tert-butyl (2S)-4,4-difluoro-2-formylpyrrolidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Compound 2b (1.33 g; 5.61 mmol) in CH2Cl2 (20 mL) was added 3,3,3-triacetoxy-3-iodophthalide (3.56 g; 8.39 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was diluted with EtOAc, and washed sequentially with saturated NaHCO3(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2c (0.58 g; 44% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 9.59 (d, 1H), 4.28-4.45 (m, 1H), 3.77-3.89 (m, 2H), 2.43-2.63 (m, 2H), 1.46-1.51 (m, 9H). washed sequentially with saturated NaHCO3(aq) and H2O The organic phase was washed with H2O dried over Na2SO4 The mixture was filtered the filtrate was evaporated under reduced pressure to give the crude material The crude material was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Compound 2b (1.33 g; 5.61 mmol) in CH2Cl2 (20 mL) was added 3,3,3-triacetoxy-3-iodophthalide (3.56 g; 8.39 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was diluted with EtOAc, and washed sequentially with saturated NaHCO3(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2c (0.58 g; 44% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 9.59 (d, 1H), 4.28-4.45 (m, 1H), 3.77-3.89 (m, 2H), 2.43-2.63 (m, 2H), 1.46-1.51 (m, 9H). washed sequentially with saturated NaHCO3(aq) and H2O The organic phase was washed with H2O dried over Na2SO4 The mixture was filtered the filtrate was evaporated under reduced pressure to give the crude material The crude material was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Compound 2b (1.33 g; 5.61 mmol) in CH2Cl2 (20 mL) was added 3,3,3-triacetoxy-3-iodophthalide (3.56 g; 8.39 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was diluted with EtOAc, and washed sequentially with saturated NaHCO3 (aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2c (0.58 g; 44% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 9.59 (d, 1H), 4.28-4.45 (m, 1H), 3.77-3.89 (m, 2H), 2.43-2.63 (m, 2H), 1.46-1.51 (m, 9H). washed sequentially with saturated NaHCO3 (aq) and H2O The organic phase was washed with H2O dried over Na2SO4 The mixture was filtered the filtrate was evaporated under reduced pressure to give the crude material The crude material was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Solution of (S)-4,4-difluoro-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 0.0042 mol) and 3-chloroaniline (0.53 mL, 0.0042 mol) in titanium tetraisopropoxide (5 mL) was allowed to stir for 12 h. The reaction was monitored by TLC. After disappearance of starting reaction on TLC, the mixture was diluted with methanol (20 mL) followed by the addition of sodium borohydride (0.33 g, 0.0084 mol) in portions. The reaction mixture was stirred for 6 h. The reaction was quenched with water and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and the volatiles were removed using a rotary evaporator to give a crude oil, which was then purified via column chromatography (5% methanol: DCM, mesh Size—100-200 silica, diameter of column—2.5 cm, height of silica—approx. 4 inch) to afford the desired (S)-2-[(3-chloro-phenylamino)-methyl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as a sticky solid (0.15 g, 12%). reaction on TLC The reaction mixture was stirred for 6 h The reaction was quenched with water extracted with DCM (3×50 mL) The organic layer was dried over anhydrous Na2SO4 the volatiles were removed a rotary evaporator to give a crude oil, which was then purified via column chromatography (5% methanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dess Martin Periodinane (0.9 g, 0.0021 mol) was added in one portion to a solution of (S)-4,4-difluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.0016 mol) in DCM (50 mL) under an inert atmosphere. The reaction was stirred until completion (about 2 h) and then quenched with saturated solution of sodium thiosulphate, extracted with DCM (3×100 mL) washed with brine (50 mL), dried over anhydrous sodium sulphate, and concentrated using a rotary evaporator to afford 0.35 g of the desired (S)-4,4-difluoro-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown colored oil product. quenched with saturated solution of sodium thiosulphate extracted with DCM (3×100 mL) washed with brine (50 mL) dried over anhydrous sodium sulphate concentrated a rotary evaporator