反应详情

To a mixture of N4-ethyl-pyridine-3,4-diamine (94 mg, 0.687 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.43 mL, 0.858 mmol), and the resulting mixture is stirred at room temperature for 1 h. Next, a solution of (2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetic acid methyl ester (100 mg, 0.343 mmol) in CH2Cl2 is added via cannula. The reaction mixture is then stirred at reflux overnight. After cooling to rt, it is treated with MeOH (˜1 mL). The mixture is further diluted with 0.5 N aq NaOH (10 mL) and then stirred vigorously for 30 min. The mixture is then extracted thrice with CH2Cl2 containing some (˜5%) MeOH, and the combined extracts are dried over K2CO3 and concentrated. The crude mixture of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-pyridin-3-yl)-2-(2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetamide is dissolved in AcOH (6 mL), and the resulting solution stirred at reflux overnight. The reaction mixture is then concentrated, and the residue is dissolved in CH2Cl2 and washed with 0.5 N aq NaOH. The aqueous layer is reextracted once with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude residue is purified by preparative TLC. Developing with 15:1 CHCl3-MeOH affords 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.10 (s, 1H), 8.47 (d, J=6.0 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=3.2 Hz, 1H), 7.31 (d, J=5.6 Hz, 1H), 6.37 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H) ppm.

1. stirringThe reaction mixture is then stirred
2. temperatureat reflux overnight
3. temperatureAfter cooling to rt
4. stirringstirred vigorously for 30 min
5. extractionThe mixture is then extracted thrice with CH2Cl2 containing some (˜5%) MeOH
6. dry with materialthe combined extracts are dried over K2CO3
7. concentrationconcentrated
8. additionThe crude mixture of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-pyridin-3-yl)-2-(2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetamide
9. dissolutionis dissolved in AcOH (6 mL)
10. stirringthe resulting solution stirred
11. temperatureat reflux overnight
12. concentrationThe reaction mixture is then concentrated
13. dissolutionthe residue is dissolved in CH2Cl2
14. washwashed with 0.5 N aq NaOH
15. dry with materialthe combined extracts are dried over K2CO3
16. concentrationconcentrated
17. customThe crude residue is purified by preparative TLC