反应详情

Under argon, 0.485 g (60% in mineral oil, 19.21 mmol) of sodium hydride was added to a solution of 5.0 g (19.21 mmol) of 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionic acid in 200 ml of absolute DMF. The mixture was stirred for 30 min at RT, 5.643 g (19.21 mmol) of 5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl methanesulfonate were then added and the mixture was stirred at RT for another 3 h. The reaction mixture was concentrated under reduced pressure, and the residue obtained was chromatographed on silica gel using CH2Cl2/MeOH/water/acetic acid 90:10:1:1. This gave two product-containing fractions which were purified by preparative HPLC. The fractions of value were combined and freeze-dried. The residue obtained was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated. The material obtained in this manner (3.7 g) was separated into its enantiomers by chiral HPLC (column Chiralpak AD-H/55, 250×4.6 mm, flow rate 1 ml/min, mobile phase heptane:isopropanol:methanol 3:1:1+0.1% TFA). 0.1 g (218 μmol) of the product obtained was dissolved in 5 ml of water/acetic acid (1:1) and freeze-dried (0.108 g, 95%).

1. stirringthe mixture was stirred at RT for another 3 h
2. concentrationThe reaction mixture was concentrated under reduced pressure
3. customthe residue obtained
4. customwas chromatographed on silica gel
5. customThis gave two product-containing fractions which
6. customwere purified by preparative HPLC
7. customfreeze-dried
8. customThe residue obtained
9. washwashed with saturated NaHCO3 solution
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated
13. customThe material obtained in this manner (3.7 g)
14. customwas separated into its enantiomers by chiral HPLC (column Chiralpak AD-H/55, 250×4.6 mm, flow rate 1 ml/min, mobile phase heptane:isopropanol:methanol 3:1:1+0.1% TFA)