General Method for the Synthesis of Mycophenolic Acid Derivatives
To a solution of mycophenolic acid (2 mmol) in absolute DMF (1.5 mL) carbonyldiimidazole (2.2 mmol) was added and stirred for 2 h at room temperature. Then appropriate amine (2.2 mmol) was added and the reaction mixture is stirred at 70 °C for 10 h. The mixture was cooled to room temperature and distilled water (10 mL) was added. The precipitate formed was filtered and crystallized from aqueous methanol.
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(thiazol-2-yl)hex-4-enamide (
1) [
75]. Yield 62%, m.p. 216–217 °C.
1H-NMR (300 MHz, DMSO-d
6) δ: 1.77 (s, 3H, CH
3), 2.05(s, 3H, CH
3(arom)), 2.26 (t, 2H, J = 7.0 Hz, CH
2C
H2), 2.48 (t, 2H, J = 7.0 Hz, C
H2CH
2), 3.29 (d, 2H, J = 6.1 Hz, C
H2CH), 3.64 (s, 3H, OCH
3), 5.16 (t, 1H, J = 6.1 Hz, CH
2C
H), 5.23 (s, 2H, OCH
2), 7.15 (s, 1H
(thiaz)), 7.42 (s, 1H
(thiaz)), 9.32 (bs, 1H, OH), 11.97 (bs, 1H, NH).
13C-NMR (500 MHz, CHCl
3-d
6): 11.50, 16.46, 23.42, 34.32, 34.76, 60.97, 68.31, 112.40, 113.39, 119.94, 123.89, 128.70, 133.54, 136.06, 146.69, 156.66, 159.59, 162.63, 168.80, 170.59. EI MS (m/z): 402 (M
+, 16), 261 (14), 207 (22), 195 (43), 159 (22), 142 (100), 127 (21), 100 (69), 91 (11), 55 (13). HRMS (ESI), m/z found 403.1322 [M + H] C
20H
23N
2O
5S. Calculated: [M + H] 403.1328.
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(5-methylthiazol-2-yl)hex-4-enamide (2). Yield 65%, m.p. 215–216 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.76 (s, 3H, CH3), 2.03(s, 3H, CH3(arom)), 2.25 (t, 2H, J = 7.5 Hz, CH2CH2), 2.31(s, 3H, CH3(thiaz)), 2.46 (t, 2H, J = 7.5 Hz, CH2CH2), 3.30 (d, 2H, J = 6.8 Hz, CH2CH), 3.66 (s, 3H, OCH3), 5.16 (t, 1H, J = 6.7 Hz, CH2CH), 5.22 (s, 2H, OCH2), 7.06 (s, 1H(thiaz)), 9.14 (bs, 1H, OH), 11.64 (bs, 1H, NH). 13C-NMR (500 MHz, CHCl3-d6): 11.48, 16.22, 22.94, 34.21, 34.30, 61.07, 69.54, 106.83, 116.42, 122.26, 124.59, 124.63, 126.99, 133.34, 133.69, 144.29, 153.72, 157.59, 163.17, 170.47, 172.15. EI MS (m/z): 416 (M+, 40), 209 (41), 195 (9), 169 (7), 156 (66), 141 (24), 114 (100), 81 (7), 69 (10), 44 (9). HRMS (ESI), m/z found 417.1479 [M + H] C21H25N2O5S. Calculated: [M + H] 417.1484.
(E)-N-(4,5-Dimethylthiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide (3). Yield 72%, m.p. 202–203 °C. 1H-NMR (500 MHz, DMSO-d6) δ: 1.79 (s, 3H, CH3), 2.05 (s, 3H(arom)), 2.12 (s, 3H, CH3(thiaz)), 2.20 (s, 3H, CH3(thiaz)), 2.22 (t, 2H, J = 7.5 Hz, CH2CH2), 2.52 (m, 2H, CH2CH2), 3.28 (d, 2H, J = 6.6 Hz, CH2CH), 3.65 (s, 3H, OCH3),5.13 (t, 1H, J = 6.6 Hz, CH2CH), 5.22 (s, 2H, OCH2), 9.37 (br, 1H, OH), 11.37 (br, 1H, NH).13C-NMR (500 MHz, DMSO-d6) 13C-NMR: 10.74, 14.26, 16.38, 22.72, 34.41,34.92, 61.02, 69.83, 106.42, 116.59, 119.87, 122.02, 123.54, 133.70, 141.30, 144.08, 153, 58, 154.34, 163.45, 170.00, 172.56. EI MS (m/z): 430 (M+, 8), 223 (21), 170 (42), 155 (20), 141 (13), 128 (100), 114 (18), 95 (17), 85 (16), 59 (10). HRMS (ESI), m/z found 431.1635 [M + H]. C22H27N2O5S. Calculated: [M + H] 431.1640.
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(4-methylthiazol-2-yl)hex-4-enamide (4). Yield 68%, m.p. 185–186 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.74 (s, 3H, CH3), 2.03 (s, 3H, CH3(arom)), 2.21 (s, 3H, CH3(thiaz)), 2.24 (m, 2H, CH2CH2), 2.44 (t, 2H, J = 7.8 Hz, CH2CH2), 3.26 (d, 2H, J = 6.6 Hz, CH2CH), 3.63 (s, 3H, OCH3), 5.13 (t, 1H, J = 6.0 Hz, CH2CH), 5.21 (s, 2H, OCH2), 6.66 (s, 1H(thiaz)), 9.32 (bs, 1H, OH) 11.88 (bs, 1H, NH). 13C-NMR (500 MHz, CHCl3-d6): 11.50, 16.40, 22.73, 34.35, 34.94, 51.09, 60.96, 69.85, 106.42, 108.00, 116.60, 121.96, 123.62, 133.66, 144.09, 146.77, 153.55, 157.60, 162.44, 170.19, 172.57. EI MS (m/z): 416 (M+, 19), 209 (29), 195 (7), 156 (60), 141 (23), 124 (11), 114 (100), 69 (8), 55 (7), 41 (6). HRMS (ESI), m/z found: 417.1479 [M + H] C21H25N2O5S. Calculated: [M + H] 417.1484.
(E)-Ethyl-2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)-4-methylthiazole-5-carboxylate (5). Yield 63%, m.p. 189–190 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.26 (t, 3H, J = 7.1 Hz, CH2CH3), 1.74 (s, 3H, CH3), 1.99 (s, 3H, CH3(arom)), 2.24 (t, 2H, J = 7.1 Hz, CH2CH2), 2.45 (m, 5H, CH3(thiaz), CH2CH2), 3.24 (d, 2H, J = 6.6 Hz, CH2CH), 3.62 (s, 3H, OCH3), 4.21 (q, 2H, J = 7.1 Hz, CH2CH3), 5.12 (m, 1H, CH2CH), 5.14 (s, 2H, OCH2), 9.28 (bs, 1H, OH), 12.32 (bs, 1H, NH). 13C-NMR (500 MHz, DMSO-d6) δ: 11.49, 14.32, 16.42, 16.98, 22.76, 34.28, 34.96, 60.85, 61.04, 62.41, 69.89, 116.61, 120.31, 121.78, 123.90, 133.37, 144.12, 148.44, 153.48, 156.14, 159.21, 170.55, 178.25. EI MS (m/z): 488 (M+, 9), 281 (33), 228 (51), 207 (24), 186 (100), 159 (44), 141 (29), 114 (22), 91 (12), 71 (10). HRMS (ESI), m/z found: 489.1683 [M + H] C24H28N2O7S. Calculated: [M + H] 489.1695.
(E)-Ethyl-2-(2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)thiazol-4-yl)acetate (6). Yield 59%, m.p. 233–234 °C. 1H-NMR (500 MHz, CHCl3-d6) δ: 1.16 (t, 3H, J = 7.0 Hz, CH2CH3), 1.74 (s, 3H, CH3), 2.03 (s, 3H, CH3(arom)), 2.23 (t, 2H, J = 7.1 Hz, CH2CH2), 2.45 (t, 2H, J = 7.0 Hz), CH2CH2), 3.26 (d, 2H, J = 6.0 Hz, CH2CH), 3.61 (s, 3H, OCH3), 3.64 (s, 2H, CH2CO), 4.06 (q, 2H, J = 7.0 Hz, CH2CH3), 5.12 (m, 1H, CH2CH), 5.21 (s, 2H, OCH2), 6.90 (s, 1H(thiaz)), 9.31 (s, 1H, OH), 12.03 (s, 1H, NH). 13C-NMR (500 MHz, DMSO-d6): 11.49, 14.32, 16.42, 16.98, 22.76, 34.28, 34.96, 60.85, 61.04, 62.41, 69.89, 116.61, 120.31, 121.78, 123.90, 133.37, 140.11, 144.12, 148.44, 153.48, 156.14, 159.21, 170.55, 178.25. EI MS (m/z): 488 (M+, 6), 281 (28), 228 (46), 207 (33), 186 (100), 159 (24), 141 (11), 128 (11), 113 (78), 91 (22), 71 (14). HRMS (ESI), m/z found: 489.1690 [M + H]. C24H28N2O7S. Calculated: [M + H] 489.1695.
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(4-(pyridin-4-yl)thiazol-2-yl)hex-4-enamide (7). Yield 56%, m.p. 193–194 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.76 (s, 3H, CH3), 1.98 (s, 3H, CH3(arom)), 2.26 (t, 2H, J = 7.5 Hz, CH2CH2), 2.52 (t, 2H, J = 7.5 Hz, CH2CH2), 3.26 (d, 2H, J = 6.6 Hz, CH2CH), 3.62 (s, 3H, O CH3), 5.15 (t, 1H, J = 6.6 Hz, CH2CH), 5.16 (s, 2H, OCH2), 7.80 (d, 2H, J = 4.8 Hz, H(py)), 7.91 (s, 1H, H(thiaz)), 8.60 (d, 2H, J = 4.8 Hz, H(py)), 9.31 (s, 1H, OH), 12.22 (1H, NH). 13C-NMR (500 MHz, DMSO-d6) 11.50, 16.40, 16.55, 19.95, 22.73, 34.55, 34.94, 60.96, 66.80, 69.02, 106.42, 108.00, 115.60, 116.60, 120.78, 121.96, 123.62, 144.09, 146.77, 153.55, 157.68, 163.44, 170.19, 172.97. EI MS (m/z): 479 (M+, 8), 272 (16), 219 (35), 207 (15), 177 (100), 159 (32), 135 (37), 105 (34), 91 (33), 77 (28), 55 (15). HRMS (ESI), m/z found: 480.1588 [M + H] C25H26N3O5S. Calculated: [M + H] 480.1593.
E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(4-(pyridin-3-yl)thiazol-2-yl)hex-4-enamide (8). Yield 61%, m.p. 182–183 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.77 (s, 3H, CH3), 2.00 (s, 3H, CH3(arom)), 2.26 (t, 2H, J = 6.8 Hz, CH2CH2), 2.53 (t, 2H, J = 6.8 Hz, CH2CH2), 3.26 (d, 2H, J = 6.5 Hz, CH2CH), 3.64 (s, 3H, OCH3), 5.15 (t, 1H, J = 6.5 Hz, CH2CH), 5.17 (s, 2H, OCH2), 7.45 (dd, 1H, J = 4.8, 7.6 Hz, H(py)), 7.74 (s, 1H, H(thiaz)), 8.19 (d, 1H, J = 7.6 Hz, H(py)), 8.50 (d, 1H, J = 4.8 Hz, H(py)), 9.08 (s, 1H, OH), 9.34 (s, 1H, H(py)), 12.21 (s, 1H, NH). 13C-NMR (500 MHz, DMSO-d6): 11.50, 16.40, 22.73, 34.33, 34.94, 60.94, 69.70, 106.42, 108.00, 116.60, 121.96, 123.62, 125.04, 133.34, 133.66, 134.55, 144.09, 146.77, 147.75, 148.56, 153.55, 157.60, 163.44, 170.19, 172.57. EI MS (m/z): 479 (M+, 9), 272 (12), 219 (27), 204 (9), 177 (100), 159 (23), 135 (37), 105 (23), 91 (23), 77 (16), 55, (14). HRMS (ESI), m/z found: 480.1588 [M + H] C25H26N3O5S. Calculated: [M + H] 480.1593.
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(4-(pyridin-2-yl)thiazol-2-yl)hex-4-enamide (9). Yield 58%, m.p. 217–218 °C. 1H-NMR (300 MHz, CHCl3-d6) δ: 1.77 (s, 3H, CH3), 2.02 (s, 3H, CH3(arom)), 2.30 (t, 2H, J = 7.2 Hz, CH2CH2), 2.52 (t, 2H, J = 7.2 Hz, CH2CH2), 3.29 (d, 2H, J = 6.7 Hz, CH2CH), 3.67 (s, 3H, OCH3), 5.13 (s, 2H, OCH2), 5.21(t, 1H, J = 6.7 Hz, CH2CH), 7.24 (m, 1H, H(py)), 7.63 (s, 1H, H(thiaz)), 7.79 (m, 1H, H(py)), 7.89 (d, 1H, J = 7.9 Hz, H(py)), 8.54 (d, 1H, J = 4.6 Hz, H(py)), 8.78 (s, 1H, OH), 11.96 (s, 1H, NH)..13C- NMR (500 MHz, DMSO-d6): 11.50, 16.40, 22.73, 34.33, 34.94, 60.94, 69.70, 106.42, 108.00, 116.60, 121.96, 123.62, 123.62, 127.00, 128.91, 133.66, 144.09, 146.77, 149.82, 150.50, 150.96, 153.55, 157.55, 163.44, 170.19, 172.57. EI MS (m/z): 479 (M+, 19), 272 (11), 219 (41), 177 (100), 159 (18), 135 (69), 105 (48), 91 (48), 78 (72), 67 (38), 55 (30). HRMS (ESI), m/z found: 480.1588 [M + H] C25H26N3O5S. Calculated: [M + H] 480.1593.
(E)-N-(Benzo[d]thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide (10). Yield 60%, m.p. 201–202 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.77 (s, 3H, CH3), 1.98 (s, 3H, CH3(arom)), 2.30 (t, 2H, J = 7.5 Hz, CH2CH2), 2.56 (t, 2H, J = 7.5 Hz, CH2CH2), 3.28 (d, 2H, J = 6.6 Hz, CH2CH), 3.65 (s, 3H, OCH3), 5.06 (s, 2H, OCH2), 5.20 (t, 1H J = 6.6 Hz, CH2CH), 7.29 (t, 1H, J = 7.5 Hz, H(arom)), 7.42 (t, 1H, J = 7.5 Hz, H(arom)), 7.68 (d, 1H, J = 8.0 Hz, H(arom)), 7.91 (d, 1H, J = 8.0 Hz, H(arom)), 9.10 (bs, 1H, OH), 12.11 (bs, 1H, NH). 13C-NMR (500 MHz, DMSO-d6): 11.45, 16.22, 22.94, 26.82, 34.21, 34.30, 61.07, 69.54, 106.65, 116.42, 120.71, 122.26, 124.59, 124.63, 126.99, 133.34, 133.69, 144.29, 153.72, 127.59, 163.17, 170.47, 172.15, 172.76. EI MS (m/z): 452 (M+, 25), 45 (40), 207 (14), 192 (49), 177 (20), 163 (6), 150 (100), 135 (10), 73 (6), 45 (14). HRMS (ESI), m/z found: 453.1479 [M + H] C24H25N2O5S. Calculated: [M + H] 453.1484.
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-N-(6-methoxybenzo[d]thiazol-2-yl)-4-methylhex-4-enamide (11). Yield 64%, m.p. 205–206 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.78 (s, 3H, CH3), 1.98 (s, 3H, CH3(arom)), 2.28 (t, 2H, J = 7.0 Hz, CH2CH2), 2.51 (t, 2H, J = 7.0 Hz, CH2CH2), 3.28 (d, 2H, J = 6.1 Hz, CH2CH), 3.65 (s, 3H, OCH3), 3.81 (s, 3H, OCH3) 5.08 (s, 2H, OCH2), 5.17 (t, 1H J = 6.1 Hz, CH2CH), 7.01 (d, 1H, J = 8.2 Hz, H(arom)), 7.52 (s, 1H, H(arom)), 7.59 (d, 1H, J = 8.2 Hz, H(arom)), 9.31 (bs, 1H, OH), 12.08 (bs, 1H, NH). 13C-NMR (500 MHz, DMSO-d6): 11.50, 16.40, 16.92, 19.95, 22.73, 34.35, 34.94, 60.96, 66.80, 69.85, 106.42, 108.00, 115.60, 116.60, 120.78, 121.96, 123.62, 133.66, 144.09, 146.77, 153.55, 157.68, 163.44, 170.194, 172.57. EI MS (m/z): 482 (M+, 13), 281 (11), 222 (25), 207 (40), 193 (25), 180 (100), 165 (77), 160 (52), 135 (54), 115 (34), 103 (24), 91 (52), 77 (37). HRMS (ESI), m/z found: 483.1584 [M + H] C25H27N2O6S. Calculated: [M + H] 483.1589
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)hex-4-enamide (12). Yield 69%, m.p. 179–180 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.73 (m, 7H, CH3, CH2CH2CH2CH2), 2.04 (s, 3H, CH3(arom)), 2.21 (m, 2H, CH2CH2), 2.42 (m, 2H, CH2CH2), 2.59 (m, 4H, CH2CH2CH2CH2), 3.27 (d, 2H, J = 6.6 Hz, CH2CH), 3.64 (s, 3H, OCH3), 5.12 (m, 1H, CH2CH), 5.21 (s, 2H, OCH2), 9.37(bs, 1H, OH), 11.76 (bs, 1H, NH). 13C-NMR (500 MHz, DMSO-d6): 11.48, 16.22, 22.94, 22.94, 24.21, 24.30, 34.21, 34.30, 61.07, 69.54, 106.83, 116.42, 122.26, 124.59., 124.63, 126.99, 133.34, 133.69, 144.29, 153.72, 157.59, 163.17, 170.47, 172.15. EI MS (m/z): 456 (M+, 7), 249 (24), 207 (9), 196 (32), 181 (16), 154 (100), 126 (58), 11 (11), 91 (14), 77 (18), 67 (24). HRMS (ESI), m/z found: 457.1792 [M + H] C24H29N2O5S. Calculated: [M + H] 457.1797.
(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-2-yl)hex-4-enamide (13). Yield 67%, m.p. 198–199 °C. 1H-NMR (300 MHz, DMSO) δ: 1.62 (m, 4H, 2x CH2), 1.75 (s, 3H, CH3), 1.78 (m, 2H, CH2), 2.07 (s, 3H, CH3(arom)), 2.24 (t, 2H, J = 7.6 Hz, CH2CH2), 2.43 (t, 2H, J = 7.6 Hz, CH2CH2), 2.65 (t, 2H, J = 5.4 Hz, CH2), 2.72 (t, 2H, t, 2H, J = 5.4 Hz, CH2), 3.29 (d, 2H, J = 6.6 Hz, CH2CH), 3.66 (s, 3H, OCH3), 5.15 (t, 1H, J = 6.6 Hz, CH2CH), 5.22 (s, 2H, OCH2), 9.13 (bs, 1H, OH), 11.57 (bs, 1H, NH). 13C-NMR (500 MHz, DMSO-d6): 11.560, 16.40, 16.92, 19.95, 22.73, 25.19, 34.35, 60.96, 66.00, 69.05, 106.42, 108.00, 115.60, 116.60, 121.96, 123.62, 133.66, 144.09, 146.77, 146.77, 153.55, 157.69, 163.44, 170.19, 172.57, 173.75. EI MS (m/z): 470 (M+, 10), 263 (36), 210 (35), 195 (24), 168 (100), 153 (8), 139 (12), 126 (14), 114 (16), 91 (13), 81 (11), 55 (9). HRMS (ESI), m/z found: 471.1948 [M + H] C25H31N2O5S. Calculated: [M + H] 471.1953.
(E)-N-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide (14). Yield 62%, m.p. 166–167 °C. 1H-NMR (300 MHz, DMSO-d6) δ: 1.76 (s, 3H, CH3), 2.06 (s, 3H, CH3(arom)), 2.25 (t, 2H, J = 7.4 Hz, CH2CH2), 2.37 (m, 2H, CH2CH2CH2), 2.46 (m, 2H, CH2CH2), 2.64 (t, 2H, J = 7.0 Hz, CH2CH2CH2), 2.79 (t, 2H, J = 7.0 Hz, CH2CH2CH2), 3.30 (d, 2H, J = 6.6 Hz, CH2CH), 3.67 (s, 3H, OCH3), 5.16 (t, 1H, J = 6.6 Hz, CH2CH), 5.22 (s, 2H, OCH2), 9.17 (bs 1H, OH), 11.68 (bs, 1H, NH). 13C-NMR (500 MHz, DMSO-d6) δ: 11.51, 16.38, 22.72, 25.72, 25.83, 31.92, 34.41, 34.92, 61.02, 69.83, 106.42, 116.59, 119.87, 122.02, 122.54, 133.78, 141.30, 144.08, 153.58, 154.34, 163.45, 170.00, 172.56. EI MS (m/z): 442 (M+, 10), 182 (11), 159 (15), 140 (100), 128 (12), 115 (15), 97 (18), 81 (45), 67 (14), 53 (15), 41 (11). HRMS (ESI), m/z found: 443.1635 [M + H] C23H27N2O5S. Calculated: [M + H] 443.1640.
(E)-6-(4,6-Dimethoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(thiazol-2-yl)hex-4-enamide (15). Yield 74%, m.p. 219–220 °C. 1H-NMR (300 MHz, DMSO) δ: 1.77 (s, 3H, CH3), 2.09 (s, 3H, CH3(arom)), 2.26 (t, 2H, J = 7.2 Hz, CH2CH2), 2.52 (m, 2H, CH2CH2), 3.28 (d, 2H, J = 6.5 Hz, CH2CH), 3.67 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.09 (t, 1H, J = 6.5 Hz, CH2CH), 5.24 (s, 2H, OCH2), 7.12 (d, 1H, J = 3.6 Hz, H(thiaz)), 7.40 (d, 1H, J = 3.6 Hz, H(thiaz)), 11.97 (s, 1H, NH). 13C-NMR (500 MHz, DMSO-d6), δ: 11.50, 16.46, 23.42, 34.32, 34.76, 60.97, 62.58, 68.31, 112.40, 113.39, 119.94, 123.89, 128.70, 133.54, 136.06, 146.69, 156.66, 159.59, 162.63, 168.80, 170.59. EI MS (m/z): 416 (M+, 5), 221 (24), 209 (15), 195 (55), 182 (14), 142 (100), 127 (16), 115 (12), 100 (56), 69 (13), 55 (16). HRMS (ESI), m/z found 417.1479 [M + H] C21H25N2O5S. Calculated: [M + H] 417.1484.
(E)-6-(4,6-Dimethoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-N-(5-methylthiazol-2-yl)hex-4-enamide (16). Yield 74%, m.p. 185–186 °C. 1H-NMR (300 MHz, DMSO) δ: 1.75 (s, 3H, CH3), 2.09 (s, 3H, CH3(arom)), 2.24 (t, 2H, J = 6.8 Hz, CH2CH2), 2.28 (s, 3H, CH3(thiaz)), 2.45 (t, 2H, J = 6.8 Hz, CH2CH2), 3.28 (d, 2H, J = 6.6 Hz, CH2CH), 3.68 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.08 (t, 1H, J = 6.6 Hz, CH2CH), 5.23 (s, 2H, OCH2), 7.05 (s, 1H, H(thiaz)), 11.76 (bs, 1H, NH). 13C-NMR (500 MHz, DMSO-d6), δ: 11.48, 16.41, 22.42, 34.45, 34.72, 46.70, 60.94, 62.58, 69.29, 112.47, 119.91, 123.95, 127.23, 128.73, 132.75, 133.56, 133.42, 141.30, 146.68, 156.66, 168.85, 170.32. EI MS (m/z): 430 (M+, 9), 221 (24), 209 (100), 196 (22), 175 (10), 156 (57), 141 (18), 127 (13), 114 (60), 91 (10). HRMS (ESI), m/z found 431.1635 [M + H] C22H27N2O5S. Calculated: [M + H] 431.1640.