反应详情

A 500 mL three necked round bottom flask equipped with a magnetic stirrer, thermometer, addition funnel and a positive nitrogen was charged with [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (12.02 g, 46.85 mmol) and methylene chloride (200.0 mL). To this solution was added triethylamine (6.53 mL, 46.85 mmol) all at once. The solution was stirred for 10 minutes then added dropwise, neat 3,5-difluorobenzoyl chloride (5.9 mL, 46.85 mmol) over a period of 20 minutes. The reaction exothermed to reflux by the end of addition. Stirred to room temperature over the weekend for convenience. Quenched reaction with 1N HCl (100.0 mL) and separated lower organic layer. Washed the organic layer with 25% brine (70.0 mL) and dried with anhydrous magnesium sulfate. Filtered precipitates and concentrated filtrate to a tan oil (20.0 g). To this oil was added 1:1 ethyl acetate/hexane (125.0 mL) with stirring. A massive off white precipitate formed. The precipitate was then filtered and the cake washed with 1:1 ethyl acetate/hexane (50.0 mL). Precipitate was then dried in a house vacuum oven at 40° C. to provide N-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (15.02 g, 80.9%); 1H NMR (CDCl3, 300 MHz) δ 1.26-1.27 (d, 6H), 1.29-1.30 (d,2H), 2.92 (m, 1H), 3.10 (m, 1H), 3.20 (1H), 3.3-3.4 (m, 1H), 7.0 (triplet, 1H), 7.20 (d, 2H), 7.40 (d, 2H), 7.60 (m, 2H), 8.19 (s, 1H); 13C NMR (CDCl3, 300 MHz) δ 17.19, 17.30, 19.75, 41.03, 50.99, 54.15, 107.68, 107.86, 108.08, 111.12, 111.33, 121.81, 128.59, 136.97, 138.77, 140.51, 162.62, 162.71, 164.12, 164.61, 164.71.

1. additionthermometer, addition funnel
2. additionthen added dropwise
3. temperatureto reflux by the end of addition
4. stirringStirred to room temperature over the weekend for convenience
5. customQuenched
6. customreaction with 1N HCl (100.0 mL)
7. customseparated lower organic layer
8. washWashed the organic layer with 25% brine (70.0 mL)
9. dry with materialdried with anhydrous magnesium sulfate
10. filtrationFiltered
11. customprecipitates
12. additionTo this oil was added 1:1 ethyl acetate/hexane (125.0 mL)
13. stirringwith stirring
14. customA massive off white precipitate formed
15. filtrationThe precipitate was then filtered
16. washthe cake washed with 1:1 ethyl acetate/hexane (50.0 mL)
17. customPrecipitate was then dried in a house vacuum oven at 40° C.