| 81% |
With sodium hydrogensulfite; In ISOPROPYLAMIDE; at 120℃; for 21h; |
Aldehyde 1e (2.05 g, 4.28 MMOL), 1,2-diamino-3, 5-difluorobenzene (617 mg, 4.28 MMOL) and sodium bisulfite (891 mg, 8.57 MMOL) were dissolved in N, N-DIMETHYLACETAMIDE (43 mL) and heated in a 120 C oilbath for 21 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with half-saturated aqueous sodium chloride solution (75 mL, a 1: 1 mixture of deionized water and saturated aqueous sodium chloride solution). The aqueous layer was back-extracted with ethyl acetate (2 x 100 mL). All the organic extracts were combined, dried over magnesium sulfate, and concentrated to a brown tar (3.39 G). This crude material was purified by silica gel chromatography (eluting with a gradient of 70% to 100% ethyl acetate in hexanes), to give benzoimidazole product 1f (2.11 g, 81%) as a tan foam : 1H NMR (CD30D) S 8.46 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.46 (dd, J=1. 3, 8. 6 Hz, 1H), 7.13 (m, 1H), 6.84 (m, 1H), 5.99 (dd, J=2. 3,9. 9 Hz, 1 H), 4.60 (s, 2H), 4.01 (m, 1 H), 3.86 (m, 1 H), 3.32 (m, 2H, obscured by solvent peak) 2.67 (m, 1H), 2.28 (s, 3H), 2.18 (m, 2H), 1.89 (m, 1H), 1.73 (m, 2H), 1.47 (s, 9H), 1.13 (t, J=7. 1 Hz, 1H). Anal. (C33H36F2N603-0. 4 H2O) C, H, N, F. |
| 81% |
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 21h; |
Aldehyde 1e (2.05 g, 4.28 mmol), 1 ,2-diamino-3,5-difluorobenzene (617 mg, 4.28 mmol) and sodium bisulfite (891 mg, 8.57 mmol) were dissolved in N,N-dimethylacetamide (43 mL) and heated in a 120 0C oilbath for 21 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with half -saturated aqueous sodium chloride solution (75 mL, a 1 :1 mixture of deionized water and saturated aqueous sodium chloride solution). The aqueous layer was back-extracted with ethyl acetate (2 x 100 mL). All the organic extracts were combined, dried over magnesium sulfate, and concentrated to a brown tar (3.39 g). This crude material was purified by silica gel chromatography (eluting with a gradient of 70% to 100% ethyl acetate in hexanes), to give benzoimidazole product If (2.11 g, 81%) as a tan foam: 1H NMR (CD3OD) delta 8.46 (s, 1 H), 8.41 (s, 1 H), 8.29 (s, 1H), 7.87 (d, J = 8.6 Hz, 1 H)1 7.46 (dd, J =1.3, 8.6 Hz1 1 H)1 7.13 (m, 1H)1 6.84 (m, 1 H)1 5.99 (dd, J =2.3, 9.9 Hz, 1 H)1 4.60 (s, 2H), 4.01 (m, 1 H)1 3.86 (m, 1 H)1 3.32 (m, 2H1 obscured by solvent peak) 2.67 (m, 1 H)1 2.28 (s, 3H), 2.18 (m, 2H), 1.89 (m, 1 H), 1.73 (m, 2H), 1.47 (s, 9H)1 1.13 (t, J =7.1 Hz1 1 H). Anal. (C33H36F2N6O3-O^ H2O) C, H1 N1 F. (g) Example |
| 81% |
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 21h; |
(d) Intermediate 1f - {5-[3-(4,6-Difluoro-1/-/-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-indazol- 5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-carbamic acid tert-butyl ester; Aldehyde 1e (2.05 g, 4.28 mmol), <strong>[2369-29-1]1,2-diamino-3,5-difluorobenzene</strong> (617 mg, 4.28 mmol) and sodium bisulfite (891 mg, 8.57 mmol) were dissolved in N,N-dimethylacetamide (43 mL) and heated in a 120 0C oilbath for 21 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with half-saturated aqueous sodium chloride solution (75 mL, a 1:1 mixture of deionized water and saturated aqueous sodium chloride solution). The aqueous layer was back-extracted with ethyl acetate (2 x 100 mL). All the organic extracts were combined, dried over magnesium sulfate, and concentrated to a brown tar (3.39 g). This crude material was purified by silica gel chromatography (eluting with a gradient of 70% to 100% ethyl acetate in hexanes), to give benzoimidazole product 1f (2.11 g, 81%) as a tan foam: 1H NMR (CD3OD) delta 8.46 (s, 1 H), 8.41 (s, 1 H), 8.29 (s, 1 H), 7.87 (d, J = 8.6 Hz, 1 H), 7.46 (dd, J =1.3, 8.6 Hz, 1H), 7.13 (m, 1H), 6.84 (m, 1H), 5.99 (dd, J =2.3, 9.9 Hz, 1H), 4.60 (s, 2H), 4.01 (m, 1H), 3.86 (m, 1H), 3.32 (m, 2H, obscured by solvent peak) 2.67 (m,1H), 2.28 (s, 3H), 2.18 (m, 2H), 1.89 (m, 1 H), 1.73 (m, 2H), 1.47 (s, 9H), 1.13 (t, J =7.1 Hz, 1H). Anal. (C33H36F2N6O3-O^ H2O) C, H, N, F. |
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