Dimethylformamide → 2,5-Dimethylbenzene-1,4-dicarboxamide

Participants

Reaction Steps

2,5-Dimethylterephthalic acid (200 mg, 1.03 mmol) was dissolved in DMF (5 mL) and HATU (392 mg, 1.03 mmol) was added and the mixture was stirred at ambient for 15 minutes. N,N-Diisopropylethylamine (0.7 mL, 3.99 mmol) was added and after 5 minutes 1-[6-(3-endo-amino-8-azabicyclo[3.2.1]oct-8-yl)pyridine-3-yl]ethanone (prepared in Example 19 Step 3) (250 mg, 1.02 mmol) was added and the mixture was stirred at 50° C. for 15 h. The mixture was cooled to ambient temperature and HATU (392 mg, 1.03 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.14 mmol) were added and the mixture was stirred at ambient for 15 minutes. Ammonia gas was bubbled into the solution and a thick precipitate formed. The mixture was stirred at 50° C. for 0.5 h and then was cooled to ambient temperature and was concentrated. The residue was treated with 1N aqueous hydrochloric acid (2 mL) and DMSO. Water was added and the precipitate was collected by filtration then further purified by reverse phase HPLC. The pure fractions were combined and concentrated to an aqueous residue. The aqueous residue was basified with sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic portion was dried over magnesium sulfate then filtered and was concentrated to afford N-[8-(5-acetylpyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-endo-yl]-2,5-dimethylbenzene-1,4-dicarboxamide (77 mg, 0.183 mmol, 18% yield). 1H NMR (400 MHz, d6-DMSO): δ 8.74 (d, 1H), 8.28 (d, 1H), 7.97 (dd, 1H), 7.71 (br s, 1H), 7.41 (br s, 1H), 7.24 (s, 1H), 7.12 (s, 1H), 6.79 (d, 1H), 4.62 (br s, 2H), 3.87 (br s, 1H), 2.45 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H), 2.27-2.18 (m, 2H), 2.15-1.94 (m, 4H), 1.89 (d, 2H); MS (EI) for C24H28N4O3: 421 (MH+).

Provenance & Evidence