反应详情

A solution of 1-(4-Chloro-butyl)-5-(2-methyl-pyridin-4-yl)-1H-pyrimidine-2,4-dione (Prep46, 74 mg, 0.25 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 57 mg, 0.25 mmol), and TEA (101 μl, 1 mmol) in absolute EtOH (3 mL) was refluxed for 48 hours. The reaction was then evaporated under vacuum and the residue was dissolved in 2N HClaq and washed with ethyl acetate. The aqueous phase was then basified with solid NaHCO3 and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated; the residue was dissolved in DCM and treated with PS-isocyanate (250 mg) resin under stirring for 2 h. After filtration and evaporation of the solvent the crude was purified by LC-MS preparative and then loaded on SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5 to give 30 mg of the title compound as free base (33%, yield). 5-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione was dissolved in dioxane and then treated with a solution of 4N HCl in dioxane (2 eq) to give the title compound as a pale yellow solid. (33 mg, 23.5%)

1. customThe reaction was then evaporated under vacuum
2. dissolutionthe residue was dissolved in 2N HClaq
3. washwashed with ethyl acetate
4. extractionextracted with ethyl acetate
5. dry with materialThe organic phase was dried (Na2SO4)
6. customevaporated
7. dissolutionthe residue was dissolved in DCM
8. additiontreated with PS-isocyanate (250 mg) resin
9. filtrationAfter filtration and evaporation of the solvent the crude
10. customwas purified by LC-MS preparative
11. washwashing with MeOH
12. washeluting with MeOH/NH3 95:5