反应详情

温度

95 °C

To a solution of (3,4-difluoro-phenyl)-[(4-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.200 g) from Example 3b) in dry 1-methyl-2-pyrrolidinone (2 ml) was added N,N-diisopropylethylamine (0.52 ml) followed by methanesulfonyl chloride (0.16 ml) in a single portion. After 3 hours the reaction was poured into ethyl acetate/water. The organic layer was separated and washed with aqueous KHSO4, aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated to a pale red oil which was dissolved in 1-methyl-2-pyrrolidinone (8 ml) and N,N-diisopropylethylamine (0.52 ml) and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (0.41 ml) were added, and the reaction heated at 95° C. overnight. After cooling to room temperature, the reaction was poured into ethyl acetate/water. The organic layer was separated and washed with aqueous KHSO4, aqueous K2CO3 and brine, dried (Na2SO4) and concentrated to a pale red oil. Purification by NPHPLC (eluting with 0-25% methanol in dichloromethane) gave a white solid which was dissolved in methanol (2 ml) and HCl (1 ml of a 4M solution in dioxane) added. After 2 hours, the solvent was removed and the residue recrystalised from isopropanol/acetonitrile to give the title compound as a white powder (0.071 g).

1. customThe organic layer was separated
2. washwashed with aqueous KHSO4, aqueous NaHCO3 and brine
3. dry with materialThe organic layer was dried (Na2SO4)
4. concentrationconcentrated to a pale red oil which
5. dissolutionwas dissolved in 1-methyl-2-pyrrolidinone (8 ml)
6. additionN,N-diisopropylethylamine (0.52 ml) and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (0.41 ml) were added
7. temperatureAfter cooling to room temperature
8. additionthe reaction was poured into ethyl acetate/water
9. customThe organic layer was separated
10. washwashed with aqueous KHSO4, aqueous K2CO3 and brine
11. dry with materialdried (Na2SO4)
12. concentrationconcentrated to a pale red oil
13. customPurification
14. washby NPHPLC (eluting with 0-25% methanol in dichloromethane)
15. customgave a white solid which
16. customthe solvent was removed
17. customthe residue recrystalised from isopropanol/acetonitrile