| 90% |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; |
Et3N (4.1 mL, 30 mmol) was added to a mixture of compound 6(1.88 g, 5.0 mmol) in DMF (20 mL). Then aminoacetonitrile hydrochloride (0.93 g, 10 mmol) was added followed by N-hydroxybenzotriazole (HOBt, 0.81 g, 6.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 g, 6.0 mmol). The mixture was stirred overnight at room temperature. After removing the solvents under reduced pressure, the residue was dissolved in CH2Cl2 (100 mL) and washed with NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on 200-300 mesh silica with EtOAc to afford momelotinib as: Yellow solid; yield 1.86 g (90%); m.p. 232-234 C (lit.14 238-243 C); IR: 3365, 3282, 1660, 1596, 1576, 1512, 1456, 1232 cm-1. Anal. calcd for C23H22N6O2: C, 66.65; H, 5.35; N, 20.28; found: C, 66.78; H, 5.49; N, 20.39%. ESI-MS: 415.1 [M + H]+, 437.1 [M + Na]+, 413.2 [M - H]-; 1H NMR (300 MHz, DMSO-d6): delta 9.47 (s, 1H), 9.32 (t, J = 5.4 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.27 (d,J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 5.1 Hz, 2H), 3.74-3.77 (m, 4H), 3.04-3.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6): delta 166.1, 162.4, 160.3, 159.2, 146.2, 139.9, 134.5, 132.8, 127.8, 126.9, 120.3, 117.5, 115.6, 107.6, 66.1, 49.2, 27.7. |
| 90% |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; |
To 2g (5.3mmol) C4 was added 4.42 ml (32mmol) triethylamine, 0.98g (10.6mmol) aminoacetonitrile hydrochloride, 1.22g (6.6mmol) EDCI, and 860 ml (6.6mmol) HOBT. It was dissolved in 20mL DMF. After reacting at room temperature overnight, concentrate to dry, by adding dichloromethane, with saturated sodium bicarbonate solution, salt water after washing, concentrating, methanol used for recrystallization to obtain the yellow solid, yield 90%. |
| 88% |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; |
To a suspension of 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid (theoretically 32.59 g, 86.6 mmol) in DMF (400 mL) was added triethylamine (72.4 mL, 519.6 mmol, 6 eq.) The mixture was sonicated to ensure dissolution. Aminoacetonitrile hydrochloride (16.02 g, 173.2 mmol) was added followed by iV-hydroxybenzotriazole (anhydrous, 14.04 g, 103.8 mmol) and l-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (19.92 g, 103.8 mmol). The suspension was stirred vigorously overnight. The solvent was evaporated under reduced pressure, the residue was diluted with 5% sodium bicarbonate (400 mL) and water (300 mL), giving a yellow solid, which was broken up and filtered. The solids were washed several times with 100 mL portions of water, triturated with hot methanol/dichloromethane (500 mL, 1:1), concentrated to a volume of approximately 300 mL), cooled and filtered. The solids were washed with cold methanol (3 x 100 mL), ether (200 mL) and hexane (200 mL) prior to drying to afford Compound 3 (31.69 g, 88%). M.p. 238-243C. Microanalysis: Found C, 66.52; H, 5.41 ; N, 20.21. C23H26N6O10S2 requires C, 66.65; H, 5.35; N 20.28%. 13C NMR (75.5MHz, J6-DMSO) delta 166.04, 162.34, 160.26, 159.14, 146.14, 139.87, 134.44, 132.73, 127.80, 126.84, 120.29, 117.49, 115.50, 107.51, 66.06, 49.16, 27.68. |
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