反应详情

N-Fmoc-L-proline (0.249 g, 0.739 mmol) was added to a stirred mixture of 2,2,2-trichloroethyl 2-[2-(aminomethyl)-4-chlorophenyl]azetidine-1-carboxylate (0.275 g, 0.739 mmol), EDC (0.213 g, 1.11 mmol) and HOAT (50 mg, 0.37 mmol) in DMF (2 mL). After 16 h the reaction mixture was partitioned between ethyl acetate and dilute HCl solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to a foam. This material was dissolved in DMF (2 mL) and piperidine (0.5 mL) and stirred for 30 min. The solution was poured into water (50 mL) and the precipitated solids were removed by filtration, washing with water (5×10 mL, which was collected and set aside) and methanol. The methanol was evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with ethyl acetate followed by chloroform/methanol/ammonium hydroxide, 90:9:1) to give 2,2,2-trichloroethyl 2-{4-chloro-2-[(L-prolylamino)methyl]phenyl}azetidine-1-carboxylate (66 mg) as a gum. The milky aqueous washings were extracted into ethyl acetate (adding brine to dispel the emulsion) and the organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give more of the desired compound (0.206 g) as a gum: MS 468.5 (M+1) with an isotope distribution consistent with four chlorines.

1. customAfter 16 h the reaction mixture was partitioned between ethyl acetate and dilute HCl solution
2. washThe organic layer was washed with water and brine
3. dry with materialdried (Na2SO4)
4. customevaporated in vacuo to a foam
5. dissolutionThis material was dissolved in DMF (2 mL)
6. additionThe solution was poured into water (50 mL)
7. customthe precipitated solids were removed by filtration
8. washwashing with water (5×10 mL, which
9. customwas collected
10. customThe methanol was evaporated in vacuo
11. customthe residue was purified by flash column chromatography on silica (eluting with ethyl acetate followed by chloroform/methanol/ammonium hydroxide, 90:9:1)