Journal of Medicinal Chemistry 1.2 mmol) and N-(2-benzoyl-4-chlorophenyl)acetamide (3a) (274 mg, 1 mmol) in EtOH (3 mL). Upon cooling, the product crystallized from the crude reaction mixture and was subsequently recovered by filtration and washed with cold EtOH (2 5 mL) to give a white crystalline solid (89 mg, 25%). 1H NMR (500 MHz, CDCl3): δ 13.32 (br s, 1H, NH), 8.70 (d, 1H, J = 9.0 Hz, ArH), 7.59 7.54 (m, 3H, 3 ArH), 7.38 7.35 (m, 2H, 2 ArH), 7.33 7.28 (m, 4H, 4 ArH), 7.23 7.21 (m, 2H, 2 ArH), 6.91 (d, 1H, J = 2.5 Hz, H-3), 4.51 (s, 2H, CH2), 1.82 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ 171.5 (C), 169.6 (C), 139.5 (C), 139.1 (C), 135.3 (C), 132.3 (CH), 131.0 (CH), 129.3 (CH), 129.1 (CH), 128.7 (CH), 128.1 (CH), 127.4 (CH), 126.7 (C), 124.4 (C), 121.8 (CH), 57.9 (CH2), 25.0 (CH3). LRMS (ES+): m/z (%) 363 (100) [35Cl M + H]+, 365 (41) [37Cl M + H]+. (R/S)-N-(2-((Benzylamino)(phenyl)methyl)-4-chlorophenyl)aceta- mide (5a). Prepared according to method C1 from N-(2-((benzyli- mino)(phenyl)methyl)-4-chlorophenyl)acetamide (4a) (109 mg, 0.3 mmol). The crude product was purified by flash column chromatogra- phy (EtOAc/hexane 0:100 f 50:50) to give a cream solid (48 mg, 44%). 1H NMR (500 MHz, CDCl3): δ 11.0 (br s, 1H, NH), 8.22 (d, 1H, J = 8.5 Hz, ArH), 7.32 7.15 (m, 10H, 10 ArH), 7.04 7.02 (m, 1H, ArH), 6.96 (d, 1H, ArH), 4.90 (s, 1H, CH), 3.71 (s, 2H, CH2), 1.98 (s, 3H, CH3). LRMS (ES+): m/z (%) 365 (100) [35Cl M + H]+, 367 (33) [37Cl M + H]+. (R/S)-3-Benzyl-6-chloro-2-methyl-4-phenyl-3,4-dihydroquinazoline (6a). Prepared according to method D from N-(2-((benzylamino)- (phenyl)methyl)-4-chlorophenyl)acetamide (5a) (48 mg, 0.13 mmol). The crude product was purified by triturating from Et2O (40 mg, 87%). 1H NMR (500 MHz, CDCl3): δ 7.69 (d, 1H, J = 8.5 Hz, ArH), 7.48 7.42 (m, 6H, 6 ArH), 7.27 7.23 (m, 3H, 3 ArH), 7.19 7.17 (m, 1H, ArH), 6.77 (d, 1H, J = 2.0 Hz, H-5), 5.53 (s, 1H, H-4), 4.89 (d, 1H, J = 16.0 Hz, CHH), 4.29 (d, 1H, J = 16.0 Hz, CHH), 2.81 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ 158.4 (C), 139.2 (C), 133.1 (C), 131.4 (C) 130.2 (CH), 130.1 (CH), 129.91 (CH), 129.88 (CH), 129.5 (CH), 128.2 (C), 127.3 (CH), 126.9 (CH), 126.8 (CH), 122.2 (C), 120.5 (CH), 62.3 (CH), 52.2 (CH2), 18.5 (CH3). LRMS (ES+): m/z (%) 347 (100) [35Cl M + H]+, 349 (34) [37Cl M + H]+. HRMS (ES+): calcd for C22H20ClN2 [M + H]+ 347.1310, found 347.1299 (3.06 ppm). N-(4-Chloro-2-(phenyl(2-(piperidin-1-yl)ethylimino)methyl)phen- yl)acetamide (7a). Prepared according to method B from 1-(2-ami- noethyl)piperidine (154 mg, 1.2 mmol) and N-(2-benzoyl-4-chloro- phenyl)acetamide (3a) (274 mg, 1 mmol). The reaction solvent was removed under reduced pressure and purified by column chromatogra- phy (MeOH/CH2Cl2 0:100 f 10:90) to give a white solid (210 mg, 54%). 1H NMR (500 MHz, CDCl3): δ 13.56 (br s, 1H, NH), 8.72 (d, 1H, J = 9.0 Hz, H-6), 7.51 7.45 (m, 3H, 3 ArH), 7.29 (dd, 1H, J = 9.0, 3.0 Hz, H-5), 7.12 7.10 (m, 2H, 2 ArH), 6.83 (d, 1H, J = 3.0 Hz, H-3), 3.43 (t, 2H, J = 7.0, CH2), 2.66 (t, 2H, J = 7.0, CH2), 2.37 2.28 (m, 4H, 2 CH2), 2.24 (s, 3H, CH3), 1.55 1.51 (m, 4H, 2 CH2), 1.43 1.38 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 171.8 (C), 169.6 (C), 139.2 (C), 135.5 (C), 132.1 (CH), 130.8 (CH), 129.1 (CH), 129.0 (CH), 127.1 (CH), 126.6 (C), 124.3 (C), 121.6 (CH), 60.2 (CH2), 54.8 (CH2), 51.1 (CH2), 25.9 (CH2), 25.5 (CH3), 24.3 (CH2). LRMS (ES+): m/z (%) 192.5 (24) [35Cl M + 2H]2+, 384 (100) [35Cl M + H]+, 386 (31) [37Cl M + H]+. (R/S)-6-Chloro-2-methyl-4-phenyl-3-(2-(piperidin-1-yl)ethyl)-3,4- dihydroquinazoline (9a). Prepared according to method C2 or method D. Method C2 from N-(4-chloro-2-(phenyl(2-(piperidin-1-yl)ethyli- mino)methyl)phenyl)acetamide (7a) (360 mg, 0.94 mmol) in EtOH (5 mL): The crude product was purified by flash column chromatog- raphy (0.5 M NH3 in MeOH/CH2Cl2 1:100 f 4:96) to give a cream solid (211 mg, 61%). Method D from N-(4-chloro-2-(phenyl(2- (piperidin-1-yl)ethylamino)methyl)phenyl)acetamide (8a) (16 mg, 0.04 mmol): Work up gave a colorless semisolid (11 mg, 71%) that required ARTICLE no further purification. 1H NMR (500 MHz, CDCl3): δ 7.32 7.24 (m, 5H, 5 ArH), 7.05 (dd, 1H, J = 8.5, 2.5 Hz, H-7), 6.99 (d, 1H, J = 8.5 Hz, H-8), 6.74 (d, 1H, J = 2.5 Hz, H-5), 5.53 (s, 1H, H-4), 3.43 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 3.16 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 2.50 (ddd, 1H, J = 12.5, 8.5, 6.0 Hz, CHH), 2.38 2.28 (m, 5H, CHH eand 2 CH2), 2.26 (s, 3H, CH3), 1.55 1.51 (m, 4H, 2 CH2), 1.43 1.37 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 156.4 (C), 143.7 (C), 139.6 (C), 129.1 (CH), 128.7 (C), 128.4 (CH), 128.3 (CH), 126.7 (CH), 126.3 (C), 126.0 (CH), 125.0 (CH), 63.2 (CH), 57.4 (CH2), 55.1 (CH2), 46.9 (CH2), 26.0 (CH2), 24.2 (CH2), 22.4 (CH3). LRMS (ES+): m/z (%) 184.5 (88) [35Cl M + 2H]2+, 185.5 (35) [37Cl M + 2H]2+, 368 (100) [35Cl M + H]+, 370 (35) [37Cl M + H]+. HRMS (ES+): calcd for C22H27ClN3 [M + H]+ 368.1888, found 368.1888 ( 0.01 ppm). (R/S)-tert-Butyl 2-(6-Chloro-2-methyl-4-phenylquinazolin-3(4H)-yl)- ethylcarbamate (11a). Two identical reactions containing N-(2-ben- zoyl-4-chlorophenyl)acetamide (3a) (1.37 g, 5.0 mmol) and N-Boc-(2- aminoethyl)amine (1.19 mL, 7.5 mmol) in EtOH (20 mL) were reacted according to method B. The two reactions were then combined and diluted with EtOH (60 mL) and reacted directly according to method C2. The product was purified by column chromatography (MeOH/ CH2Cl2 2:98 f 10:90) to give a white solid (1.19 g, 30%). 1H NMR (500 MHz, CDCl3): δ 7.33 7.26 (m, 5H, 5 ArH), 7.08 (dd, 1H, J = 8.5, 2.0 Hz, H-7), 7.05 (d, 1H, J = 8.5 Hz, H-8), 6.76 (d, 1H, J = 2.0 Hz, H-5), 5.44 (s, 1H, H-4), 3.57 3.52 (m, 1H, CHH), 3.25 3.14 (m, 3H, CHH and CH2), 2.25 (s, 3H, CH3), 1.40 (s, 9H, 3 CH3). 13C NMR (125 MHz, DMSO-d6): δ 156.6 (C), 155.9 (C), 143.3 (C), 129.3 (CH), 129.1 (C), 128.6 (CH), 128.5 (CH), 126.6 (CH), 126.1 (CH), 126.0 (C), 125.0 (CH), 79.9 (C), 62.5 (CH), 48.4 (CH2), 38.2 (CH2), 28.3 (CH3), 22.3 (CH3). LRMS (ES+): m/z (%) 400 (100) [35Cl M + H]+, 402 (41) [37Cl M + H]+. HRMS (ES+): calcd for C22H27N3O2 [M + H]+ 400.1786, found 400.1796 ( 2.33 ppm). (R/S)-N-(2-(6-Chloro-2-methyl-4-phenylquinazolin-3(4H)-yl)ethyl)- benzamide (11d). Prepared according to method E from tert-butyl 2-(6- chloro-2-methyl-4-phenylquinazolin-3(4H)-yl)ethylcarbamate (11a) (120 mg, 0.3 mmol) and benzoyl chloride (84 mg, 0.6 mmol). The product was purified by flash column chromatography (0.5 M NH3 MeOH/CH2Cl2 0:100 f 10:90) to give a clear glass (53 mg, 44%). 1H NMR (500 MHz, CDCl3): δ 7.68 7.66 (m, 2H, 2 ArH), 7.53 7.50 (m, 1H, ArH), 7.44 7.41 (m, 2H, 2 ArH), 7.36 7.30 (m, 5H, 5 ArH), 7.11 (dd, 1H, J = 8.5, 2.5 Hz, H-7), 7.06 (d, 1H, J = 8.5 Hz, H-8), 6.78 (d, 1H, J = 2.5 Hz, H-5), 6.27 (br s, 1H, NH), 5.47 (s, 1H, H-4), 3.68 3.43 (m, 4H, 2 CH2), 2.29 (s, 3H, CH3). 13C NMR (125 MHz, DMSO-d6): δ 168.0 (C), 156.5 (C), 143.6 (C), 139.4 (C), 133.7 (C), 132.0 (CH), 129.3 (CH), 129.2 (C), 128.8 (CH), 128.63 (CH), 128.55 (CH), 126.8 (CH), 126.5 (CH), 126.1 (C), 126.0 (CH), 125.3 (CH), 63.0 (CH), 48.5 (CH2), 38.3 (CH2), 22.6 (CH3). LRMS (ES+): m/z (%) 404 (100) [35Cl M + H]+, 406 (35) [37Cl M + H]+. HRMS (ES+): calcd for C24H23N3O1 [M + H]+ 404.1524, found 404.1520 (1.01 ppm). Synthesis of (2-Amino-5-bromophenyl)(phenyl)methanone (2c). NBS (1.87 g, 10.5 mmol) was added to a suspension of 2-aminobenzo- phenone (1.97 g, 10 mmol) and tosic acid-derivatized silica gel (0.68 mmol/g, 150 mg) in MeCN/Et2O (1:3, 50 mL). The reaction mixture was stirred for 30 min, filtered, the silica washed with CH2Cl2 (10 mL), and the combined filtrate removed under reduced pressure. The crude aryl bromide was purified by flash column chromatography (CH2Cl2) to give a yellow solid (2.25 g, 82%). 1H NMR (500 MHz, CDCl3): δ 7.66 7.64 (m, 2H, 2 ArH), 7.60 7.57 (m, 2H, 2 ArH), 7.52 7.49 (m, 2H, 2 ArH), 7.38 (dd, 1H, J = 8.5, 2.0 Hz, H-4), 6.67 (d, 1H, J = 8.5 Hz, H-3), 6.11 (br s, 2H, NH2). 13C NMR (125 MHz, CDCl3): δ 198.0 (C), 149.7 (C), 139.3 (C), 136.9 (CH), 136.2 (CH), 131.6 (CH), 129.1 (CH), 128.4 (CH), 119.4 (C), 118.8 (CH), 106.6 (C). LRMS (ES+): m/z (%) 276 (100) [79Br M + H]+, 278 (100) [80Br M + H]+. 6526 dx.doi.org/10.1021/jm200312v |J. Med. Chem. 2011, 54, 6514–6530