反应详情

Heat a mixture of 2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazole dihydroiodide (0.83 g, 1.53 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.713 g, 1.51 mmol, example 47.2), diisopropylethylamine (1 mL, 5.74 mmol) and acetonitrile (15 mL) at 90° C. for 72 hours. Concentrate to dryness and dissolve the residue in dichloromethane. Wash the dichloromethane phase with NaHCO3 (10%, 10 mL) and brine (four 10 mL portions), dry (Na2SO4) the organic phase, filter and evaporate. Purify the residue by silica gel chromatography (3.5×35 cm) eluting with 95:5:0.05 dichloromethane:methanol:30% ammonium hydroxide solution. Concentrate the desired fractions to afford 0.19 g of the title compound, Rf=0.80 (silica gel, 90:10:0.1 dichloromethane:methanol:30% ammonium hydroxide solution). The product may be converted to the dihydrochloride by methods as are well known in the art.

1. temperatureHeat
2. concentrationConcentrate to dryness
3. dissolutiondissolve the residue in dichloromethane
4. washWash the dichloromethane phase with NaHCO3 (10%, 10 mL) and brine (four 10 mL portions)
5. dry with materialdry (Na2SO4) the organic phase
6. filtrationfilter
7. customevaporate
8. customPurify the residue by silica gel chromatography (3.5×35 cm)
9. washeluting with 95:5:0.05 dichloromethane
10. concentrationConcentrate the desired fractions