3-Hydroxy-2,2-dimethylpropionic acid → 2,2-dimethyl-3-(2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol

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Reaction Steps

To a stirred solution of 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihyrdochloride (59.3 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), and diisopropylethylamine (70 μL, 0.40 mmol) in 1 mL DMF was added HATU (57 mg, 0.15 mmol). The resulting mixture was stirred at ambient temperature for 24 h and then diluted with methylene chloride and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), concentrated by evaporation, and purified by chromatography (5% (2M NH3/MeOH) in CHCl3) to afford 2,2-dimethyl-3-(2-{2-[(1R,5S)-3(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol (29.3 mg. 55%) as amorphous solid. 1H NMR (400 MHz, CDCl3), δ 7.65 (m, 1H), 7.44-7.26 (m, 6H), 7.19-7.10 (m, 2H), 4.80 (br., 1H), 4.69 (m, 1H), 3.75-3.37 (m, 8H), 3.35-3.16 (m, 3H), 2.58 (s, 3H), 2.46-2.34 (m, 2H), 2.13-1.84 (m, 8H), 1.68-1.59 (m, 2H), 1.23 (s, 3H), 1.02 (s, 3H); ESI-MS 531 (M+H), 553 (M+Na).

Provenance & Evidence