diethyl 2-(cyanomethyl)propanedioate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Cyanomethyl)malonic acid diethyl ester (G. Casini et al, Ann. Chim. (Rome), 51, 366-74 (1961) (81 g) was reacted with sodium hydride (8.9 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (G. E. Hawkins & A. Roe, J. Org. Chem., 14, 328 (1949)) (58.5 g) was added and the internal temperature was raised to 95°-105° C. (some tetrahydrofuran was distilled off) over 11 hours. The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3), the chloroform extracts were dried and concentrated in vacuo to give an oil (132 g). The oil was distilled under vacuum, the distillate collected at 60°-98° C. (vapour temp.) 0.2 mm Hg was discarded. The residues from the distillation (65 g) were dissolved in chloroform and filtered through a silica column and then concentrated, treated with charcoal and recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (30 g) m.p. 78°-80° C. was distilled off) over 11 hours The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3) the chloroform extracts were dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Cyanomethyl)malonic acid diethyl ester (G. Casini et al, Ann. Chim. (Rome), 51, 366-74 (1961) (81 g) was reacted with sodium hydride (8.9 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (G. E. Hawkins & A. Roe, J. Org. Chem., 14, 328 (1949)) (58.5 g) was added and the internal temperature was raised to 95°-105° C. (some tetrahydrofuran was distilled off) over 11 hours. The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3), the chloroform extracts were dried and concentrated in vacuo to give an oil (132 g). The oil was distilled under vacuum, the distillate collected at 60°-98° C. (vapour temp.) 0.2 mm Hg was discarded. The residues from the distillation (65 g) were dissolved in chloroform and filtered through a silica column and then concentrated, treated with charcoal and recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (30 g) m.p. 78°-80° C. was distilled off) over 11 hours The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3) the chloroform extracts were dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Cyanomethyl)malonic acid diethyl ester (G. Casini et al, Ann. Chim. (Rome), 51, 366-74 (1961) (81 g) was reacted with sodium hydride (8.9 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (G. E. Hawkins & A. Roe, J. Org. Chem., 14, 328 (1949)) (58.5 g) was added and the internal temperature was raised to 95°-105° C. (some tetrahydrofuran was distilled off) over 11 hours. The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3), the chloroform extracts were dried and concentrated in vacuo to give an oil (132 g). The oil was distilled under vacuum, the distillate collected at 60°-98° C. (vapour temp.) 0.2 mm Hg was discarded. The residues from the distillation (65 g) were dissolved in chloroform and filtered through a silica column and then concentrated, treated with charcoal and recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (30 g) m.p. 78°-80° C. was distilled off) over 11 hours The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3) the chloroform extracts were dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Cyanomethyl)malonic acid diethyl ester (G. Casini et al, Ann. Chim. (Rome), 51, 366-74 (1961) (81 g) was reacted with sodium hydride (8.9 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (G.E. Hawkins and A. Roe, J. Org. Chem., 14, 328 (1949)) (58.5 g) was added and the internal temperature was raised to 95°-105° C. (some tetrahydrofuran was distilled off) over 11 hours. The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3), the chloroform extracts were dried and concentrated in vacuo to give an oil (132 g). The oil was distilled under vacuum, the distillate collected at 60°-98° C. (vapour temp.) 0.2 mm Hg was discarded. The residues from the distillation (65 g) were dissolved in chloroform and filtered through a silica column and then concentrated, treated with charcoal and recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (30 g) m.p. 78°-80° C. was distilled off) over 11 hours The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3) the chloroform extracts were dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (53% dispersion in oil) (5.17 g, 0.1 mole) was washed by decantation with hexane (2×150 ml), tetrahydrofuran (THF) (150 ml) and was finally suspended in THF (150 ml). Diethyl 2-(cyanomethyl)malonate (26.4 g, 0.11 mole) in THF (20 ml) was added dropwise over 45 minutes keeping the internal temperature at 18° C. to 22° C. (with ice bath cooling). The resulting suspension cleared over 15 minutes when 2-chloro-5-nitropyridine (14.22 g, 0.09 mole) was added to give a deep magenta solution. The resulting solution was refluxed for 3 hours and the solvent was removed on the rotary evaporator. The resulting oil was partitioned between water (200 ml) and chloroform (200 ml), the pH was adjusted to ~7 (concentrated hydrochloric acid), and the chloroform was run off. The aqueous layer was extracted with a further (2×250 ml) chloroform, the extracts were combined, dried over magnesium sulphate and the solvent was removed to give the title compound as an amber oil. Ether (25 ml) was added and the solution was allowed to crystallise to give the title compound (18.48 g). m.p. 66°-68° C. at 18° C. to 22° C. (with ice bath cooling) to give a deep magenta solution The resulting solution was refluxed for 3 hours the solvent was removed on the rotary evaporator The resulting oil was partitioned between water (200 ml) and chloroform (200 ml) The aqueous layer was extracted with a further (2×250 ml) chloroform dried over magnesium sulphate the solvent was removed