4-Methylmorpholine → HCID 9925762, compound

Under a nitrogen atmosphere, tert-butyl cyanoacetate (0.57 ml) was added dropwise to a mixture of tetrahydrofuran (5 ml) and sodium hydride (160 mg, 60% oily) with stirring under ice-cooling. The resulting mixture was stirred for 10 minutes under ice-cooling, then stirred at room temperature for 20 minutes, and again stirred at 0° C. Separately, isobutyl chloroformate (0.26 ml) was added dropwise to a tetrahydrofuran solution (20 ml) of (R)-2-(2-fluoro-biphenyl-4-yl)-propionic acid (449 mg, 93% e.e.) and N-methylmorpholine (0.22 ml) at -15° C. with stirring. After 5 minutes, this solution was added dropwise to the previous mixture. After 20 minutes, this was poured into a saturated aqueous sodium bicarbonate solution and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. To the viscous residue thus obtained were added hydroxylamine hydrochloride (278 mg) and ethanol (10 ml), and the resulting mixture was stirred for 4 hours with heating under reflux. After cooling to room temperature, ethanol was removed by distillation, and a saturated aqueous sodium bicarbonate solution was added to the residue and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/2), to obtain the desired compound (226 mg, 93% e.e.).

1. temperaturecooling
2. stirringThe resulting mixture was stirred for 10 minutes under ice-
3. temperaturecooling
4. stirringstirred at room temperature for 20 minutes
5. stirringagain stirred at 0° C
6. stirringwith stirring
7. additionthis solution was added dropwise to the previous mixture
8. waitAfter 20 minutes
9. extractionthe resulting mixture was subjected to extraction with ethyl acetate
10. dry with materialThe organic layer was dried over sodium sulfate
11. concentrationconcentrated under reduced pressure
12. customTo the viscous residue thus obtained
13. stirringthe resulting mixture was stirred for 4 hours
14. temperaturewith heating
15. temperatureunder reflux
16. customethanol was removed by distillation
17. additiona saturated aqueous sodium bicarbonate solution was added to the residue
18. extractionthe resulting mixture was subjected to extraction with ethyl acetate
19. dry with materialThe organic layer was dried over sodium sulfate
20. concentrationconcentrated under reduced pressure
21. customThe residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/2)

ORD record

ord-1036c1c2c39c401d80da623499e68dcd

Source dataset

uspto-grants-2000_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06100260