Potassium Phosphate, Tribasic → HCID 58498059, compound

Temperature

85 °C

[2-(4-Chloro-phenyl)-2-hydroxy-2-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (5 g, 10.6 mmol) was combined with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (4.1 g, 21.11 mmol) and potassium phosphate (tribasic, 7.88 g, 37.10 mmol) in a round-bottomed flask. The solids were then dissolved in a solvent mixture of 1:1:1:1 ethanol, methanol, toluene and water (33 mL of each solvent). The solution was degassed with nitrogen and tetrakistriphenylphosphine palladium (0) (0.612 g, 0.53 mmol) was added. The mixture was degassed with nitrogen and then heated at 85° C. under nitrogen for 2 hours. The reaction mixture was then allowed to cool to room temperature. Additional batches of reagents were then added: potassium phosphate (7.88 g, 37.10 mmol) and pyrazole boronate (4.1 g, 21.11 mmol). The reaction mixture was degassed with nitrogen and a further batch of tetrakistriphenylphosphine palladium (0) (0.101 g, 0.087 mmol) was added. The reaction mixture was degassed and then heated at 85° C. under nitrogen for 17 hours. Additional batches of reagents were added again (refer to quantities above) and heating was continued at 85° C. under nitrogen for a further 6.5 hours. The reaction mixture was then allowed to cool to room temperature and was evaporated in vacuo to remove the organic solvent. The residual aqueous layer was diluted with aqueous 2N NaOH solution (150 mL) then extracted with ethyl acetate (150 mL). The organic layer was separated off and washed with aqueous 2N NaOH solution (150 mL) followed by brine (150 mL). The organic layer was separated off, dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether. The solid was filtered in vacuo then dried to afford the title compound as a white solid (2.55 g, 58%). LC/MS: (PS-B5) Rt 3.05 [M+H]+ 414.18. 1H NMR (Me-d3-OD) 7.95 (2H, br s), 7.55 (2H, d), 7.48-7.41 (4H, m), 7.31 (2H, d), 3.87 (2H, q), 1.35 (9H, s).

1. additionwas added
2. customThe mixture was degassed with nitrogen
3. temperatureto cool to room temperature
4. additionAdditional batches of reagents were then added
5. customThe reaction mixture was degassed with nitrogen
6. customThe reaction mixture was degassed
7. temperatureheated at 85° C. under nitrogen for 17 hours
8. additionAdditional batches of reagents were added again (refer to quantities above)
9. temperatureheating
10. temperatureto cool to room temperature
11. customwas evaporated in vacuo
12. customto remove the organic solvent
13. additionThe residual aqueous layer was diluted with aqueous 2N NaOH solution (150 mL)
14. extractionthen extracted with ethyl acetate (150 mL)
15. customThe organic layer was separated off
16. washwashed with aqueous 2N NaOH solution (150 mL)
17. customThe organic layer was separated off
18. dry with materialdried (MgSO4)
19. concentrationconcentrated in vacuo
20. customThe residue was triturated with diethyl ether
21. filtrationThe solid was filtered in vacuo
22. customthen dried

ORD record

ord-23a34ec934734af0876e341855d9b255

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08497294B2