反应详情

To a stirred solution of methyl (2E)-3-(2,4-difluorophenyl)acrylate from preparation 3 (10 g, 50.5 mmol) and N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (preparation 4) (10.3 g, 50.5 mmol) in dichloromethane (200 mL) at room temperature under dry nitrogen was added trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 17 hours. To the reaction mixture was then added a further portion of N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (from preparation 4) (3.9 g, 19.2 mmol) and trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 18 hours, then quenched by the addition of saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) using a pre-packed column (Redisep™ Disposable Columns for Flash Chromatography by Isco, 40 g column) eluting with 5% ethyl acetate in pentane increasing polarity with a linear gradient up to 100% ethyl acetate over the course of 1 hour. The residue was then subjected to chiral HPLC (eluting with 95:5 hexane:isopropyl alcohol at 80 mL/min at ambient temperature on a Chirapak AD500*80 mm column) to afford the desired enantiomer of the title compound, which we designate here Enantiomer 1, and which was obtained as the faster running enantiomer (retention time 8 minutes) as a clear oil (6.1 g, 80%) with enantiomeric excess of >99% as determined by chiral HPLC with reference to a racemic standard. The undesired enantiomer was obtained as the slower eluting component (Enantiomer 2, retention time 8.7 min) 1H NMR (400 MHz, CDCl3) δH 1.10 (9H, s), 2.80 (1H, m), 3.00 (1H, m), 3.15 (3H, m), 3.60 (3H, s), 3.80 (1H, m), 6.80 (2H, m), 7.40 (1H, m); LRMS (APCI) 298 (100%) [MH+].

1. stirringThe resulting mixture was stirred at room temperature under dry nitrogen for 18 hours
2. customquenched by the addition of saturated sodium bicarbonate solution (200 mL)
3. extractionextracted with ethyl acetate (3×75 mL)
4. dry with materialThe combined organic layers were dried (magnesium sulfate)
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco)
8. washeluting with 5% ethyl acetate in pentane increasing polarity with a linear gradient up to 100% ethyl acetate over the course of 1 hour
9. washeluting with 95:5 hexane