反应详情

温度

40 °C

HATU (0.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (0.2 ml) and added to 2-methyl-1,3-thiazole-4-carboxylic acid (0.1 mmol) also in DMF (0.2 ml). DIPEA (0.05 ml 0.3 mmol) was added and the mixture was left to stand for 5 mins. 3-Fluoro-6-{6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-amine (0.1 mmol) was dissolved in DMF (0.2 ml) and to this was added the acid containing mixture. The solution was shaken for 5 minutes and left to stand at room temperature overnight. A further portion of HATU (0.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (0.2 mL) and added to further 2-methyl-1,3-thiazole-4-carboxylic acid (0.1 mmol), also in N,N-Dimethylformamide (DMF) (0.2 mL). DIPEA (0.3 mmol) was added and the mixture left to stand for 5 mins, then the resultant solution was added to the vessel containing the reaction mixture. Solutions were shaken for 5 minutes and then placed in the oven at 40° C. for 1 hour. DMF was removed by vacuum centrifugation (not to dryness) and the residue was dissolved in chloroform (0.3 ml). The solution was loaded onto aminopropyl SPE cartridge (500 mg) that had been preconditioned with MeOH followed by chloroform (2 ml each). The column was eluted with 10% MeOH in EtOAc (5 ml) and the fractions obtained were blown down under a stream of nitrogen. The residue was dissolved in DMSO (0.5 ml) and purified by Mass Directed AutoPrep on an Xbridge column using Acetonitrile/Water as eluent with an ammonium carbonate modifier. The solvent was evaporated in vacuo using the Genevac. The residue was dissolved in isopropanol (0.3 ml) and NaOH (2M, aqueous, 0.3 ml) was added. The solution was left for 32 hours at room temperature, then heated at 40° C. overnight. The reaction mixture was neutralised using 2 M, aqueous HCl and then blown down under a stream of nitrogen. The residue was dissolved in DMSO (0.5 ml) and purified by Mass Directed AutoPrep on an Xbridge column using Acetonitrile/Water with a formic acid modifier. The solvent was evaporated by vacuum centrifugation to give the title compound (4 mg).

1. waitthe mixture was left
2. additionto this was added the acid
3. additioncontaining mixture
4. waitleft
5. waitto stand at room temperature overnight
6. waitthe mixture left
7. waitto stand for 5 mins
8. additioncontaining the reaction mixture
9. stirringSolutions were shaken for 5 minutes
10. waitplaced in the oven at 40° C. for 1 hour
11. customDMF was removed by vacuum centrifugation (not to dryness) and the residue
12. dissolutionwas dissolved in chloroform (0.3 ml)
13. washThe column was eluted with 10% MeOH in EtOAc (5 ml)
14. customthe fractions obtained
15. custompurified by Mass Directed AutoPrep on an Xbridge column
16. customThe solvent was evaporated in vacuo
17. dissolutionThe residue was dissolved in isopropanol (0.3 ml)
18. additionNaOH (2M, aqueous, 0.3 ml) was added
19. waitThe solution was left for 32 hours at room temperature
20. dissolutionThe residue was dissolved in DMSO (0.5 ml)
21. custompurified by Mass Directed AutoPrep on an Xbridge column
22. customThe solvent was evaporated by vacuum centrifugation