1,1'-Carbonyldiimidazole → N-methyl-1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxamide

Temperature

60 °C

1-{4-[2-(Pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid (100 mg, 0.266 mmol) and 1,1′-carbonyldiimidazole (86 mg, 0.53 mmol) were dissolved in dry THF (2 mL) under a N2 atmosphere. The reaction mixture was heated at 60° C. for 1 h and then cooled to rt. Methylamine hydrochloride (27 mg, 0.40 mmol) and N,N′-diisopropylethylamine (52 mg, 0.40 mmol, 70 μL) were added and the reaction was allowed to stir at rt. After 18 h, the reaction mixture was concentrated in vacuo, diluted with CH2Cl2 (2 mL), and washed with distilled water (1 mL). The aqueous phase was back extracted with CH2Cl2 (2 mL×5) and the combined organic extracts were concentrated in vacuo. The resulting yellow solid was purified using the Waters mass-directed HPLC purification system to give N-methyl-1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxamide as a white powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.57 (s, 1H), 8.49 (brq, J=4.4 Hz, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.19 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.85 (dd, J=8.6, 1.4 Hz, 1H), 7.74 (ddd, J=8.8, 6.8, 2.0 Hz, 1H), 7.61 (ddd, J=5.2, 3.2, 3.2 Hz, 2H), 7.55 (d, J=9.2 Hz, 1H), 7.23 (ddd, J=5.8, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J=7.2, 5.2, 1.2 Hz, 1H), 6.88 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.63 (m, 2H), 4.43 (m, 2H), 2.82 (d, J=4.8 Hz, 3H). MS(ES+): m/z 389 [MH+].

1. temperaturecooled to rt
2. concentrationthe reaction mixture was concentrated in vacuo
3. additiondiluted with CH2Cl2 (2 mL)
4. washwashed with distilled water (1 mL)
5. extractionThe aqueous phase was back extracted with CH2Cl2 (2 mL×5)
6. concentrationthe combined organic extracts were concentrated in vacuo
7. customThe resulting yellow solid was purified
8. customthe Waters mass-directed HPLC purification system

ORD record

ord-5db542b4a1fc41bfbeaa46f55044a2af

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07521448B2