2-(Methoxyimino)-propanedioic Acid 1,3-Diethyl Ester

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolve 21 wt % NaOEt in EtOH solution (164 g, 0.507 mol) in 2B-3 ethanol (331 mL) and add 1,2-phenylenediamine (27.4 g, 0.253 mol). Stir the resulting mixture allow to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution. Add 2-methoxyimino-malonic acid diethyl ester (51.5 g, 0.253 mol). Heat the resulting mixture to 70° C. and stir under nitrogen for approximately 4 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Allow the reaction mixture to cool to ambient temperature. Lower the pH of the reaction mixture from 11.6 to 1.2 by the addition of 700 mL of aqueous 1N HCl solution. Concentrate the reaction mixture in vacuo to remove the ethanol. Filter the resulting amber slurry through a glass frit. Collect the solid and rinse with aqueous 1N HCl and dry under vacuum at 50° C. to afford 42 g (76% yield) of the title compound as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 11.1 (s, 1H), 10.9 (s, 1H), 7.22 (s, 4H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7; 159.4, 148.1, 128.5, 127.8, 125.8, 125.7, 122.8, 122.7, 63.1; IR (CHCl3) 3062, 2970, 2902, 1704, 1656, 1606, 1505, 1414, 1058, 1043, 754 cm−1; UV (EtOH) λmax 278 nm (ε 4623), 276 nm (ε 4618), 216 nm (ε 41495); HRMS (ES+) exact mass calc'd for C10H9N3O3 242.0542, Found 242.0553; Anal. calc'd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.60; H, 4.15; N, 18.94. to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution stir under nitrogen for approximately 4 hours to cool to ambient temperature Concentrate the reaction mixture in vacuo to remove the ethanol Filter the resulting amber slurry through a glass frit Collect the solid rinse with aqueous 1N HCl dry under vacuum at 50° C.

反应条件: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine diethylketomalonate (50 g, 0.287 mol) in 3A ethanol (250 mL) and add N-methylhydroxylamine-HCl (23.9 g, 0.287 mol). Add pyridine (22.7 g, 0.287 mol) and heat to reflux (78° C.) the colorless homogeneous solution with stirring under nitrogen for approximately 2.5 hours before cooling to ambient temperature. Stir at ambient temperature for approximately 48 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Concentrate the reaction mixture in vacuo to a wet, waxy white solid and partition between 100 mL of EtOAc and 100 mL of H2O. Extract the aqueous layer with 3×100 mL portions of EtOAc. Combine the EtOAc layers, wash with 100 mL of brine, dry over MgSO4, filter, and evaporate down to a yellow oil. Absorb the crude product onto silica gel 60 (Merck, 230-400 mesh) and elute with 4 L of a 9:1 hexanes:EtOAc solution as eluent. Evaporate the eluent in vacuo to afford 56.3 g (96.6% yield) of the title compound as a pale yellow homogeneous oil; 1H NMR (300 MHz, CDCl3) δ 4.29 (m, 4H), 4.05 (s, 3H), 1.259 (t, 6H, J=7.32 Hz); 13C NMR (75 MHz, CDCl3) δ 159.9, 158.9, 143.3, 64.2, 62.3, 62.1, 13.7; IR (CHCl3) 3029, 2986, 2944, 1744, 1605, 1329, 1301, 1264, 1237, 1103, 1043 cm−1; UV (EtOH) λmax 231 nm (ε 8582); HRMS (ES) exact mass calc'd for C8H13NO5 203.0794, Found 203.0797. Anal. calc'd for C8H13NO5: C, 47.29; H, 6.45; N, 6.89. Found: C, 46.28; H, 6.36; N, 4.86. before cooling to ambient temperature Stir at ambient temperature for approximately 48 hours Concentrate the reaction mixture in vacuo to a wet, waxy white solid partition between 100 mL of EtOAc and 100 mL of H2O Extract the aqueous layer with 3×100 mL portions of EtOAc wash with 100 mL of brine dry over MgSO4 filter evaporate down to a yellow oil Absorb the crude product onto silica gel 60 (Merck, 230-400 mesh) elute with 4 L of a 9:1 hexanes Evaporate the eluent in vacuo

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolve 21 wt % NaOEt in EtOH solution (164 g, 0.507 mol) in 2B-3 ethanol (331 mL) and add 1,2-phenylenediamine (27.4 g, 0.253 mol). Stir the resulting mixture allow to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution. Add 2-methoxyimino-malonic acid diethyl ester (51.5 g, 0.253 mol). Heat the resulting mixture to 70° C. and stir under nitrogen for approximately 4 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Allow the reaction mixture to cool to ambient temperature. Lower the pH of the reaction mixture from 11.6 to 1.2 by the addition of 700 mL of aqueous 1N HCl solution. Concentrate the reaction mixture in vacuo to remove the ethanol. Filter the resulting amber slurry through a glass frit. Collect the solid and rinse with aqueous 1N HCl and dry under vacuum at 50° C. to afford 42 g (76% yield) of the title compound as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 11.1 (s, 1H), 10.9 (s, 1H), 7.22 (s, 4H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7; 159.4, 148.1, 128.5, 127.8, 125.8, 125.7, 122.8, 122.7, 63.1; IR (CHCl3) 3062, 2970, 2902, 1704, 1656, 1606, 1505, 1414, 1058, 1043, 754 cm−1; UV (EtOH) λmax 278 nm (ε 4623), 276 nm (ε 4618), 216 nm (ε 41495); HRMS (ES+) exact mass calc'd for C10H9N3O3 242.0542, Found 242.0553; Anal. calc'd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.60; H, 4.15; N, 18.94. to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution stir under nitrogen for approximately 4 hours to cool to ambient temperature Concentrate the reaction mixture in vacuo to remove the ethanol Filter the resulting amber slurry through a glass frit Collect the solid rinse with aqueous 1N HCl dry under vacuum at 50° C.

反应条件: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine diethylketomalonate (50 g, 0.287 mol) in 3A ethanol (250 mL) and add N-methylhydroxylamine-HCl (23.9 g, 0.287 mol). Add pyridine (22.7 g, 0.287 mol) and heat to reflux (78° C.) the colorless homogeneous solution with stirring under nitrogen for approximately 2.5 hours before cooling to ambient temperature. Stir at ambient temperature for approximately 48 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Concentrate the reaction mixture in vacuo to a wet, waxy white solid and partition between 100 mL of EtOAc and 100 mL of H2O. Extract the aqueous layer with 3×100 mL portions of EtOAc. Combine the EtOAc layers, wash with 100 mL of brine, dry over MgSO4, filter, and evaporate down to a yellow oil. Absorb the crude product onto silica gel 60 (Merck, 230-400 mesh) and elute with 4 L of a 9:1 hexanes:EtOAc solution as eluent. Evaporate the eluent in vacuo to afford 56.3 g (96.6% yield) of the title compound as a pale yellow homogeneous oil; 1H NMR (300 MHz, CDCl3) δ 4.29 (m, 4H), 4.05 (s, 3H), 1.259 (t, 6H, J=7.32 Hz); 13C NMR (75 MHz, CDCl3) δ 159.9, 158.9, 143.3, 64.2, 62.3, 62.1, 13.7; IR (CHCl3) 3029, 2986, 2944, 1744, 1605, 1329, 1301, 1264, 1237, 1103, 1043 cm−1; UV (EtOH) λmax 231 nm (ε 8582); HRMS (ES) exact mass calc'd for C8H13NO5 203.0794, Found 203.0797. Anal. calc'd for C8H13NO5: C, 47.29; H, 6.45; N, 6.89. Found: C, 46.28; H, 6.36; N, 4.86. before cooling to ambient temperature Stir at ambient temperature for approximately 48 hours Concentrate the reaction mixture in vacuo to a wet, waxy white solid partition between 100 mL of EtOAc and 100 mL of H2O Extract the aqueous layer with 3×100 mL portions of EtOAc wash with 100 mL of brine dry over MgSO4 filter evaporate down to a yellow oil Absorb the crude product onto silica gel 60 (Merck, 230-400 mesh) elute with 4 L of a 9:1 hexanes Evaporate the eluent in vacuo

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

实验步骤: A mixture of iN sodium methylate (162 ml), o-phenylenediamine (17.5 g, 162 mmol) and diethyl 2-(methoxyimino)malonate (32.91 g, 162 mmol) is heated to reflux for 5 hr. After cooling, the mixture is acidified with 2N HCl (162 ml) and pale yellowish crystals (14.3 g, 41%) are filtered off. is heated to reflux for 5 hr After cooling are filtered off

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

实验步骤: A solution of diethyl ketomalonate 1 (51.0 g, 0.293 mmol), o-methylhydroxylamine hydrochloride (24.46 g, 0.293 mmol) and pyridine (23.2 g, 0.293 mmol) in ethanol (250 ml) is heated to reflux for 3 hr. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dilute hydrogen chloride, aqueous sodium hydrogencarbonate solution, and water successively. After drying over sodium sulfate, the solvent is removed under reduced pressure. The resultant residue is distilled under reduced pressure at 80°-85° C./0.5 mmHg to obtain Compound 2 (55.5 g, 93.2%). NNMR (CDCl3)δ: 1.35 (3H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz), 4.11 (3H, s), 4.36 (2H, q, J=7.1 Hz), 4.37 (2H, q, J=7.1 Hz). to reflux for 3 hr The solvent is removed under reduced pressure The residue is dissolved in ethyl acetate washed with water, dilute hydrogen chloride, aqueous sodium hydrogencarbonate solution, and water successively After drying over sodium sulfate the solvent is removed under reduced pressure The resultant residue is distilled under reduced pressure at 80°-85° C./0.5 mmHg

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolve 21 wt % NaOEt in EtOH solution (164 g, 0.507 mol) in 2B-3 ethanol (331 mL) and add 1,2-phenylenediamine (27.4 g, 0.253 mol). Stir the resulting mixture allow to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution. Add 2-methoxyimino-malonic acid diethyl ester (51.5 g, 0.253 mol). Heat the resulting mixture to 70° C. and stir under nitrogen for approximately 4 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Allow the reaction mixture to cool to ambient temperature. Lower the pH of the reaction mixture from 11.6 to 1.2 by the addition of 700 mL of aqueous 1N HCl solution. Concentrate the reaction mixture in vacuo to remove the ethanol. Filter the resulting amber slurry through a glass frit. Collect the solid and rinse with aqueous 1N HCl and dry under vacuum at 50° C. to afford 42 g (76% yield) of the title compound as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 11.1 (s, 1H), 10.9 (s, 1H), 7.22 (s, 4H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7; 159.4, 148.1, 128.5, 127.8, 125.8, 125.7, 122.8, 122.7, 63.1; IR (CHCl3) 3062, 2970, 2902, 1704, 1656, 1606, 1505, 1414, 1058, 1043, 754 cm−1; UV (EtOH) λmax 278 nm (ε 4623), 276 nm (ε 4618), 216 nm (ε 41495); HRMS (ES+) exact mass calc'd for C10H9N3O3 242.0542, Found 242.0553; Anal. calc'd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.60; H, 4.15; N, 18.94. to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution stir under nitrogen for approximately 4 hours to cool to ambient temperature Concentrate the reaction mixture in vacuo to remove the ethanol Filter the resulting amber slurry through a glass frit Collect the solid rinse with aqueous 1N HCl dry under vacuum at 50° C.

反应条件: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine diethylketomalonate (50 g, 0.287 mol) in 3A ethanol (250 mL) and add N-methylhydroxylamine-HCl (23.9 g, 0.287 mol). Add pyridine (22.7 g, 0.287 mol) and heat to reflux (78° C.) the colorless homogeneous solution with stirring under nitrogen for approximately 2.5 hours before cooling to ambient temperature. Stir at ambient temperature for approximately 48 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Concentrate the reaction mixture in vacuo to a wet, waxy white solid and partition between 100 mL of EtOAc and 100 mL of H2O. Extract the aqueous layer with 3×100 mL portions of EtOAc. Combine the EtOAc layers, wash with 100 mL of brine, dry over MgSO4, filter, and evaporate down to a yellow oil. Absorb the crude product onto silica gel 60 (Merck, 230-400 mesh) and elute with 4 L of a 9:1 hexanes:EtOAc solution as eluent. Evaporate the eluent in vacuo to afford 56.3 g (96.6% yield) of the title compound as a pale yellow homogeneous oil; 1H NMR (300 MHz, CDCl3) δ 4.29 (m, 4H), 4.05 (s, 3H), 1.259 (t, 6H, J=7.32 Hz); 13C NMR (75 MHz, CDCl3) δ 159.9, 158.9, 143.3, 64.2, 62.3, 62.1, 13.7; IR (CHCl3) 3029, 2986, 2944, 1744, 1605, 1329, 1301, 1264, 1237, 1103, 1043 cm−1; UV (EtOH) λmax 231 nm (ε 8582); HRMS (ES) exact mass calc'd for C8H13NO5 203.0794, Found 203.0797. Anal. calc'd for C8H13NO5: C, 47.29; H, 6.45; N, 6.89. Found: C, 46.28; H, 6.36; N, 4.86. before cooling to ambient temperature Stir at ambient temperature for approximately 48 hours Concentrate the reaction mixture in vacuo to a wet, waxy white solid partition between 100 mL of EtOAc and 100 mL of H2O Extract the aqueous layer with 3×100 mL portions of EtOAc wash with 100 mL of brine dry over MgSO4 filter evaporate down to a yellow oil Absorb the crude product onto silica gel 60 (Merck, 230-400 mesh) elute with 4 L of a 9:1 hexanes Evaporate the eluent in vacuo