反应详情

温度

-20 °C

A solution of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (280 g, 1.0 mol) in tetrahydrofuran (2.8 L) at room temperature under an atmosphere of nitrogen was treated with 1.0 M borane-THF complex in THF (1.2 L, 1.2 mol) in small portions, stirred for 15 minutes, and then cooled to −20° C. The reaction mixture was treated with a solution of 1-{4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-yl}ethanone (380 g, 1.0 mol) in anhydrous tetrahydrofuran (3.0 L) dropwise over 60 min with the internal temperature rising from −20 to −12° C. The flask that contained the ketone was rinsed with tetrahydrofuran (500 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at −12 to −10° C. for 30 minutes. The reaction mixture was quenched with water (440 mL, 24 mol) at −10° C. over 10 minutes (temperature rose to 0° C.), warmed to room temperature, treated with 10% potassium carbonate in water (3.0 L, 2.1 mol), and stirred for 20 minutes. The organic layer was separated, diluted with ethyl acetate (2 L) and hexanes (0.5 L) and washed with 0.5 M citric acid in water (3.0 L, 1.5 mol), 1.0 M hydrogen chloride in water (3.0 L, 3.0 mol), and 0.5 M citric acid in water (3.0 L, 1.5 mol). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (470 g, theoretical 380 g). The main impurities were the alcohol with triazene moiety removed and the hydrolyzed ligand. The product had ˜91 ee %. This material was used directly in the next step without further purification.

1. customrising from −20 to −12° C
2. washwas rinsed with tetrahydrofuran (500 mL)
3. additionadded dropwise to the reaction mixture
4. stirringThe reaction mixture was stirred at −12 to −10° C. for 30 minutes
5. temperaturewarmed to room temperature
6. stirringstirred for 20 minutes
7. customThe organic layer was separated
8. additiondiluted with ethyl acetate (2 L) and hexanes (0.5 L)
9. washThe organic layer was washed with brine
10. dry with materialdried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated