Luận án Nghiên cứu tổng hợp một số dẫn xuất Tritecpenoit khung lupan và thăm dò hoạt tính sinh học của chúng

22,0 Hz, H-11); 2,99-3,03 (1H, m, H-19); 2,19 (1H, t, J=2,5 Hz, H-3’); 1,68 (3H, s, H-30); 1,18 (3H, s, H-26); 0,99 (3H, s, H-27); 0,98 (3H, d, J=5,0 Hz, H-23); 0,97 (3H, s, H-25). 13C-NMR (CDCl3, 125 MHz) δ ppm: 214,2 (C-3); 175,8 (C-28); 150,1 (C-20); 109,9 (C-29); 80,0 (C-2’); 71,2 (C-11); 70,7 (C-3’); 55,5 (C-1’); 53,9; 53,4; 49,5; 49,1; 46,4; 44,9; 38,1; 38,0; 37,9; 37,6; 36,5; 33,9; 33,6; 30,7; 29,3; 29,0; 25,6; 24,9; 22,0; 19,5; 17,2; 14,4; 13,7; 12,0. 53 Hợp chất 174. Chất rắn màu trắng, hiệu suất 93%, điểm chảy 256-258 oC. IR (ATR) 3361, 2929, 2879, 2106, 1726, 1683, 1656, 1510, 1465, 1384, 1315, 1236, 1205, 1082, 1031, 975, 868, 725, 648 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,46 (1H, t, J=5,5 Hz, NH); 4,48 (1H, dd, J=5,0; 11,0 Hz, H-3); 4,10 (1H, dd, J=2,5; 17,5 Hz, H-1’a); 3,92 (1H, dd, J=2,5; 17,5 Hz, H-1’b); 2,68 (1H, dd, J=3,5; 13,0 Hz, H-13); 2,62 (1H, dt, J=4,0; 13,5 Hz, H-20); 2,22 (1H, m, H-3’); 2,04 (3H, s, CH3COO); 1,25 (3H, d, J=7,0 Hz, H-29); 1,23 (3H, d, J=6,5 Hz, H-30); 1,03 (1H, s, H-26); 0,93 (1H, s, H-27); 0,90 (1H, s, H-23); 0,85 (3H, s, H-25); 0,83 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 207,3 (C-21); 173,4 (C-28); 172,7; 171,1 (CH3COO); 147,9 (C-18, C-19); 80,9 (C-3); 79,5 (C-2’); 71,7 (C-3’); 55,6; 53,6; 51,2; 49,3; 48,6; 45,6; 41,6; 38,7; 37,9; 37,3; 34,9; 34,1; 33,1; 29,7; 29,2; 28,1; 25,8; 25,4; 25,1; 23,7; 21,4; 20,6; 20,1; 18,3; 16,9; 16,8; 16,6; 16,0. 2.3.2. Quy trình tổng hợp các dẫn chất este 169b, 169c, 177a-c, 175a-c Dung dịch gồm hợp chất 169 hoặc 172 (1 mol) và anhidrit axit (4 mol trong piridin (5ml) được khuấy trong 12 giờ ở 120oC. Sau khi phản ứng kết thúc, để nguội, thêm dung dịch HCl 10% vào đến môi trường axit, chiết lấy sản phẩm bằng dung môi diclometan. Pha hữu cơ được rửa 3 lần với dung dịch muối ăn 1M, làm khô bằng Na2SO4, sau đó cất đuổi dung môi ở áp suất thấp. Phần cặn đó được tiến hành chạy cột dùng silica gel thu được hợp chất 169b, 169c, 177a- c, 175a-c, 176a-b với hiệu suất cao 54 Hợp chất 169b. Chất rắn màu trắng, hiệu suất 93 %, điểm chảy 242-244 oC. IR (ATR) 3304, 2949, 2868, 2139, 1703, 1672, 1494, 1319, 1261, 1180, 1045, 975, 1045, 975, 785, 725 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,73 (1H, t, J=5,0 Hz, NH); 4,73 (1H, d, J=2,0 Hz, H-29a); 4,59 (1H, bs, H-29b); 4,50 (1H, t, J=8,0 Hz, H-3); 4,07 (1H, dd, J=2,5; 17,0 Hz, H-1’a); 3,97 (1H, dd, J=2,5; 17,0 Hz, H-1’a); 3,12 (1H, m, H-19); 2,60-2,69 (4H, m, H-2”, H-3”); 2,20 (1H, t, J=2,5 Hz, H-3’); 1,68 (3H, s, H-30); 0,96 (3H, s, H-26); 0,93 (3H, s, H-27); 0,84 (3H, s, H-23); 0,83 (3H, s, H-25); 0,82 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177,2 (C-28); 176,1 (C-1”); 172,0 (C-4”); 150,9 (C- 20); 109,6 (C-29); 81,7 (C-3); 80,3 (C-2’); 71,3 (C-3’); 55,8; 55,6; 55,5; 50,5; 50,2; 46,7; 42,5; 40,8; 38,4; 38,1; 37,9; 37,8; 37,1; 34,3; 33,6; 30,8; 29,4; 29,3; 29,0; 28,9; 27,9; 25,6; 23,6; 20,9; 19,5; 18,2; 16,5; 16,2; 16,1; 14,6. Hợp chất 169c. Chất rắn màu trắng, hiệu suất 39 %, điểm chảy 222-224 oC. IR (ATR) 3302, 2941, 2866, 2137, 1703, 1672, 1494, 1261, 1180, 1045, 1045, 787 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,73 (1H, t, J=5,0 Hz, NH); 4,73 (1H, s, H-29a); 4,59 (1H, s, H-29b); 4,48 (1H, t, J=8,0 Hz, H-3); 4,07 (1H, dd, J=2,5; 17,5 Hz, H-1’a); 3,97 (1H, dd, J=2,5; 17,5 Hz, H-1’b); 3,12 (1H, m, 55 H-19); 2,35-2,47 (6H, m, H-2”, H-3”, H-4”); 2,20 (1H, t, J=2,5 Hz, H-3’); 1,68 (3H, s, H-30); 0,96 (3H, s, H-26); 0,94 (3H, s, H-27); 0,84 (3H, s, H-23); 0,83 (3H, s, H-25); 0,82 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 109,5 (C-29); 81,1 (C-3); 80,1 (C-2’); 71,2 (C-3’); 55,7; 55,5; 50,6; 50,2; 46,8; 42,5; 40,8; 38,4; 38,1; 37,8; 37,8; 37,1; 34,3; 33,7 (C-4’); 33,6 (C-2’); 32,9; 30,8; 29,4 (C-30); 28,0 (C-23); 25,6; 23,8; 20,9; 20,0 (C-24); 19,5; 19,2; 16,6 (C-25); 16,2 (C-26); 16,1; 14,6 (C-27). Hợp chất 177a. Chất rắn màu trắng, hiệu suất 56%, điểm chảy 234-236 oC. IR (ATR) 3410, 3296, 3099, 2924, 2868, 2123, 1734, 1705, 1635, 1504, 1368, 1344, 1195, 1056, 1195, 1056, 868, 800, 699 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,77 (1H, t, J=5,5 Hz, NH); 4,73 (1H, d, J=1,5 Hz, H-29a); 4,59 (1H, s, H-29b); 4,36 (1H, dd, J=5,5; 11,0 Hz, H-3); 4,07 (1H, dd, J=2,5; 11,0 Hz, H-1’a); 3,97 (1H, dd, J=2,5; 11,0 Hz, H-1’a); 3,12 (1H, m, H-19); 2,65-2,69 (2H, m, H-2”); 2,58-2,61 (2H, m, H-3”); 2,20 (1H, t, J=2,5 Hz, H-3’); 1,68 (3H, s, H-30); 0,96 (3H, s, H-26); 0,94 (3H, s, H-27); 0,79 (3H, s, H-25); 0,78 (3H, d, J=6,5 Hz, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177,4 (C-28); 175,9 (C- 1”); 171,9 (C-5”); 150,8 (C-20); 109,5 (C-29); 80,1 (C-2’); 79,5 (C-3); 71,2 (C- 3’); 55,7; 51,4; 50,2; 48,4; 46,7; 42,6; 40,4; 38,1; 37,7; 37,6; 36,4; 35,3; 33,6; 33,4; 30,8; 29,3; 29,2; 29,0; 28,9; 26,7; 25,6; 21,3; 20,8; 19,5; 16,2; 15,0; 14,5; 13,9. 56 Hợp chất 177b. Chất rắn màu trắng, hiệu suất 60 %, điểm chảy 192-194 oC. IR (ATR) 3618, 3321, 2926, 2825, 2127, 1737, 1654, 1629, 1516, 1413, 1384, 1315, 1242, 1195, 1083, 1039, 868, 665 cm-1.1H-NMR (CDCl3, 500 MHz) δ ppm: 5,75 (1H, t, J=5,0 Hz, NH); 4,73 (1H, d, J=2,0 Hz, H-29a); 4,60 (1H, s, H-29b); 4,36 (1H, dd, J=5,5; 10,5 Hz, H-3); 4,08 (1H, dd, J=2,5; 17,5 Hz, H-1’a); 3,98 (1H, dd, J=2,5; 17,5 Hz, H-1’b); 3,12 (1H, m, H-19); 2,36-2,45 (4H, m, H-2”, H-4”); 2,23-2,29 (2H, m, H-3”); 2,20 (1H, t, J=2,0 Hz, H-3’); 1,68 (3H, s, H-30); 0,97 (3H, s, H-26); 0,93 (3H, s, H-27); 0,79 (3H, s, H-25); 0,78 (3H, d, J=6,5 Hz, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177,8 (C- 28); 175,9 (C-1”); 172,7 (C-5”); 150,8 (C-20); 109,5 (C-29); 80,1 (C-2’); 79,0 (C-3); 71,2 (C-3’); 55,7; 51,4; 50,2; 48,4; 46,7; 42,6; 40,4; 38,1; 37,7; 37,6; 36,5; 35,3; 33,6; 33,5; 33,4; 32,9; 30,8; 29,3; 29,0; 26,8; 25,6; 21,3; 20,8; 20,0; 19,5; 16,2; 15,1; 14,5; 13,9.. Hợp chất 177c. Chất rắn màu trắng, hiệu suất 90 %, điểm chảy 232-234 oC. IR (ATR)3307, 2937, 2868, 2137, 1712, 1658, 1504, 1450, 1375, 1201, 1157, 877, 727, 648 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,76 (1H, t, J=5,0 Hz, NH); 4,73 (1H, d, J=1,0 Hz, H-29a); 4,58 (1H, d, J=0,5 Hz, H-29b); 57 4,35-4,38 (1H, m, H-3); 4,07 (1H, dd, J=2,5; 17,5 Hz, H-1’a); 3,98 (1H, dd, J=2,5; 17,5 Hz, H-1’b); 3,12 (1H, m, H-19); 2,37-2,45 (4H, m, H-2”, H-4”); 2,22-2,30 (2H, m, H-3”); 2,20 (1H, t, J=2,0 Hz, H-3’); 1,68 (3H, s, H-30); 1,04 (3H, d, J=6,5 Hz, H-6”); 0,96 (3H, s, H-26); 0,94 (3H, s, H-27); 0,79 (3H, s, H- 25); 0,78 (3H, d, J=6,5 Hz, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177,3 (C-28); 175,9 (C-1”); 172,2 (C-5”); 150,8 (C-20); 109,5 (C-29); 80,1 (C-2’); 79,1 (C-3); 71,2 (C-3’); 55,7; 51,4; 50,2; 48,4; 46,7; 42,6; 41,2; 40,4; 38,1; 37,8; 37,7; 37,6; 36,5; 35,3; 33,6; 33,4; 30,8; 29,3; 29,0; 27,4; 26,8; 25,6; 21,3; 20,8; 19,7; 19,5; 16,2; 15,1; 14,5; 13,9. Hợp chất 175a. Chất rắn màu trắng, hiệu suất 40%, điểm chảy 202-204 oC. IR (ATR) 3361, 2922, 2858, 2131, 1791, 1774, 1691, 1668, 1523, 1423, 1273, 1190, 1087, 1039, 875, 862, 663 cm-1.1H-NMR (CDCl3, 500 MHz) δ ppm: 5,76 (1H, t, J=5,5 Hz, NH); 4,72 (1H, s, H-29a); 4,64 (1H, dd, J=5,0; 11,0 Hz, H-3); 4,59 (1H, s, H-29b); 4,05 (1H, m, H-1’a); 3,98 (1H, m, H-1’b); 3,88 (3H, s, COOCH3 ); 3,12 (1H, m, H-19); 2,19 (1H, t, J=2,5 Hz, H-3’); 1,67 (3H, s, H- 30); 0,95 ( 3H, s, H-26); 0,93 (3H, s, H-27); 0,89 (3H, s, H-23); 0,87 (3H, s, H- 25); 0,86 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 171,2 (C-28); 158,7 (C-1”); 157,7 (C-2”); 150,8 (C-20); 128,6; 124,7; 120,6; 109,5 (C-29); 84,8 (C-3); 80,2 (C-2’); 71,1 (C-3’); 60,4; 57,0; 55,7; 55,4 (COOCH3); 53,3; 50,5; 50,5; 50,16; 49,13; 46,70; 42,46; 40,82; 38,46; 38,33; 38,06; 37,70; 37,12; 36,64; 34,28; 33,91; 33,58; 30,79; 29,37; 28,98; 28,45; 27,88; 25,61; 25,53; 24,91. 58 Hợp chất 175b. chất rắn màu trắng, hiệu suất 47 %, điểm chảy 212-214 oC. IR (ATR) 3310, 2999, 2924, 2133, 1749, 1724, 1643, 1514, 1334, 1247, 1195, 1080, 898, 871 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,72 (1H, t, J=5,0 Hz, -CONH ); 4,73 (1H, d, J= 1,5 Hz, H-29a); 4,59 (1H, s, H-29b); 4,53 (1H, m, H-3); 4,07 (1H, dd, J= 2,5; 5,0; 17,5 Hz, H-1’a); 3,96 (1H, dd, J= 2,5; 5,0; 17,5 Hz, H-1’b); 3,73 (3H, s, O-CH3); 3,12 (1H, m, H-19); 2,19 (1H, t, J=2,5 Hz, C≡CH); 2,04 (2H, s, H-2’’); 1,68 (3H, s, H-30); 0,96 (3H, s, H-26); 0,93 (3H, s, H-27); 0,85 (3H, s, H-23); 0,83 (3H, s, H-25); 0,81 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 171,3 (C-28); 167,3 (C-2”); 166,4 (C-3”); 150,9 (C-20); 109,6 (C-29); 82,6 (C-3); 80,3 (C-2’); 71,3 (C-3’); 60,5 (COOCH3); 55,8; 55,6; 52,5; 50,7; 50,3; 46,9; 42,6; 41,9; 41,0; 38,5; 38,0; 37,9; 37,2; 34,5; 33,7; 30,9; 29,5; 29,1; 27,9; 25,7; 23,7; 21,2; 19,6; 18,3; 16,5; 16,3; 14,8; 14,3. Hợp chất 175c. Chất rắn màu trắng, hiệu suất 50 %, điểm chảy 226-228 oC. IR (ATR) 3321, 2926, 2852, 2129, 1739, 1714, 1651, 1625, 1571, 1242, 1193, 1083, 1039, 875 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,71 (1H, t, J=5,0 Hz, NH); 4,74 ( 1H, s, H-29a); 4,59 (1H, J=1,0 Hz, H-29b); 4,47 (H, t, 59 J=9,5 Hz, H-3); 4,05-4,09 (1H, m, H-1’a); 3,97 (1H, dd, J=3,0; 16,5 Hz, H-1’b); 3,66 ( 3H, s, COOCH3 ); 3,12 (1H, m, H-19); 2,27-2,38 (4H, m, H-2”, H-5”); 2,20 (1H, t, J=2,5Hz, H-3’); 1,9-1,97 (4H, m, H-3”, H-4”); 1,68 (3H, s, H-30); 1,59 (3H, s, H-26); 0,97 (3H, s, H-27); 0,94 (3H, s, H-23); 0,84 (3H, s, H-25); 0,82 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 175,9 (C-28); 173,8 (C- 1”); 173,1 (C-6”); 150,8 (C-20); 109,5 (C-29); 80,9 (C-3); 80,2 (C-2’); 71,1 (C- 3’); 55,7; 55,5; 51,5; 50,6; 50,2; 49,2; 46,8; 42,5; 40,8; 38,4; 37,9; 37,8; 37,2; 34,4; 33,9; 33,72; 30,8; 29,4; 29,0; 28,0; 25,6; 24,9; 24,6; 24,4; 20,9; 19,5; 18,2; 16,6; 16,2; 16,1; 14,7. Hợp chất 183a. Chất rắn màu trắng, hiệu suất 88%, điểm chảy 214-216 oC. IR (ATR) 3441, 3302, 2997, 2924, 2862, 2117, 1789, 1741, 1647, 1500, 1411, 1332, 1273, 1195, 868, 794 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,73 (1H, t, J=5,5 Hz, NH); 4,74 (2H, s, H-29); 4,60 (1H, m, H-3); 4,07 (1H, dd, J=2,5; 15,0 Hz, H-1’a); 3,97 (1H, dd, J=2,5; 15,0 Hz, H-1’a); 3,74 (3H, s, OCH3); 3,13 (1H, m, H-19); 2,22-2,30 (2H, m, H-2”); 2,20 (1H, t, J=2,5 Hz, H- 3’); 1,69 (3H, s, H-30); 0,97 (3H, s, H-26); 0,94 (3H, s, H-27); 0,82 (3H, d, J=6,5 Hz, H-24); 0,79 (3H, s, H-25). 60 Hợp chất 183b. Chất rắn màu trắng, hiệu suất 68 %, điểm chảy 238- 240oC. IR (ATR) 3307, 2928, 2878, 2113, 1789, 1735, 1654, 1647, 1512, 1139, 1136, 1078, 871 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 5,79 (1H, t, J=5,5 Hz, NH); 4,73 (1H, s, H-29a); 4,58 (1H, s, H-29b); 4,31-4,37 (1H, m, H-3); 4,05 (1H, dd, J=2,5; 15,0 Hz, H-1’a); 3,97 (1H, dd, J=2,5; 15,0 Hz, H-1’a); 3,66 (3H, s, OCH3); 3,10-3,15 (1H, m, H-19); 2,19-2,30 (4H, m, H-2”, H-5”); 2,16 (1H, t, J=2,5 Hz, H-3’); 1,65 (3H, s, H-30); 0,96 (3H, s, H-26); 0,82 (3H, d, J=6,5 Hz, H-24); 0,79 (6H, s, H-25, H-27). 13C-NMR (CDCl3, 125 MHz) δ ppm: 175,8 (C-28); 173,7 (C-1”); 173,1 (C-6”); 150,7 (C-20); 109,4 (C-29); 80,1 (C-3); 78,8 (C-2’); 71,2 (C-3’); 55,7; 55,6; 51,5; 51,4; 50,0; 48,4; 46,7,46,3, 42,6, 42,5, 40,4, 37,7, 36,7, 36,4, 35,3, 34,3, 33,8, 33,7, 30,8, 29,3, 28,8, 25,6; 24,9; 24,6; 24,4; 20,9; 19,5; 18,2; 16,3; 16,2; 15,9; 14,4. 2.3.3. Quy trình chung tổng hợp các lai triterpenoid-AZT Hợp chất 169a-c, 170, 171a-b, 177a-c, 172, 173, 174, 175a-c, 183a-b (1 mol), AZT (0.8 mol) và CuI ( 0.2 mol) được hòa tan trong t-BuOH (5ml), khuấy hỗn hợp phản ứng ở 70oC trong 20 giờ. Hỗn hợp sau phản ứng được chiết với EtOAc, rửa nhiều lần với nước, dung dịch Na2S2O3 và dung dịch muối ăn. Pha hữu cơ được làm khô bằng Na2SO4, sau đó cất đuổi dung môi ở áp suất thấp. Phần cặn đó được tiến hành chạy cột dùng silica gel thu được hợp chất 178a-c, 179, 180a-b, 181a-d, 182, 184, 185a-c và 186a-b 61 Hợp chất 178a. chất rắn màu trắng, hiệu suất 20 %, điểm chảy 237-239 oC. IR (ATR) 3739, 2939, 2868, 1689, 1591, 1504, 1263, 1209, 1043, 783 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7,75 (1H, s, H triazol); 7,44 (1H, s, H thymidine); 6,22 (1H, t, J=6,5 Hz, H-1’); 5,36-5,40 (1H, m, H-4’); 4,72 (1H, s, H-29a); 4,59 (1H, s, H29b); 4,52; 4,50 (1H, dd, J=2,5, 11,0 Hz, CONHCH2); 4,38-4,39 (1H, m, H-3’); 4,02 (1H, d, J=10,5 Hz, H5’a); 3,77 (1H, d, J=10,5 Hz, H-5’b); 3,17 (1H, dd, J=4,5; 9,5 Hz, H-3); 3,11-3,14 (1H, m, H-19); 2,96 (2H, m, H-2’); 1,95 (3H, s, CH3); 1,63 (3H, s, H-30); 0,92 (3H, s, H-26); 0,90 (3H, s, H-23); 0,79 (3H, s, H-27); 0,76 (3H, s, H-25); 0,75 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177,2 (C-28); 164,6 (CO thymidine); 150,7 (C-20); 150,6 (NCONH thymidine); 145,6 (=C= triazol); 137,8 (-CH= thymidine); 122,1 (-CH= triazol); 110,3 (-C= thymidine); 109,7 (C-29); 86,0 (C-1’); 85,0 (C-4’); 78,6 (C-3); 60,5; 60,4; 58,7; 55,5; 55,2; 50,4; 49,9; 46,7; 42,2; 40,6; 38,7; 38,6; 37,9; 37,8; 37,7; 37,0; 34,1; 33,0; 30,7; 29,2; 27,7; 26,9; 25,4; 20,7; 19,2; 18,1; 15,9; 15,7; 15,2; 14,4; 12,1 (CH3 thymidine). Hợp chất 178b chất rắn màu trắng, hiệu suất 56 % , điểm chảy 207-208 oC. IR (ATR) 3336, 2931, 1872, 1695, 1664, 1537, 1462, 1413, 1271, 1197, 1083, 1039, 875 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.75 (1H, s, H triazol); 7.68 (1H, s, H thymidine); 6.30 (1H, t, J=6.5 Hz, H-1’); 5.23-5.27 (1H, 62 m, H-4”); 4.62 (1H, s, H-29a); 4.50 (1H, s, H29b); 4.33-4.37 (2H, m, CH2NH); 4.45 (1H, dd, J=5.0, 11.0 Hz, H-3); 4.24-4.25 (1H, m, H-3”); 4.02 (1H, d, J=12.5 Hz, H-5”a); 3.75 (1H, dd, J=1.5, 12.0 Hz, H5”b); 2.98-3.00 (1H, m, H- 19); 2.92-2.96 (1H, m, H-2”a); 2.62-2.66 (1H, m, H-2”b); 1.84 (3H, s, CH3); 1.58 (3H, s, H-30); 0.82 (3H, s, H-26, H-23); 0.71 (3H, s, H-27); 0.70 (3H, s, H- 25); 0.62 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177.3 (C-28); 177.2 (C-1’); 173.7 (C-4’); 164.5 (CO thymidine); 150.7 (C-20); 150.6 (NCONH); 145.4 (=C= triazol); 136.7 (-CH= thymidine); 124.0 (-CH= triazol); 110.9 (-C= thymidine); 109.3 (C-29); 86.0 (C-1”); 84.9 (C-4”); 81.1 (C-3); 63.2; 60.5; 58.8; 55.5; 55.2; 50.2; 49.9; 46.7; 42.2; 40.6; 38.1; 37.9; 37.7; 37.6; 37.9; 36.9; 34.0; 32.9; 31.3; 30.6; 29.5; 29.1; 27.6; 25.3; 23.4; 20.7; 19.1; 17.9; 16.2; 15.9; 15.6; 14.4; 12.4 (CH3 thymidine). Hợp chất 178c. chất rắn màu trắng, hiệu suất 42%, điểm chảy 256-257oC. IR(ATR) 3704, 3307, 2933, 2866, 1735, 1645, 1512, 1246, 1195, 1080, 754 cm- 1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.75 (1H, s, H triazol); 7.64 (1H, s, H thymidine); 6.29 (1H, t, J=6.5 Hz, H-1’); 5.27-5.31 (1H, m, H-4”); 4.67 (1H, s, H-29a); 4.55 (1H, s, H29b); 4.41 (2H, dd, J=2.5; 12.5 Hz, CH2CONH); 4.33 (1H, d, J=8.0 Hz, H-3); 4.28-4.30 (1H, m, H-3”); 3.92 (1H, dd, J=2.0, 12.5 Hz, H-5”a); 3.69 (1H, dd, J=2,0, 12.5 Hz, H5”b); 2.98-3.10 (1H, m, H-19); 2.70- 2.75 (2H, m, H-2”); 2.28-2.35 (4H, m, H-2’ and H-4’); 1.90-2.0 (2H, m, H-3’); 1.89 (3H, s, CH3 thymidine); 1.63 (3H, s, H-30); 0.90 (3H, s, H-26); 0.79 (3H, s, 63 H-23); 0.78 (3H, s, H-27); 0.76 (3H, s, H-25); 0.68 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 173.1 (C-28); 168.2 (C-1’); 166.2 (C-4’); 164.5 (CO thymidine); 150.6 (C-20); 150.4 (NCONH); 143.4 (=C= triazol); 136.9 (-CH= thymidine); 123.0 (-CH= triazol); 111.3 (-C= thymidine); 109.4 (C-29); 86.8 (C- 1”); 85.1 (C-4”); 81.0 (C-3); 63.5; 60.7; 58.7 (C-5”); 55.6; 55.3; 50.3; 50.0; 46.9; 42.3; 40.7; 38.2; 38.0; 37.8; 37.7; 37.6; 37.1; 37.1; 34.1; 33.7; 33.1; 30.7; 29.2; 27.8 (C-23); 25.4; 23.6; 20.8; 20.2; 19.3; 18.0; 16.4; 16.0; 15.7; 14.5; 12.3 (CH3 thymidine). Hợp chất 179. chất rắn màu trắng, hiệu suất 64 %, điểm chảy 232-234 oC. IR (ATR) 3730, 3354, 2922, 2858, 1741, 1693, 1662, 1527, 1462, 1271, 1195, 1083, 1037, 759 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.75 (1H, s, H triazole); 7.66 (1H, d, J=1.0 Hz, H thymidine); 6.29 (1H, t, J=6.5 Hz, H-1”); 5.25-5.29 (2H, m, H-4”, H-12); 5.16, 5.07 (2H, s, COOCH2); 5.06 (1H, d, J=2.5 Hz, H-12); 4.19-4.25 (1H, m, H-3”); 3.84 (1H, d, J=11.5 Hz, H-5”a); 3.64 (1H, d, J=11.5 Hz, H5”b); 3.09 (1H, m, H-3); 2.89-2.91 (1H, m, H-2a”); 2.62-2.63 (1H, m, H-2”b); 1.78 (3H, s, CH3 thymindine); 0.98 (3H, s, H-26); 1.86 (6H, d, J=10.0 Hz, H-29, H-30); 0.71 (6H, s, H-27, H-23); 0.69 (3H, s, H-25); 0.68 (3H, s, H-24); 0.42 (3H, s, H-24). 13C-NMR (CDCl3, 125 MHz) δ ppm: 178.9 (C-28); 164.6 (CO thymidine); 150.6 (NCONH); 143.2 (=C= triazol); 138.6 (-CH= thymidine); 136.8 (C-13); 125.9 (C-12); 122.9 (-CH= triazol); 111.0 (-C= thymidine); 85.9 (C-1”); 84.9 (C-4”); 78.6 (C-3); 60.6; 58.8; 54.8; 53.0; 47.5; 64 47.2; 42.0; 39.4; 39.2; 38.7; 38.4; 38.4; 37.8; 36.9; 36.5; 34.5; 32.5; 30.5; 27.9; 27.5; 26.6; 24.4; 23.1; 20.9; 18.1; 16.9; 16.3; 15.4; 15.2; 12.1 (CH3 thymidine). Hợp chất 180a, chất rắn màu trắng, hiệu suất 43%, điểm chảy: 198-199 oC, IR(ATR) 3306, 2935, 2866, 1791, 1689, 1504, 2342, 1265, 1207, 1091, 1012, 881 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.77 (1H, s, H triazole); 7.59 (1H, d, J=1.0 Hz, H thymidine); 6.27 (1H, t, J=6.0 Hz, H-1”); 5.35 (1H, m, H-4”); 4.70 (1H, s, H-29a); 4.56 (1H, s, H-29b); 4.40 (2H, s, CONHCH2), 4.33- 4.35 (1H, m, H-3”); 3.92 (1H, d, J=12.0 Hz, H-5”a); 3.72 (1H, d, J=12.0 Hz, H5”b); 3.06 (1H, d, J=4.0 Hz, H-3), 2.94-2.98 (2H, m, H-19); 1.90 (3H, s, CH3); 1.64 (3H, s, H-30); 1.10 (6H, s, H-24, H-27); 0.94 (3H, s, H-25); 0.78 (3H, s, H- 26). 13C-NMR (CDCl3, 125 MHz) δ ppm: 214.7 (C-3); 176.8 (C-28); 164.0 (CO thymidine); 150.1 (C-20); 150.0 (NCONH); 143.4 (=C= triazol); 137.2 (-CH= thymidine); 124.2 (-CH= triazol); 111.2 (-C= thymidine); 109.8 (C-29); 87.5 (C- 1”); 85.2 (C-4”); 63.0; 61.2 (C-3”); 61.2, 59.0 (C-5”); 55.5; 53.8; 54.3; 49.4, 46.4; 44.9; 42.3; 42.1; 42.0; 38.1; 38.0; 37.6; 37.5; 37.4 (C-2”); 36.5; 34.5; 33.8; 33.2; 30.2; 29.2; 21.9; 19.3; 16.8; 14.3; 13.7; 12.4; 12.0 (CH3 thymidine). 65 Hợp chất 180b. chất rắn màu trắng, hiệu suất 38%, điểm chảy: 265-266 oC. IR (ATR) 3352, 2922, 2868, 1691, 1670, 1519, 1460, 1382, 1271, 1195, 1083, 1038, 869 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.84 (1H, s, H triazol); 7.57 (1H, s, H thymidine); 6.27 (1H, t, J=6.0 Hz, H-1”); 5.36-5.40 (1H, m, H-4”); 4.72 (1H, s, H-29a); 4.61 (1H, s, H29b); 4.41 (2H, d, J=12.5 Hz, CONHCH2); 4.32-4.34 (1H, m, H-3”); 3.95 (1H, d, J=12.0 Hz, H-5”a); 3.75 (1H, d, J=12.0 Hz, H5”b); 2.88-3.01 (2H, m, H-2”a, H-19); 2.80-2.84 (1H, m, H-2”b); 1.90 (3H, s, CH3 thymidine); 1.64 (3H, s, H-30); 1.31 (3H, s, H-26); 1.13 (3H, s, H-26); 0.96 (3H, d, J=6.5 Hz, H-24), 0.73 (3H, s, H-25). 13C-NMR (CDCl3, 125 MHz) δ ppm: 213.0 (C-3); 211.4 (C-11); 176.3 (C-28); 164.2 (CO thymidine); 150.6 (C-20); 149.3 (NCONH); 145.2 (=C= triazol); 137.3 (-CH= thymidine); 123.0 (-CH= triazol); 111.2 (-C= thymidine); 110.4 (C-29); 87.4 (C- 1”); 85.1 (C-4”); 63.7 ; 62.0; 61.2; 59.1; 55.5; 53.4; 49.7; 46.1; 45.1; 44.4; 44.0; 42.6; 39.5; 38.9; 37.8; 37.5; 37.3; 35.7; 34.6; 33.1; 32.1; 30.5; 28.9; 21.6; 19.4; 17.9; 14.3; 13.4; 12.4; 11.4. 66 Hợp chất 181a. chất rắn màu trắng, hiệu suất 50% , điểm chảy: 262-264 oC. IR (ATR) 3709, 3421, 2931, 2870, 1703, 1689, 1552, 1382, 1365, 1263, 1211, 1157, 1043, 819 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.74 (1H, s, H triazol); 7.70 (1H, s, H thymidine); 6.29 (1H, t, J=6.5 Hz, H-1”); 5.21-5.27 (1H, m, H-4”); 4.63 (1H, s, H-29a); 4.51 (1H, s, H29b); 4.26 (2H, dd, J=2.5, 12.5 Hz, CONHCH2); 4.23-4.25 (1H, m, H-3”); 4.22 (1H, d, J=8.0, H-3); 3.88 (1H, d, J=5.5, 12.5 Hz, H-5”a); 3.63 (1H, dd, J=5.5, 12.5 Hz, H5”b); 2.95-3.03 (1H, m, H-19); 2.90-2.94 (1H, m, H-2”a); 2.60-2.64 (1H, m, H-2”b); 2.40-2.50 (4H, m, H-2’, H-3’); 1.85 (3H, s, CH3 thymidine); 1.59 (3H, s, H-30); 0.85 (6H, s, H- 27); 0.70 (3H, d, J=7.0 Hz, H-24); 0.68 (3H, s, H-26); 0.63 (3H, s, H-25). 13C- NMR (CDCl3, 125 MHz) δ ppm: 177.2 (C-28); 173.2 (C-1’); 164.5 (CO thymidine); 150.6 (C-20); 150.4 (NCONH); 145.3 (=C= triazol); 136.6 (-CH= thymidine); 123.0 (-CH= triazol); 110.8 (-C= thymidine); 109.2 (C-29); 85.9 (C- 1”); 84.9 (C-4”); 77.2 (C-3); 60.3; 58.6; 55.5; 51.1; 49.9; 48.1; 46.7; 42.2; 40.2; 37.8; 37.6; 37.4; 36.2; 35.1; 34.0; 33.1; 32.9; 30.6; 30.2; 29.0; 26.4; 25.4; 21.1; 20.6; 19.1; 15.7; 14.8; 14.2; 13.6; 12.1 (CH3 thymidine). 67 Hợp chất 181b, chất rắn màu trắng, hiệu suất 56%, điểm chảy: 256-258 oC, IR (ATR) 3732, 3300, 2926, 2868, 1789, 1741, 1641, 1511, 1197, 868 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.75 (1H, s, -CH= thymidine); 7.67 (1H, d, J=1.0 Hz, -CH= triazole); 7.09 (1H, t, J=5.5 Hz, NH); 6.30 (1H, t, J=6.0 Hz, H- 1”); 5.26 (1H, m, H-4”); 4.66 (1H, s, H-29a); 4.53 (1H, s, H-29b); 4.38-4.40 (1H, m, NH-CH2-a); 4.26-4.31 (3H, m, NH-CH2-b, H-3, H-3”); 3.90 (1H, dd, J=2.5, 12.5 Hz, H-5”a); 3.66 (1H, dd, J=2.5, 12.5 Hz, H-5”b); 2.90-3.00 (2H, m, H-19, H-2”a); 2.66-2.69 (1H, m, H-2”b); 2.21-2.32 (4H, m, H-2”, H-4”); 1.88 (3H, s, CH3 thymidine); 1.61 (3H, s, H-30); 0.87 (3H, s, H-26); 0.71 (3H, d, J=6.5 Hz, H-23); 0.69 (3H, s, H-27); 0.65 (3H, s, H-25). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177.2 (C-28); 173.2 (C-1’); 171.5 (C-5”); 164.4 (-C=O thymidine); 150.7 (C-20); 150.5 (NCONH thymidine); 145.4 (Cquat triazole); 136.9 (-CH= thymidine); 123.1 (-CH= triazole); 111.0 (Cquat); 109.4 (C-29); 86.5 (C-1”); 85.1 (C-4”); 79.0 (C-3); 60.6; 58.7; 55.6; 51.2; 50.0; 49.8; 48.2; 46.8; 42.4; 40.3; 38.0; 37.8; 37.7; 37.5; 36.3; 35.2; 34.1; 33.8; 33.2; 33.1; 30.7; 29.1; 26.6; 25.5; 21.1; 20.9; 20.3; 19.2; 15.8; 15.0; 14.3; 13.7; 12.2 (CH3 thymidine). 68 Hợp chất 181c. chất rắn màu trắng, hiệu suất 60%, điểm chảy: 238-240 oC. IR (ATR) 3392, 2933, 2868, 1693, 1639, 1519, 1467, 1280, 1240, 761 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.73 (1H, s, H triazole); 7.68 (1H, s, H thymidine); 6.30 (1H, t, J=6.5 Hz, H-1”); 5.24-5.26 (1H, m, H-4”); 4.67 (1H, s, H-29a); 4.55 (1H, s, H29b); 4.38 (1H, m, H-3); 4.24-4.29 (2H, m, CH2CONH); 4.28-4.30 (1H, m, H-3”); 3.89 (1H, dd, J=2.0, 11.5 Hz, H-5”a); 3.66 (1H, d, J=11.5 Hz, H5”b); 2.98-3.10 (1H, m, H-19); 2.85-2.90 (1H, m, H-2”a); 2.63- 2.70 (1H, m, H-2”b); 2.22-2.39 (4H, m, H-2’ and H-4’); 2.10-2.15 (1H, m, H- 3’); 1.86 (3H, s, CH3 thymidine); 1.60 (3H, s, H-30); 0.95 (3H, d, J=7.0 Hz, CH3CH); 0.84 (3H, s, H-27); 0.76 (3H, s, H-26); 0.71 (3H, d, J=7.5 Hz, H-24); 0.68 (3H, s, H-25). 13C-NMR (CDCl3, 125 MHz) δ ppm: 177.2 (C-28); 172.6 (C-1’); 164.2 (C-4’); 162.5 (CO thymidine); 150.6 (C-20); 150.4 (NCONH); 145.4 (=C= triazole); 136.7 (-CH= thymidine); 123.0 (-CH= triazole); 110.9 (- C= thymidine); 109.3 (C-29); 86.2 (C-1”); 85.0 (C-4”); 79.0 (C-3); 60.5; 58.7 (C-5”); 55.5; 51.2; 49.9 (C-19); 46.8; 42.3; 40.2; 38.0; 37.7; 37.6; 37.4; 37.1; 36.4; 36.2; 35.1; 34.1; 33.1; 33.0; 30.7; 29.5; 27.4 (C-23); 25.4; 21.1; 20.6; 19.6; 19.1; 15.7; 14.9; 14.3; 13.9; 12.3 (CH3 thymidine). 69 Hợp chất 181d, chất rắn màu trắng, hiệu suất 48%, điểm chảy: 256-258 oC, IR(ATR) 3762, 3390, 2937, 2868, 1697, 1639, 1515, 1467, 1287, 1240, 771 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.77 (1H, s, -CH= thymidine); 7.64 (1H, d, J=1.0 Hz, -CH= triazole); 6.85 (1H, t, J=5.0 Hz, NH); 6.27 (1H, t, J=6.0 Hz, H-1”); 5.30 (1H, dd, J=6.0, 14.5 Hz, H-4”); 4.69 (1H, d, J=1.5 Hz, H-29a); 4.56 (1H, s, H-29b); 4.46 (1H, dd, J=6.0, 15.0 Hz, NH-CH2-a); 4.30-4.34 (2H, m, NH-CH2-b, H-3”); 3.94 (1H, dd, J=2.5, 12.5 Hz, H-5”a); 3.69 (1H, dd, J=2.5, 12.5 Hz, H-5”b); 2.95-3.10 (3H, m, H-3, H-19, H-2”a); 2.66-2.69 (1H, m, H-2”b); 1.91 (3H, s, CH3 thymidine); 1.64 (3H, s, H-30); 0.90 (3H, s, H-26); 0.89 (3H, d, J= 6.5 Hz, H-23); 0.69 (3H, s, H-27); 0.67 (3H, s, H-25). 13C-NMR (CDCl3, 125 MHz) δ ppm: 176.9 (C-28); 164.4 (-C=O thymidine); 150.7 (C-20); 150.5 (NCONH thymidine); 145.6 (Cquat triazole); 137.2 (-CH= thymidine); 123.0 (N-CH= triazole); 111.1(Cquat thymidine); 109.4 (C-29); 87.5 (C-1”); 85.2 (C-4”); 58.8; 55.7; 55.6; 51.3; 50.1; 49.7; 49.5; 48.4; 46.9; 42.4; 40.3; 38.3; 38.1; 37.9; 37.8; 37.6; 36.5; 34.4; 33.3; 30.8; 30.6; 29.2; 25.6; 21.2; 20.8; 19.4; 15.9; 15.0; 14.4; 13.9; 12.4 (CH3 thymidine). 70 Hợp chất 182. chất rắn màu trắng, hiệu suất 67%, điểm chảy: 246-248 oC. IR(ATR)3732, 3307, 2929, 2873, 1743, 1710, 1638, 1519, 1267, 1240, 1197, 1083, 1037, 873 cm-1. 1H-NMR (CDCl3, 500 MHz) δ ppm: 7.77 (1H, s, H triazol); 7.59 (1H, s, H thymidine); 6.88 (1H, t, J=5.5 Hz, NH); 6.27 (1H, t, J=6.0 Hz, H-1”); 5.33-5.46 (1H, m, H-4”); 4.70 (1H, s, H-29a); 4.56 (1H, s, H29b); 4.41 (2H, d, J=12.5 Hz, CONHCH2); 4.32-4.34 (1H, m, H-3”); 3.93 (1H, d, J=12.0 Hz, H-5”a); 3.74 (1H, d, J=12.0 Hz, H5”b); 3.04-3.08 (1H, m, H-11); 2.88-3.01 (2H, m, H-2”a, H-19); 2.78-2.81 (1H, m, H-2”b); 1.90 (3H, s, CH3 thymidine); 1.64 (3H, s, H-30); 1.08 (6H, s, H-26, H-27); 0.95 (3H, d, J=6.5 Hz, H-24), 0.92 (3H, s, H-25). 13C-NMR (CDCl3, 125 MHz) δ ppm: 214.0 (C-3); 176.8 (C-28); 164.2 (CO thymidine); 150.6 (C-20); 150.1 (NCONH); 145.2 (=C= triazol); 137.2 (-CH= thymidine); 123.0 (-CH= triazol); 111.2 (-C= thymidine); 109.4 (C-29); 87.5 (C-1”); 85.1 (C-4”); 63.7; 62.0; 61.2; 59.0; 55.5; 53.8; 49.4; 46.4; 44.9; 42.3; 42.2;