2-(ethoxymethylidene)propanedinitrile

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: First ethoxymethylenemalononitrile (2.43 g, 19.9 mmol) and then 8 ml of triethylamine are added to a solution of cyclohexylhydrazine hydrochloride (3 g, 19.9 mmol) in 36 ml of ethanol at room temperature. The mixture is refluxed for 20 min and then cooled. The solvent is stripped off in a rotary evaporator, and the residue is taken up in DCM, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel (mobile phase: dichloromethane/methanol 0-10%). The mixture is refluxed for 20 min cooled The solvent is stripped off in a rotary evaporator washed with aqueous sodium bicarbonate solution dried over sodium sulfate filtered concentrated in vacuo The crude product is chromatographed on silica gel (mobile phase: dichloromethane/methanol 0-10%)

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

Procedure: To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride (12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added 2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed by triethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for 10 min and then heated to reflux for 1.5 h. The contents were cooled to RT and solvents removed under reduced pressure. The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAc layer was separated, washed with 50 mL of brine, dried and concentrated. The concentrated solid was stirred in 50 mL of hexanes for 5 min, filtered through a flitted funnel, and dried in a vacuum oven at 45° C. for 2 h to afford 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brown solid. This material was used without further purification. MS (ES+): 221.1 (M+H)+. (B): A mixture of 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64 mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reaction mixture was concentrated to half of its volume, cooled with an ice bath, pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL of EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as a brown amorphous solid. This material was used without further purification. MS (ES+): 196.1 (M+H)+. heated to reflux for 1.5 h The contents were cooled to RT solvents removed under reduced pressure The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc The EtOAc layer was separated washed with 50 mL of brine dried concentrated The concentrated solid was stirred in 50 mL of hexanes for 5 min filtered through a flitted funnel dried in a vacuum oven at 45° C. for 2 h

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

Procedure: A mixture of 2.0 g (13.1 mmol) 3-Hydrazino-1-methyl-5-methylmercaptopyrazole and 1.8 g (14.4 mmol) ethoxymethylenemalononitrile in 25 ml ethanol was stirred for 30 minutes at room temperature and heated at boiling point for 3 hours. The reaction mixture was concentrated and the residue purified by silica gel chromatography (hexane/ethyl acetate 1:1). heated for 3 hours The reaction mixture was concentrated the residue purified by silica gel chromatography (hexane/ethyl acetate 1:1)

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

Procedure: 22.5 g (0.13 mol) 5-Difluoromethoxy-3-hydrazino-1-methylpyrazole was dissolved in 310 ml ethanol and treated with 15.4 g (0.13 mol) ethoxymethylenemalononitrile. After the mixture had been heated under reflux for one hour it was cooled. The precipitate was suction filtered and washed with a small amount of ethanol. After the mixture had been heated under reflux for one hour it was cooled filtered washed with a small amount of ethanol

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

Procedure: A two-liter, four necked flask is charged with 1332 g (9 moles) of orthoformic acid triethyl ester, 198 g (3 moles) of malonic acid dinitrile and 4 g of acetic acid anhydride. With vigorous stirring, the solution is heated to ebullition. At about 110° C. sump temperature, alcohol begins to distil out through the top of the column. During the course of the reaction, approximately 8 g of acetic acid anhydride is fed in continuously, and the heating of the reaction mixture and the reflux flow are so regulated that the temperature at the top of the condenser is between 75° and 79° C. The condensed distillate is collected and consists substantially of ethanol, acetic acid ethyl ester, formic acid ethyl ester and a small amount of orthoformic acid triethyl ester. During the reaction the sump temperature rises slowly to 130 to 140 degrees C. After 2 to 3 hours the reaction has ended. The unreacted orthoformic acid triethyl ester is distilled out through the column and is fed back to the next batch. Then ethoxymethylene malonic acid dinitrile is separated from the remainder through a simple distillation bridge at 0.1 to 0.02 Torr. In this manner, 361 g of ethoxymethylene malonic acid dinitrile is obtained, with a melting point of 64° C. and a purity of better than 99%. This corresponds to a yield of 98.7% with respect to the malonic acid dinitrile charged. With vigorous stirring, the solution is heated to ebullition At about 110° C. to distil out through the top of the column During the course of the reaction, approximately 8 g of acetic acid anhydride heating of the reaction mixture is between 75° and 79° C The condensed distillate is collected During the reaction the sump temperature rises slowly to 130 to 140 degrees C The unreacted orthoformic acid triethyl ester is distilled out through the column Then ethoxymethylene malonic acid dinitrile is separated from the remainder through a simple distillation bridge at 0.1 to 0.02 Torr

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

Procedure: The title compound was prepared as an orange solid, m.p. 208.5-209.5° C. by the procedure of Preparation A starting with ethoxymethylenemalononitrile and 2,4,6-trichlorophenylhydrazine.

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

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

Procedure: According to H.-W-. Schmidt et al. (Liebigs Ann. Chem. 1979, 2005-10), ethyl acetate (42 g, 323 mmol) is added to a solution of sodium (15 g, 23 mmol) in ethanol (4.0 l) and the mixture is stirred at room temperature for 30 minutes. Ethoxymethylene-malononitrile (40.6 g, 332 mmol) is added. After 30 minutes at 80° C., the reaction mixture is allowed to cool to room temperature and the resulting precipitate is filtered off with suction. The precipitate is dissolved using water, and the aqueous phase is acidified with concentrated hydrochloric acid and the resulting precipitate is filtered off with suction again. After recrystallization from acetic acid, the crystals are filtered off with suction, washed with water and subsequently dried. The desired product is obtained in 29% yield (21.5 g). After 30 minutes at 80° C. to cool to room temperature the resulting precipitate is filtered off with suction The precipitate is dissolved the resulting precipitate is filtered off with suction again After recrystallization from acetic acid the crystals are filtered off with suction washed with water subsequently dried

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

Procedure: According to H.-W-. Schmidt et al. (Liebigs Ann. Chem. 1979, 2005-10), ethyl acetate (42 g, 323 mmol) is added to a solution of sodium (15 g, 23 mmol) in ethanol (4.0 l) and the mixture is stirred at room temperature for 30 minutes. Ethoxymethylene-malononitrile (40.6 g, 332 mmol) is added. After 30 minutes at 80° C., the reaction mixture is allowed to cool to room temperature and the resulting precipitate is filtered off with suction. The precipitate is dissolved using water, and the aqueous phase is acidified with concentrated hydrochloric acid and the resulting precipitate is filtered off with suction again. After recrystallization from acetic acid, the crystals are filtered off with suction, washed with water and subsequently dried. The desired product is obtained in 29% yield (21.5 g). After 30 minutes at 80° C. to cool to room temperature the resulting precipitate is filtered off with suction The precipitate is dissolved the resulting precipitate is filtered off with suction again After recrystallization from acetic acid the crystals are filtered off with suction washed with water subsequently dried