Water → 4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenol

Temperature

80 °C

(5-chloro-2-hydroxyphenyl)boronic acid (16.10 g, 93.38 mmol) and 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole or 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 869, 22.95 g, 83.12 mmol) in 1,2-dimethoxyethane (300 mL, 3000 mmol) and 2 M of potassium carbonate in water (116 mL, 2.10E2 mmol) was added tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol). The solution was sparged 3 times with Ar and heated at 80° C. for 4 hours. Additional (5-chloro-2-hydroxyphenyl)boronic acid (2.866 g, 16.62 mmol) was added to the reaction. The reaction was heated at 80° C. for another 18 hours. The cooled reaction was poured into a separatory funnel and the phases separated. The aqueous phase was washed two times with dichloromethane (250 mL). The combined organic phase was washed with brine then dried over anhydrous magnesium sulfate and treated with activated carbon. The mixture was filtered through diatomacious earth and the filtrate evaporated to a residue. The crude product was separated into two portions and each purified by column chromatography (80 g silica gel column, hexanes to 20% ethyl acetate gradient elution). Product fractions were combined and evaporated to give a thick oil which formed a waxy solid upon standing. The solid was triturated with hexanes and filtered to give 17.71 g of tan powder after vacuum drying.

1. customThe solution was sparged 3 times with Ar
2. temperatureThe reaction was heated at 80° C. for another 18 hours
3. customThe cooled reaction
4. additionwas poured into a separatory funnel
5. customthe phases separated
6. washThe aqueous phase was washed two times with dichloromethane (250 mL)
7. washThe combined organic phase was washed with brine
8. dry with materialthen dried over anhydrous magnesium sulfate
9. additiontreated with activated carbon
10. filtrationThe mixture was filtered through diatomacious earth
11. customthe filtrate evaporated to a residue
12. customThe crude product was separated into two portions
13. customeach purified by column chromatography (80 g silica gel column, hexanes to 20% ethyl acetate gradient elution)
14. customevaporated
15. customto give a thick oil which
16. customformed a waxy solid
17. customThe solid was triturated with hexanes
18. filtrationfiltered

ORD record

ord-e838303e723c45d7a361b381b5fe9e3a

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541588B2