反应详情

温度

-5 °C

To a solution of (4S,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 57, 778 mg, 3 mmol) and HOBt (551 mg, 3.60 mmol) in DMF (23 mL) was added NMM (0.33 mL, 3 mmol) and the mixture cooled to −5° C. EDCI (690 mg, 3.60 mmol) was added and the reaction stirred at −5° C. for 90 minutes. A solution of 3′,4′-diamino-2-fluorobiphenyl-4-carbonitrile (Preparation 79, 750 mg, 3.30 mmol) in DMF (7 mL) was added and the reaction was allowed to warm to room temperature for 3 days. The reaction was poured in EtOAc (120 mL), washed with 3% aqueous NaHCO3 solution (4×120 mL), brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:1. The residue was dissolved in AcOH (7 mL) and stirred at 40° C. for 18 hours. The reaction was concentrated in vacuo and treated with saturated aqueous NaHCO3 solution (15 mL), extracted into EtOAc (2×15 mL), the organic layers combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with acetone:heptanes 1:3. The residue was dissolved in 4M HCl in dioxane with 1 drop of water and stirred at room temperature for 2 hours. The reaction was eluted through an SCX column washing through with MeOH followed by 3N NH3 in MeOH and the filtrate concentrated in vacuo. The residue was treated with water (1 mL) and MeOH (0.5 mL) and freeze dried to afford the title compound (125 mg, 75%).

1. temperatureto warm to room temperature for 3 days
2. washwashed with 3% aqueous NaHCO3 solution (4×120 mL), brine (30 mL)
3. dry with materialdried over Na2SO4
4. concentrationconcentrated in vacuo
5. customThe residue was purified
6. washeluting with EtOAc:Heptane 1:1
7. dissolutionThe residue was dissolved in AcOH (7 mL)
8. stirringstirred at 40° C. for 18 hours
9. concentrationThe reaction was concentrated in vacuo
10. additiontreated with saturated aqueous NaHCO3 solution (15 mL)
11. extractionextracted into EtOAc (2×15 mL)
12. dry with materialdried over Na2SO4
13. concentrationconcentrated in vacuo
14. customThe residue was purified
15. washeluting with acetone:heptanes 1:3
16. dissolutionThe residue was dissolved in 4M HCl in dioxane with 1 drop of water
17. stirringstirred at room temperature for 2 hours
18. washThe reaction was eluted through an SCX column
19. washwashing through with MeOH
20. concentrationthe filtrate concentrated in vacuo
21. additionThe residue was treated with water (1 mL) and MeOH (0.5 mL)
22. customfreeze dried