To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (250 mg, 0.48 mmol) in CH3CN (10 ml) was added 1-methylpiperazine (0.21 ml, 1.9 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-(4-methyl-piperazin-1-yl)-acetamide as a white solid (70 mg, 25% yield): mp, 205–207° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 2.36 (s, 3H, CH3), 2.64 (broad, 8H, CH2 on piperazine ring), 2.99 (S, 3H, NCH3), 3.21 (d, J=2 Hz, 2H, CH2NCO), 3.73 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.88 (s, 3H, OCH3), 4.05–4.20 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.39 (d, J=15 Hz, 1H, CHHN), 5.74–5.80 (m, 1H, NCH), 6.86–6.98 (m, 3H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.55 (d, J=8 Hz, 1H, Ar), 11.45 (s, 1H, NHCO); 13C NMR (CDCl3) δ 14.73, 41.37, 46.11, 46.81, 51.57, 53.46, 54.81, 55.76, 55.98, 62.18, 64.62, 111.61, 112.42, 119.46, 119.77, 119.87, 122.32, 129.20, 132.95, 135.98, 139.21, 148.93, 149.87, 168.50, 170.01. Anal Calcd for C27H35ClN4O6S: C, 56.00; H, 6.09; N, 9.67. Found: C, 55.82; H, 5.79; N, 9.42.
