1-O-tert-butyl 2-O-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate

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

実験手順: To a solution of commercially available methyl 5-oxo-L-prolinate (20 g, 140 mmol) in DCM (200 ml) were added triethylamine (19.6 ml, 140 mmol), DMAP (17.2 g, 140 mmol) and then dropwise a solution of BOC2O (61 g, 280 mmol) in DCM (100 ml). The resulting red mixture was stirred at room temperature for 2 hours. Then the solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6) to afford (after a trituration in hexane/diethylether 1:1) the title compound as a white solid (32.4 g, 96%); Rf (cyclohexanes:ethyl acetate=65:35): 0.21; 1H NMR (300 MHz, CDCl3) δ(ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H). Then the solvent was removed under reduced pressure the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This compound is prepared as described by Gu et al, Tetrahedron Lett., 2003, 44, 3203-3205. Lithium hexamethyldisilazide in THF (1.0 M; 8.47 mL, 8.47 mmol) was added dropwise over 30 min. to a solution of 1-tert-butyl 2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in THF (20 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h. Methyl iodide (1.30 mL, 20.9 mmol) was then added dropwise over 10 min. After stirring at −78° C. for 2 h, the reaction mixture was allowed to warm to room temperature and stirred for 14 h. The reaction was then quenched with AcOH (1.00 mL, 17.6 mmol), and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound (0.47 g, 22%). LCMS calc. for C12H19NNaO5 (M+Na)+: m/z=280.1. found 280.1. 1H NMR (CDCl3, 400 MHz) δ 4.57 (1H, dd, J=1.6 and 9.6 Hz), 3.77 (3H, s), 2.68 (1H, m), 2.27 (1H, m), 1.93 (1H, m), 1.49 (9H, s), 1.21 (3H, d, J=6.8 Hz) ppm. This compound is prepared After stirring at −78° C. for 2 h to warm to room temperature stirred for 14 h the reaction mixture was concentrated under reduced pressure The residue was diluted with EtOAc (100 mL) washed with brine (100 mL) dried over Na2SO4 concentrated under reduced pressure The resulting residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes)

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

実験手順: To a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.0 g of the title compound. The property values of the compound are as follows. followed by extraction with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (heptane-ethyl acetate system)

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

実験手順: To a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.0 g of the title compound. The property values of the compound are as follows. followed by extraction with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (heptane-ethyl acetate system)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: n-Butyl lithium 1.6M solution in hexanes (0.88 ml, 1.4 mmol) was added dropwise to a solution of commercially available 1-bromo-4-[(phenylmethyl)oxy]benzene (390 mg, 1.48 mmol) in dry THF (2 ml) at −78° C. under nitrogen atmosphere. The resulting suspension was stirred at −78° C. for 40 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 300 mg, 1.23 mmol) in dry THF (2.4 ml) previously cooled to −78° C. The mixture was stirred at −78° C. for 40 minutes and at 40° C. for 1 h, then it was quenched at −40° C. with an aqueous saturated ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give the crude material, which was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (95:5), thus affording the title compound as a white solid (170 mg, 32%); Rf (cyclohexane:ethyl acetate=8:2): 0.30; 1HNMR (300 MHz, CDCl3) δ(ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03 (d, 2H), 5.20 (bs, 1H), 5.15 (s, 2H), 4.45-4.35 (m, 1H), 3.78 (s, 3H), 3.15-2.95 (m, 2H), 2.36-2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.45 (s, 9H). previously cooled to −78° C The mixture was stirred at −78° C. for 40 minutes and at 40° C. for 1 h it was quenched at −40° C. with an aqueous saturated ammonium chloride solution The mixture was diluted with water extracted with ethyl acetate The organic phase was then washed with brine dried over Na2SO4 evaporated under reduced pressure to give the crude material, which was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (95:5)

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1,2-Dibromethane (106 uL, 232 mg, 1.233 mmol) was added to a suspension of magnesium (300 mg, 12.33 mmol) in dry THF (3 mL). Then a solution of 4-bromo-1-{[(2-fluorophenyl)methyl]oxy}-2-(methyloxy)benzene (D59, 2.40 g, 8.22 mmol), prepared with analogous procedure to that described hereinabove, in dry THF (17 ml) was added dropwise. The mixture was heated under reflux for 1.5 h. The grignard formation was followed via HPLC (Rt(HPLC, 1-fluoro-2-({[2-(methyloxy)phenyl]oxy}methyl)benzene): 5.59 min, Rt (HPLC, D59): 6.24 min). When the reaction stopped, additional 1,2-dibromethane (0.1 eq) was added. After the grignard formation was complete, the mixture was added dropwise to a solution 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 1 g, 4.11 mmol) in dry THF (20 ml) at −65° C. Stirring at −65° C. was continued for 3.5 h. Then isopropanol and diethylether were added, the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was purified with flash chromatography using a cyclohexanes/ethyl acetate (40% to 100%) gradient to afford the title compound (900 mg, 46%). MS: (ES/+) m/z: 376 [M-BOC+], C25H30FNO7 requires 475; UPLC: 0.84 min, m/z: 476 [MH+], 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.6 (m, 2H), 7.4 (m, 2H), 7.3-7.2 (m, 4H), 5.2 (s, 2H), 4.1 (m, 1H), 3.8 (s, 3H), 3.6 (s, 3H), 3.2-3.0 (m, 2H), 2.1-2.0 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H). The mixture was heated under reflux for 1.5 h 5.59 min, Rt (HPLC, D59) 6.24 min the organic layer was washed with aqueous ammonium chloride solution dried (Na2SO4) evaporated The residue was purified with flash chromatography

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1,2-Dibromethane (106 uL, 232 mg, 1.233 mmol) was added to a suspension of magnesium (300 mg, 12.33 mmol) in dry THF (3 mL). Then a solution of 4-bromo-1-{[(2-fluorophenyl)methyl]oxy}-2-(methyloxy)benzene (D59, 2.40 g, 8.22 mmol), prepared with analogous procedure to that described hereinabove, in dry THF (17 ml) was added dropwise. The mixture was heated under reflux for 1.5 h. The grignard formation was followed via HPLC (Rt(HPLC, 1-fluoro-2-({[2-(methyloxy)phenyl]oxy}methyl)benzene): 5.59 min, Rt (HPLC, D59): 6.24 min). When the reaction stopped, additional 1,2-dibromethane (0.1 eq) was added. After the grignard formation was complete, the mixture was added dropwise to a solution 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 1 g, 4.11 mmol) in dry THF (20 ml) at −65° C. Stirring at −65° C. was continued for 3.5 h. Then isopropanol and diethylether were added, the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was purified with flash chromatography using a cyclohexanes/ethyl acetate (40% to 100%) gradient to afford the title compound (900 mg, 46%). MS: (ES/+) m/z: 376 [M-BOC+], C25H30FNO7 requires 475; UPLC: 0.84 min, m/z: 476 [MH+], 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.6 (m, 2H), 7.4 (m, 2H), 7.3-7.2 (m, 4H), 5.2 (s, 2H), 4.1 (m, 1H), 3.8 (s, 3H), 3.6 (s, 3H), 3.2-3.0 (m, 2H), 2.1-2.0 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H). The mixture was heated under reflux for 1.5 h 5.59 min, Rt (HPLC, D59) 6.24 min the organic layer was washed with aqueous ammonium chloride solution dried (Na2SO4) evaporated The residue was purified with flash chromatography

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1,2-Dibromethane (106 uL, 232 mg, 1.233 mmol) was added to a suspension of magnesium (300 mg, 12.33 mmol) in dry THF (3 mL). Then a solution of 4-bromo-1-{[(2-fluorophenyl)methyl]oxy}-2-(methyloxy)benzene (D59, 2.40 g, 8.22 mmol), prepared with analogous procedure to that described hereinabove, in dry THF (17 ml) was added dropwise. The mixture was heated under reflux for 1.5 h. The grignard formation was followed via HPLC (Rt(HPLC, 1-fluoro-2-({[2-(methyloxy)phenyl]oxy}methyl)benzene): 5.59 min, Rt (HPLC, D59): 6.24 min). When the reaction stopped, additional 1,2-dibromethane (0.1 eq) was added. After the grignard formation was complete, the mixture was added dropwise to a solution 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 1 g, 4.11 mmol) in dry THF (20 ml) at −65° C. Stirring at −65° C. was continued for 3.5 h. Then isopropanol and diethylether were added, the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was purified with flash chromatography using a cyclohexanes/ethyl acetate (40% to 100%) gradient to afford the title compound (900 mg, 46%). MS: (ES/+) m/z: 376 [M-BOC+], C25H30FNO7 requires 475; UPLC: 0.84 min, m/z: 476 [MH+], 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.6 (m, 2H), 7.4 (m, 2H), 7.3-7.2 (m, 4H), 5.2 (s, 2H), 4.1 (m, 1H), 3.8 (s, 3H), 3.6 (s, 3H), 3.2-3.0 (m, 2H), 2.1-2.0 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H). The mixture was heated under reflux for 1.5 h 5.59 min, Rt (HPLC, D59) 6.24 min the organic layer was washed with aqueous ammonium chloride solution dried (Na2SO4) evaporated The residue was purified with flash chromatography

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

実験手順: The title compound was synthesized (420 mg, 6%) following Description 6 from 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 3.69 g, 15.2 mmol) and 3-bromophenyl phenylmethyl ether (D48); Rt (HPLC): 6.2 min.

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

実験手順: The title compound was synthesized (420 mg, 6%) following Description 6 from 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 3.69 g, 15.2 mmol) and 3-bromophenyl phenylmethyl ether (D48); Rt (HPLC): 6.2 min.

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-bromo-3-fluorophenyl (2-fluorophenyl)methyl ether (D41, 500 mg, 1.67 mmol) and TMEDA (178 mg, 1.53 mmol) in dry THF (7 ml) at −78° C. under nitrogen atmosphere was added n-butyllithium 1.6M solution in hexanes (1 ml, 1.6 mmol) dropwise. The resulting suspension was stirred at −78° C. for 15 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 338 mg, 1.39 mmol) in dry THF (2 ml). The mixture was stirred at −78° C. for 1 h, then it was quenched with a saturated ammonium chloride aqueous solution. The phases were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (9:1 to 85:15) affording the title compound as a white solid (254 mg, 39%); 1H NMR (300 MHz, CDCl3-d) δ (ppm): 8.00-7.80 (m, 1H); 7.53-7.42 (m, 1H); 7.42-7.25 (m, 1H); 7.23-7.05 (m, 2H); 6.90-6.80 (m, 1H); 6.75-6.65 (m, 1H); 5.18 (s, 2H); 4.50-4.30 (m, 1H); 3.71 (s, 3H); 3.18-2.85 (m, 2H); 2.40-2.20 (m, 1H); 2.15-1.90 (m, 1H); 1.40 (s, 9H). The mixture was stirred at −78° C. for 1 h it was quenched with a saturated ammonium chloride aqueous solution The phases were separated the organic layer was washed with brine dried over Na2SO4 filtered evaporated under reduced pressure The resulting residue was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (9:1 to 85:15)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-bromo-3-fluorophenyl (2-fluorophenyl)methyl ether (D41, 500 mg, 1.67 mmol) and TMEDA (178 mg, 1.53 mmol) in dry THF (7 ml) at −78° C. under nitrogen atmosphere was added n-butyllithium 1.6M solution in hexanes (1 ml, 1.6 mmol) dropwise. The resulting suspension was stirred at −78° C. for 15 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 338 mg, 1.39 mmol) in dry THF (2 ml). The mixture was stirred at −78° C. for 1 h, then it was quenched with a saturated ammonium chloride aqueous solution. The phases were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (9:1 to 85:15) affording the title compound as a white solid (254 mg, 39%); 1H NMR (300 MHz, CDCl3-d) δ (ppm): 8.00-7.80 (m, 1H); 7.53-7.42 (m, 1H); 7.42-7.25 (m, 1H); 7.23-7.05 (m, 2H); 6.90-6.80 (m, 1H); 6.75-6.65 (m, 1H); 5.18 (s, 2H); 4.50-4.30 (m, 1H); 3.71 (s, 3H); 3.18-2.85 (m, 2H); 2.40-2.20 (m, 1H); 2.15-1.90 (m, 1H); 1.40 (s, 9H). The mixture was stirred at −78° C. for 1 h it was quenched with a saturated ammonium chloride aqueous solution The phases were separated the organic layer was washed with brine dried over Na2SO4 filtered evaporated under reduced pressure The resulting residue was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (9:1 to 85:15)