反应详情

N-t-butoxycarbonyl(3,5-difluorophenyl)alanal (EXAMPLE 2, 265 mg, 0.91 mmol) and L-alanyl-L-valinamide (180 mg, 0.96 mmol) are combined in 10 mL of dry THF under nitrogen. Sodium triacetoxycyanoborohydride (300 mg, 1.4 mmol) is added, followed by 3 mL of methanol. The mixture is stirred 3 days, concentrated, and dissolved in ethyl acetate and 5 mL of methanol. The organic phase is washed with 1 N NaHCO3, water, and brine, dried over Na2SO4, and concentrated. The residue, 275 mg, is dissolved in ethyl ether and ethereal HCl is added. The mother liquor is removed, and the residue is washed with ether to afford 70 mg of a waxy solid. This solid is stirred with 1 mL of TFA and 2 mL of dichloromethane for 1 h. It is concentrated, neutralized with several mL of 1 N NaHCO3, and extracted into ethyl acetate containing several mL of methanol. The organic phase is washed with brine and dried over Na2SO4, and concentrated to 100 mg of a film, which includes TFA. This is dissolved in 1 mL of dry DMF and combined with a solution of 3-[(dipropylamino)carbonyl]benzoic acid, (38 mg, 0.15 mmol), EDC (29 mg, 0.15 mmol) and HOBT (20 mg, 0.15 mmol) in 2 mL of DMF which had been previously stirred together for 2 h. The resulting mixture is stirred under nitrogen for 6 days. It is quenched with water and 1 N KH2PO4 and extracted into a large volume of ethyl acetate containing 7% methanol. The organic phase is washed with 1 N NaHCO3 and brine, dried over Na2SO4, and concentrated chromatography on silica gel, eluting with 5% to 7% methanol in dichloromethane affords, after addition of ethereal HCl to the product-containing fractions and concentration, the title compound as a tan, friable glass (15 mg, 0.025 mmol, 18%). HRMS (ESI) calcd for C31H43F2N5O4+H1 588.3361, found 588.3364

1. concentrationconcentrated
2. dissolutiondissolved in ethyl acetate
3. washThe organic phase is washed with 1 N NaHCO3, water, and brine
4. dry with materialdried over Na2SO4
5. concentrationconcentrated
6. dissolutionThe residue, 275 mg, is dissolved in ethyl ether
7. additionethereal HCl is added
8. customThe mother liquor is removed
9. washthe residue is washed with ether
10. customto afford 70 mg of a waxy solid
11. concentrationIt is concentrated
12. extractionextracted into ethyl acetate containing several mL of methanol
13. washThe organic phase is washed with brine
14. dry with materialdried over Na2SO4
15. concentrationconcentrated to 100 mg of a film, which
16. dissolutionThis is dissolved in 1 mL of dry DMF
17. stirringhad been previously stirred together for 2 h
18. stirringThe resulting mixture is stirred under nitrogen for 6 days
19. customIt is quenched with water and 1 N KH2PO4
20. extractionextracted into a large volume of ethyl acetate containing 7% methanol
21. washThe organic phase is washed with 1 N NaHCO3 and brine
22. dry with materialdried over Na2SO4
23. concentrationconcentrated chromatography on silica gel
24. washeluting with 5% to 7% methanol in dichloromethane
25. customaffords
26. concentrationto the product-containing fractions and concentration