.07 (m, 2H, CH2NCH3), 1.95-1.88 (m, 2H, CH2CS), 1.55 (d, J=6.12 Hz, 3H, CH3CH), 1.48 (m, 2H, CH2CS) ppm; 13C NMR (CDCl3, 300 MHz) δ 166.92 and 163.54 (C), 130.05 (CH), 129.93 (CH), 129.58 (C), 116.60 (CH), 116.30 (CH), 60.76 (C), 60.24 (CH), 54.05 (CH2), 53.22 (CH2), 46.03 (CH3), 37.16 (CH2), 37.05 (CH2), 25.56 (CH3) ppm.
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