4-Methylmorpholine → 7-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-6-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide

Participants

Reaction Conditions

Reaction Steps

Compound 8e (76 mg, 0.23 mmol) was added to a suspension of O-(2-tert-butoxy-ethyl)-hydroxylamine (see, WO05/110410, 47 mg, 0.36 mmol), HATU (103 mg, 0.27 mmol), and N-methylmorpholine (0.10 mL, 0.90 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 16 h and concentrated in vacuo. The resulting oil was dissolved in 3 mL of TFA and allowed to stir at RT for 2 h. Then MeOH (3 mL) was added and made basic with potassium carbonate. It was allowed to stir for 30 minutes, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile) to give 4 mg (5%) of Example 8 as a white solid. 1H NMR (400 MHz, MeOD): δ 7.43 (d, 1H, J=8.9 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.43 (t, 1H, J=8.6 Hz), 4.14 (t, 2H, J=7.3 Hz), 3.85 (m, 2H), 3.67 (m, 2H), 3.29 (t. 2H, J=7.6 Hz), 2.09-2.27 (m, 2H), 1.83 (s, 3H). MS (ES) [m+H] calc'd for C18H19FIN3O4, 488. found 488.

Provenance & Evidence