ethyl (E)-3-(dimethylamino)prop-2-enoate

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

実験手順: To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol, PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg, 3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture was heated under reflux conditions overnight. The reaction mixture was cooled and concentrated to dryness. The residue was adjusted to pH>8 with sat'd. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=5/1) to give the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'd for C11H12N4O2, 233; Found, 233. before the mixture was heated under reflux conditions overnight The reaction mixture was cooled concentrated to dryness aq. NaHCO3 and extracted with EtOAc The combined organic layers were washed with brine dried concentrated to dryness The residue was purified by flash column chromatography (PE/EtOAc=5/1)

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

実験手順: To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol, PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg, 3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture was heated under reflux conditions overnight. The reaction mixture was cooled and concentrated to dryness. The residue was adjusted to pH>8 with sat'd. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=5/1) to give the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'd for C11H12N4O2, 233; Found, 233. before the mixture was heated under reflux conditions overnight The reaction mixture was cooled concentrated to dryness aq. NaHCO3 and extracted with EtOAc The combined organic layers were washed with brine dried concentrated to dryness The residue was purified by flash column chromatography (PE/EtOAc=5/1)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 2-chloro-2-oxoacetate (99 g, 725 mmol) was dissolved in 2-methyltetrahydrofuran (800 ml) and 4-(dimethylamino)-pyridine (1.25 g, 10.0 mmol) was added. The mixture was cooled to −5° C. and a solution of triethylamine (76.2 g, 753 mmol) and (E)-ethyl 3-(dimethylamino)acrylate (106 g, 740 mmol) in 2-methyltetrahydrofuran (70 ml) was added via dropping funnel. The mixture was stirred for 3 h at ca. 0° C. After that, 5% (m/m) aqueous sodium chloride solution (250 mL) was added, the mixture was concentrated in vacuo to remove the 2-methyltetrahydrofuran. Ethyl acetate (800 mL) and 5% (m/m) aqueous sodium chloride solution (250 mL) were added, the organic phase was washed with 5% (m/m) aqueous sodium chloride solution (4×250 mL), the combined aqueous layers reextracted with ethyl acetate (2×300 mL) and the combined organic extracts concentrated in vacuo. The residue was filtered over silica gel (500 g, eluting with ethyl acetate/n-heptane 3:2 (v/v)) and the combined filtrates concentrated in vacuo to afford 146 g crude product as an orange oil. The crude product was dissolved at room temperature in tert-butylmethylether (1 L) and cooled to 1° C. Crystallization started at ca. 13° C. The suspension was filtered and washed with few cold tert-butylmethylether to afford 116.6 g of the title compound as light yellow crystals (66%, purity 99.9% by HPLC). MS (GC-split): m/z=243 [M]+. 1H NMR (CDCl3, 600 MHz); δ 1.26 (t, J=7.1 Hz, 3H), 1.36 (t, J=7.1 Hz, 3H), 3.03 (s, 3H), 3.36 (s, 3H), 4.17 (q, J=7.1 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 7.85 (s, 1H). The product was isolated as single isomer. the mixture was concentrated in vacuo to remove the 2-methyltetrahydrofuran Ethyl acetate (800 mL) and 5% (m/m) aqueous sodium chloride solution (250 mL) were added the organic phase was washed with 5% (m/m) aqueous sodium chloride solution (4×250 mL) the combined organic extracts concentrated in vacuo The residue was filtered over silica gel (500 g, eluting with ethyl acetate/n-heptane 3:2 (v/v)) the combined filtrates concentrated in vacuo to afford 146 g crude product as an orange oil cooled to 1° C Crystallization started at ca. 13° C The suspension was filtered washed with few cold tert-butylmethylether

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 2-chloro-2-oxoacetate (99 g, 725 mmol) was dissolved in 2-methyltetrahydrofuran (800 ml) and 4-(dimethylamino)-pyridine (1.25 g, 10.0 mmol) was added. The mixture was cooled to −5° C. and a solution of triethylamine (76.2 g, 753 mmol) and (E)-ethyl 3-(dimethylamino)acrylate (106 g, 740 mmol) in 2-methyltetrahydrofuran (70 ml) was added via dropping funnel. The mixture was stirred for 3 h at ca. 0° C. After that, 5% (m/m) aqueous sodium chloride solution (250 mL) was added, the mixture was concentrated in vacuo to remove the 2-methyltetrahydrofuran. Ethyl acetate (800 mL) and 5% (m/m) aqueous sodium chloride solution (250 mL) were added, the organic phase was washed with 5% (m/m) aqueous sodium chloride solution (4×250 mL), the combined aqueous layers reextracted with ethyl acetate (2×300 mL) and the combined organic extracts concentrated in vacuo. The residue was filtered over silica gel (500 g, eluting with ethyl acetate/n-heptane 3:2 (v/v)) and the combined filtrates concentrated in vacuo to afford 146 g crude product as an orange oil. The crude product was dissolved at room temperature in tert-butylmethylether (1 L) and cooled to 1° C. Crystallization started at ca. 13° C. The suspension was filtered and washed with few cold tert-butylmethylether to afford 116.6 g of the title compound as light yellow crystals (66%, purity 99.9% by HPLC). MS (GC-split): m/z=243 [M]+. 1H NMR (CDCl3, 600 MHz); δ 1.26 (t, J=7.1 Hz, 3H), 1.36 (t, J=7.1 Hz, 3H), 3.03 (s, 3H), 3.36 (s, 3H), 4.17 (q, J=7.1 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 7.85 (s, 1H). The product was isolated as single isomer. the mixture was concentrated in vacuo to remove the 2-methyltetrahydrofuran Ethyl acetate (800 mL) and 5% (m/m) aqueous sodium chloride solution (250 mL) were added the organic phase was washed with 5% (m/m) aqueous sodium chloride solution (4×250 mL) the combined organic extracts concentrated in vacuo The residue was filtered over silica gel (500 g, eluting with ethyl acetate/n-heptane 3:2 (v/v)) the combined filtrates concentrated in vacuo to afford 146 g crude product as an orange oil cooled to 1° C Crystallization started at ca. 13° C The suspension was filtered washed with few cold tert-butylmethylether

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

実験手順: To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol, PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg, 3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture was heated under reflux conditions overnight. The reaction mixture was cooled and concentrated to dryness. The residue was adjusted to pH >8 with sat'd. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=5/1) to give the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'd for C11H12N4O2, 233. Found, 233. before the mixture was heated under reflux conditions overnight The reaction mixture was cooled concentrated to dryness aq. NaHCO3 and extracted with EtOAc The combined organic layers were washed with brine dried concentrated to dryness The residue was purified by flash column chromatography (PE/EtOAc=5/1)

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

実験手順: To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol, PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg, 3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture was heated under reflux conditions overnight. The reaction mixture was cooled and concentrated to dryness. The residue was adjusted to pH >8 with sat'd. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=5/1) to give the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'd for C11H12N4O2, 233. Found, 233. before the mixture was heated under reflux conditions overnight The reaction mixture was cooled concentrated to dryness aq. NaHCO3 and extracted with EtOAc The combined organic layers were washed with brine dried concentrated to dryness The residue was purified by flash column chromatography (PE/EtOAc=5/1)

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-cyclopropyl-2-chloro-2-hydroxyimino-acetamide (2 g, 12.3 mmol) and (E)-3-(dimethylamino)-acrylic acid ethyl ester (1.76 ml, 12.3 mmol) in THF (25 ml) was heated at 75° C. for 2 h. The reaction was then cooled to r.t., poured into 100 mL ethyl acetate and extracted with 1 M HCl. The aqueous layers were back-extracted with ethyl acetate. The organic phase was washed with water and brine, dried and evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (1.6 g, 58%). The reaction was then cooled to r.t. extracted with 1 M HCl The aqueous layers were back-extracted with ethyl acetate The organic phase was washed with water and brine dried evaporated The product was obtained after purification by silica gel chromatography

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-cyclopropyl-2-chloro-2-hydroxyimino-acetamide (2 g, 12.3 mmol) and (E)-3-(dimethylamino)-acrylic acid ethyl ester (1.76 ml, 12.3 mmol) in THF (25 ml) was heated at 75° C. for 2 h. The reaction was then cooled to r.t., poured into 100 mL ethyl acetate and extracted with 1 M HCl. The aqueous layers were back-extracted with ethyl acetate. The organic phase was washed with water and brine, dried and evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (1.6 g, 58%). The reaction was then cooled to r.t. extracted with 1 M HCl The aqueous layers were back-extracted with ethyl acetate The organic phase was washed with water and brine dried evaporated The product was obtained after purification by silica gel chromatography

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-cyclopropyl-2-chloro-2-hydroxyimino-acetamide (2 g, 12.3 mmol) and (E)-3-(dimethylamino)-acrylic acid ethyl ester (1.76 ml, 12.3 mmol) in THF (25 ml) was heated at 75° C. for 2 h. The reaction was then cooled to r.t., poured into 100 mL ethyl acetate and extracted with 1 M HCl. The aqueous layers were back-extracted with ethyl acetate. The organic phase was washed with water and brine, dried and evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (1.6 g, 58%). The reaction was then cooled to r.t. extracted with 1 M HCl The aqueous layers were back-extracted with ethyl acetate The organic phase was washed with water and brine dried evaporated The product was obtained after purification by silica gel chromatography

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-cyclopropyl-2-chloro-2-hydroxyimino-acetamide (2 g, 12.3 mmol) and (E)-3-(dimethylamino)-acrylic acid ethyl ester (1.76 ml, 12.3 mmol) in THF (25 ml) was heated at 75° C. for 2 h. The reaction was then cooled to r.t., poured into 100 mL ethyl acetate and extracted with 1 M HCl. The aqueous layers were back-extracted with ethyl acetate. The organic phase was washed with water and brine, dried and evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (1.6 g, 58%). The reaction was then cooled to r.t. extracted with 1 M HCl The aqueous layers were back-extracted with ethyl acetate The organic phase was washed with water and brine dried evaporated The product was obtained after purification by silica gel chromatography