To a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and an addition funnel was added NaH (1.45 g, 0.061 mol) and THF (300 mL). The stirred suspension was cooled to 0° C. and (1-isopropyl-piperidin-4-yl)-methanol (9.5 g, 0.06 mol) was added. The cooling bath was removed, and the reaction warmed to rt. After 2 h, a solution of (2-chloro-3-methyl-3H-imidazol-4-yl)-(4-chloro-phenyl)-methanone (15.56 g, 0.061 mol) in dry THF (100 mL) was added. The reaction mixture was stirred at 60° C. and monitored by HPLC every 4-8 h. After 36 h, the reaction was judged complete. The reaction mixture was cooled to rt, poured into ice-cold water, and extracted with EtOAc (2×250 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to provide the crude material as a brown solid. Recrystallization from EtOAc afforded the desired product (17.5 g, 78%) as a white crystalline solid. mp 126-127° C. IR (film): 2963, 1615, 1585, 1529, 1481, 1362, 1287, 1213, 1173, 1104, 1020, 897, 846, 727, 698 cm−1. 1H NMR (400 MHz, CDCl3): δ7.67 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.13 (s, 1H), 4.22 (d, J=6.0 Hz, 2H), 3.68 (s, 3H), 2.84 (m, 2H), 2.61 (m, 1H), 2.09 (m, 2H), 1.74 (m, 3H), 1.30 (m, 2H), 0.97 (d, J=6.5 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ183.4, 157.0, 138.3, 138.2, 137.3, 130.2, 128.7, 127.1, 74.9, 54.6, 48.4, 35.9, 30.7, 29.1, 18.3. HRMS (EI): m/z calcd for C20H27ClN3O2 [M+H]+, 376.1792; found, 376.1801. Anal. Calcd for C20H26ClN3O2: C, 63.91; H, 6.97; N, 11.17. Found: C, 63.55; H, 6.77; N, 11.05. Step E: (4-Chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone maleate salt. A 500-mL, 3-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet, reflux condenser and an addition funnel was charged with (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone (15.4 g, 40.96 mol), EtOH (170 mL), and maleic acid (4.75 g, 40.96 mol). The mixture was heated on a heating mantle at 70-75° C. until a clear solution was obtained. The heat source was removed and the reaction mixture was cooled to rt. The solution was transferred to a 2-L beaker, washing with 25 mL of EtOH. The solution was diluted with 750 mL of Et2O with vigorous stirring. The white precipitate that formed was filtered and dried in vacuo to afford the maleate salt as a white powder. Recrystallization from water afforded the maleate salt (18.8 g, 93%) as colorless needles. mp 161-162° C. IR (film): 2963, 1625, 1586, 1532, 1466, 1361, 1257, 1172, 1087, 1025, 956, 757, 698 cm−1. 1H NMR (400 MHz, CDCl3): δ7.71 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.17 (s, 1H), 6.27 (s, 2H), 4.36 (d, J=6.0 Hz, 2H), 3.73 (s, 3H), 3.53 (m, 3H), 2.74 (bt, J=11.6 Hz, 2H), 2.24-1.92 (m, 5H), 1.34 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ183.9, 169.7, 156.6, 138.8, 138.2, 137.5, 136.0, 130.6, 129.1, 127.7, 73.2, 57.9, 48.3, 34.4, 31.1, 26.0, 17.0. Anal. Calcd for C24H30ClN3O6: C, 58.21; H, 6.07; N, 8.35. Found: C, 58.6; H, 6.07; N, 8.35.
