2,5-二氢-4-羟基-2-氧代-1H-吡咯-1-甲酸叔丁酯

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

实验步骤: A solution of 200 mg (0.888 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A), 353 mg (0.888 mmol, approx. 50% purity) tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [W.-R. Li et al., J. Org. Chem. 2002, 67, 4702-4706] and 102 mg (1.332 mmol) ammonium acetate in acetic acid (4 ml) was stirred at 100° C. for 45 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified first by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 10:1 v/v) and then by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 31 mg (11% of th.) of the title compound. The reaction mixture was concentrated under reduced pressure the residue was purified first by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 10:1 v/v)

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

实验步骤: To tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (680 mg, 3.41 mmol) in DCM (12 mL) was added DIEA (1.192 mL, 6.83 mmol) and tosyl chloride (651 mg, 3.41 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (0 to 50% EtOAc/heptane). Pure fractions were combined, evaporated and dried to give desired product as a white solid (0.98 g, 81%). LCMS (m/z): 354.1 (MH+), 0.97 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=8.22 Hz, 2H) 7.54 (d, J=7.83 Hz, 2H) 5.77 (s, 1H) 4.33 (s, 2H) 2.43 (s, 3H) 1.41 (s, 9H). washed with saturated sodium bicarbonate The organic layer was separated washed with brine dried over sodium sulfate filtered evaporated The crude product was purified by flash chromatography (0 to 50% EtOAc/heptane) evaporated dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To Boc-Gly-OH (1 g, 5.71 mmol) in DCM (12 mL) under N2 atmosphere at 0° C. was added DMAP (1.743 g, 14.27 mmol) and Meldrum's acid (0.987 g, 6.85 mmol). A solution of isopropyl chloroformate (8.56 mL, 8.56 mmol) in toluene was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with 15% KHSO4 twice, dried over sodium sulfate, filtered and evaporated. The crude product was taken in 50 mL of EtOAc and refluxed for 1 h. After volatile materials were evaporated, the crude product was triturated with EtOAC and the resulting solid was filtered and dried to provide a yellow solid (75%). LCMS (m/z): 200.1 (MH+), 0.504 min. The reaction mixture was washed with 15% KHSO4 twice dried over sodium sulfate filtered evaporated refluxed for 1 h After volatile materials were evaporated the crude product was triturated with EtOAC the resulting solid was filtered dried

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

实验步骤: A solution of 200 mg (0.888 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A), 353 mg (0.888 mmol, approx. 50% purity) tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [W.-R. Li et al., J. Org. Chem. 2002, 67, 4702-4706] and 102 mg (1.332 mmol) ammonium acetate in acetic acid (4 ml) was stirred at 100° C. for 45 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified first by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 10:1 v/v) and then by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 31 mg (11% of th.) of the title compound. The reaction mixture was concentrated under reduced pressure the residue was purified first by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 10:1 v/v)

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

实验步骤: To tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (680 mg, 3.41 mmol) in DCM (12 mL) was added DIEA (1.192 mL, 6.83 mmol) and tosyl chloride (651 mg, 3.41 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (0 to 50% EtOAc/heptane). Pure fractions were combined, evaporated and dried to give desired product as a white solid (0.98 g, 81%). LCMS (m/z): 354.1 (MH+), 0.97 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=8.22 Hz, 2H) 7.54 (d, J=7.83 Hz, 2H) 5.77 (s, 1H) 4.33 (s, 2H) 2.43 (s, 3H) 1.41 (s, 9H). washed with saturated sodium bicarbonate The organic layer was separated washed with brine dried over sodium sulfate filtered evaporated The crude product was purified by flash chromatography (0 to 50% EtOAc/heptane) evaporated dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To Boc-Gly-OH (1 g, 5.71 mmol) in DCM (12 mL) under N2 atmosphere at 0° C. was added DMAP (1.743 g, 14.27 mmol) and Meldrum's acid (0.987 g, 6.85 mmol). A solution of isopropyl chloroformate (8.56 mL, 8.56 mmol) in toluene was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with 15% KHSO4 twice, dried over sodium sulfate, filtered and evaporated. The crude product was taken in 50 mL of EtOAc and refluxed for 1 h. After volatile materials were evaporated, the crude product was triturated with EtOAC and the resulting solid was filtered and dried to provide a yellow solid (75%). LCMS (m/z): 200.1 (MH+), 0.504 min. The reaction mixture was washed with 15% KHSO4 twice dried over sodium sulfate filtered evaporated refluxed for 1 h After volatile materials were evaporated the crude product was triturated with EtOAC the resulting solid was filtered dried

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

实验步骤: A solution of 200 mg (0.888 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A), 353 mg (0.888 mmol, approx. 50% purity) tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [W.-R. Li et al., J. Org. Chem. 2002, 67, 4702-4706] and 102 mg (1.332 mmol) ammonium acetate in acetic acid (4 ml) was stirred at 100° C. for 45 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified first by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 10:1 v/v) and then by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 31 mg (11% of th.) of the title compound. The reaction mixture was concentrated under reduced pressure the residue was purified first by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 10:1 v/v)