反应详情

To a cold (0-4° C.) stirred solution of 4-iodobenzene-1,2-diamine (1.3 g, 5.3 mmol) and (2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidine-2-carboxylic acid (1.52 g, 4.99 mmol) in DMF (23.8 ml) is sequentially added HATU (2.321 g, 6.103 mmol) and 2,4,6-collidine (1.052 ml, 7.964 mmol). The reaction mixture is stirred at rt overnight, diluted with water, extracted with ethyl acetate. Combined extracts are washed with water, saturated bicarbonate solution, brine, dried (Na2SO4), concentrated and dried under high vacuum to afford crude amide. The resulting residue dissolved in acetic acid (28 ml) is heated at 60° C. for 8 hours. Acetic acid is removed, the residue neutralized with sat. NaHCO3 solution, and diluted with ethyl acetate (20 ml). The aqueous solution is extracted with ethyl acetate, combined organic extracts are washed with aq. NaHCO3 solution, brine, dried (Na2SO4), and concentrated. The concentrate is purified by flash column chromatography on silica gel using ethyl acetate-hexanes (1:1 to 7:3) as eluent afforded methyl N-[(1S)-1-[(2S,5S)-2-(5-iodo-1H-benzimidazol-2-yl)-5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (2.3 g, 2.28 mmol, 92%).

1. extractionextracted with ethyl acetate
2. washCombined extracts are washed with water, saturated bicarbonate solution, brine
3. dry with materialdried (Na2SO4)
4. concentrationconcentrated
5. customdried under high vacuum
6. customto afford crude amide
7. temperatureis heated at 60° C. for 8 hours
8. customAcetic acid is removed
9. additiondiluted with ethyl acetate (20 ml)
10. extractionThe aqueous solution is extracted with ethyl acetate
11. washare washed with aq. NaHCO3 solution, brine
12. dry with materialdried (Na2SO4)
13. concentrationconcentrated
14. customThe concentrate is purified by flash column chromatography on silica gel