ethyl N-(2-cyanoacetyl)carbamate

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

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

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

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

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

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

Procedure: To a stirred and cooled (5-10 degrees C) mixture of 15.2 parts of 4-amino-2,6-dichloro-α-(4-chlorophenyl)-benzeneacetonitrile (intermediate 2), 14.4 parts of concentrate hydrochloric acid and 125 parts of acetic acid is added dropwise, during a 30 minutes period, a solution of 3.5 parts of sodium nitrite in 15 parts of water at about 10 degrees C. Upon completion, the whole is stirred for 30 minutes and then 10 parts of sodium acetate and 7.8 parts of ethyl(2-cyanoacetyl)carbamate are added, during a period of 2 hours, at room temperature. The reaction mixture is poured into 500 parts of water. The product is filtered off, washed with water and dissolved in dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo. The residue is stirred in 2-propanol. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding ethyl[2-[[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]hydrazono]-2-cyanoacetyl]carbamate (intermediate 3). cooled is added dropwise, during a 30 minutes period at about 10 degrees C Upon completion, the whole is stirred for 30 minutes The product is filtered off washed with water dissolved in dichloromethane The organic layer is dried filtered evaporated The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions are collected the eluent is evaporated in vacuo The residue is stirred in 2-propanol The product is filtered off washed with 2,2'-oxybispropane dried

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

Procedure: A mixture of 9.18 g of 32A, 10 mL of 12N hydrochloric acid and 10 mL of water was heated on a steam bath for 1 hour, then 10 mL of water was added and the mixture was stirred at room temperature overnight. Then 30 mL of water was added, the mixture was cooled to 0° C. and stirred while a solution of 3.45 g of sodium nitrite in 10 mL of water was added dropwise over 15 minutes, then was stirred for 1 hour at 0° C. The resulting mixture was added slowly to a stirred mixture of 7.8 g of N-cyanoacetylurethane, 35 mL of pyridine and 900 mL of water, at 0° C. The resulting mixture was stirred at 0° C. for 1.5 hours, and filtered. The collected solid phase was washed with water, dried under reduced pressure and recrystallized from acetone/petroleum ether to give ethyl N-((7-chloro-2,3-dihydro-2-methyl- 4-benzofuranylhydrazono)cyanoacetyl)carbamate (32B), as a solid, m.p.: 175°-177° C. (with decomposition). was heated on a steam bath for 1 hour the mixture was cooled to 0° C. was added dropwise over 15 minutes was stirred for 1 hour at 0° C The resulting mixture was stirred at 0° C. for 1.5 hours filtered The collected solid phase was washed with water dried under reduced pressure recrystallized from acetone/petroleum ether

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-2-methyl-2H-pyridazin-3-one (94) (148 mg, 0.45 mmol) in water (6 mL) and concentrated hydrochloric acid (3 mL) cooled to 0° C. was treated with a solution of sodium nitrite (37.3 mg, 0.54 mmol) in water (0.5 mL) via Pasteur pipette under the surface of the reaction mixture. This was followed by a water rinse (0.5 mL) of the Pasteur pipette. The resulting pale yellow solution was stirred at 0° C. for 45 min. At this time, the reaction was filtered through a pad of cotton and was drained directly into a solution of cyanoacetylurethane (77.3 mg, 0.49 mmol), pyridine (3 mL) and water (9 mL) cooled to 0° C. Upon mixing, orange-red solids immediately formed. This mixture was stirred at 0° C. for 30 min. At this time, the solids were collected by filtration through filter paper. The solids were washed with water and petroleum ether, air-dried under house vacuum, and then dried under vacuum to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (95) (192 mg, 86%) as an orange solid; ES-HRMS m/e calcd for C21H22Cl2N6O4 (M+H)+ 493.1153, found 493.1155. Exact Mass=492.1080; Molecular weight=493.3533. rinse (0.5 mL) of the Pasteur pipette At this time, the reaction was filtered through a pad of cotton cooled to 0° C Upon mixing orange-red solids immediately formed This mixture was stirred at 0° C. for 30 min At this time, the solids were collected by filtration through filter paper The solids were washed with water and petroleum ether air-dried under house vacuum dried under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-2-methyl-2H-pyridazin-3-one (94) (148 mg, 0.45 mmol) in water (6 mL) and concentrated hydrochloric acid (3 mL) cooled to 0° C. was treated with a solution of sodium nitrite (37.3 mg, 0.54 mmol) in water (0.5 mL) via Pasteur pipette under the surface of the reaction mixture. This was followed by a water rinse (0.5 mL) of the Pasteur pipette. The resulting pale yellow solution was stirred at 0° C. for 45 min. At this time, the reaction was filtered through a pad of cotton and was drained directly into a solution of cyanoacetylurethane (77.3 mg, 0.49 mmol), pyridine (3 mL) and water (9 mL) cooled to 0° C. Upon mixing, orange-red solids immediately formed. This mixture was stirred at 0° C. for 30 min. At this time, the solids were collected by filtration through filter paper. The solids were washed with water and petroleum ether, air-dried under house vacuum, and then dried under vacuum to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (95) (192 mg, 86%) as an orange solid; ES-HRMS m/e calcd for C21H22Cl2N6O4 (M+H)+ 493.1153, found 493.1155. Exact Mass=492.1080; Molecular weight=493.3533. rinse (0.5 mL) of the Pasteur pipette At this time, the reaction was filtered through a pad of cotton cooled to 0° C Upon mixing orange-red solids immediately formed This mixture was stirred at 0° C. for 30 min At this time, the solids were collected by filtration through filter paper The solids were washed with water and petroleum ether air-dried under house vacuum dried under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-(4-amino-2,6-dichloro-phenylsulfanyl)-4-isopropyl-2H-pyridazin-3-one (85) (3.40 g, 10.4 mmol) in water (135 mL) and concentrated hydrochloric acid (68 mL) cooled to 0° C. was treated with a solution of sodium nitrite (853 mg, 12.36 mmol) in water (7.0 mL) via Pasteur pipette under the surface of the reaction mixture. This was followed by a water rinse (1.0 mL) of the Pasteur pipette. The resulting yellow mixture was stirred at 0° C. for 30 min. More concentrated hydrochloric acid (7.0 mL) was added. The reaction was stirred at 0° C. for an additional 1.3 h. The solids were removed by filtration through filter paper and were rinsed with water. The clear, yellow diazonium salt solution of the filtrate was quickly poured into a solution of cyanoacetylurethane (1.77 g, 11.33 mmol), pyridine (75 mL) and water (204 mL) cooled to 0° C. Upon mixing, orange-red solids immediately formed. This mixture was stirred at 0° C. for 1 h. At this time, the solids were collected by filtration through filter paper. The solids were washed with water, air-dried under house vacuum for 2 h, and then dried under vacuum to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (86) (2.98 g, 58%) as an orange solid; ES(+)-HRMS m/e calcd for C19H18Cl2N6O4S (M+H)+ 497.0560, found 497.0559. Exact Mass=496.0487; Molecular weight=497.36 rinse (1.0 mL) of the Pasteur pipette More concentrated hydrochloric acid (7.0 mL) was added The reaction was stirred at 0° C. for an additional 1.3 h The solids were removed by filtration through filter paper were rinsed with water cooled to 0° C Upon mixing orange-red solids immediately formed This mixture was stirred at 0° C. for 1 h At this time, the solids were collected by filtration through filter paper The solids were washed with water air-dried under house vacuum for 2 h dried under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-(4-amino-2,6-dichloro-phenylsulfanyl)-4-isopropyl-2H-pyridazin-3-one (85) (3.40 g, 10.4 mmol) in water (135 mL) and concentrated hydrochloric acid (68 mL) cooled to 0° C. was treated with a solution of sodium nitrite (853 mg, 12.36 mmol) in water (7.0 mL) via Pasteur pipette under the surface of the reaction mixture. This was followed by a water rinse (1.0 mL) of the Pasteur pipette. The resulting yellow mixture was stirred at 0° C. for 30 min. More concentrated hydrochloric acid (7.0 mL) was added. The reaction was stirred at 0° C. for an additional 1.3 h. The solids were removed by filtration through filter paper and were rinsed with water. The clear, yellow diazonium salt solution of the filtrate was quickly poured into a solution of cyanoacetylurethane (1.77 g, 11.33 mmol), pyridine (75 mL) and water (204 mL) cooled to 0° C. Upon mixing, orange-red solids immediately formed. This mixture was stirred at 0° C. for 1 h. At this time, the solids were collected by filtration through filter paper. The solids were washed with water, air-dried under house vacuum for 2 h, and then dried under vacuum to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (86) (2.98 g, 58%) as an orange solid; ES(+)-HRMS m/e calcd for C19H18Cl2N6O4S (M+H)+ 497.0560, found 497.0559. Exact Mass=496.0487; Molecular weight=497.36 rinse (1.0 mL) of the Pasteur pipette More concentrated hydrochloric acid (7.0 mL) was added The reaction was stirred at 0° C. for an additional 1.3 h The solids were removed by filtration through filter paper were rinsed with water cooled to 0° C Upon mixing orange-red solids immediately formed This mixture was stirred at 0° C. for 1 h At this time, the solids were collected by filtration through filter paper The solids were washed with water air-dried under house vacuum for 2 h dried under vacuum

Conditions: temp:7.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl-2H-pyridazin-3-one (67) (10 g, 30.47 mmol) in glacial acetic acid (60 mL) and concentrated hydrochloric acid (9.06 mL) cooled to 5-10° C. was treated dropwise with a solution of sodium nitrite (2.3 g, 32.3 mmol) in water (6 mL). The reaction was stirred at 5-10° C. for 30 min. At this time, the reaction was treated with N-cyanoacetylurethane (5.34 g, 33.52 mmol) followed by a solution of sodium acetate (7.5 g, 91.41 mmol) in water (22.5 mL). The reaction was stirred at 5-10° C. for 30 min and then was diluted with water (50 mL). The resulting solids were collected by filtration, washed with a 1:1 mixture of glacial acetic acid:water (40 mL) followed by water (2×60 mL), dried under house vacuum, and then dried under vacuum at 50° C. to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (68) (15.04 g, 95%) as an orange solid; ES(+)-LRMS for C20H20Cl2N6O5 (M+H)+ at m/z=495. Exact Mass=494.0872; Molecular Weight=495.33. The reaction was stirred at 5-10° C. for 30 min The resulting solids were collected by filtration washed with a 1:1 mixture of glacial acetic acid dried under house vacuum dried under vacuum at 50° C.