Sodium Hydroxide → [5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester

Temperature

0 °C

2,2,2-Trichloroethyl chloroformate (3.24 mL, 23.5 mmol) was added dropwise over 5 min to a solution of Intermediate 110a (4.11 g, 22.4 mmol) in NaOH (1M in water, 33.6 mL, 33.6 mmol) and EtOAc (35 mL) cooled at 0° C. under argon atmosphere. The reaction mixture was stirred at RT for 5 h. Additional 2,2,2-trichloroethyl chloroformate (462 μL) was added and stirring at RT was continued for 16 h. Additional NaOH (1M in water, 15 mL) and 2,2,2-trichloroethyl chloroformate (462 μL) were added and stirring at RT was continued for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was dissolved in cyclohexane (100 mL) and left to stand for 5 days. The resulting suspension was filtered and the solid collected by filtration washing with additional cyclohexane affording the title compound (3.64 g, 45%) as a white solid. The filtrate was concentrated in vacuo and the resultant residue was purified by FCC on silica, using a mixture of 50% EtOAc in cyclohexane, then partitioned between DCM and water. The organic layer was dried through a phase separator and concentrated in vacuo to afford additional title compound (1.43 g, 18%) as an orange gum. LCMS (Method 3): Rt 3.72 min, m/z 358 [MH+].

1. stirringstirring at RT
2. waitwas continued for 16 h
3. stirringstirring at RT
4. waitwas continued for 1 h
5. extractionThe aqueous layer was extracted with EtOAc (×3)
6. washthe combined organic layers were washed with brine
7. dry with materialdried (Na2SO4)
8. concentrationconcentrated in vacuo
9. dissolutionThe resultant residue was dissolved in cyclohexane (100 mL)
10. waitleft
11. waitto stand for 5 days
12. filtrationThe resulting suspension was filtered
13. filtrationthe solid collected by filtration
14. washwashing with additional cyclohexane affording the title compound (3.64 g, 45%) as a white solid
15. concentrationThe filtrate was concentrated in vacuo
16. customthe resultant residue was purified by FCC on silica
17. additiona mixture of 50% EtOAc in cyclohexane
18. custompartitioned between DCM and water
19. customThe organic layer was dried through a phase separator
20. concentrationconcentrated in vacuo

ORD record

ord-712b4b5256174342b9eb83f38f0b20bf

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09315503B2