Reaction Steps
Prepared using General Procedure 5. To a stirred solution of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1.1 g, 2.3 mmol) in 1,4-dioxane (10 mL) was added 4N HCl solution of in 1,4-dioxane (10 mL). The reaction mixture was stirred at 55° C. for 2.5 h. Upon cooling to 0° C., the reaction mixture was diluted with diethyl ether (100 mL) and the resulting solid was filtered and dried to afford 980 mg (96%) of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 as off-white solid. LCMS-ESI (m/z) calculated for C21H20N4OS, 376.1; found 377.1 (M+H). tR=2.35 min. 1H NMR (400 MHz, DMSO) δ 8.64-8.51 (m, 3H), 8.41 (d, J=2.3 Hz, 1H), 8.32 (dd, J=8.9, 2.4 Hz, 1H), 7.99 (d, J=7.4 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.59-7.49 (m, 2H), 4.95 (dt, J=12.2, 6.1 Hz, 1H), 4.84 (s, 1H), 3.54-3.32 (m, 1H), 3.30-3.15 (m, 1H), 2.65-2.53 (m, 1H), 2.12 (ddd, J=13.9, 5.6, 3.0 Hz, 1H), 1.37 (dd, J=10.4, 6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.61, 166.11, 161.5, 143.05, 141.73, 134.16, 133.45, 129.74, 128.26, 127.84, 126.47, 122.33, 115.79, 115.2, 102.53, 72.43, 54.75, 31.48, 30.12, 21.74. Chiral HPLC: (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 was eluted using 30% EtOH in hexanes plus 0.1% DEA: 99.0% ee, tR=34.2 min.
