反应详情

2-(6-Chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (84 mg, 0.137 mmol) was suspended in dichloromethane (2 ml) and cooled in an ice bath. Trifluoroacetic acid (0.9 ml) was slowly added and the reaction was stirred at room temperature for 3 h then evaporated. The residue was dissolved in dichloromethane (1.4 ml) and ethylenediamine (0.55 ml, 8.25 mmol) was added. The reaction was stirred for 8 h. Water was added giving a cloudy mixture, which was extracted with ethyl acetate eight times. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. Drying agent was filtered off and rinsed with 10% methanol/dichloromethane, and evaporated to a residue. This was combined with solid which had appeared in the aqueous layer. The combined material was purified by silica gel chromatography (methanol/dichloromethane) to give 32 mg (48%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. (M+H)+=481; mp=267-268° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.00 (s, 1H), 8.54 (d, J=7.2 Hz, 1H), 8.49 (d, J=10.6 Hz, 1H), 7.86-7.90 (m, 1H), 7.18 (d, J=10.2 Hz, 1H), 4.42-4.69 (m, 3H), 4.18 (s, 3H), 4.07-4.17 (m, 1H), 3.95-4.05 (m, 1H), 3.76-3.87 (m, 1H), 1.32-1.41 (m, 3H).

1. temperaturecooled in an ice bath
2. customthen evaporated
3. dissolutionThe residue was dissolved in dichloromethane (1.4 ml)
4. stirringThe reaction was stirred for 8 h
5. customgiving a cloudy mixture, which
6. extractionwas extracted with ethyl acetate eight times
7. washThe combined organic layers were washed with sodium chloride solution
8. dry with materialdried over sodium sulfate
9. customDrying agent
10. filtrationwas filtered off
11. washrinsed with 10% methanol/dichloromethane
12. customevaporated to a residue
13. customThe combined material was purified by silica gel chromatography (methanol/dichloromethane)