Diisopropylethylamine → N-[6-(6-fluoro-1H-indol-4-yl)-1H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence