Synthesis of novel isoxazolyl bis-thiazolo[3,2-a]pyrimidines

Kini, 1991, J. Med. Chem., 34, 3006, 10.1021/jm00114a008 Nagahara, 1990, J. Med. Chem., 22, 407, 10.1021/jm00163a064 R.K. Robins, H.B. Cottam, WO89/05649. Baxter, 2006, Bioorg. Med. Chem. Lett., 16, 960, 10.1016/j.bmcl.2005.10.091 Walters, 2007, Bioorg. Med. Chem. Lett., 17, 2731, 10.1016/j.bmcl.2007.02.080 D. Carson, WO00/69861. Liang, 2007, Chin. J. Org. Chem., 27, 166 Li, 2010, Chin. J. Org. Chem., 28, 977, 10.1002/cjoc.201090181 Amr, 2008, Monatsh. Chem., 139, 1409, 10.1007/s00706-008-0937-x Hola, 2004, Eur. J. Med. Chem., 39, 777, 10.1016/j.ejmech.2004.06.001 Ashok, 2007, Eur. J. Med. Chem., 42, 380, 10.1016/j.ejmech.2006.09.003 Liu, 2005, J. Org. Chem., 70, 10194, 10.1021/jo0517702 Daidone, 1999, Arch. Pharm. Med. Chem., 50, 332 Tomita, 1973, Ann. Sankyo Res. Lab., 1, 25 Talley, 1999, Prog. Med. Chem., 13, 201, 10.1016/S0079-6468(08)70048-1 Talley, 2000, J. Med. Chem., 43, 775, 10.1021/jm990577v Haripara, 2004, Indian J. Heterocycl. Chem., 13, 221 Uno, 1979, J. Med. Chem., 22, 180, 10.1021/jm00188a011 Li, 2003, J. Med. Chem., 46, 1706, 10.1021/jm020471r Rajanarendar, 2011, Bioorg. Med. Chem. Lett., 20, 6025 Rajanarendar, 2012, Eur. J. Med. Chem. Lett., 50, 274, 10.1016/j.ejmech.2012.02.004 Rajanarendar, 2009, Chin. Chem. Lett., 1, 1, 10.1016/j.cclet.2008.10.022 Rajanarendar, 2011, Chin. J. Chem., 29, 769, 10.1002/cjoc.201190155 Rajanarendar, 2011, Chin. Chem. Lett., 21, 927, 10.1016/j.cclet.2010.03.014 Analytical data for compound 5: pale yellow; yield 80%, mp 156–158°C; IR (KBr, cm−1): 3350, 3325 (NH2), 1615 (CN), 1560, 1365 (NO2); 1H NMR (300MHz, CDCl3): δ 2.32 (s, 3H, CH3), 3.83 (m, 2H, CH2), 4.10 (s, 4H, 2NH2), 4.81 (m, 1H, Ar–CH), 5.25 (d, 1H, CH), 7.13 (s, 1H, thiazole-CH), 7.20–8.00 (m, 5H, ArH). EI-MS [M]+ m/z 442. 13C NMR (75MHz, CDCl3): δ 11.41, 34.26, 48.75, 50.13, 105.36, 115.26, 124.13, 124.75, 125.35, 126.13, 126.42, 140.36, 150.38, 152.45, 159.96, 162.36. Anal. Calcd. for C19H18N6O3S2: C, 51.57; H, 4.10; N, 18.99. Found: C, 51.52; H, 4.17; N, 19.03%. Zhu, 2012, Tetrahedron, 68, 173, 10.1016/j.tet.2011.10.074 Analytical data for compounds: 7a: pale yellow; yield 82%, mp 165–167°C; IR (KBr, cm−1): 1625 (CN), 1555, 1360 (NO2); 1H NMR (300MHz, CDCl3): δ 2.33 (s, 3H, CH3), 3.72 (m, 2H, CH2), 4.14 (m, 1H, J=4Hz, benzylic-H), 4.80 (m, 1H, CH), 5.23 (d, 2H, Ar–CH), 5.53 (d, 2H, J=4Hz, CH), 7.12 (s, 2H, thiazole-CH), 7.28–7.84 (m, 25H, ArH). EI-MS [M]+ m/z 822. 13C NMR (75MHz, CDCl3): δ 12.01, 34.56, 47.98, 50.48, 61.43, 94.28, 105.36, 115.28, 124.13, 124.21, 124.75, 125.35, 126.03, 126.13, 126.49, 126.67, 126.81, 127.01, 127.13, 127.45, 127.98, 128.11, 128.34, 135.68, 136.73, 140.36, 143.69, 150.58, 152.40, 159.78, 162.42. Anal. Calcd. for C49H38N6O3S2: C, 71.51; H, 4.65; N, 10.21. Found: C, 71.58; H, 4.58; N, 10.18%. 7b: pale yellow; yield 80%, mp 168–170°C; IR (KBr, cm−1): 1620 (CN), 1542, 1358 (NO2); 1H NMR (300MHz, CDCl3): δ 2.28 (s, 3H, CH3), 3.68 (m, 2H, CH2), 4.10 (m, 1H, J=4Hz, benzylic-H), 4.78 (m, 1H, CH), 5.38 (d, 2H, Ar–CH), 5.50 (d, 2H, J=4Hz, CH), 7.00 (s, 2H, thiazole-CH), 7.12–7.92 (m, 23H, ArH). EI-MS [M]+ m/z 890. 13C NMR (75MHz, CDCl3): δ 12.14, 35.56, 47.08, 51.08, 61.72, 94.18, 105.31, 115.15, 124.10, 124.28, 124.62, 125.32, 126.01, 126.10, 126.42, 126.54, 126.79, 127.11, 127.23, 127.37, 127.65, 128.14, 130.13, 134.98, 136.52, 140.13, 143.40, 150.28, 152.31, 159.16, 162.38. Anal. Calcd. for C49H36N6Cl2O3S2: C, 65.99; H, 4.07; N, 9.42. Found: C, 65.95; H, 4.11; N, 9.38%. 7c: pale yellow; yield 84%, mp 164–166°C; IR (KBr, cm−1): 1630 (CN), 1545, 1351 (NO2); 1H NMR (300MHz, CDCl3): δ 2.29 (s, 3H, CH3), 2.81 (s, 6H, Ar–CH3), 3.52 (m, 2H, CH2), 4.06 (m, 2H, J=4Hz, benzylic-H), 4.63(m, 1H, CH), 5.28 (d, 2H, Ar–CH), 5.41 (d, 2H, CH, J=4Hz), 7.03 (s, 2H, thiazole-CH), 7.14–8.03 (m, 23H, ArH). EI-MS [M]+ m/z 850. 13C NMR (75MHz, CDCl3): δ 12.57, 28.46, 35.16, 48.01, 51.28, 67.53, 91.38, 104.86, 117.11, 124.41, 124.63, 124.82, 125.97, 126.23, 126.41, 126.53, 126.48, 126.73, 127.11, 127.46, 127.88, 128.34, 128.56, 135.41, 136.63, 138.45, 141.06, 142.89, 151.08, 152.68, 159.67, 161.81. Anal. Calcd. for C51H42N6O3S2: C, 71.98; H, 4.97; N, 9.87. Found: C, 71.92; H, 4.99; N, 9.91%. 7d: pale yellow; yield 81%, mp 171–173°C; IR (KBr, cm−1): 1620 (CN), 1543, 1349 (NO2); 1H NMR (300MHz, CDCl3): δ 2.21 (s, 3H, CH3), 3.41 (m, 2H, CH2), 3.61 (s, 6H, OCH3), 4.11 (m, 1H, J=4Hz, benzylic-H), 4.54(m, 1H, CH), 5.31 (d, 2H, Ar–CH), 5.46 (d, 2H, J=4Hz, CH), 7.18 (s, 1H, thiazole-CH), 7.21–8.22 (m, 23H, ArH). EI-MS [M]+ m/z 882. 13C NMR (75MHz, CDCl3): δ 11.86, 33.97, 47.51, 50.36, 58.13, 61.43, 92.07, 106.11, 115.37, 124.26, 124.37, 124.67, 126.16, 126.34, 126.67, 126.71, 126.79, 127.11, 127.18, 127.54, 127.81, 128.00, 128.37, 135.59, 136.41, 140.71, 143.73, 150.42, 152.57, 159.81, 161.45, 162.42. Anal. Calcd. for C51H42N6O5S2: C, 69.37; H, 4.79; N, 9.52. Found: C, 69.41; H, 4.77; N, 9.48%. 7e: pale yellow; yield 79%, mp 155–157°C; IR (KBr, cm−1): 1615 (CN), 1540, 1357 (NO2); 1H NMR (300MHz, CDCl3): δ 2.23 (s, 3H, CH3), 3.33 (m, 2H, CH2), 4.20 (m, 1H, J=4Hz, benzylic-H), 4.43(m, 1H, CH), 5.25 (d, 2H, Ar–CH), 5.47 (d, 2H, J=4Hz, CH), 7.18 (s, 2H, thiazole-CH), 7.20–8.31 (m, 23H, ArH), 9.01 (bs, 2H, OH, D2O, exchangeable). EI-MS [M]+ m/z 854. 13C NMR (75MHz, CDCl3): δ 12.23, 35.41, 48.03, 50.12, 61.72, 94.10, 105.46, 115.56, 123.98, 124.10, 124.47, 125.91, 126.01, 126.23, 126.77, 126.92, 127.12, 127.29, 127.61, 127.83, 128.03, 128.54, 135.72, 136.54, 140.36, 143.51, 150.51, 152.57, 158.11, 159.67, 162.81. Anal. Calcd. for C49H38N6O5S2: C, 68.83; H, 4.48; N, 9.83. Found: C, 68.89; H, 4.51; N, 9.79%. 7f: pale yellow; yield 82%, mp 173–175°C; IR (KBr, cm−1): 1635 (CN), 1535, 1341 (NO2); 1H NMR (300MHz, CDCl3) δ: 2.30 (s, 3H, CH3), 2.83 (s, 6H, Ar–CH3), 3.50 (m, 2H, CH2), 4.16 (m, 1H, J=4Hz, benzylic-H), 4.58(m, 1H, CH), 5.18 (m, 2H, Ar–CH), 5.39 (d, 2H, J=4Hz, CH), 7.11 (s, 2H, thiazole-CH), 7.23–7.91 (m, 23H, ArH). EI-MS [M]+ m/z 850. 13C NMR (75MHz, CDCl3): δ 12.13, 29.01, 35.14, 48.41, 51.38, 67.51, 91.32, 104.86, 117.13, 124.51, 124.68, 124.73, 125.71, 126.11, 126.29, 126.42, 126.61, 126.79, 127.09, 127.25, 127.58, 128.21, 128.38, 135.35, 136.28, 138.15, 141.11, 142.68, 151.31, 152.52, 159.45, 161.69. Anal. Calcd. for C51H42N6O3S2: C, 71.98; H, 4.97; N, 9.87. Found: C, 71.94; H, 4.91; N, 9.81%. 7g: pale yellow; yield 85%, mp 169–171°C; IR (KBr, cm−1): 1618 (CN), 1531, 1339 (NO2); 1H NMR (300MHz, CDCl3) δ 2.25 (s, 3H, CH3), 3.43 (m, 2H, CH2), 3.63 (s, 6H, OCH3), 4.21 (m, 1H, J=4Hz, benzylic-H), 4.64 (m, 1H, CH), 5.38 (m, 2H, Ar–CH), 5.41 (d, 2H, J=4Hz, CH), 7.01 (s, 2H, thiazole-CH), 7.10–8.23 (m, 23H, ArH). EI-MS [M]+ m/z 882. 13C NMR (75MHz, CDCl3): δ 12.16, 34.17, 47.45, 50.21, 58.14, 61.31, 92.16, 106.23, 115.41, 124.11, 124.21, 124.46, 126.31, 126.42, 126.54, 126.63, 126.85, 127.30, 127.45, 127.58, 127.74, 128.07, 128.24, 135.28, 136.38, 140.51, 143.58, 150.27, 152.37, 159.69, 161.23, 161.81 Anal. Calcd. for C51H42N6O5S2: C, 69.37; H, 4.79; N, 9.52. Found: C, 69.32; H, 4.81; N, 9.47%. 7h: pale yellow; yield 80%, mp 174–176°C; IR (KBr, cm−1): 1627 (CN), 1538, 1338 (NO2); 1H NMR (300MHz, CDCl3): δ 2.30 (s, 3H, CH3), 3.52 (m, 2H, CH2), 4.21 (m, 1H, J=4Hz, benzylic-H), 4.61 (m, 1H, CH), 5.27 (m, 2H, Ar–CH), 5.47 (d, 2H, J=4Hz, CH), 7.08 (s, 2H, thiazole-CH), 7.13–7.82 (m, 23H, ArH). EI-MS [M]+ m/z 890. 13C NMR (75MHz, CDCl3): δ 12.23, 34.89, 46.88, 51.26, 61.41, 94.05, 105.10, 115.24, 124.28, 124.34, 124.57, 125.41, 126.27, 126.36, 126.58, 126.68, 126.77, 127.19, 127.31, 127.49, 127.58, 128.37, 130.31, 134.69, 136.71, 140.21, 143.38, 150.36, 152.27, 159.23, 162.46. Anal. Calcd. for C49H36N6Cl2O3S2: C, 65.99; H, 4.07; N, 9.42. Found: C, 65.92; H, 4.02; N, 9.39%. 7i: pale yellow; yield 80%, mp 170–172°C; IR (KBr, cm−1): 1631 (CN), 1528, 1315 (NO2); 1H NMR (300MHz, CDCl3): δ 2.26 (s, 3H, CH3), 3.41 (m, 2H, CH2), 4.25 (m, 1H, J=4Hz, benzylic-H), 4.66 (m, 1H, CH), 5.20 (m, 2H, Ar–CH), 5.41 (d, 2H, J=4Hz, CH), 7.11(s, 2H, thiazole-CH), 7.20–7.91(m, 23H, ArH). EI-MS [M]+ m/z 890. 13C NMR (75MHz, CDCl3): δ 12.31, 35.31, 47.45, 51.46, 61.51, 94.27, 105.11, 115.38, 124.22, 124.31, 124.60, 125.41, 126.06, 126.23, 126.53, 126.61, 126.81, 127.00, 127.11, 127.41, 127.53, 128.23, 130.22, 134.73, 136.45, 140.17, 143.26, 150.31, 152.38, 159.47, 162.56. Anal. Calcd. for C49H36N6Cl2O3S2: C, 65.99; H, 4.07; N, 9.42. Found: C, 66.02; H, 4.10; N, 9.47%.