Triphenylphosphine → tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

Diisopropyl azodicarboxylate (3.60 mL, 18.3 mmol) was added dropwise to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (A110) (2.45 g, 12.2 mmol), 4-nitro-1H-pyrazole (1.38 g, 12.2 mmol) and PPh3 (4.79 g, 18.3 mmol) in THF (25 mL) at 0° C. The resulting mixture was maintained at this temperature for 10 minutes and then warmed to room temperature at which it was stirred for 6 days. The mixture was diluted with hexanes (80 mL) and EtOAc (20 mL) and stirred for 5 hours at room temperature before filtering, washing the filter cake with hexanes (50 mL) and concentrating the filtrate in vacuo. The resulting oil was purified by silica gel column chromatography (Biotage Isolera, 2×40 g SiO2 cartridges, 0-50% EtOAc in cyclohexane) to give a residue that was dissolved in EtOH (200 mL). 10% Pd/C (53% water; 0.500 g) was added and the resulting suspension stirred under an atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered through Celite, washing with EtOAc (ca. 100 mL) and then the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in EtOAc (200 mL) and washed with water (2×100 mL) and then aqueous 2 M HCl (100 mL). The acidic layer was basified with aqueous 2 M NaOH to pH 13 and extracted with EtOAc (2×100 mL). The combined organic layers from the basified extraction were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound A124 as a purple oil (1.39 g, 34%); 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=0.9 Hz, 1H), 7.02 (d, J=0.9 Hz, 1H), 4.20 (s, 2H), 4.11 (m, 1H), 2.95-2.76 (m, 4H), 2.11-2.02 (m, 2H), 1.83 (qd, J=12.3, 4.5 Hz, 2H), 1.46 (s, 9H).

1. temperatureThe resulting mixture was maintained at this temperature for 10 minutes
2. stirringstirred for 5 hours at room temperature
3. filtrationbefore filtering
4. washwashing the filter cake with hexanes (50 mL)
5. concentrationconcentrating the filtrate in vacuo
6. customThe resulting oil was purified by silica gel column chromatography (Biotage Isolera, 2×40 g SiO2 cartridges, 0-50% EtOAc in cyclohexane)
7. customto give a residue that
8. stirringthe resulting suspension stirred under an atmosphere of hydrogen at room temperature for 18 hours
9. filtrationThe mixture was filtered through Celite
10. washwashing with EtOAc (ca. 100 mL)
11. concentrationthe filtrate was concentrated under reduced pressure
12. dissolutionThe resulting oil was dissolved in EtOAc (200 mL)
13. washwashed with water (2×100 mL)
14. extractionextracted with EtOAc (2×100 mL)
15. extractionThe combined organic layers from the basified extraction
16. washwere washed with brine (50 mL)
17. dry with materialdried (Na2SO4)
18. filtrationfiltered
19. concentrationconcentrated under reduced pressure

ORD record

ord-914677be7b454a1f895f1d1fce339dc9

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09266864B2