Hydrochloric Acid → HCID 24769019, compound

Temperature

-10 °C

To a solution of 4-bromobenzaldehyde (3.06 g, 16.5 mmol) in toluene (60 ml) was added 5-fluoro-2-methoxyphenyl boronic acid (3.10 g, 18.2 mmol), 2M sodium carbonate solution (16.5 ml) and tetrakis(triphenylphosphine)palladium (0) (1 g, 0.86 mmol). The solution was refluxed for 48 h then cooled to ambient temperature, washed with water, brine and dried over anhydrous sodium sulfate. Evaporation of solvent gave a residue that was flash chromatographed over silica gel eluting with 1:1 ethyl acetate/heptane. Evaporation of solvent gave 5′-fluoro-2′-methoxy-biphenyl-4-carbaldehyde (2.63 g) as a crystalline solid. To a solution of 5′-fluoro-2′-methoxy-biphenyl-4-carbaldehyde (1.5 g, 6.9 mmol) in tetrahydrofuran (20 ml) was added titanium tetraisopropoxide (10 ml) and (±)-tert-butyl sulfinamine. The solution was stirred for 48 h then poured into brine and dichloromethane added with stirring. The organic layer was separated, dried over anhydrous magnesium sulfate and the solvent evaporated. Heptane was added to the oil which induced crystallisation and gave 2-methyl-propane sulfinic acid 5′-fluoro-2′-methoxy-biphenyl-4-ylmethylene amide (1.85 g) as a white solid. To a solution of 2-methyl-propane sulfinic acid 5′-fluoro-2′-methoxy-biphenyl-4-ylmethylene amide (1 g, 3 mmol) and tetrabutyl ammonium difluorotriphenylsilica gelte (1.8 g, 3.3 mmol) in tetrahydrofuran (50 ml) at −55° C. was added trifluoromethyltrimethylsilane with stirring. The reaction mixture was kept below −40° C. for 3 h then warmed to −10° C. for 1 h. The reaction mixture was cooled to −30° C. then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, evaporated to a low volume and heptane added. The crystalline 2-methyl-propane sulfinic acid [2,2,2-trifluoro-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (0.75 g) was collected by filtration. To a solution of 2-methyl-propane sulfinic acid [2,2,2-trifluoro-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (0.73 g, 1.8 mmol) in methanol (10 ml) at room temperature was added a 1M solution of Hydrogen chloride in ether with stirring. The reaction mixture was stirred for 2 h, then the solvent was evaporated and ether added. The crystalline 2,2,2-trifluoro-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine hydrochloride (0.38 g) was collected by filtration. To a solution of 2,2,2-trifluoro-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine hyrochloride (60 mg, 0.15 mmol) in pyridine (3 ml) was added 2-trifluoromethoxyphenyl sulfonyl chloride with stirring. The reaction was stirred for 3 days at 100° C. then cooled to room temperature and 5M Hydrogen chloride and dichloromethane added. The organic layer was separated and the solvent evaporated. The residue was flash chromatographed over silica gel eluting with 1:1 heptane/dichloromethane and the solvent evaporated to give the title compound (29 mg). 1H NMR (400 MHz, CDCl3): 7.58-7.41 (m, 4H), 7.27-7.11 (m, 3H), 7.04-6.90 (m, 3H), 5.51 (d, 1H), 5.00 (app quin, 1H), 3.78 (s, 3H) ppm; MS (ESI) m/z: 546 [M+Na]+.

1. temperatureThe reaction mixture was cooled to −30° C.
2. customthen quenched with saturated ammonium chloride solution
3. extractionextracted with ethyl acetate
4. dry with materialThe organic phase was dried over anhydrous magnesium sulfate
5. customevaporated to a low volume and heptane
6. additionadded
7. filtrationThe crystalline 2-methyl-propane sulfinic acid [2,2,2-trifluoro-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (0.75 g) was collected by filtration
8. stirringwith stirring
9. stirringThe reaction mixture was stirred for 2 h
10. customthe solvent was evaporated
11. additionether added
12. filtrationThe crystalline 2,2,2-trifluoro-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine hydrochloride (0.38 g) was collected by filtration
13. stirringwith stirring
14. stirringThe reaction was stirred for 3 days at 100° C.
15. temperaturethen cooled to room temperature
16. customThe organic layer was separated
17. customthe solvent evaporated
18. customchromatographed over silica gel eluting with 1:1 heptane/dichloromethane
19. customthe solvent evaporated

ORD record

ord-e73eed74752b49feb81f080e50c0c279

Source dataset

uspto-grants-2011_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07960365B2