反应详情

温度

40 °C

Isobutylchloroformate (0.17 g, 0.125 mmol) was added to a cooled mixture of N-(tert-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51, 0.28 g, 0.12 mmol) and NMM (0.137 g, 0.135 mmol) in THF (10 mL) at −78° C. The reaction was stirred at this temperature for 1 hour and then added dropwise to a cooled solution of 4′,5′-diamino-2′-fluorobiphenyl-4-carbonitrile (Preparation 76, 0.28 g, 0.12 mmol) at −78° C. and stirred at this temperature for 3 hours. The reaction was partitioned between EtOAc (70 mL) and saturated aqueous NaHCO3 solution (30 mL), the organic layer was collected and concentrated in vacuo to afford a brown residue that was dissolved in AcOH (5 mL) and heated to 40° C. for 2 days followed by 50° C. for 1 day. The reaction was concentrated in vacuo and purified using silica gel column chromatography to afford a beige solid that was dissolved in TFA/DCM (0.2 mL/3 mL) and stirred at room temperature for 5 hours. The reaction was partitioned between saturated aqueous Na2CO3 solution (10 mL) and EtOAc (30 mL). The organic layer was collected and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with a gradient of acetonitrile in 0.5% formic acid in water followed by elution through an SCX cartridge to afford the title compound that contains some of the other diastereomer.

1. stirringstirred at this temperature for 3 hours
2. customThe reaction was partitioned between EtOAc (70 mL) and saturated aqueous NaHCO3 solution (30 mL)
3. customthe organic layer was collected
4. concentrationconcentrated in vacuo
5. customto afford a brown residue that
6. waitfollowed by 50° C. for 1 day
7. concentrationThe reaction was concentrated in vacuo
8. custompurified
9. customto afford a beige solid
10. stirringstirred at room temperature for 5 hours
11. customThe reaction was partitioned between saturated aqueous Na2CO3 solution (10 mL) and EtOAc (30 mL)
12. customThe organic layer was collected
13. concentrationconcentrated in vacuo
14. customThe residue was purified
15. washeluting with a gradient of acetonitrile in 0.5% formic acid in water
16. washfollowed by elution through an SCX cartridge