Acetic Acid → HCID 11065277, compound

To a mixture of rel-(1R,2S)-2-(methoxycarbonyl)cyclobutanecarboxylic acid (1.3 g) and acetone (15 ml) were added triethylamine (1.7 ml) and ethyl chloroformate (1.1 ml) at −10° C., followed by stirring under ice-cooling for 2 hours. To a reaction mixture was added an aqueous solution (3.3 ml) of sodium azide (1.1 g) under ice-cooling, followed by stirring at room temperature for 4 hours. To the reaction mixture were added water and diethyl ether, and the aqueous layer was then extracted with diethyl ether. The organic layer was combined and washed with a 10% aqueous citric acid solution, a saturated sodium bicarbonate solution, water, and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added toluene (20 ml) and benzyl alcohol (2.5 ml), followed by stirring at 130° C. for 21 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→4:1). To the purified product thus obtained was added pyridine (15 ml), and further added anhydrous acetic acid (3.0 ml) under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to the residue, followed by stirring. To the reaction mixture were added ethyl acetate and water, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was combined and washed with a 10% aqueous citric acid solution, a saturated sodium bicarbonate solution, water, and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1→5:1→4:1) to obtain methyl rel-(1R,2S)-2-{[(benzyloxy)carbonyl]amino}cyclobutanecarboxylate (1.1 g).

1. temperaturecooling for 2 hours
2. temperaturecooling
3. stirringby stirring at room temperature for 4 hours
4. extractionthe aqueous layer was then extracted with diethyl ether
5. washwashed with a 10% aqueous citric acid solution
6. dry with materiala saturated sodium bicarbonate solution, water, and saturated brine in this order, dried over anhydrous magnesium sulfate
7. concentrationconcentrated under reduced pressure
8. additionTo the residue were added toluene (20 ml) and benzyl alcohol (2.5 ml)
9. stirringby stirring at 130° C. for 21 hours
10. concentrationThe reaction mixture was concentrated under reduced pressure
11. customthe residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→4:1)
12. customTo the purified product thus obtained
13. temperaturecooling
14. stirringby stirring at room temperature for 1 hour
15. concentrationThe reaction mixture was concentrated under reduced pressure
16. additiona saturated sodium bicarbonate solution was added to the residue
17. stirringby stirring
18. additionTo the reaction mixture were added ethyl acetate and water
19. customthe aqueous layer was separated
20. extractionextracted with ethyl acetate
21. washwashed with a 10% aqueous citric acid solution
22. dry with materiala saturated sodium bicarbonate solution, water, and saturated brine in this order, dried over anhydrous magnesium sulfate
23. concentrationconcentrated under reduced pressure
24. customThe residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1→5:1→4:1)

ORD record

ord-2a47d704725a49ea85b46288b2a386af

Source dataset

uspto-grants-2011_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08030489B2