反应详情

To a clear solution of 4-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-indazol-3-amine (200 mg, 0.76 mmol, 1 equiv), (3-methylphenyl)acetic acid (114 mg, 0.76 mmol, 1 equiv), and DIEA (145 uL, 0.83 mmol, 1.1 equiv) in 4 mL of DCM was added at rt in one portion solid HATU (316 mg, 0.83 mmol, 1.1 equiv). The mixture as stirred at rt for 20 h. LCMS showed conversion complete. The suspension was filtered. The filtrate was absorbed onto a dryload cartridge. Purification was done on an SF25-24 g silica gel cartridge using gradient elution of 1% EtOAc in hexane to 100% EtOAc. The product eluted in the 100% EtOAc as a broad but well-defined peak. Concentration in vacuo gave a white foam (320 mg). LCMS showed it was only 84% pure with a major impurity at 11%. This material was dissolved in EtOAc (75 mL), and washed with water (25 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. LCMS showed the impurities still present. The material was dissolved in EtOAc (1 mL) with some material still sticked to the wall of the 100 mL recovery flask, to which was added 3 mL of MTBE. The mixture turned cloudy initially, and was immersed in a water bath at (40° C.). The cloudiness disappeared and then solids began to form on the walls. A spatula was used to scratch the flask. The mixture was then cooled to room temperature and the suspension was filtered. The solids (light tan colored) was washed with MTBE (2 mL). Both LCMS and NMR showed this lot was quite pure. The solid was dried under vacuum at 65° C. for 16 h to give 210 mg as tan-colored solids. LC-MS (ES) m/z=397 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.23 (t, J=8.3 Hz, 2H), 3.78 (s, 3H), 3.83 (s, 2H), 4.23 (t, J=8.6 Hz, 2H), 4.38 (s, 2H), 6.78 (d, J=5.8 Hz, 1H), 7.05-7.15 (m, 13H), 7.20-7.26 (m, 2H), 7.28-7.38 (m, 3H), 8.16 (d, J=8.3 Hz, 1H).

1. filtrationThe suspension was filtered
2. customThe filtrate was absorbed onto a dryload cartridge
3. customPurification
4. washelution of 1% EtOAc in hexane to 100% EtOAc
5. washThe product eluted in the 100% EtOAc as a broad but well-defined peak
6. concentrationConcentration in vacuo