Lithium Hydroxide → N-(Methylsulfonyl)-4-({4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}methyl)benzamide diethylamine salt

Temperature

60 °C

To a solution of methyl 4-(bromomethyl)benzoate (114 mg, 0.5 mmol) in anhydrous N,N-dimethylformamide (1.05 mL) in an ArQule™ vial was added potassium carbonate (138 mg, 1.0 mmol) followed by a solution of 4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol (Preparation 6, 121 mg, 0.5 mmol) in N,N-dimethylformamide (1.5 mL). The reaction vessel was sealed and heated to 60° C. with stirring for 16 hours and then cooled to room temperature. The reaction mixture was partitioned between diethyl ether (5 mL) and water (5 mL) and the organic extracts were concentrated in vacuo. The crude residue was dissolved in tetrahydrofuran (2 mL), lithium hydroxide (60 mg, 2.5 mmole) added and water (1 mL). The ArQule™ vial was sealed and the reaction mixture heated to 55° C. with stirring for 6 hours. The resulting solution was diluted with water (5 mL) and washed with diethyl ether (3 mL). The aqueous extract was then acidified with aqueous 2 M hydrogen chloride solution and extracted with ethyl acetate (5 mL). The organic extracts were separated and evaporated in vacuo. The crude residue was dissolved in dichloromethane (2.5 mL) to which 4-dimethylaminopyridine (122 mg, 1.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol) were added. The reaction mixture was stirred in a sealed vessel until solubilised, then methanesulphonamide (95 mg, 1.0 mmole) was added. The reaction vessel was sealed and heated to 40° C. with stirring overnight. The reaction mixture was diluted with further dichloromethane (5 mL), and partitioned with 2 M aqueous hydrogen chloride solution (5 mL). The organic extract was passed through a phase separation cartridge, and evaporated in vacuo. The crude residue was dissolved in dimethylsulphoxide (50 mg/mL) and purified by B-HPLC to afford the title compound (50.6 mg, 22%) as the diethylamine salt.

1. customThe reaction vessel was sealed
2. temperaturecooled to room temperature
3. customThe reaction mixture was partitioned between diethyl ether (5 mL) and water (5 mL)
4. concentrationthe organic extracts were concentrated in vacuo
5. dissolutionThe crude residue was dissolved in tetrahydrofuran (2 mL)
6. customThe ArQule™ vial was sealed
7. temperaturethe reaction mixture heated to 55° C.
8. stirringwith stirring for 6 hours
9. washwashed with diethyl ether (3 mL)
10. extractionThe aqueous extract
11. extractionextracted with ethyl acetate (5 mL)
12. customThe organic extracts were separated
13. customevaporated in vacuo
14. additionwere added
15. additionwas added
16. customThe reaction vessel was sealed
17. temperatureheated to 40° C.
18. stirringwith stirring overnight
19. custompartitioned with 2 M aqueous hydrogen chloride solution (5 mL)
20. extractionThe organic extract
21. customwas passed through a phase separation cartridge
22. customevaporated in vacuo
23. dissolutionThe crude residue was dissolved in dimethylsulphoxide (50 mg/mL)
24. custompurified by B-HPLC

ORD record

ord-da64c33fe3a047e4972e49b66aa5f38f

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09096500B2