反应详情

To a solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (2.50 g, 4.63 mmol) in dichloromethane (50 ml), pyridine (749 ml, 9.27 mmol) was added, and triphosgene (2.75 g, 9.27 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. To this, dichloroethane (100 ml) was added, and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (4.99 g, 18.5 mmol) obtained in Step D was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1), to obtain a mixture of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazine-1-carbonyl)-2,6-difluoro-phenyl]-amide and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone. This was dissolved in TFA (40 ml), and N-acetylcysteine (1.13 g, 6.95 mmol) was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure. 5M-NaOH aqueous solution was added to adjust the pH to 8, and 500 ml of water was added, followed by extraction with dichloromethane (1 l×3). The solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=40/1 to 10/1), followed by further washing with methanol (100 ml), to obtain the desired compound as a yellow solid (1.31 g, 51%).

1. distillationthe solvent was distilled off under reduced pressure
2. additionTo this, dichloroethane (100 ml) was added
3. temperatureby refluxing for 14 hours
4. distillationThe solvent was distilled off under reduced pressure
5. customfollowed by purification by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1)
6. customto obtain
7. temperatureby refluxing for 14 hours
8. distillationThe solvent was distilled off under reduced pressure
9. addition5M-NaOH aqueous solution was added
10. additionwas added
11. extractionfollowed by extraction with dichloromethane (1 l×3)
12. distillationThe solvent was distilled off under reduced pressure
13. customThis was purified by silica gel column chromatography (dichloromethane/methanol=40/1 to 10/1)
14. washby further washing with methanol (100 ml)