Benzyl Alcohol → (3R,5S)-5-(benzyloxycarbonylamino)-1-tert-butoxycarbonyl-piperidine-3-carboxylic acid

Temperature

30 °C

Under a nitrogen stream, (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (30.0 g, 104 mmol), triethylamine (31.7 g, 313 mmol) and toluene (180 mL) were charged. A solution of diphenylphosphoryl azide (28.7 g, 313 mmol) in toluene (30.0 mL) was added dropwise at 15-35° C. After stirring at 30±5° C. for 30 min, the mixture was heated to 65-75° C. and stirred for 30 min. Benzylalcohol (12.4 g, 115 mmol) was added dropwise at 60-70° C. The mixture was heated to 80-90° C. and stirred for 3 hr. The reaction mixture was allowed to cool to 20-30° C., a solution of sodium nitrite (7.20 g, 104 mmol) in water (150 mL) was added, the mixture was stirred for 1 hr, and the aqueous layer was partitioned. The organic layer was washed successively with 5 w/v % sodium bicarbonate water (150 mL), 20 w/v % aqueous citric acid solution (150 mL) and 5 w/v % brine (150 mL), and the organic layer was concentrated under reduced pressure. To the residue was added methanol (60.0 mL), and the mixture was concentrated under reduced pressure. A similar operation was performed once more. To the residue was added methanol to give the content (90.0 g). 2N Aqueous sodium hydroxide solution (62.6 mL, 125 mmol) was added at 15-35° C., and the mixture was stirred at 30±5° C. for 1 hr. Methanol (120 mL) and 20 w/v % aqueous citric acid solution (300 mL) were added at 20-30° C. to adjust the mixture to pH 3.0-3.5. After stirring at 50-60° C. for 30 min, the mixture was allowed to cool to 20-30° C. and stirred for 1 hr. Furthermore, the mixture was stirred at 0-10° C. for 1 hr. The precipitated crystals were collected by filtration, washed with water (90.0 mL), and dried under reduced pressure at 50° C. to give (3R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid as a white crystalline powder (35.0 g, yield 88.6%).

1. temperaturethe mixture was heated to 65-75° C.
2. stirringstirred for 30 min
3. temperatureThe mixture was heated to 80-90° C.
4. stirringstirred for 3 hr
5. temperatureto cool to 20-30° C.
6. stirringthe mixture was stirred for 1 hr
7. customthe aqueous layer was partitioned
8. washThe organic layer was washed successively with 5 w/v % sodium bicarbonate water (150 mL), 20 w/v % aqueous citric acid solution (150 mL) and 5 w/v % brine (150 mL)
9. concentrationthe organic layer was concentrated under reduced pressure
10. additionTo the residue was added methanol (60.0 mL)
11. concentrationthe mixture was concentrated under reduced pressure
12. additionTo the residue was added methanol
13. customto give the content (90.0 g)
14. stirringthe mixture was stirred at 30±5° C. for 1 hr
15. stirringAfter stirring at 50-60° C. for 30 min
16. temperatureto cool to 20-30° C.
17. stirringstirred for 1 hr
18. stirringFurthermore, the mixture was stirred at 0-10° C. for 1 hr
19. filtrationThe precipitated crystals were collected by filtration
20. washwashed with water (90.0 mL)
21. customdried under reduced pressure at 50° C.

ORD record

ord-a098f58dd5084c3a81504af6cec0afa0

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09018374B2