3-(2,4-二氟苯基)丙烯酸甲酯

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trifluoroacetic acid (2.42 mL, 31.5 mmol) in dichloromethane (5 mL) was added at 0-5° C. to a stirred solution of N-benzyl-N-(methoxymethyl)trimethylsilylamine (45.1 g, 190 mmol) and methyl (2E)-3-(2,4-difluorophenyl)acrylate (from preparation 3) (25.1 g, 126 mmol) in dichloromethane (100 mL). After stirring overnight at room temperature, the organic solution was washed with saturated sodium bicarbonate solution and then brine. The resulting organic solution was dried over anhydrous sodium sulfate, filtered and then evaporated. The residue was purified by flash chromatography on silica gel eluting with toluene:tetrahydrofuran mixture (11:1) to afford the title compound (31.6 mL, 71%) as a colourless oil. the organic solution was washed with saturated sodium bicarbonate solution The resulting organic solution was dried over anhydrous sodium sulfate filtered evaporated The residue was purified by flash chromatography on silica gel eluting with toluene

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,4-difluorocinnamic acid (20 g, 135 mmol) in N,N-dimethylformamide (500 mL) at room temperature under dry nitrogen was added potassium carbonate (90 g, 675 mmol) then iodomethane (21 mL, 337.5 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 7 hours before being quenched by the addition of water (1 L) and extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over 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, 120 g column) eluting with 2% ethyl acetate in pentane increasing polarity in a linear gradient to 10% ethyl acetate in pentane over 1 hour to afford the title compound as a white solid (20.5 g, 77%). 1H NMR (400 MHz, CDCl3) δH 3.80 (3H, s), 6.50 (1H, d), 6.85 (1H, m), 7.50 (1H, m), 7.75 (1H, d); LRMS (APCI) 216 [MNH4+], 199 [MH+]. before being quenched by the addition of water (1 L) extracted with diethyl ether (3×200 mL) The combined organic extracts were dried over magnesium sulfate filtered concentrated in vacuo The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) eluting with 2% ethyl acetate in pentane increasing polarity in a linear gradient to 10% ethyl acetate in pentane over 1 hour

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 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+]. The resulting mixture was stirred at room temperature under dry nitrogen for 18 hours quenched by the addition of saturated sodium bicarbonate solution (200 mL) extracted with ethyl acetate (3×75 mL) The combined organic layers were dried (magnesium sulfate) filtered concentrated in vacuo The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) eluting with 5% ethyl acetate in pentane increasing polarity with a linear gradient up to 100% ethyl acetate over the course of 1 hour eluting with 95:5 hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Trifluoroacetic acid (116 μL, 1.51 mmol) was added to a solution of N-tert-butyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine from Step B (3.07 g, 15.1 mmol) and methyl (2E)-3-(2,4-difluorophenyl)prop-2-enoate (2.99 g, 15.1 mmol) in methylene chloride (60 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methlene chloride. The combined organic extracs were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by normal phase medium pressure liquid chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) gave the racemic title compound as a colorless liquid. The racemic titled compound was resolved into its enantiomeric components using preparative chiral high pressure liquid chromatography on CHIRALPAK AD Phase (5% isopropanol/heptanes as eluent) to give in order of elution: methyl (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer of the titled compound as a colorless oil followed by the methyl (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer of the title compound as a colorless oil. extracted three times with methlene chloride The combined organic extracs were washed with brine dried (Na2SO4) concentrated in vacuo Purification of the residue by normal phase medium pressure liquid chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent)