4-Methylmorpholine → HCID 178461819, compound

Temperature

-78 °C

To a cooled solution (−78° C.) of (2S,3R)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-methyl-4-oxobutanoic acid (Preparation 66, 4.10 g, 12.2 mmol) in tetrahydrofuran (50 mL) was added N-methylmorpholine (2.0 mL, 18.23 mmol) followed by isobutyl chloroformate (1.67 mL, 12.8 mmol) and the resulting white suspension stirred at −78° C. for 30 minutes. A solution of 4-(tert-butyl)benzene-1,2-diamine (2.40 g, 14.6 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (200 mL) and washed with aqueous saturated sodium bicarbonate (3×50 mL), water (2×50 mL). The organic layer was concentrated in vacuo and purified by silica gel column chromatography eluting with a gradient of dichloromethane: EtOAc. The residue was dissolved in methanol (50 mL) and palladium hydroxide was added (20% wt % on carbon, 0.43 g). The reaction mixture was stirred under a hydrogen atmosphere (2 atm) at room temperature for 1 hour. The reaction mixture was filtered through a small pad of Arbocel and concentrated in vacuo. The residue was dissolved in acetic acid (100 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase column chromatography eluting with a gradient of water/MeCN to afford the title compound as off-white solid (3.54 g, 78%).

1. temperatureto warm up to room temperature
2. stirringstirred at room temperature for 1 hour
3. concentrationThe reaction mixture was concentrated in vacuo
4. dissolutionThe crude product was dissolved in ethyl acetate (200 mL)
5. washwashed with aqueous saturated sodium bicarbonate (3×50 mL), water (2×50 mL)
6. concentrationThe organic layer was concentrated in vacuo
7. custompurified by silica gel column chromatography
8. washeluting with a gradient of dichloromethane
9. dissolutionThe residue was dissolved in methanol (50 mL)
10. additionpalladium hydroxide was added (20% wt % on carbon, 0.43 g)
11. stirringThe reaction mixture was stirred under a hydrogen atmosphere (2 atm) at room temperature for 1 hour
12. filtrationThe reaction mixture was filtered through a small pad of Arbocel
13. concentrationconcentrated in vacuo
14. dissolutionThe residue was dissolved in acetic acid (100 mL)
15. stirringstirred at room temperature for 72 hours
16. concentrationThe reaction mixture was concentrated in vacuo
17. customThe crude product was purified by reverse phase column chromatography
18. washeluting with a gradient of water/MeCN

ORD record

ord-a3249bd7e8484a69ba2602435b9deb86

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08927587B2