Dichloromethane → (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide

Temperature

120 °C

A mixture of 4-bromo-2-hydroxyacetophenone (0.460 g, 2.0 mmol), titanium tetraethoxide (1.0 g, 4.0 mmol) and (R)-2-methyl-2-propanesulfinamide (0.266 g, 2.2 mmol) in dichloromethane (3.0 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was cooled in ice and added to a stirred mixture of sodium borohydride (0.30 g, 8.0 mmol) in tetrahydrofuran (50 ml). This mixture was stirred for 1 h at ambient temperature, treated with brine (30 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated The residue was flash chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide. A mixture of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide (0.130 g, 0.4 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid (0.150 g, 0.8 mmol), tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.02 mmol), 2M aqueous sodium carbonate solution (2 ml), toluene (1 ml) and ethanol (1 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent evaporated and the residue dissolved in methanol. This solution was treated with 2M hydrogen chloride in diethyl ether solution. After standing for 2 hours, the mixture was poured onto an SCX column, washed with methanol and then eluted with 1M ammonia in methanol solution. The solvent was evaporated and the residue flash chromatographed on silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol to give (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine. The title compound was prepared in a similar manner to 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 30) using (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine instead of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. MS (ESI) m/z: 505.0 [M+H]+.

1. temperatureThe mixture was cooled in ice
2. extractionextracted with ethyl acetate
3. washThe combined organic extracts were washed with brine
4. dry with materialdried over anhydrous sodium sulfate
5. customthe solvent evaporated The residue
6. customchromatographed on silica gel eluting with 3:1 heptane/ethyl acetate

ORD record

ord-27a3b8c9de244132b4783392a039750b

Source dataset

uspto-grants-2011_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07960365B2