反应详情

TSTU (106 mg, 0.33 mmol) was added in one portion to a stirred solution of 8-[(2R)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (144 mg, 0.30 mmol, >98% enantiomeric purity, made from the second eluting ester enantiomer from chiral separation of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate—see below) and DIPEA (0.057 mL, 0.33 mmol) at room temperature and the resulting mixture was stirred for 1.5 h. Morpholine (0.052 mL, 0.60 mmol) was then added to the reaction mixture and stirring was continued over the week-end. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one (69 mg, 44%) as a pale yellow solid.

1. washsecond eluting ester enantiomer
2. customfrom chiral separation of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate—
3. customat room temperature
4. stirringstirring
5. customThe reaction mixture was purified by preparative HPLC
6. customThe fractions were evaporated to dryness
7. dissolutionthe residue was dissolved in DCM
8. dry with materialdried over MgSO4
9. concentrationconcentrated
10. customThe remaining solid was triturated with diethyl ether
11. filtrationfiltered
12. washwashed with diethyl ether
13. customdried under vacuum at 50° C.